RESUMO
An asymptomatic infant of Ghanaian descent had hemoglobin F only detected on newborn screening. ß-globin gene sequencing identified the intervening sequence (IVS)-II-849 (A â G) mutation with no normal ß-globin gene. ß-globin/δ-globin gene sequencing showed that both parents were heterozygous for the IVS-II-849 (A â G) mutation. The mother was heterozygous for the HbA2' δ-globin mutation (δ16 (A13) Gly â Arg), thus ß-thalassemia trait was unrecognized due to coinheritance of HbA2'. The infant developed anemia, splenomegaly, and began transfusion therapy by the age 6 of months. This is the first report of ß-thalassemia major with homozygous IVS-II-849 (A â G) mutations. This case highlights the importance of δ-globin gene mutations in prenatal testing.
Assuntos
Hemoglobina Fetal , Talassemia beta/diagnóstico , Talassemia beta/genética , Cromatografia Líquida de Alta Pressão , Hemoglobina A2/genética , Humanos , Recém-Nascido , Focalização Isoelétrica , MasculinoRESUMO
Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma in the United States. DLBCL comprises biologically distinct subtypes including germinal center-like (GCB) and activated-B-cell-like DLBCL (ABC). The most aggressive type, ABC-DLBCL, displays dysregulation of both canonical and noncanonical NF-κB pathway as well as genomic instability. Although, much is known about the tumorigenic roles of the canonical NF-kB pathway, the precise role of the noncanonical NF-kB pathway remains unknown. Here we show that activation of the noncanonical NF-κB pathway regulates chromosome stability, DNA damage response and centrosome duplication in DLBCL. Analysis of 92 DLBCL samples revealed that activation of the noncanonical NF-κB pathway is associated with low levels of DNA damage and centrosome amplification. Inhibiting the noncanonical pathway in lymphoma cells uncovered baseline DNA damage and prevented doxorubicin-induced DNA damage repair. In addition, it triggered centrosome amplification and chromosome instability, indicated by anaphase bridges, multipolar spindles and chromosome missegregation. We determined that the noncanonical NF-κB pathway execute these functions through the regulation of GADD45α and REDD1 in a p53-independent manner, while it collaborates with p53 to regulate cyclin G2 expression. Furthermore, this pathway regulates GADD45α, REDD1 and cyclin G2 through direct binding of NF-κB sites to their promoter region. Overall, these results indicate that the noncanonical NF-κB pathway plays a central role in maintaining genome integrity in DLBCL. Our data suggests that inhibition of the noncanonical NF-kB pathway should be considered as an important component in DLBCL therapeutic approach.
Assuntos
Instabilidade Cromossômica , Cromossomos Humanos/genética , Linfoma Difuso de Grandes Células B/genética , NF-kappa B/metabolismo , Transdução de Sinais , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/genética , Centrossomo/metabolismo , Ciclina G2/metabolismo , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , Doxorrubicina/farmacologia , Humanos , Cariótipo , Dados de Sequência Molecular , Proteínas Nucleares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismoRESUMO
Researchers have developed computer-aided decision support systems for translational medicine that aim to objectively and efficiently diagnose cancer using histopathological images. However, the performance of such systems is confounded by nonbiological experimental variations or "batch effects" that can commonly occur in histopathological data, especially when images are acquired using different imaging devices and patient samples. This is even more problematic in large-scale studies in which cross-laboratory sharing of large volumes of data is necessary. Batch effects can change quantitative morphological image features and decrease the prediction performance. Using four batches of renal tumor images, we compare one image-level and five feature-level batch effect removal methods. Principal component variation analysis shows that batch is a large source of variance in image features. Results show that feature-level normalization methods reduce batch-contributed variance to almost zero. Moreover, feature-level normalization, especially ComBatN, improves cross-batch and combined-batch prediction performance. Compared to no normalization, ComBatN improves performance in 83% and 90% of cross-batch and combined-batch prediction models, respectively.
Assuntos
Histocitoquímica/métodos , Interpretação de Imagem Assistida por Computador/métodos , Aplicações da Informática Médica , Neoplasias/diagnóstico , Neoplasias/patologia , Análise por Conglomerados , Humanos , Processamento de Imagem Assistida por Computador , Neoplasias/químicaRESUMO
Clear cell papillary renal cell carcinoma is a distinct variant of renal cell carcinoma that shares some overlapping histological and immunohistochemical features of clear cell renal cell carcinoma and papillary renal cell carcinoma. Although the clear cell papillary renal cell carcinoma immunohistochemical profile is well described, clear cell papillary renal cell carcinoma mRNA expression has not been well characterized. We investigated the clear cell papillary renal cell carcinoma gene expression profile using previously identified candidate genes. We selected 17 clear cell papillary renal cell carcinoma, 15 clear cell renal cell carcinoma, and 13 papillary renal cell carcinoma cases for molecular analysis following histological review. cDNA from formalin-fixed paraffin-embedded tissue was prepared. Quantitative real-time PCR targeting alpha-methylacyl coenzyme-A racemase (AMACR), BMP and activin membrane-bound inhibitor homolog (BAMBI), carbonic anhydrase IX (CA9), ceruloplasmin (CP), nicotinamide N-methyltransferase (NNMT), schwannomin-interacting protein 1 (SCHIP1), solute carrier family 34 (sodium phosphate) member 2 (SLC34A2), and vimentin (VIM) was performed. Gene expression data were normalized relative to 28S ribosomal RNA. Clear cell papillary renal cell carcinoma expressed all eight genes at variable levels. Compared with papillary renal cell carcinoma, clear cell papillary renal cell carcinoma expressed more CA9, CP, NNMT, and VIM, less AMACR, BAMBI, and SLC34A2, and similar levels of SCHIP1. Compared with clear cell renal cell carcinoma, clear cell papillary renal cell carcinoma expressed slightly less NNMT, but similar levels of the other seven genes. Although clear cell papillary renal cell carcinoma exhibits a unique molecular signature, it expresses several genes at comparable levels to clear cell renal cell carcinoma relative to papillary renal cell carcinoma. Understanding the molecular pathogenesis of clear cell papillary renal cell carcinoma will have a key role in future sub-classifications of this unique tumor.
Assuntos
Carcinoma Papilar/genética , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Transcriptoma , Adulto , Idoso , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Semiconductor quantum dots (QDs) are light-emitting particles on the nanometer scale that have emerged as a new class of fluorescent labels for chemical analysis, molecular imaging, and biomedical diagnostics. Compared with traditional fluorescent probes, QDs have unique optical and electronic properties such as size-tunable light emission, narrow and symmetric emission spectra, and broad absorption spectra that enable the simultaneous excitation of multiple fluorescence colors. QDs are also considerably brighter and more resistant to photobleaching than are organic dyes and fluorescent proteins. These properties are well suited for dynamic imaging at the single-molecule level and for multiplexed biomedical diagnostics at ultrahigh sensitivity. Here, we discuss the fundamental properties of QDs; the development of next-generation QDs; and their applications in bioanalytical chemistry, dynamic cellular imaging, and medical diagnostics. For in vivo and clinical imaging, the potential toxicity of QDs remains a major concern. However, the toxic nature of cadmium-containing QDs is no longer a factor for in vitro diagnostics, so the use of multicolor QDs for molecular diagnostics and pathology is probably the most important and clinically relevant application for semiconductor QDs in the immediate future.
Assuntos
Pontos Quânticos , Semicondutores , Biomarcadores Tumorais/análise , Compostos de Cádmio , DNA/análise , Diagnóstico por Imagem , Humanos , Imuno-Histoquímica/métodos , Hibridização in Situ Fluorescente , Masculino , Nanopartículas , Nanotecnologia/métodos , Neoplasias/diagnóstico , Polietilenoglicóis/química , Próstata/metabolismo , Compostos de Selênio , TelúrioRESUMO
BACKGROUND: Automatic cancer diagnostic systems based on histological image classification are important for improving therapeutic decisions. Previous studies propose textural and morphological features for such systems. These features capture patterns in histological images that are useful for both cancer grading and subtyping. However, because many of these features lack a clear biological interpretation, pathologists may be reluctant to adopt these features for clinical diagnosis. METHODS: We examine the utility of biologically interpretable shape-based features for classification of histological renal tumor images. Using Fourier shape descriptors, we extract shape-based features that capture the distribution of stain-enhanced cellular and tissue structures in each image and evaluate these features using a multi-class prediction model. We compare the predictive performance of the shape-based diagnostic model to that of traditional models, i.e., using textural, morphological and topological features. RESULTS: The shape-based model, with an average accuracy of 77%, outperforms or complements traditional models. We identify the most informative shapes for each renal tumor subtype from the top-selected features. Results suggest that these shapes are not only accurate diagnostic features, but also correlate with known biological characteristics of renal tumors. CONCLUSIONS: Shape-based analysis of histological renal tumor images accurately classifies disease subtypes and reveals biologically insightful discriminatory features. This method for shape-based analysis can be extended to other histological datasets to aid pathologists in diagnostic and therapeutic decisions.
Assuntos
Algoritmos , Inteligência Artificial , Biópsia/métodos , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Neoplasias/patologia , Reconhecimento Automatizado de Padrão/métodos , Humanos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
We have developed omniBiomarker, a web-based application that uses knowledge from the NCI Cancer Gene Index to guide the selection of biologically relevant algorithms for identifying biomarkers. Biomarker identification from high-throughput genomic expression data is difficult because of data properties (i.e., small-sample size compared to large-feature size) as well as the large number of available feature selection algorithms. Thus, it is unclear which algorithm should be used for a particular dataset. These factors lead to instability in biomarker identification and affect the reproducibility of results. We introduce a method for computing the biological relevance of feature selection algorithms using an externally validated knowledge base of manually curated cancer biomarkers. Results suggest that knowledge-driven biomarker identification can improve microarray-based clinical prediction performance. omniBiomarker can be accessed at http://omnibiomarker.bme.gatech.edu/.
Assuntos
Algoritmos , Biomarcadores Tumorais/classificação , Biologia Computacional/métodos , Internet , Bases de Conhecimento , Software , Perfilação da Expressão Gênica/métodos , Humanos , Aprendizado de MáquinaRESUMO
Inflammation has classically been defined histopathologically, especially by the presence of immune cell infiltrates. However, more recent studies suggest a role for "low-grade" inflammation in a variety of disorders ranging from metabolic syndrome to cancer, which is defined by modest elevations in pro-inflammatory gene expression. Consequently, there is a need for cost-effective, non-invasive biomarkers that, ideally, would have the sensitivity to detect low-grade inflammation and have a dynamic range broad enough to reflect classic robust intestinal inflammation. Herein, we report that, for assessment of intestinal inflammation, fecal lipocalin 2 (Lcn-2), measured by ELISA, serves this purpose. Specifically, using a well-characterized mouse model of DSS colitis, we observed that fecal Lcn-2 and intestinal expression of pro-inflammatory cytokines (IL-1ß, CXCL1, TNFα) are modestly but significantly induced by very low concentrations of DSS (0.25 and 0.5%), and become markedly elevated at higher concentrations of DSS (1.0 and 4.0%). As expected, careful histopathologic analysis noted only modest immune infiltrates at low DSS concentration and robust colitis at higher DSS concentrations. In accordance, increased levels of the neutrophil product myeloperoxidase (MPO) was only detected in mice given 1.0 and 4.0% DSS. In addition, fecal Lcn-2 marks the severity of spontaneous colitis development in IL-10 deficient mice. Unlike histopathology, MPO, and q-RT-PCR, the assay of fecal Lcn-2 requires only a stool sample, permits measurement over time, and can detect inflammation as early as 1 day following DSS administration. Thus, assay of fecal Lcn-2 by ELISA can function as a non-invasive, sensitive, dynamic, stable and cost-effective means to monitor intestinal inflammation in mice.
Assuntos
Proteínas de Fase Aguda/biossíntese , Proteínas de Fase Aguda/fisiologia , Biomarcadores/metabolismo , Fezes , Mucosa Intestinal/metabolismo , Lipocalinas/biossíntese , Lipocalinas/fisiologia , Proteínas Oncogênicas/biossíntese , Proteínas Oncogênicas/fisiologia , Animais , Quimiocina CXCL1/biossíntese , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Inflamação , Interleucina-10/metabolismo , Interleucina-1beta/biossíntese , Lipocalina-2 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/metabolismo , Peroxidase/metabolismo , Fator de Necrose Tumoral alfa/biossínteseRESUMO
BACKGROUND: To examine factors that affect accuracy and reliability of prostate cancer grade we compared Gleason scores documented in pathology reports and those assigned by urologic pathologists in a population-based study. METHODS: A stratified random sample of 318 prostate cancer cases was selected to ensure representation of whites and African-Americans and to include facilities of various types. The slides borrowed from reporting facilities were scanned and the resulting digital images were re-reviewed by two urologic pathologists. If the two urologic pathologists disagreed, a third urologic pathologist was asked to help arrive at a final "gold standard" result. The agreements between reviewers and between the pathology reports and the "gold standard" were examined by calculating kappa statistics. The determinants of discordance in Gleason scores were evaluated using multivariate models with results expressed as odds ratios (OR) and 95% confidence intervals (CI). RESULTS: The kappa values (95% CI) reflecting agreement between the pathology reports and the "gold standard," were 0.61 (95% CI: 0.54, 0.68) for biopsies, and 0.37 (0.23, 0.51) for prostatectomies. Sixty three percent of discordant biopsies and 72% of discordant prostatectomies showed only minimal differences. Using freestanding laboratories as reference, the likelihood of discordance between pathology reports and expert-assigned biopsy Gleason scores was particularly elevated for small community hospitals (OR = 2.98; 95% CI: 1.73, 5.14). CONCLUSIONS: The level of agreement between pathology reports and expert review depends on the type of diagnosing facility, but may also depend on the level of expertise and specialization of individual pathologists.
Assuntos
Adenocarcinoma/patologia , Gradação de Tumores/normas , Variações Dependentes do Observador , Neoplasias da Próstata/patologia , Adenocarcinoma/cirurgia , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Vigilância da População , Prostatectomia , Neoplasias da Próstata/cirurgia , Reprodutibilidade dos TestesRESUMO
Combining multiple microarray datasets increases sample size and leads to improved reproducibility in identification of informative genes and subsequent clinical prediction. Although microarrays have increased the rate of genomic data collection, sample size is still a major issue when identifying informative genetic biomarkers. Because of this, feature selection methods often suffer from false discoveries, resulting in poorly performing predictive models. We develop a simple meta-analysis-based feature selection method that captures the knowledge in each individual dataset and combines the results using a simple rank average. In a comprehensive study that measures robustness in terms of clinical application (i.e., breast, renal, and pancreatic cancer), microarray platform heterogeneity, and classifier (i.e., logistic regression, diagonal LDA, and linear SVM), we compare the rank average meta-analysis method to five other meta-analysis methods. Results indicate that rank average meta-analysis consistently performs well compared to five other meta-analysis methods.
Assuntos
Algoritmos , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Metanálise como Assunto , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Neoplasias da Mama/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Pancreáticas/genética , Receptores de Estrogênio/genética , Reprodutibilidade dos TestesRESUMO
The bag-of-features method has emerged as a useful and flexible tool that can capture medically relevant image characteristics. In this paper, we study the effect of scale and rotation invariance in the bag-of-features framework for Renal Cell Carcinoma subtype classification. We estimated the performance of different features by linear support vector machine over 10 iterations of 3-fold cross validation. For a very heterogeneous dataset labeled by an expert pathologist, we achieve a classification accuracy of 88% with four subtypes. Our study shows that rotation invariance is more important than scale invariance but combining both properties gives better classification performance.
Assuntos
Carcinoma de Células Renais/diagnóstico , Diagnóstico por Computador/métodos , Neoplasias Renais/diagnóstico , Algoritmos , Carcinoma de Células Renais/patologia , Diagnóstico por Imagem/métodos , Humanos , Processamento de Imagem Assistida por Computador/métodos , Neoplasias Renais/patologia , Imageamento por Ressonância Magnética/métodos , Oncologia/métodos , Modelos Estatísticos , Reprodutibilidade dos Testes , Tomografia Computadorizada por Raios X/métodosRESUMO
BACKGROUND: In previous work, we reported the development of caCORRECT, a novel microarray quality control system built to identify and correct spatial artifacts commonly found on Affymetrix arrays. We have made recent improvements to caCORRECT, including the development of a model-based data-replacement strategy and integration with typical microarray workflows via caCORRECT's web portal and caBIG grid services. In this report, we demonstrate that caCORRECT improves the reproducibility and reliability of experimental results across several common Affymetrix microarray platforms. caCORRECT represents an advance over state-of-art quality control methods such as Harshlighting, and acts to improve gene expression calculation techniques such as PLIER, RMA and MAS5.0, because it incorporates spatial information into outlier detection as well as outlier information into probe normalization. The ability of caCORRECT to recover accurate gene expressions from low quality probe intensity data is assessed using a combination of real and synthetic artifacts with PCR follow-up confirmation and the affycomp spike in data. The caCORRECT tool can be accessed at the website: http://cacorrect.bme.gatech.edu. RESULTS: We demonstrate that (1) caCORRECT's artifact-aware normalization avoids the undesirable global data warping that happens when any damaged chips are processed without caCORRECT; (2) When used upstream of RMA, PLIER, or MAS5.0, the data imputation of caCORRECT generally improves the accuracy of microarray gene expression in the presence of artifacts more than using Harshlighting or not using any quality control; (3) Biomarkers selected from artifactual microarray data which have undergone the quality control procedures of caCORRECT are more likely to be reliable, as shown by both spike in and PCR validation experiments. Finally, we present a case study of the use of caCORRECT to reliably identify biomarkers for renal cell carcinoma, yielding two diagnostic biomarkers with potential clinical utility, PRKAB1 and NNMT. CONCLUSIONS: caCORRECT is shown to improve the accuracy of gene expression, and the reproducibility of experimental results in clinical application. This study suggests that caCORRECT will be useful to clean up possible artifacts in new as well as archived microarray data.
Assuntos
Perfilação da Expressão Gênica/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Artefatos , Carcinoma de Células Renais/genética , Seguimentos , Humanos , Análise de Sequência com Séries de Oligonucleotídeos/normas , Controle de Qualidade , Reprodutibilidade dos TestesRESUMO
A patient with localized kidney cancer underwent potentially curative nephrectomy. Routinely post-operative serum C-Reactive Protein (CRP) values were measured. At 25 months post-operatively, lung imaging suggested possible metastasis. However, CRP levels remained at baseline. Subsequent resection revealed a benign mass. CRP values have been shown to carry prognostic significance for overall and disease free survival. This case suggests a novel use for CRP: a sensitive biomarker of disease recurrence and metastasis.
Assuntos
Proteína C-Reativa/metabolismo , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/secundário , Neoplasias Renais/diagnóstico , Idoso , Biomarcadores Tumorais/sangue , Carcinoma de Células Renais/cirurgia , Humanos , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/secundário , Masculino , Metástase Neoplásica/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Cuidados Pós-OperatóriosRESUMO
C-reactive protein is produced in response to cytokines such as interleukin (IL)-6. It is known that increased plasma IL-6 levels induce increased hepatic and intratumoral production of C-reactive protein. Cyclooxygenase enzyme-2 is induced by various stimuli, including inflammation and various growth factors. Expression of these two markers has not been well studied in clear cell renal cell carcinoma. The objective of this study is to correlate the expression of C-reactive protein and cyclooxygenase enzyme-2 in clear cell renal cell carcinoma with pathologic parameters. A search of the surgical pathology and consultation files at our institution was performed for nephrectomy specimens with clear cell renal cell carcinoma from 2007 to 2008. Immunohistochemical stains for C-reactive protein and cyclooxygenase enzyme-2 were performed. Staining intensity was graded as 0, 1+, 2+, and 3+. The staining intensity was then correlated with pathologic stage and Fuhrman nuclear grade for each case. A total of 110 cases were identified. Strong expression of C-reactive protein was associated with higher Fuhrman nuclear grade and pathologic stage, and the strength of correlation was statistically significant (p = 0.01 and p = 0.001), respectively. However, cyclooxygenase enzyme-2 expression did not show statistically significant correlation with both pathologic stage and Fuhrman nuclear grade (p = 0.1 and p = 0.15), respectively. To our knowledge, this is the largest study to date correlating the expression of both C-reactive protein and cyclooxygenase enzyme-2 in tissue with pathologic parameters in patients with clear cell renal cell carcinoma, which could have significant prognostic and therapeutic implications.
Assuntos
Proteína C-Reativa/metabolismo , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Ciclo-Oxigenase 2/metabolismo , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/cirurgia , Feminino , Humanos , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nefrectomia , Prognóstico , Estudos RetrospectivosRESUMO
Computer-aided histological image classification systems are important for making objective and timely cancer diagnostic decisions. These systems use combinations of image features that quantify a variety of image properties. Because researchers tend to validate their diagnostic systems on specific cancer endpoints, it is difficult to predict which image features will perform well given a new cancer endpoint. In this paper, we define a comprehensive set of common image features (consisting of 12 distinct feature subsets) that quantify a variety of image properties. We use a data-mining approach to determine which feature subsets and image properties emerge as part of an "optimal" diagnostic model when applied to specific cancer endpoints. Our goal is to assess the performance of such comprehensive image feature sets for application to a wide variety of diagnostic problems. We perform this study on 12 endpoints including 6 renal tumor subtype endpoints and 6 renal cancer grade endpoints. Keywords-histology, image mining, computer-aided diagnosis.
RESUMO
Chromophobe renal cell carcinoma (RCC) is a histologic subtype of RCC that portends a favorable prognosis. It is controversial whether the Fuhrman nuclear grade of chromophobe RCC has prognostic utility. Irregular nuclei, prominent nucleoli, and nuclear pleomorphism are inherently present in chromophobe RCC. Hence, the Fuhrman nuclear grade is higher even though the majority of these tumors have a favorable outcome. In this study, the prognostic utility of a novel 3-tiered tumor grading system in which the innate nuclear atypia of chromophobe RCC was discounted, herein referred to as chromophobe tumor grade from a series of 124 chromophobe RCC, was compared with Fuhrman nuclear grade. Chromophobe tumor grade is based on the assessment of geographic nuclear crowding and anaplasia. The Fuhrman nuclear grade distribution between the tumors was grade 1 (1%), grade 2 (19%), grade 3 (74%), and grade 4 (6%), whereas the chromophobe tumor grade distribution was grade 1 (74%), grade 2 (16%), and grade 3 (10%). Neither Fuhrman nuclear grade nor chromophobe tumor grade was significantly associated with patient's age or sex and chromophobe RCC cell types, but both showed a significant association with tumor size. Both Fuhrman nuclear grade and chromophobe tumor grade showed statistically significant positive associations with broad alveolar growth, necrosis, vascular invasion, and with pathologic stage; however, all these associations tended to be dictated by tumors with sarcomatoid change. When tumors with sarcomatoid change were excluded, a strong positive association persisted between chromophobe tumor grade and pathologic stage. In contrast, there was no such association between Fuhrman nuclear grade and stage in nonsarcomatoid chromophobe RCCs. Characterizing aggressive chromophobe RCC with aggressive behavior with the time from surgery to first occurrence of metastasis, local recurrence, or death owing to disease, we found that both Fuhrman nuclear grade and chromophobe tumor grade were highly associated with adverse outcome. However, as with the pathologic stage, only a significant association between chromophobe tumor grade and outcome was retained among nonsarcomatoid chromophobe RCCs. Multivariable Cox regression analysis also tended to support chromophobe tumor grade rather than Fuhrman nuclear grade as an independent predictor of adverse outcome, controlling for other univariably significant risk factors [estimated relative hazard=3.68 (P=0.026) vs. 1.86 (P=0.42)]. In conclusion, the novel chromophobe tumor grading system proposed herewith provides superior prognostic value to that of the Fuhrman nuclear grade in chromophobe RCC and will potentially help stratify patients of chromophobe RCC who are at a greater risk of disease progression.
Assuntos
Carcinoma de Células Renais/patologia , Núcleo Celular/patologia , Neoplasias Renais/patologia , Carcinoma de Células Renais/classificação , Carcinoma de Células Renais/mortalidade , Núcleo Celular/classificação , Feminino , Humanos , Neoplasias Renais/classificação , Neoplasias Renais/mortalidade , Masculino , Recidiva Local de Neoplasia , Valor Preditivo dos Testes , Prognóstico , Taxa de SobrevidaRESUMO
C-reactive protein (CRP) is an acute-phase reactant that can increase dramatically in response to a variety of pathologic states. Elevated pre- and postoperative CRP levels have been associated with an increased tumor burden and metastasis in kidney cancer. We report on a case that serves to highlight a potentially novel use for CRP monitoring in the postoperative management of renal cell carcinoma. Recently, we treated a patient who presented with a localized renal cell carcinoma and an elevated preoperative CRP level. Surgical pathology demonstrated negative surgical margins and absence of nodal metastasis. Postoperatively, the patient's serum CRP levels remained relatively low, consistent with his continued negative staging on CT scans. However, at 6 months postoperatively, the patient's CRP level increased 13-fold. His subsequent CT scan revealed "multiple pulmonary nodules consistent with progression of metastatic disease." This case demonstrates the potential for monitoring CRP in addition to, or instead of, standard restaging imaging.
Assuntos
Biomarcadores Tumorais/sangue , Proteína C-Reativa/metabolismo , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/patologia , Neoplasias Renais/sangue , Neoplasias Renais/patologia , Metástase Neoplásica/patologia , Carcinoma de Células Renais/cirurgia , Humanos , Neoplasias Renais/cirurgiaRESUMO
Tumor heterogeneity is one of the most important and challenging problems not only in studying the mechanisms of cancer development but also in developing therapeutics to eradicate cancer cells. Here we report the use of multiplexed quantum dots (QDs) and wavelength-resolved spectral imaging for molecular mapping of tumor heterogeneity on human prostate cancer tissue specimens. By using a panel of just four protein biomarkers (E-cadherin, high-molecular-weight cytokeratin, p63, and alpha-methylacyl CoA racemase), we show that structurally distinct prostate glands and single cancer cells can be detected and characterized within the complex microenvironments of radical prostatectomy and needle biopsy tissue specimens. The results reveal extensive tumor heterogeneity at the molecular, cellular, and architectural levels, allowing direct visualization of human prostate glands undergoing structural transitions from a double layer of basal and luminal cells to a single layer of malignant cells. For clinical diagnostic applications, multiplexed QD mapping provides correlated molecular and morphological information that is not available from traditional tissue staining and molecular profiling methods.