Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 45
Filtrar
Filtros adicionais











País/Região como assunto
Intervalo de ano
1.
Cancer Prev Res (Phila) ; 12(7): 433-448, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31088824

RESUMO

Colorectal cancer is a leading cause of cancer deaths. The renin-angiotensin system (RAS) is upregulated in colorectal cancer, and epidemiologic studies suggest RAS inhibitors reduce cancer risk. Because vitamin D (VD) receptor negatively regulates renin, we examined anticancer efficacy of VD and losartan (L), an angiotensin receptor blocker. Control Apc+/LoxP mice and tumor-forming Apc+/LoxP Cdx2P-Cre mice were randomized to unsupplemented Western diet (UN), or diets supplemented with VD, L, or VD+L, the latter to assess additive or synergistic effects. At 6 months, mice were killed. Plasma Ca2+, 25(OH)D3, 1α, 25(OH)2D3, renin, and angiotensin II (Ang II) were quantified. Colonic transcripts were assessed by qPCR and proteins by immunostaining and blotting. Cancer incidence and tumor burden were significantly lower in Cre+ VD and Cre+ L, but not in the Cre+ VD+L group. In Apc+/LoxP mice, VD increased plasma 1,25(OH)2D3 and colonic VDR. In Apc+/LoxP-Cdx2P-Cre mice, plasma renin and Ang II, and colonic tumor AT1, AT2, and Cyp27B1 were increased and VDR downregulated. L increased, whereas VD decreased plasma renin and Ang II in Cre+ mice. VD or L inhibited tumor development, while exerting differential effects on plasma VD metabolites and RAS components. We speculate that AT1 is critical for tumor development, whereas RAS suppression plays a key role in VD chemoprevention. When combined with L, VD no longer increases active VD and colonic VDR in Cre- mice nor suppresses renin and Ang II in Cre+ mice, likely contributing to lack of chemopreventive efficacy of the combination.

2.
Clin Lymphoma Myeloma Leuk ; 19(7): 431-440.e13, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31056348

RESUMO

BACKGROUND: With proven single-agent activity and favorable toxicity profile of MEK-1/2 inhibition in advanced leukemia, investigation into combination strategies to overcome proposed resistance pathways is warranted. Resistance to MEK inhibition is secondary to upstream hyperactivation of RAS/RAF or activation of the PI3K/PTEN/AKT/mTOR pathway. This phase II multi-institution Cancer Therapy Evaluation Program-sponsored study was conducted to determine efficacy and safety of the combination of the ATP-competitive pan-AKT inhibitor GSK2141795, targeting the PI3K/AKT pathway, and the MEK inhibitor trametinib in RAS-mutated relapsed/refractory acute myeloid leukemia (AML). PATIENTS AND METHODS: The primary objective was to determine the proportion of patients achieving a complete remission. Secondary objectives included assessment of toxicity profile and biologic effects of this combination. Twenty-three patients with RAS-mutated AML received the combination. Two dose levels were explored (dose level 1: 2 mg trametinib, 25 mg GSK2141795 and dose level 2: 1.5 mg trametinib, 50 mg GSK2141795). RESULTS: Dose level 1 was identified as the recommended phase II dose. No complete remissions were identified in either cohort. Minor responses were recognized in 5 (22%) patients. The most common drug-related toxicities included rash and diarrhea, with dose-limiting toxicities of mucositis and colitis. Longitudinal correlative assessment of the modulation of MEK and AKT pathways using reverse phase protein array and phospho-flow analysis revealed significant and near significant down-modulation of pERK and pS6, respectively. Combined MEK and AKT inhibition had no clinical activity in patients with RAS-mutated AML. CONCLUSION: Further investigation is required to explore the discrepancy between the activity of this combination on leukemia cells and the lack of clinical efficacy.

3.
Per Med ; 15(3): 199-208, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29843583

RESUMO

Genomic medicine is transforming patient care. However, the speed of development has left a knowledge gap between discovery and effective implementation into clinical practice. Since 2010, the Training Residents in Genomics (TRIG) Working Group has found success in building a rigorous genomics curriculum with implementation tools aimed at pathology residents in postgraduate training years 1-4. Based on the TRIG model, the interprofessional Undergraduate Training in Genomics (UTRIG) Working Group was formed. Under the aegis of the Undergraduate Medical Educators Section of the Association of Pathology Chairs and representation from nine additional professional societies, UTRIG's collaborative goal is building medical student genomic literacy through development of a ready-to-use genomics curriculum. Key elements to the UTRIG curriculum are expert consensus-driven objectives, active learning methods, rigorous assessment and integration.

4.
J Mol Diagn ; 20(1): 31-33, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29155048

RESUMO

This commentary highlights the article by Hata et al that examines markers for assessing pancreatic neoplastic progression.


Assuntos
Cisto Pancreático/diagnóstico , Cisto Pancreático/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Patologia Molecular/métodos , Telômero/genética , Humanos , Telomerase/metabolismo , Homeostase do Telômero/genética
5.
Lung Cancer ; 106: 17-21, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28285689

RESUMO

INTRODUCTION: The degree and duration of response to epidermal growth factor receptor (EGFR) inhibitors in EGFR mutated lung cancer are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors, which is currently unknown in view of the prevailing single gene assay diagnostic paradigm in clinical practice, could play a role in clinical outcomes and/or mechanisms of resistance. METHODS: We retrospectively probed our institutional lung cancer database for tumors with EGFR kinase domain mutations that were also evaluated by more comprehensive molecular profiling, and evaluated tumor response to EGFR tyrosine kinase inhibitors (TKIs). RESULTS: Out of 171 EGFR mutated tumor-patient cases, 20 were sequenced using at least a limited comprehensive genomic profiling platform. 50% harbored concurrent TP53 mutation, 10% PIK3CA mutation, 5% PTEN mutation, among others. The response rate to EGFR TKIs, the median progression-free survival (PFS) to TKIs, the percentage of EGFR-T790M TKI resistance and survival had higher trends in EGFR mutant/TP53 wild-type cases when compared to EGFR mutant/TP53 mutant tumors (all p >0.05 without statistical significance); with a significantly longer median PFS in EGFR-exon 19 deletion mutant/TP53 wild-type cancers treated with 1st generation EGFR TKIs (p=0.035). CONCLUSIONS: Concurrent mutations, specifically TP53, are common in EGFR mutated lung cancer and may alter clinical outcomes. Additional cohorts will be needed to determine if comprehensive molecular profiling adds clinically relevant information to single gene assay identification in oncogene-driven lung cancers.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Mutação , PTEN Fosfo-Hidrolase/genética , Proteína Supressora de Tumor p53/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/farmacologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Fosfatidilinositol 3-Quinases/genética , Inibidores de Proteínas Quinases/farmacologia , Estudos Retrospectivos , Resultado do Tratamento
6.
Clin Cancer Res ; 23(2): 549-561, 2017 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-27489286

RESUMO

PURPOSE: Epidermal growth factor receptors (EGFR) are required for tumor promotion by Western diet. The metalloprotease, ADAM17 activates EGFR by releasing pro-EGFR ligands. ADAM17 is regulated by G-protein-coupled receptors, including CXCR4. Here we investigated CXCR4-ADAM17 crosstalk and examined the role of ADAM17 in tumorigenesis. EXPERIMENTAL DESIGN: We used CXCR4 inhibitor, AMD3100 and ADAM17 inhibitor, BMS566394 to assess CXCR4-ADAM17 crosstalk in colon cancer cells. We compared the expression of CXCR4 ligand, CXCL2, and ADAM17 in mice fed Western diet versus standard diet. Separately, mice were treated with marimastat, a broad-spectrum ADAM17 inhibitor, or AMD3100 to assess EGFR activation by ADAM17 and CXCR4. Using Apc-mutant Min mice, we investigated the effects of ADAM17/10 inhibitor INCB3619 on tumorigenesis. To assess the effects of colonocyte ADAM17, mice with ADAM17 conditional deletion were treated with azoxymethane (AOM). ADAM17 expression was also compared in colonocytes from primary human colon cancers and adjacent mucosa. RESULTS: CXCL12 treatment activated colon cancer cell EGFR signals, and CXCR4 or ADAM17 blockade reduced this activation. In vivo, Western diet increased CXCL12 in stromal cells and TGFα in colonocytes. Marimastat or AMD3100 caused >50% reduction in EGFR signals (P < 0.05). In Min mice, INCB3619 reduced EGFR signals in adenomas and inhibited intestinal tumor multiplicity (P < 0.05). In the AOM model, colonocyte ADAM17 deletion reduced EGFR signals and colonic tumor development (P < 0.05). Finally, ADAM17 was upregulated >2.5-fold in human malignant colonocytes. CONCLUSIONS: ADAM17 is a Western diet-inducible enzyme activated by CXCL12-CXCR4 signaling, suggesting the pathway: Western diet→CXCL12→CXCR4→ADAM17→TGFα→EGFR. ADAM17 might serve as a druggable target in chemoprevention strategies. Clin Cancer Res; 23(2); 549-61. ©2016 AACR.


Assuntos
Proteína ADAM17/genética , Quimiocina CXCL2/genética , Neoplasias do Colo/genética , Receptores CXCR4/genética , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Neoplasias do Colo/etiologia , Neoplasias do Colo/patologia , Dieta Ocidental/efeitos adversos , Receptores ErbB/genética , Humanos , Ligantes , Camundongos , Piperidinas/administração & dosagem , Transdução de Sinais/genética , Compostos de Espiro/administração & dosagem , Fator de Crescimento Transformador alfa/genética
7.
J Mol Diagn ; 18(5): 605-619, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27542512

RESUMO

Clinical utility describes the benefits of each laboratory test for that patient. Many stakeholders have adopted narrow definitions for the clinical utility of molecular testing as applied to targeted pharmacotherapy in oncology, regardless of the population tested or the purpose of the testing. This definition does not address all of the important applications of molecular diagnostic testing. Definitions consistent with a patient-centered approach emphasize and recognize that a clinical test result's utility depends on the context in which it is used and are particularly relevant to molecular diagnostic testing because of the nature of the information they provide. Debates surrounding levels and types of evidence needed to properly evaluate the clinical value of molecular diagnostics are increasingly important because the growing body of knowledge, stemming from the increase of genomic medicine, provides many new opportunities for molecular testing to improve health care. We address the challenges in defining the clinical utility of molecular diagnostics for inherited diseases or cancer and provide assessment recommendations. Starting with a modified analytic validity, clinical validity, clinical utility, and ethical, legal, and social implications model for addressing clinical utility of molecular diagnostics with a variety of testing purposes, we recommend promotion of patient-centered definitions of clinical utility that appropriately recognize the valuable contribution of molecular diagnostic testing to improve patient care.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Técnicas de Diagnóstico Molecular , Neoplasias/diagnóstico , Neoplasias/genética , Doenças Assintomáticas , Ensaios Clínicos como Assunto , Assistência à Saúde , Humanos , Oncologia , Patologia Molecular , Prognóstico
8.
Expert Rev Mol Diagn ; 16(8): 827-38, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27253039

RESUMO

INTRODUCTION: Next-Generation-Sequencing (NGS) has enabled gene mutation profiling - cataloguing sequence variants and modifications in clinical assays encompassing tens to thousands of genes in tumors and in germlines. The clinical benefit of applying multi-gene NGS to diverse applications in various malignancies remains to be demonstrated. AREAS COVERED: Applications of gene mutation profiling in oncology include screening cancer-prone families, classification of malignancies, treatment selection, and monitoring the response to treatment of solid tumors (the 'liquid biopsy'). Google Scholar was used to search PubMed for the period 2011-2016 using combinations of the following search terms: 'clinical utility', NGS, 'molecular diagnostics'. Expert commentary: Clinical studies are in progress pairing mutation profiling with streamlined new trial designs to speed identification of promising drug-target combinations and to see if genotype-informed treatment selection will improve outcome across a spectrum of histologies. The analytical advantages and falling cost of NGS make focused gene panels likely to become the dominant modality in molecular diagnostic testing even if trials eventually discourage use of large panels to test all malignancies.


Assuntos
Variação Genética , Técnicas de Diagnóstico Molecular , Neoplasias/diagnóstico , Neoplasias/genética , Biomarcadores Tumorais , Terapia Combinada , Análise Custo-Benefício , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Detecção Precoce de Câncer/métodos , Detecção Precoce de Câncer/normas , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Instabilidade de Microssatélites , Mutação , Neoplasias/mortalidade , Neoplasias/terapia , Prognóstico , Reprodutibilidade dos Testes , Resultado do Tratamento
9.
J Mol Diagn ; 18(2): 153-62, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26857063

RESUMO

Molecular pathology is an essential element of pathology training. As more molecular tests have become available, there is an increasing need for pathology trainees to receive a strong foundation in molecular pathology. Appointed by the Training and Education Committee of the Association for Molecular Pathology, the Molecular Curriculum Task Force has developed a suggested curriculum in molecular pathology for residents. The foundations of molecular pathology are presented as a series of goals and objectives that residency programs can use to develop their educational programs. As pathologists continue to expand their roles to include regular clinical consultations in the realm of molecular testing, a strong foundation in molecular pathology and genomic medicine has become essential to the practice of pathology.


Assuntos
Currículo , Patologia Molecular/educação , Técnicas de Laboratório Clínico , Educação de Pós-Graduação em Medicina , Genômica , Humanos , Infecção , Internato e Residência , Neoplasias , Farmacogenética
10.
Cancer Treat Commun ; 4: 174-181, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26601054

RESUMO

INTRODUCTION: Tumor genotyping using single gene assays (SGAs) is standard practice in advanced non-small-cell lung cancer (NSCLC). We evaluated how the introduction of next generation sequencing (NGS) into day-to-day clinical practice altered therapeutic decision-making. METHODS: Clinicopathologic data, tumor genotype, and clinical decisions were retrospectively compiled over 6 months following introduction of NGS assay use at our institution in 82 patient-tumor samples (7 by primary NGS, 22 by sequential SGAs followed by NGS, and 53 by SGAs). RESULTS: SGAs identified abnormalities in 34 samples, and all patients with advanced EGFR-mutated or ALK-rearranged tumors received approved tyrosine kinase inhibitors (TKIs) or were consented for clinical trials. NGS was more commonly requested for EGFR, ALK, and KRAS-negative tumors (p<0.0001). NGS was successful in 24/29 (82.7%) tumors. Of 17 adenocarcinomas (ACs), 11 (7 from patients with ≤15 pack-years of smoking) had abnormalities in a known driver oncogene. This led to a change in decision-making in 8 patients, trial consideration in 6, and off-label TKI use in 2. Of 7 squamous cell (SC) carcinomas, 1 had a driver aberration (FGFR1); 6 had other genomic events (all with TP53 mutations). In no cases were clinical decisions altered (p=0.0538 when compared to ACs). CONCLUSIONS: Targeted NGS can identify a significant number of therapeutically-relevant driver events in lung ACs; particularly in never or light smokers. For SC lung cancers, NGS is less likely to alter current practice. Further research into the cost effectiveness and optimal use of NGS and improved provider training in genomic oncology are warranted.

11.
J Mol Diagn ; 17(2): 107-17, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25684271

RESUMO

Advances in sequencing technologies have facilitated concurrent testing for many disorders, and the results generated may provide information about a patient's health that is unrelated to the clinical indication, commonly referred to as incidental findings. This is a paradigm shift from traditional genetic testing in which testing and reporting are tailored to a patient's specific clinical condition. Clinical laboratories and physicians are wrestling with this increased complexity in genomic testing and reporting of the incidental findings to patients. An enormous amount of discussion has taken place since the release of a set of recommendations from the American College of Medical Genetics and Genomics. This discussion has largely focused on the content of the incidental findings, but the laboratory perspective and patient autonomy have been overlooked. This report by the Association of Molecular Pathology workgroup discusses the pros and cons of next-generation sequencing technology, potential benefits, and harms for reporting of incidental findings, including the effect on both the laboratory and the patient, and compares those with other areas of medicine. The importance of genetic counseling to preserve patient autonomy is also reviewed. The discussion and recommendations presented by the workgroup underline the need for continued research and discussion among all stakeholders to improve our understanding of the effect of different policies on patients, providers, and laboratories.


Assuntos
Achados Incidentais , Patologia Molecular/métodos , Aconselhamento Genético , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
12.
Cancer Lett ; 359(2): 269-74, 2015 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-25641339

RESUMO

Biomarkers predicting which patients with advanced radioiodine-resistant differentiated thyroid cancer (DTC) may benefit from multi-kinase inhibitors are unavailable. We aimed to describe molecular markers in DTC that correlate with clinical outcome to axitinib. Pretreatment thyroid cancer blocks from 18 patients treated with axitinib were collected and genomic DNA was isolated. The OncoCarta™ Mutation Panel was used to test for 238 oncogenic mutations. Copy number of VEGFR1-3 and PIK3CA was determined using qPCR on enriched tumor samples. Genomic DNA was analyzed for all coding regions of VEGFR1-3 with custom primers. Protein expressions of VEGFR1-3, c-Met, and PIK3CA were evaluated with immunohistochemistry. Clinical response to axitinib, including best response (BR) and progression free survival (PFS), was ascertained from corresponding patients. Fisher's exact test and logistic regression models were used to correlate BR with molecular findings. Cox proportional hazards regression was used to correlate PFS with molecular defects. A total of 22 pathology samples (10 primary, 12 metastatic) were identified. In patients with 2 samples (n = 4), genetic results were concordant and only included once for analysis. Tumors from 4 patients (22%) harbored BRAF V600E mutations, 2 (11%) had KRAS mutations (G12A, G13D) and 2 (11%) had HRAS mutations (Q61R, Q61K). One metastatic sample with mutated KRAS also harbored a PIK3CA (H1047R) mutation. qPCR showed increased copy numbers of PIK3CA in 6 (33%) tumors, VEGFR1 in 0 (0%) tumors, VEGFR2 in 4 (22%) tumors, and VEGFR3 in 6 (33%) tumors. VEGFR sequencing was significant for a possibly damaging non-synonymous SNP in VEGFR2 (G539R) in 2 samples (11%), a possibly damaging SNP in VEGFR3 (E350V) in 1 sample (6%), and a potentially novel mutation in VEGFR2 (T439I) in 2 samples (11%). Immunohistochemistry (VEGFR1, -2, -3; c-MET; PIK3CA) revealed positive staining in the majority of samples. No significant relationship was seen between BR or PFS and the presence of molecular alterations. Molecular evaluation of DTC specimens did not predict clinical response to axitinib but our data were limited by sample size. We did identify molecular changes in VEGFR that should be further explored. While DTC is genetically heterogeneous, primary and metastatic lesions showed identical oncogenic alterations in four cases.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Papilar/genética , Imidazóis/farmacologia , Indazóis/farmacologia , Radioisótopos do Iodo/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Neoplasias da Glândula Tireoide/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Axitinibe , Carcinoma Papilar/tratamento farmacológico , Carcinoma Papilar/radioterapia , Classe I de Fosfatidilinositol 3-Quinases , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Amplificação de Genes , Estudos de Associação Genética , Humanos , Radioisótopos do Iodo/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/genética , Polimorfismo de Nucleotídeo Único , Tolerância a Radiação , Compostos Radiofarmacêuticos/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/radioterapia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética
13.
Am J Physiol Gastrointest Liver Physiol ; 308(3): G179-87, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25477374

RESUMO

The colon differs regionally in local luminal environment, excretory function, and gene expression. Polycistronic microRNA (miR)-143 and miR-145 are downregulated early in colon cancer. We asked if these microRNAs (miRNAs) might be differentially expressed in the proximal vs. the distal colon, contributing to regional differences in protein expression. Primary transcripts and mature miR-143 and miR-145 were quantified by real-time PCR, putative targets were measured by Western blotting, and DNA methylation was assessed by sequencing bisulfite-treated DNA in proximal and distal normal colonic mucosa as well as colon cancers. Putative targets of these miRNAs were assessed following transfection with miR-143 or miR-145. Mean expression of mature miR-143 and miR-145 was 2.0-fold (P < 0.001) and 1.8-fold (P = 0.03) higher, respectively, in proximal than distal colon. DNA methylation or primary transcript expression of these miRNAs did not differ by location. In agreement with increased expression of miR-143 and miR-145 in proximal colon, predicted targets of these miRNAs, apoptosis inhibitor 5 (API5), ERK5, K-RAS, and insulin receptor substrate 1 (IRS-1), which are cell cycle and survival regulators, were expressed at a lower level in proximal than distal colon. Transfection of HCA-7 colon cancer cells with miR-145 downregulated IRS-1, and transfection of HT-29 colon cancer cells with miR-143 decreased K-RAS and ERK5 expression. In conclusion, miR-143 and miR-145 and the predicted target proteins API5, ERK5, K-RAS, and IRS-1 display regional differences in expression in the colon. We speculate that differences in these tumor suppressors might contribute to regional differences in normal colonic gene expression and modulate site-specific differences in malignant predisposition.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Colo/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , MicroRNAs/metabolismo , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas ras/metabolismo , Adulto , Ciclo Celular , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Proteínas Proto-Oncogênicas p21(ras) , Reação em Cadeia da Polimerase em Tempo Real/métodos , Adulto Jovem
14.
Cytojournal ; 11(Suppl 1): 4, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25191518

RESUMO

The Papanicolaou Society of Cytopathology has developed a set of guidelines for pancreatobiliary cytology including indications for endoscopic ultrasound guided fine needle aspiration, terminology and nomenclature of pancreatobiliary disease, ancillary testing and post-biopsy management. All documents are based on the expertise of the authors, a review of the literature, discussion of the draft document at several national and international meetings and synthesis of selected online comments of the draft document. This document presents the results of these discussions regarding the use of ancillary testing in the cytologic diagnosis of biliary and pancreatic lesions. Currently, fluorescence in-situ hybridization (FISH) appears to be the most clinically relevant ancillary technique for cytology of bile duct strictures. The addition of FISH analysis to routine cytologic evaluation appears to yield the highest sensitivity without loss in specificity. Loss of immunohistochemical staining for the protein product of the SMAD4 gene and positive staining for mesothelin support a diagnosis of ductal adenocarcinoma. Immunohistochemical markers for endocrine and exocrine differentiation are sufficient for a diagnosis of endocrine and acinar tumors. Nuclear staining for beta-catenin supports a diagnosis of solid-pseudopapillary neoplasm. Cyst fluid analysis for amylase and carcinoembryonic antigen aids in the pre-operative classification of pancreatic cysts. A number of gene mutations (KRAS, GNAS, von Hippel-Lindau, RNF43 and CTNNB1) may be of aid in the diagnosis of cystic neoplasms. Other ancillary techniques do not appear to improve diagnostic sensitivity sufficiently to justify their increased costs.

15.
Clin Cancer Res ; 20(22): 5848-5859, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25212605

RESUMO

PURPOSE: We previously showed that EGF receptor (EGFR) promotes tumorigenesis in the azoxymethane/dextran sulfate sodium (AOM/DSS) model, whereas vitamin D suppresses tumorigenesis. EGFR-vitamin D receptor (VDR) interactions, however, are incompletely understood. Vitamin D inhibits the renin-angiotensin system (RAS), whereas RAS can activate EGFR. We aimed to elucidate EGFR-VDR cross-talk in colorectal carcinogenesis. EXPERIMENTAL DESIGN: To examine VDR-RAS interactions, we treated Vdr(+/+) and Vdr(-/-) mice with AOM/DSS. Effects of VDR on RAS and EGFR were examined by Western blotting, immunostaining, and real-time PCR. We also examined the effect of vitamin D3 on colonic RAS in Vdr(+/+) mice. EGFR regulation of VDR was examined in hypomorphic Egfr(Waved2) (Wa2) and Egfr(wild-type) mice. Angiotensin II (Ang II)-induced EGFR activation was studied in cell culture. RESULTS: Vdr deletion significantly increased tumorigenesis, activated EGFR and ß-catenin signaling, and increased colonic RAS components, including renin and angiotensin II. Dietary VD3 supplementation suppressed colonic renin. Renin was increased in human colon cancers. In studies in vitro, Ang II activated EGFR and stimulated colon cancer cell proliferation by an EGFR-mediated mechanism. Ang II also activated macrophages and colonic fibroblasts. Compared with tumors from Egfr(Waved2) mice, tumors from Egfr(wild-type) mice showed upregulated Snail1, a suppressor of VDR, and downregulated VDR. CONCLUSIONS: VDR suppresses the colonic RAS cascade, limits EGFR signals, and inhibits colitis-associated tumorigenesis, whereas EGFR increases Snail1 and downregulates VDR in colonic tumors. Taken together, these results uncover a RAS-dependent mechanism mediating EGFR and VDR cross-talk in colon cancer.


Assuntos
Colite/complicações , Neoplasias do Colo/etiologia , Neoplasias do Colo/metabolismo , Receptores ErbB/metabolismo , Receptor Cross-Talk , Receptores de Calcitriol/metabolismo , Sistema Renina-Angiotensina , Angiotensina II/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Colite/genética , Colite/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptores de Calcitriol/genética , Transdução de Sinais , Fatores de Transcrição da Família Snail , Fatores de Transcrição/metabolismo
16.
Leuk Res ; 38(9): 1091-6, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25088808

RESUMO

Myeloid sarcoma (MS) is a presentation of acute myeloid leukemia (AML) as a tumor mass outside of the bone marrow. Viable cells from MS are frequently unavailable for cytogenetic studies. We therefore investigated whether chromosomal microarray analysis (CMA) using formalin-fixed paraffin-embedded (FFPE) tissues can detect clinically important genetic abnormalities in MS. CMA successfully identified genomic aberrations in six cases of MS, and in two cases it revealed multiple abnormalities equivalent to a complex karyotype, thus predicting a poor outcome. CMA using FFPE material is therefore a feasible and clinically applicable approach for detection of prognostically significant genomic abnormalities in MS.


Assuntos
Aberrações Cromossômicas , Análise Citogenética/métodos , Análise em Microsséries/métodos , Inclusão em Parafina , Sarcoma Mieloide/genética , Adulto , Idoso , Medula Óssea/patologia , Feminino , Formaldeído/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Sarcoma Mieloide/sangue , Sarcoma Mieloide/patologia , Fixação de Tecidos/métodos
17.
Diagn Cytopathol ; 42(4): 351-62, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24639398

RESUMO

The Papanicolaou Society of Cytopathology has developed a set of guidelines for pancreatobiliary cytology including indications for endoscopic ultrasound-guided fine-needle aspiration, terminology and nomenclature of pancreatobiliary disease, ancillary testing, and post-biopsy management. All documents are based on the expertise of the authors, a review of the literature, discussions of the draft document at several national and international meetings, and synthesis of selected online comments of the draft document. This document presents the results of these discussions regarding the use of ancillary testing in the cytologic diagnosis of biliary and pancreatic lesions. Currently, fluorescence in situ hybridization (FISH) appears to be the most clinically relevant ancillary technique for cytology of bile duct strictures. The addition of FISH analysis to routine cytologic evaluation appears to yield the highest sensitivity without loss in specificity. Loss of immunohistochemical staining for the protein product of the SMAD4 gene and positive staining for mesothelin support a diagnosis of ductal adenocarcinoma. Immunohistochemical markers for endocrine and exocrine differentiation are sufficient for a diagnosis of endocrine and acinar tumors. Nuclear staining for beta-catenin supports a diagnosis of solid-pseudopapilary neoplasm. Cyst fluid analysis for amylase and carcinoembryonic antigen aids in the preoperative classification of pancreatic cysts. Many gene mutations (KRAS, GNAS, VHL, RNF43, and CTNNB1) may be of aid in the diagnosis of cystic neoplasms. Other ancillary techniques do not appear to improve diagnostic sensitivity sufficiently to justify their increased costs.


Assuntos
Neoplasias dos Ductos Biliares/diagnóstico , Ductos Biliares/patologia , Citodiagnóstico/métodos , Pâncreas/patologia , Neoplasias Pancreáticas/diagnóstico , Sociedades Médicas , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Constrição Patológica , Humanos , Ductos Pancreáticos/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia
18.
J Mol Diagn ; 16(2): 174-9, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24389534

RESUMO

Monitoring BCR-ABL1 fusion transcripts by real-time quantitative RT-PCR has become an important clinical test for the management of patients with chronic myeloid leukemia. However, it has some inherent limitations with regard to its lower limit of detection and limit of quantification. Improvement in the lower limit of detection could aid clinicians in selecting candidates for discontinuation of tyrosine kinase inhibitors without relapse. Improvement in the limit of quantification may also avoid unnecessary testing or changes in therapy. Here, we demonstrate the advantages of droplet digital RT-PCR with regard to simplicity, lower limit of detection, and limit of quantification. We expect the advantages of droplet digital RT-PCR will make it the preferred method for quantification of BCR-ABL1 fusion transcripts.


Assuntos
Proteínas de Fusão bcr-abl/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Reação em Cadeia da Polimerase em Tempo Real/normas , Transcrição Genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
19.
Hum Pathol ; 45(3): 621-7, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24457081

RESUMO

Autoimmune pancreatitis (AIP) often manifests as a mass lesion causing obstructive jaundice, clinically mimicking pancreatic carcinoma. A diagnosis of AIP may obviate the need for surgical resection, as most patients respond to steroid treatment. However, it is not clear whether these 2 conditions can coexist. In this study, 105 specimens resected for pancreatic ductal adenocarcinoma (PDAC) that also have changes of chronic pancreatitis were examined for features considered to be characteristic of AIP. Of 105 cases of PDAC with changes of chronic pancreatitis, 10 (9.5%) exhibited histologic features of AIP, including exuberant fibrosis, lymphoplasmacytic infiltration, obliterative phlebitis, or granulocytic epithelial lesions. Of these 10 cases, 7 had more than 20 immunoglobulin G4+ plasma cells per high-power field. Of these 7 cases, 5 were analyzed for Kirsten rat sarcoma viral oncogene mutation and SMAD4 expression. Three cases showed K-ras mutation and/or loss of SMAD4 expression in benign AIP-like areas. These findings suggest 2 possibilities: first, AIP-like lesions may occur in a small but significant portion of PDAC cases; second, some PDACs may arise in a background of AIP. Therefore, caution is necessary when making a diagnosis of AIP by needle biopsy of a mass lesion, and patients with a tentative AIP diagnosis should be closely followed up clinically.


Assuntos
Doenças Autoimunes/diagnóstico , Carcinoma Ductal Pancreático/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Pancreatite/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Humanos , Imunoglobulina G/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Pancreatite/metabolismo , Pancreatite/patologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas p21(ras) , Proteína Smad4/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismo
20.
Blood Cells Mol Dis ; 52(1): 68-75, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23910958

RESUMO

The BCL6 gene, which is expressed in certain B- and T-cell human lymphomas, is involved with chromosomal rearrangements and mutations in a number of these neoplasms. Lymphomagenesis is believed to evolve through a multi-step accumulation of genetic alterations in these tumors. We used retroviral insertional mutagenesis in transgenic mice expressing the human BCL6 transgene in order to identify genes that cooperate with BCL6 during lymphomatous transformation. We previously reported PIM1 as the most frequently recurring cooperating gene in this model. We now report three newly identified cooperating genes-GFI1B, EVI5, and MYB-that we identified in the lymphomas of retroviral-injected BCL6 transgenic mice (but not in retroviral-injected non-transgenic controls); mRNA and protein expression of GFI1B and EVI5 were decreased in the murine tumors, whereas MYB mRNA and protein expression were increased or decreased. These findings correlated with protein expression in human lymphomas, both B- and T-cell. Improved therapy of lymphomas may necessitate the development of combinations of drugs that target the alterations specific to each neoplasm.


Assuntos
Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Linfoma de Células B/genética , Linfoma de Células T/genética , Proteínas Oncogênicas v-myb/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Proteínas de Ligação a DNA/metabolismo , Feminino , Vetores Genéticos , Humanos , Imuno-Histoquímica , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Oncogênicas v-myb/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Repressoras/metabolismo , Retroviridae/genética , Transdução de Sinais , Fatores de Transcrição/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA