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BACKGROUND: Clinical guidelines reserve endoscopic surveillance after a gastric intestinal metaplasia (GIM) diagnosis for high-risk patients. However, it is unclear how closely guidelines are followed in clinical practice. We examined the effectiveness of a standardized protocol for the management of GIM among gastroenterologists at a US hospital. METHODS: This was a preintervention and postintervention study, which included developing a protocol and education of gastroenterologists on GIM management. For the preintervention study, 50 patients with GIM were randomly selected from a histopathology database at the Houston VA Hospital between January 2016 and December 2019. For the postintervention study, we assessed change in GIM management in a cohort of 50 patients with GIM between April 2020 and January 2021 and surveyed 10 gastroenterologists. The durability of the intervention was assessed in a cohort of 50 GIM patients diagnosed between April 2021 and July 2021. RESULTS: In the preintervention cohort, GIM location was specified (antrum and corpus separated) in 11 patients (22%), and Helicobacter pylori testing was recommended in 11 of 26 patients (42%) without previous testing. Gastric mapping biopsies were recommended in 14% and surveillance endoscopy in 2%. In the postintervention cohort, gastric biopsy location was specified in 45 patients (90%, P <0.001) and H. pylori testing was recommended in 26 of 27 patients without prior testing (96%, P <0.001). Because gastric biopsy location was known in 90% of patients ( P <0.001), gastric mapping was not necessary, and surveillance endoscopy was recommended in 42% ( P <0.001). One year after the intervention, all metrics remained elevated compared with the preintervention cohort. CONCLUSIONS: GIM management guidelines are not consistently followed. A protocol for GIM management and education of gastroenterologists increased adherence to H. pylori testing and GIM surveillance recommendations.
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Gastroenterólogos , Infecciones por Helicobacter , Helicobacter pylori , Lesiones Precancerosas , Neoplasias Gástricas , Humanos , Gastroscopía , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/terapia , Neoplasias Gástricas/epidemiología , Metaplasia/diagnóstico , Metaplasia/terapia , Lesiones Precancerosas/diagnóstico , Lesiones Precancerosas/terapia , Lesiones Precancerosas/epidemiología , Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/epidemiologíaRESUMEN
BACKGROUND & AIMS: Limitations of endoscopic sampling may result in missed dysplasia at the diagnosis of Barrett's esophagus (BE). However, the role of close follow-up endoscopy is unclear. The aim was to evaluate the proportion of patients diagnosed with "missed" dysplasia within 18 months of their index nondysplastic BE (NDBE) diagnosis. METHODS: This was a retrospective analysis of a cohort of BE patients diagnosed during 1990-2019 at the Houston VA. Patients with BE on index esophagogastroduodenoscopy (EGD) were classified as NDBE, indefinite dysplasia, or dysplastic (low- or high-grade dysplasia) based on initial biopsies. We identified NDBE patients who had follow-up EGD within 3-18 months after index EGD. We used logistic regression models to estimate odds ratios and 95% confidence intervals for risk factors of dysplasia on follow-up EGD. RESULTS: We identified 614 patients who had BE on index EGD. Among those with NDBE and follow-up EGD within 3-18 months (n = 271), 4.1% had definite dysplasia on follow-up, and an additional 14.0% had indefinite dysplasia. Proportions of definite or indefinite dysplasia at follow-up within 3-18 months significantly decreased from 32.6% among patients with index EGD before 2009 to 11.7% among patients with index EGD after 2013 (P for trend = .068). Those with any indefinite or definite dysplastic BE at follow-up within 3-18 months after index EGD (n = 49) were more likely to have BE length ≥3 cm on index EGD (odds ratio, 3.39; 95% confidence interval, 1.63-7.08) than those with persistent NDBE or no BE on follow-up. CONCLUSIONS: The occurrence of missed dysplasia on an index EGD has decreased over time. However, those with long segment BE were more than 3 times as likely to have missed dysplasia, and this group could benefit from dysplasia surveillance within 18 months of BE diagnosis.
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Adenocarcinoma , Esófago de Barrett , Neoplasias Esofágicas , Veteranos , Adenocarcinoma/patología , Esófago de Barrett/diagnóstico , Esófago de Barrett/epidemiología , Esófago de Barrett/patología , Progresión de la Enfermedad , Endoscopía Gastrointestinal , Neoplasias Esofágicas/diagnóstico , Humanos , Prevalencia , Estudios RetrospectivosRESUMEN
BACKGROUND AND AIMS: Risk of esophageal adenocarcinoma (EAC) in those with Barrett's esophagus (BE) is 11-fold greater than the general population. It remains unclear which BE patients are at highest risk of progression to EAC. We aimed to validate a predictive model risk-stratifying BE patients. METHODS: We conducted a retrospective cohort study at the Houston Veteran Affairs Medical Center of consecutive patients with a new diagnosis of BE from November 1990 to January 2019. Study follow-up was through February 2020. Patients were excluded if they had no follow-up EGD with esophageal biopsy sampling after the initial BE-diagnosing EGD or evidence of high-grade dysplasia (HGD) or EAC on initial EGD. We performed an external validation study of a risk model containing sex, smoking, BE length, and low-grade dysplasia (LGD) status and assessed discriminatory ability using the area under the receiver operating characteristic curve (AUROC). RESULTS: Among 608 BE patients, 24 progressed to HGD/EAC. The points-based model discriminated well with an AUROC of .72 (95% confidence interval [CI], .63-.82). When categorized into low-, intermediate-, and high-risk groups according to published cutoffs, the AUROC was poor at .57. Restructured into low-risk versus high-risk groups, the AUROC was .72 (95% CI, .64-.80). Excluding baseline LGD did not reduce discriminatory ability (AUROC, .73; 95% CI, .64-.82). CONCLUSIONS: This external validation provides further evidence that the model including sex, LGD status, smoking status, and BE length may help to risk stratify BE patients. A simplified version excluding LGD status and/or reducing the number of risk groups has increased utility in clinical practice without loss of discriminatory ability.
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Esófago de Barrett , Neoplasias Esofágicas , Lesiones Precancerosas , Veteranos , Adenocarcinoma , Esófago de Barrett/patología , Progresión de la Enfermedad , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/epidemiología , Neoplasias Esofágicas/etiología , Humanos , Hiperplasia , Lesiones Precancerosas/patología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Duodenal eosinophilia may play a role in functional dyspepsia (FD), but existing study results are conflicted. We investigated the association between duodenal eosinophils (count and degranulation) and FD symptoms, accounting for atopic conditions, medications, and seasonal variations. METHODS: In a cross-sectional study conducted in the Michael E. DeBakey VA Medical Center in Houston, Texas, we analyzed duodenal histopathology of 436 patient samples from a prospective cohort with a validated symptom survey data and chart reviews. FD was defined using Rome II symptom criteria. Eosinophil count was number per 5 high-power fields (HPF), and eosinophil degranulation was eosinophilic granules in the stroma both determined by two independent investigators. RESULTS: The study cohort was predominantly male (87.4%) with a mean age of 59.3 (standard deviation (SD) ± 9.8). Mean and median eosinophil counts were 75.5 (± 47.8) and 63 (IQR: 43, 101) per five HPF, respectively. Duodenal eosinophilia (defined as ≥ 63 per 5 HPF) and eosinophil degranulation were present in 50.5% and 23.1% of patient samples, respectively. FD was observed in 178 patients (41.7%), but neither the mean eosinophil count nor duodenal eosinophilia was associated with FD. Eosinophil degranulation was independently associated with FD overall (OR 1.74; 95% CI 1.08, 2.78; p = 0.02) and early satiety (OR 2.04; 95% CI 1.26, 3.30; p = 0.004). CONCLUSIONS: In this large, ethnically diverse cohort of adult patients, we found no significant association between duodenal eosinophilia and FD. However, the presence of duodenal eosinophilic degranulation, an activated eosinophil marker, was significantly associated with FD, especially early satiety.
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Degranulación de la Célula , Duodeno/patología , Dispepsia/etnología , Dispepsia/patología , Eosinofilia/patología , Eosinófilos/fisiología , Anciano , Estudios de Cohortes , Duodeno/citología , Dispepsia/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estados Unidos/epidemiología , VeteranosRESUMEN
The androgen receptor (AR) is a key driver of prostate cancer (PC), even in the state of castration-resistant PC (CRPC) and frequently even after treatment with second-line hormonal therapies such as abiraterone and enzalutamide. The persistence of AR activity via both ligand-dependent and ligand-independent mechanisms (including constitutively active AR splice variants) highlights the unmet need for alternative approaches to block AR signaling in CRPC. We investigated the transcription factor GATA-binding protein 2 (GATA2) as a regulator of AR signaling and an actionable therapeutic target in PC. We demonstrate that GATA2 directly promotes expression of both full-length and splice-variant AR, resulting in a strong positive correlation between GATA2 and AR expression in both PC cell lines and patient specimens. Conversely, GATA2 expression is repressed by androgen and AR, suggesting a negative feedback regulatory loop that, upon androgen deprivation, derepresses GATA2 to contribute to AR overexpression in CRPC. Simultaneously, GATA2 is necessary for optimal transcriptional activity of both full-length and splice-variant AR. GATA2 colocalizes with AR and Forkhead box protein A1 on chromatin to enhance recruitment of steroid receptor coactivators and formation of the transcriptional holocomplex. In agreement with these important functions, high GATA2 expression and transcriptional activity predicted worse clinical outcome in PC patients. A GATA2 small molecule inhibitor suppressed the expression and transcriptional function of both full-length and splice-variant AR and exerted potent anticancer activity against PC cell lines. We propose pharmacological inhibition of GATA2 as a first-in-field approach to target AR expression and function and improve outcomes in CRPC.
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Factor de Transcripción GATA2/fisiología , Coactivadores de Receptor Nuclear/metabolismo , Receptores Androgénicos/metabolismo , Proliferación Celular , Cromatina/metabolismo , Elementos de Facilitación Genéticos , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Humanos , Masculino , Pronóstico , Receptores Androgénicos/fisiología , Transducción de Señal , Transcripción Genética/fisiologíaRESUMEN
BACKGROUND AND AIMS: Previous studies show that microendoscopic images can be interpreted visually to identify the presence of neoplasia in patients with Barrett's esophagus (BE), but this approach is subjective and requires clinical expertise. This study describes an approach for quantitative image analysis of microendoscopic images to identify neoplastic lesions in patients with BE. METHODS: Images were acquired from 230 sites from 58 patients by using a fiberoptic high-resolution microendoscope during standard endoscopic procedures. Images were analyzed by a fully automated image processing algorithm, which automatically selected a region of interest and calculated quantitative image features. Image features were used to develop an algorithm to identify the presence of neoplasia; results were compared with a histopathology diagnosis. RESULTS: A sequential classification algorithm that used image features related to glandular and cellular morphology resulted in a sensitivity of 84% and a specificity of 85%. Applying the algorithm to an independent validation set resulted in a sensitivity of 88% and a specificity of 85%. CONCLUSIONS: This pilot study demonstrates that automated analysis of microendoscopic images can provide an objective, quantitative framework to assist clinicians in evaluating esophageal lesions from patients with BE. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01384227 and NCT02018367.).
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Adenocarcinoma/patología , Algoritmos , Esófago de Barrett/patología , Neoplasias Esofágicas/patología , Esófago/patología , Adenocarcinoma/diagnóstico , Esófago de Barrett/diagnóstico , Neoplasias Esofágicas/diagnóstico , Esofagoscopía , Humanos , Procesamiento de Imagen Asistido por Computador , Microscopía Intravital , Proyectos Piloto , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Non-palpable thyroid nodules can be difficult to access by conventional ultrasound-guided fine needle aspiration, particularly when they are intrathoracic. Many of these patients are subject to multiple follow up scans or invasive diagnostic procedures such as mediastinoscopy or surgical resection. We aim to describe the feasibility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for diagnosis of thyroid lesions. METHODS: All EBUS-TBNA performed at our institutions from February 2010 to February 2013 were screened, and those in which a thyroid biopsy was performed were reviewed. RESULTS: We identified 12 cases of EBUS-TBNA thyroid biopsy. Nine patients had an indication for EBUS in addition to their thyroid lesions. The median age was 64 years (range 44 to 84 years), and 10 patients were male. Median lesion size was 22.5 mm (range, 10 to 43 mm). Five lesions were strictly intrathoracic. All cases were sampled with a 22G needle and rapid on-site cytologic examination. Adequate samples were obtained in all 12 cases. Malignancy was identified in 3 of the 12 patients (metastatic breast adenocarcinoma, large B-cell lymphoma, and metastatic lung adenocarcinoma). The remaining 9 samples were deemed to be benign nodules. Seven of these were confirmed by clinical follow-up (n = 3), biopsies (n = 3), or surgery (n = 1).There were no EBUS-related complications. CONCLUSIONS: EBUS-TBNA might be a safe and effective alternative for sampling thyroid lesions, particularly useful for those located below the thoracic inlet. Further prospective studies are required to compare its diagnostic yield and safety profile with standard techniques.
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Adenocarcinoma/diagnóstico , Biopsia con Aguja Fina , Neoplasias de la Mama/diagnóstico , Broncoscopía , Endoscopía , Neoplasias Pulmonares/diagnóstico , Neoplasias de la Tiroides/diagnóstico , Ultrasonografía Intervencional , Adenocarcinoma/patología , Anciano , Anciano de 80 o más Años , Biopsia con Aguja Fina/instrumentación , Biopsia con Aguja Fina/métodos , Neoplasias de la Mama/patología , Análisis Costo-Beneficio , Estudios de Factibilidad , Femenino , Humanos , Biopsia Guiada por Imagen , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Prospectivos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Neoplasias de la Tiroides/patologíaRESUMEN
In this manuscript we assessed the utility of a low-cost 3D printed microscope to evaluate esophageal biopsies. We conducted a comparative analysis between the traditional microscope and our 3-D printed microscope, utilizing a set of esophageal biopsy samples obtained from patients undergoing screening endoscopy. Two pathologists independently examined 30 esophageal biopsies by light microscopy and digital images obtained using a low-cost 3D printed microscope (Observer 1 and 2). The glass slide consensus diagnosis was compared to the findings of 2 additional pathologist who independently just reviewed the digital images (Observer 3 and 4). The intra-observer agreement was substantial to almost perfect for observer 1 (k:0.64) and 2 (k:0.84). All four observers had 100% sensitivity and negative predictive value, whereas specificity ranged from 59% to 100% and positive predictive value ranged from 21% to 100%. The PPV and specificity were lower for the two Observers (3 and 4) who just examined the digital images. Overall, our results suggest that telepathology may be used with high sensitivity and specificity, utilizing the pictures produced by our 3D-printed microscope.
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INTRODUCTION: We hypothesized that cells present in normal tissue that bear cancer stem cell markers may represent a cancer cell of origin or a microenvironment primed for tumor development, and that their presence may correlate with the clinically defined subtypes of breast cancer that show increased tumorigenicity and stem cell features. methods: Normal tissues sampled at least 5 cm from primary tumors (normal adjacent tissue) were obtained from 61 chemotherapy-naive patients with breast cancer treated with mastectomy. Samples were stained simultaneously with immunofluorescence for CD44/CD49f/CD133/2 stem cell markers. We assessed the association between CD44+CD49f+CD133/2+ staining in normal adjacent tissue and breast cancer receptor subtype (defined by the expression of the estrogen (ER), progesterone (PR), or human epidermal growth factor-2 (Her2) receptors). We also examined the correlation between CD44+CD49f+CD133/2+ immunofluorescence and each of two previously published gene signatures, one derived from stem-cell enriched tissue and one from BRCA mutated tissue expected to have defective DNA repair. RESULTS: Patients with triple negative breast cancer (ER/PR/HER2) expressed CD44+CD49f+CD133/2+ in 9 of 9 normal adjacent tissue samples compared with 7 of 52 ER+ and/or Her2+ tumors (P < 0.001). Further, expression of CD44+CD49f+CD133/2+ by normal adjacent tissue correlated positively with a stem cell-derived tumorigenic signature (P <0.001) and inversely with a defective DNA-repair signature (P <0.001). CONCLUSION: Normal cells bearing cancer stem cell markers are associated with the triple negative receptor subtype of breast cancer. This study suggests stem cell staining and gene expression signatures from normal breast tissues represent novel tissue-based risk biomarkers for triple negative breast cancer. Validation of these results in additional studies of normal tissue from cancer-free women could lay the foundation for future targeted triple negative breast cancer prevention strategies.
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Reparación del ADN , Células Madre Neoplásicas/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Antígeno AC133 , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Superficie , Biomarcadores/metabolismo , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Factores Epidemiológicos , Femenino , Perfilación de la Expresión Génica , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Receptores de Hialuranos/genética , Receptores de Hialuranos/metabolismo , Integrina alfa6/genética , Integrina alfa6/metabolismo , Glándulas Mamarias Humanas/metabolismo , Péptidos/genética , Péptidos/metabolismo , Neoplasias de la Mama Triple Negativas/mortalidadRESUMEN
OBJECTIVE: Most patients with epithelial ovarian cancer achieve a complete clinical remission (CCR) with normal CA-125 but will still relapse and die from their disease. The present study was designed to determine whether CA-125 levels before, during, and after primary treatment provide prognostic information for both type I and type II ovarian cancer. METHODS: In this retrospective study, we identified 410 patients with epithelial ovarian cancer who had achieved a CCR between 1984 and 2011. A Cox proportional hazards model and log-rank test were used to assess associations between the nadir CA-125, histotype, and prognosis. RESULTS: The baseline serum CA-125 concentration was higher in patients with type II ovarian cancer than in those with type I ovarian cancer (P < 0.001). The nadir CA-125 was an independent predictor of progression-free survival (PFS; P < 0.001) and overall survival (OS; P = 0.035) duration. The PFS and OS durations were 21.7 and 79.4 months in patients with CA-125 of 10 U/mL or less and 13.6 and 64.6 months in those with CA-125 of 11 to 35 U/mL, respectively (P = 0.01 and P = 0.002, respectively). Histotype was an independent predictor of PFS (P = 0.041): the PFS and OS durations of the patients with type I ovarian cancer were longer than those of the patients with type II ovarian cancer (P < 0.001 and P < 0.001, respectively). CONCLUSIONS: The nadir CA-125 and histotype are predictive of PFS and OS durations in patients with ovarian cancers who experienced a CCR. Progression-free survival and OS durations were shorter in the patients with CA-125 levels of 11 to 35 U/mL and type II disease than in those with CA-125 levels of 10 U/mL or less and type I ovarian cancer.
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Adenocarcinoma de Células Claras/mortalidad , Adenocarcinoma Mucinoso/mortalidad , Antígeno Ca-125/metabolismo , Carcinoma de Células Transicionales/mortalidad , Cistadenocarcinoma Seroso/mortalidad , Neoplasias Endometriales/mortalidad , Neoplasias Ováricas/mortalidad , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/patología , Adenocarcinoma de Células Claras/terapia , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Mucinoso/terapia , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Transicionales/metabolismo , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/terapia , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patología , Cistadenocarcinoma Seroso/terapia , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Neoplasias Endometriales/terapia , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Estadificación de Neoplasias , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
As a putative marker for cancer stem cells in human malignant tumors, including ovarian cancer, CD133 expression may define a tumor-initiating subpopulation of cells and is associated with the clinical outcome of patients. However, at this time its clinical significance in ovarian cancer remains uncertain. The aim of this study was to clarify the clinical role of CD133 expression in human ovarian cancer. Immunohistochemical staining of CD133 expression was performed in 400 ovarian carcinoma samples using tissue microarray. The associations among CD133 expression and clinical factors (diagnosis, tumor grade, cancer stage, and clinical response to chemotherapy), overall survival and disease-free survival time were analyzed. CD133 expression was found in 31% of ovarian carcinoma samples. Fisher's exact test and one-way analysis of variance suggested that CD133 expression was associated with high-grade serous carcinoma (P=0.035), late-stage disease (P<0.001), ascites level (P=0.010), and non-response to chemotherapy (P=0.023). CD133 expression was also associated with shorter overall survival time (P=0.007) and shorter disease-free survival time (P<0.001) by log-rank test. Moreover, CD133 expression was an independent predictor of shorter disease-free survival time in an unconditional logistic regression analysis with multiple covariates (P=0.024). Our results thus show that CD133 expression is a predictor of poor clinical outcome for patients with ovarian cancer, supporting the proposed link between CD133 and cancer stem cells.
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Antígenos CD/metabolismo , Biomarcadores de Tumor/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Glicoproteínas/metabolismo , Neoplasias Ováricas/metabolismo , Péptidos/metabolismo , Antígeno AC133 , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada , Cistadenocarcinoma Seroso/mortalidad , Cistadenocarcinoma Seroso/terapia , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/terapia , Pronóstico , Tasa de Supervivencia , Análisis de Matrices Tisulares , Adulto JovenRESUMEN
Aurora kinase A (AURKA), a serine/threonine kinase, has been shown to regulate the cell cycle checkpoint and maintain genomic integrity. AURKA is overexpressed in various carcinomas. Breast cancer 2, early onset (BRCA2) has an important role in maintaining genomic stability and acts as a tumor suppressor. Our recent study suggested that AURKA regulates genomic instability and tumorigenesis through cell cycle dysregulation and suppression of BRCA2 expression. However, the expression of AURKA, BRCA2 and their clinical significance is unknown in endometrioid ovarian cancer. In this study, we determined AURKA and BRCA2 expression in endometrioid ovarian carcinoma and correlated them with clinicopathologic characteristics and patient survival. Immunohistochemical staining was performed in 51 primary endometrioid ovarian carcinoma tumor samples, using tissue microarray. We then analyzed the associations between AURKA and BRCA2 expression and clinical factors (tumor grade, disease stage, surgical type, clinical response, and relapse) and overall and disease-free survival durations. AURKA and BRCA2 expression were found in 48 and 29% of the samples, respectively. The results of Fisher's exact test suggested that AURKA expression was significantly associated with no family history of ovarian cancer (P=0.03) and that BRCA2 expression was associated with early-stage disease (P=0.03), low ascites incidence (P=0.03), younger age (<60) at diagnosis (P=0.03), and low-grade tumors (P<0.01). The nuclear BRCA2 score was negatively correlated with AURKA score (P=0.019, two-tailed Pearson correlation). A log-rank test demonstrated that AURKA expression was associated with shorter overall (P=0.001) and disease-free (P=0.009) survival durations, and that BRCA2 expression was associated with longer overall (P=0.000) and disease-free (P=0.002) durations. Patients with BRCA2-positive and AURKA-negative tumors had higher overall (P=0.001) and disease-free (P=0.001) survival rates than did patients with AURKA-positive and BRCA2-negative tumors. Our results demonstrate that a negative regulatory loop exists between AURKA and BRCA2 expression in the ovarian endometrioid carcinoma. AURKA expression is an unfavorable prognostic factor in patients with endometrioid ovarian cancer and BRCA2 is favorable, combination of these two markers may better predict the prognosis of patients with endometrioid ovarian carcinoma than individual marker alone.
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Proteína BRCA2/metabolismo , Carcinoma Endometrioide/diagnóstico , Neoplasias Ováricas/diagnóstico , Proteínas Serina-Treonina Quinasas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Aurora Quinasa A , Aurora Quinasas , Biomarcadores de Tumor/metabolismo , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/mortalidad , Femenino , Humanos , Técnicas para Inmunoenzimas , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/mortalidad , Pronóstico , Tasa de Supervivencia , Adulto JovenRESUMEN
AIMS: The aim of this study was to review the clinicopathological characteristics of neuroendocrine tumours (NETs) metastasizing to the breast, in order to identify features that could be useful in distinguishing these metastatic lesions from primary breast neoplasms. METHODS AND RESULTS: Eighteen metastatic NETs in the breast were identified from two large hospitals over a 15-year period. Eleven (62%) tumours originated in the gastrointestinal tract, 5 (28%) originated in the lung, and the other two were of indeterminate origin. Eight (44%) cases were initially misdiagnosed as primary mammary carcinomas. In retrospect, all metastatic tumours exhibited architectural and cytological features that would suggest neuroendocrine differentiation. Immunohistochemistry can further aid in the distinction between metastatic neuroendocrine and primary mammary carcinoma. All 11 tumours from the gastrointestinal tract expressed CDX-2, 3 (60%) of five tumours from the lung expressed thyroid transcription factor-1, and only 2 (11%) of 18 showed weak oestrogen receptor positivity. Additionally, unlike primary carcinomas, the majority (82%) of metastatic NETs were negative for cytokeratin 7, and all were negative for gross cystic disease fluid protein 15 and mammoglobin. CONCLUSIONS: There is a high propensity for metastatic NETs to mimic primary breast carcinomas. Careful attention to cytological and architectural features can help to identify cases that require further immunophenotypic workup with a panel of tissue-specific antibodies. However, clinical history is paramount for optimal diagnosis.
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Neoplasias de la Mama/secundario , Neoplasias Gastrointestinales/patología , Neoplasias Pulmonares/patología , Tumores Neuroendocrinos/secundario , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/patología , Diagnóstico Diferencial , Femenino , Neoplasias Gastrointestinales/metabolismo , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/metabolismo , Persona de Mediana Edad , Tumores Neuroendocrinos/metabolismoRESUMEN
Mutations in the beta-catenin gene are common in ovarian endometrioid carcinoma. Few studies have addressed the association of beta-catenin expression with tumor characteristics and patient outcome, yielding controversial results. The purpose of this study was to retrospectively assess the expression of beta-catenin in ovarian endometrioid carcinoma and correlate its expression with the Gynecologic Oncology Group's (GOG) grading system, clinicopathological characteristics, and patient survival. A total of 49 patients with primary ovarian endometrioid carcinoma were included in this study. A four-tier score grading system was used for the membranous staining (negative, weak, moderate, and strong) and the percentage of positive cells for the nuclear staining of beta-catenin. The status of five morphometric parameters, nuclear morphology (uniform or pleomorphic), mitotic count, glandular pattern, degree of squamous differentiation, and status of papillary pattern, was assessed. We found that a low membranous expression of beta-catenin and a high mitotic count (>15 per 10 high-power fields) were significantly associated with poor prognosis and early recurrence of ovarian endometrioid carcinoma. In addition, cases with nuclear expression of beta-catenin showed an intermediate overall survival risk and late disease recurrence. Young age at the time of diagnosis, advanced disease stage, and suboptimal debulking were among the clinical factors predicting poor survival and early disease recurrence. The presence of squamous differentiation, a papillary pattern or nuclear pleomorphism did not show any correlation with overall survival or disease-free survival. Low membranous expression of beta-catenin and high mitotic count are poor prognostic indicators in patients with ovarian endometrioid carcinoma, whereas the GOG grading system showed no prognostic value. Our data suggest that there is a need to define a better grading system for ovarian endometrioid carcinoma. Molecular markers such as beta-catenin and mitotic count could aid in defining this grading system.
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Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/patología , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , beta Catenina/biosíntesis , Biomarcadores de Tumor/análisis , Carcinoma Endometrioide/mortalidad , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Índice Mitótico , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Neoplasias Ováricas/mortalidad , Pronóstico , Estudios Retrospectivos , Análisis de Matrices TisularesRESUMEN
In March and early April 2009, cases of a new swine-origin influenza A (H1N1) virus were diagnosed in Mexico and the United States. Influenza virus presents as a respiratory infection with high morbidity and mortality. We describe the postmortem findings of eight confirmed cases of influenza A/H1N1 in a medical examiner setting. The eight cases falling under the jurisdiction of the Harris County Medical Examiner (Houston, TX, USA) with confirmed influenza A/H1N1 infection between June and September 2009 were included in this study. All cases were males between 6 months and 54 years of age. All adult patients had a body mass index from 31 to 49.8 kg/m(2). Five cases had comorbid conditions including one case with sleep apnea and mental retardation, three cases with chronic ethanolism, and one case with thymoma, sarcoidosis, and myasthenia gravis. The remaining three cases had no pre-existing medical conditions. All patients presented with severe flu-like symptoms; yet, only five were febrile. Rapid influenza diagnostic tests were performed in three cases by primary-care physicians, two of which were negative. None of the patients received antiviral medication. The average disease duration time was 8.2 days (3-14 days). A wide range of histopathological findings including tracheitis, necrotizing bronchiolitis, alveolitis, intra-alveolar hemorrhage, and hyaline membranes, both in a focal and in a diffuse distribution, were identified. Influenza A/H1N1 viral infection presents with a wide range of histological findings in a diffuse or focal distribution; most consistently with tracheitis, necrotizing bronchiolitis, and alveolitis with extensive alveolar hemorrhage. These histopathological findings at autopsy along with a clinical history of flu-like symptoms should raise suspicion for influenza A/H1N1 infection, and postmortem analysis by the reverse transcription-polymerase chain reaction (RT-PCR) is recommended for an accurate diagnosis.
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Subtipo H1N1 del Virus de la Influenza A/patogenicidad , Gripe Humana/patología , Pulmón/patología , Adulto , Autopsia , Índice de Masa Corporal , Bronquiolitis/patología , Bronquiolitis/virología , Comorbilidad , Hemorragia/patología , Hemorragia/virología , Humanos , Lactante , Subtipo H1N1 del Virus de la Influenza A/genética , Subtipo H1N1 del Virus de la Influenza A/aislamiento & purificación , Gripe Humana/mortalidad , Gripe Humana/virología , Pulmón/virología , Masculino , Persona de Mediana Edad , Necrosis , Alveolos Pulmonares/patología , Alveolos Pulmonares/virología , ARN Viral/aislamiento & purificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Texas , Traqueítis/patología , Traqueítis/virologíaRESUMEN
Aldehyde dehydrogenase 1 (ALDH1), a detoxifying enzyme responsible for the oxidation of intracellular aldehydes, was shown to have a function in the early differentiation of stem cells, through its function in oxidizing retinol to retinoic acid. It has been shown that ALDH1 is a predictor of poor clinical outcome in breast cancer. The authors hypothesized that the level of ALDH1 expression may be correlated with the clinical outcome of patients with ovarian cancer. Immunohistochemical staining of ALDH1 expression was analyzed in 442 primary ovarian carcinomas using tissue microarray. The associations between the expression of the ALDH1 and clinical factors (diagnosis, tumor grade, stage, and clinical response to chemotherapy), as well as overall and disease-free survival, were analyzed. Expression of ALDH1 was found in 48.9% of the samples. Fisher's exact test suggested that high expression of ALDH1 was significantly associated with endometrioid adenocarcinoma (P<0.0001), early-stage disease (P=0.006), complete response to chemotherapy (P<0.05), and a low serum level of CA125 (P=0.02). High percentage of cells expressing ALDH1 was associated with a longer overall survival time (P=0.01) and disease-free survival time (P=0.006) by log-rank test. In contrast to its function in breast cancer, ALDH1 was a favorable prognostic factor in ovarian carcinoma. ALDH1 therefore may have a different function in ovarian cancer than it does in breast cancer.
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Aldehído Deshidrogenasa/biosíntesis , Biomarcadores de Tumor/análisis , Isoenzimas/biosíntesis , Neoplasias Ováricas/patología , Adulto , Anciano , Anciano de 80 o más Años , Familia de Aldehído Deshidrogenasa 1 , Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/mortalidad , Pronóstico , Retinal-Deshidrogenasa , Análisis de Matrices TisularesRESUMEN
OBJECTIVE: To describe a biinstitutional experience with fine needle aspiration (FNA) of breast lesions occurring in men over a period of over 10 years and to assess the role of FNA in detecting male breast cancer. STUDY DESIGN: Computer patient records were searched from January 1990 to September 2007. Male patients who had a diagnosis of carcinoma on breast biopsy or resection were identified, and detailed chart review was done to assess demographics and correlate biopsy and FNA results. RESULTS: A total of 346, 792 patients' charts were searched, and 217 male patients were found to have had a breast mass and subsequent FNA. Combined in both institutions, FNA results were positive for carcinoma in 12 (5.5%) cases, negative in 181 (83.4%) cases, suspicious in 5 (2.3%) cases, indeterminate/inconclusive in 3 (1.4%) cases and unsatisfactory in 16 (7.4%) cases. Matching biopsies to confirm FNA results were available in 26 (12%) of the 217 cases. The calculated sensitivity and specificity for the malignant cases reached 100%. When suspicious cases were calculated for diagnostic accuracy, the sensitivity was 67% and the specificity 100%. CONCLUSION: This biinstitutional study demonstrates that FNA is a reliable but underutilized procedure for the management of male breast lesions.
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Biopsia con Aguja Fina , Neoplasias de la Mama Masculina/patología , Carcinoma/patología , Adulto , Anciano , Biopsia , Biopsia con Aguja Fina/métodos , Mama/patología , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y EspecificidadRESUMEN
PURPOSE: The function of tumor susceptibility gene 101 (TSG101) in ovarian carcinogenesis is largely unexplored. The aim of this study is to investigate the role of TSG101 in human ovarian cancer development, to examine the expression levels of TSG101 in ovarian carcinomas, and to correlate the results with clinicopathologic variables and survival. EXPERIMENTAL DESIGN: Human ovarian cancer tissue arrays that contain duplicates of 422 cases of primary ovarian carcinoma were used to probe the expression levels of TSG101 and p21 in epithelial ovarian cancer. In vitro studies in ovarian cancer cells using TSG101-specific small interfering RNA (siRNA) were done to further elucidate the mechanism of TSG101-mediated p21 regulation. RESULTS: We show that TSG101 is increasingly overexpressed in borderline tumors and low-grade and high-grade carcinomas. Patients with low expression of TSG101 survive longer than those with high expression. Suppressing TSG101 by siRNA in ovarian cancer cells led to growth inhibition, cell cycle arrest, and apoptosis with concurrent increases in p21 mRNA and protein. Consistent with this negative association between TSG101 and p21, expression levels of these two markers are inversely correlated in ovarian cancer. CONCLUSIONS: TSG101 negatively regulates p21 levels, and up-regulation of TSG101 is associated with poor prognosis in ovarian cancer.
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Carcinoma/genética , Carcinoma/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/biosíntesis , Proteínas de Unión al ADN/biosíntesis , Regulación Neoplásica de la Expresión Génica , Neoplasias Ováricas/metabolismo , Factores de Transcripción/biosíntesis , Regulación hacia Arriba , Anciano , Progresión de la Enfermedad , Complejos de Clasificación Endosomal Requeridos para el Transporte , Femenino , Humanos , Persona de Mediana Edad , Pronóstico , ARN Interferente Pequeño/metabolismo , Factores de Tiempo , TransfecciónRESUMEN
INTRODUCTION: Aberrant DNA methylation has been found frequently in human breast cancers, associated with the loss of expression of a number of regulatory genes for growth and correlated to clinical outcomes. The present study was undertaken to determine whether methylation of a set of growth-suppressor genes would correlate to the expression of estrogen receptors (ERs) and progesterone receptors (PRs). METHODS: We used a pyrosequencing methylation analysis to study the methylation of 12 known growth-suppressor genes in 90 pairs of malignant/normal breast tissues. We also examined the expression of ERs and PRs in those specimens by immunohistochemistry. Mutations of p53 in tumor cells were detected by direct sequencing. RESULTS: Twelve tumor-suppressor genes: ARHI, RASSF1A, HIN-1, RARbeta2, hMLH1, 14-3-3 sigma, RIZ1, p16, E-cadherin, RIL, CDH13, and NKD2 were selected for this methylation study. Five of them (RIL, HIN-1, RASSF1A, CDH13, and RARbeta2) were frequently methylated in breast cancers (57%, 49%, 58%, 44%, and 17%, respectively) but not the normal breast (0-4%). Two panels of methylation profiles were defined. The methylation of the HIN-1/RASSFIA panel strongly correlated to the expression of ERs, PRs, and hormone receptors (HRs; which were defined as 'positive' if ERs and/or PRs were positive; p < 0.001). Conversely, the methylation of the RIL/CDH13 panel strongly correlated to negative ER, PR, and HR expression (p = 0.001, 0.025, and 0.001, respectively). The subset of triple-negative breast cancers (in other words, those with negative ER, PR, and HER-2/neu status) was positively associated with the methylation of the RIL/CDH13 panel and negatively associated with the HIN-1/RASSF1A panel. Mutations of p53 were found in nine breast tumors (11%), seven of which lacked methylation in both panels. CONCLUSION: We have defined two panels (HIN-1/RASSFIA, and RIL/CDH13) of methylation profiles, which correlated, either positively or negatively, to HR status.
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Neoplasias de la Mama/genética , Islas de CpG , Metilación de ADN , Genes Supresores de Tumor/fisiología , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patología , ADN de Neoplasias/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Metástasis Linfática/patología , Persona de Mediana Edad , Regiones Promotoras GenéticasRESUMEN
PURPOSE: ARHI expression is lost or markedly down-regulated in the majority of ovarian cancers. The mechanism by which ARHI is down-regulated in ovarian cancers is still not clear. Our previous reports indicated that ARHI promoter activity was reduced in ovarian cancer cells, due in part to the effects of negative regulatory transcription factor(s). EXPERIMENTAL DESIGN AND RESULTS: We now show that E2F1 and E2F4, but not E2F2, E2F3, or E2F5, bind to the ARHI promoter and repress its activity in ovarian cancer cells. Consistent with this observation, immunochemical staining of cell lines and of 364 samples of ovarian cancer tissue show that the expression of E2F1 and E2F4 proteins is much higher in ovarian cancer cells than in normal ovarian epithelial cells, and that increased expression of E2Fs was negatively correlated with ARHI expression (P < 0.05). Mutation of the putative E2F binding site in the ARHI promoter reversed this inhibitory effect and significantly increased ARHI promoter activity. In addition to the effects of transcriptional regulation, ARHI mRNA also exhibited a significantly reduced half-life in ovarian cancer cells when compared with that in normal ovarian epithelial cells (P < 0.01), suggesting posttranscriptional regulation of ARHI expression. ARHI mRNA contains AU-rich elements (ARE) in the 3'-untranslated region. We have found that these AREs interact with HuR, an ARE-binding protein that stabilizes bound mRNAs, possibly contributing to the rapid turnover of ARHI mRNA. Finally, reduced HuR ARE binding activity was observed in ovarian cancer cells when compared with normal ovarian surface epithelium. CONCLUSIONS: Taken together, our data suggest that ARHI expression is regulated at both the transcriptional and the posttranscriptional levels, contributing to the dramatic decrease in ARHI expression in ovarian cancers.