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1.
Cancer Causes Control ; 31(7): 631-640, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32358694

RESUMO

PURPOSE: BRAF mutation and DNA hypermethylation have linked sessile serrated adenomas/polyps (SSA/Ps) to serrated colorectal cancer (CRC) in cross-sectional studies, but they have not been evaluated in a longitudinal study. We aimed to evaluate the associations between molecular markers of serrated polyps and subsequent advanced colorectal neoplasia. METHODS: Study subjects included Kaiser Permanente Washington members aged 20-75 years who received an index colonoscopy between 1/1/1998 and 12/31/2007 and had hyperplastic polyps (HPs) or SSA/Ps according to study pathology review. Polyps from index colonoscopies were removed and assayed for BRAF mutation, CpG island methylator phenotype (CIMP), and MLH1 methylation. Pathology reports and biopsies from the subsequent lower gastrointestinal endoscopy through 1/1/2013 were reviewed for advanced colorectal neoplasia. We identified additional incident CRC cases through linkage to the Seattle-Puget Sound Surveillance Epidemiology and End Results registry. We used generalized estimating equations to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) for subsequent advanced colorectal neoplasia, comparing index serrated polyps with different molecular markers. RESULTS: We included 553 individuals with index serrated polyps (420 HPs and 133 SSA/Ps) and 795 subsequent endoscopies. The prevalence of BRAF-mutant, CIMP-high, and MLH1-methylated serrated polyps were 51%, 4%, and 2%, respectively. BRAF and CIMP were not associated with subsequent advanced colorectal neoplasia. MLH1-methylated SSP/As were significantly more likely to have subsequent advanced neoplasia (OR = 4.66, 95% CI 1.06-20.51). CONCLUSION: Our results suggest that BRAF-mutant and CIMP-high serrated polyps are not associated with subsequent advanced colorectal neoplasia. Among SSA/Ps, MLH1 methylation may be an important marker to identify high-risk CRC precursors.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Pólipos Intestinais/genética , Pólipos Intestinais/patologia , Adenoma/genética , Adenoma/patologia , Adulto , Idoso , Estudos de Casos e Controles , Colonoscopia , Neoplasias Colorretais/epidemiologia , Estudos Transversais , Metilação de DNA , Feminino , Humanos , Pólipos Intestinais/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Proteínas Proto-Oncogênicas B-raf/genética , Programa de SEER , Washington/epidemiologia , Adulto Jovem
2.
Cancer Causes Control ; 30(9): 979-987, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31290073

RESUMO

PURPOSE: Colorectal cancer (CRC) screening guidelines recommend increased surveillance of individuals with sessile serrated adenomas/polyps (SSA/Ps), but there is uncertainty about the risk associated with SSA/Ps. We aimed to determine the association between SSA/Ps and subsequent advanced colorectal neoplasia. METHODS: This case-control study included Kaiser Permanente Washington (KPWA) members who received an index colonoscopy between 1/1/1998 and 12/31/2007, and had hyperplastic polyps (HPs) or SSA/Ps but no conventional adenomas according to study pathologist histologic review. Subsequent pathology reports and biopsies through 1/1/2013 were reviewed for advanced colorectal neoplasia. We linked to the Seattle-Puget Sound Surveillance Epidemiology and End Results (SEER) registry to identify additional CRC cases. We used generalized estimating equations with a logit link to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for advanced colorectal neoplasia, comparing those with SSA/Ps to those with HPs. RESULTS: There were 161 individuals with index SSA/Ps, 548 with HPs, and 918 subsequent endoscopies included in analyses. Of those with index SSA/Ps, 19 had subsequent advanced colorectal neoplasia; 39 with HPs had subsequent advanced colorectal neoplasia. Compared to those with HPs, those with SSA/Ps were not statistically significantly more likely to have subsequent advanced colorectal neoplasia (adjusted OR 1.79; CI 0.98-3.28). Polyp size ≥ 10 mm, right colon location, and the presence of multiple serrated polyps were also not associated with advanced colorectal neoplasia. CONCLUSIONS: Our results suggest that there is not a strong association between SSA/Ps and subsequent advanced colorectal neoplasia during the 5 years following SSA/P removal.


Assuntos
Adenoma/epidemiologia , Pólipos do Colo/epidemiologia , Neoplasias Colorretais/epidemiologia , Adenoma/diagnóstico , Adulto , Idoso , Biópsia , Estudos de Casos e Controles , Pólipos do Colo/diagnóstico , Colonoscopia , Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances
3.
BMC Cancer ; 18(1): 513, 2018 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-29720120

RESUMO

BACKGROUND: Short telomeres have been associated with increased risk of many cancers, particularly cancers of the gastrointestinal tract including esophagus and stomach. However, the association between telomere length (TL) and colorectal cancer and its precursors, colorectal polyps, is not clear. METHODS: We investigated the relationship between TL and risk of colorectal polyp subtypes in a colonoscopy-based study in western Washington. Participants were 35-79 year-old enrollees at an integrated health care system, who underwent a colonoscopy between 1998 and 2007 (n = 190), completed a self-administered questionnaire, provided blood samples, and were distinguished as having adenomas, serrated polyps, or as polyp-free controls through a standardized pathology review. Telomere length (T) relative to a single copy gene (S) was measured in circulating leukocytes from stored buffy coat samples using quantitative polymerase chain reaction. Multivariable polytomous logistic regression was used to compare case groups with polyp-free controls and other case groups; adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated. RESULTS: TL in the shortest tertile (T/S ratio < 0.58) was associated with increased risk of adenomas and serrated polyps [OR (95%CI) were 1.77(0.81-3.88) and 2.98(1.15-7.77), respectively). When evaluated by lesion severity within each pathway, short TL was more strongly associated with advanced adenomas and sessile serrated polyps [OR (95% CI) = 1.90(0.76-4.73) and 3.82(0.86-16.86), respectively], although the associations were not statistically significant. CONCLUSIONS: Our results suggest that short TL may be associated with an increased risk of colorectal polyps in both the adenoma-carcinoma and serrated pathways. The risk was particularly notable for sessile serrated polyps, although the association was not statistically significant and sample size was limited.


Assuntos
Pólipos do Colo/patologia , Telômero/patologia , Adenoma/patologia , Adulto , Idoso , Carcinoma/patologia , Estudos de Casos e Controles , Colonoscopia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
4.
Helicobacter ; 23(2): e12472, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29480566

RESUMO

BACKGROUND: Treatment of Helicobacter pylori infection is often empiric; however, current guidelines for management of Helicobacter pylori infection advise against the use of standard triple therapy (clarithromycin, amoxicillin, and proton-pump inhibitor) when clarithromycin resistance exceeds 20%. We developed and tested a new culture-free assay to detect clarithromycin resistance-conferring mutations to determine the prevalence of H. pylori clarithromycin resistance in patients from the United States Pacific Northwest. MATERIALS AND METHODS: Droplet digital PCR (ddPCR) was used to detect the H. pylori 23S rRNA gene, and resistance-conferring mutations, in archived, formalin-fixed, paraffin-embedded (FFPE) gastric tissue and to retrospectively determine the prevalence of clarithromycin-resistant H. pylori among 110 patients at an academic medical center in the Northwest United States between 2012 and 2014. RESULTS: Of 102 patients with the H. pylori 23S rRNA gene detected by the ddPCR assay, 45 (44%) had clarithromycin resistance mutations. Thirty-three of the 45 patients with clarithromycin resistance mutations had a mix of wild-type and resistance alleles. Prevalence of clarithromycin resistance mutations differed among racial groups and was highest among Asians, with mutations detected in 14 (67%) of the 21 patient samples. CONCLUSIONS: The prevalence of clarithromycin resistance detected in this region exceeds 20%, indicating that standard triple therapy should not be the first-line antibiotic treatment for H. pylori infection. Culture-free assays for detecting clarithromycin resistance mutations can be performed on archived tissue samples and will aid in informing tailored treatment for effective H. pylori eradication.


Assuntos
Claritromicina/farmacologia , Farmacorresistência Bacteriana/genética , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/genética , Humanos , Mutação/genética , Reação em Cadeia da Polimerase , Prevalência , Estudos Retrospectivos
5.
Cancer Causes Control ; 28(3): 241-246, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28205046

RESUMO

BACKGROUND: Oral contraceptives (OC) are associated with a decreased risk of colorectal cancers; however, a recent study reported an increased risk of small colorectal adenomas associated with OC use. To determine if these results were replicable in a different study population, we investigated the relationship between OC use and other reproductive factors and risk of colorectal polyps in a case-control study in western Washington. METHODS: Study participants were 24-79-year-old female enrollees at an integrated health care system in western Washington who were diagnosed as having adenomas (n = 299), serrated polyps (n = 337), both types of polyps (n = 105) or as polyp-free controls (n = 615) through an index colonoscopy and completed a structured interview to collect reproductive history information. Multivariable polytomous logistic regression was used to compare case groups to controls and to each other; odds ratios (OR) and 95% confidence intervals were estimated. RESULTS: There was no association between OC use, duration of use, or recency of use and the risk of either adenomas or serrated polyps [adjusted OR for OC ever use (95% CI) 0.85 (0.58-1.23) and 0.96 (0.66-1.40), respectively], and associations did not differ by lesion severity within the adenoma or serrated pathways. Further, no associations were observed between other reproductive factors and risk of colorectal polyp subtypes. CONCLUSIONS: Our results suggest that reproductive factors, including OC use, are not associated with early colorectal cancer precursor lesions.


Assuntos
Pólipos do Colo/epidemiologia , Anticoncepcionais Orais , História Reprodutiva , Adenoma/epidemiologia , Adulto , Idoso , Estudos de Casos e Controles , Pólipos do Colo/diagnóstico , Colonoscopia , Neoplasias Colorretais/epidemiologia , Anticoncepcionais Orais/administração & dosagem , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Washington
6.
Cancer ; 122(3): 393-401, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26480326

RESUMO

BACKGROUND: Lynch syndrome confers a hereditary predisposition to colorectal and other cancers. Universal tumor screening (UTS) for Lynch syndrome is recommended by several professional societies, but the implementation can be complex. This article describes the evaluation, process development, and initiation of Lynch syndrome UTS at a tertiary referral cancer center. METHODS: A multidisciplinary team developed the new process design. Issues in 5 themes were noted: timing, funding, second-opinion patients, result processing, and the role of genetics providers. A committee approach was used to examine each issue for process-improvement development. RESULTS: The issues related to testing were addressed individually for the successful implementation of UTS at the institutional level. In the conventional-care period, 9 of 30 cases (30%) received Lynch syndrome screening, and 4 cases were referred to medical genetics. During the 6 months following the implementation of UTS, 32 of 44 patients (73%) received Lynch syndrome screening. The 13 unscreened patients all had identified reasons for nonscreening (eg, financial limitations). Ten patients were referred to medical genetics, which identified no new cases of Lynch syndrome, but a low-risk adenomatous polyposis coli (APC) variant was detected in 1 individual. CONCLUSIONS: The implementation of effective Lynch syndrome UTS can feasibly alter practice at the institutional level. This experience with the assessment and management of issues relevant to the successful implementation of a new clinical care paradigm based on emerging technology has implications for the uptake of advances across molecular oncology into clinical practice, and this is highly relevant in the current era of rapidly evolving genomic technology.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Detecção Precoce de Câncer/métodos , Testes Genéticos/estatística & dados numéricos , Programas de Rastreamento/métodos , Oncologia/métodos , Patologia Molecular , Adulto , Idoso , Institutos de Câncer , Neoplasias Colorretais/complicações , Neoplasias Colorretais/economia , Neoplasias Colorretais Hereditárias sem Polipose/economia , Detecção Precoce de Câncer/economia , Estudos de Viabilidade , Feminino , Aconselhamento Genético , Predisposição Genética para Doença , Testes Genéticos/economia , Humanos , Masculino , Programas de Rastreamento/economia , Pessoa de Meia-Idade , Patologia Molecular/métodos , Encaminhamento e Consulta , Centros de Atenção Terciária , Washington
7.
PLoS Genet ; 9(1): e1003169, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23341773

RESUMO

In oral squamous cell carcinoma (OSCC), metastasis to lymph nodes is associated with a 50% reduction in 5-year survival. To identify a metastatic gene set based on DNA copy number abnormalities (CNAs) of differentially expressed genes, we compared DNA and RNA of OSCC cells laser-microdissected from non-metastatic primary tumors (n = 17) with those from lymph node metastases (n = 20), using Affymetrix 250K Nsp single-nucleotide polymorphism (SNP) arrays and U133 Plus 2.0 arrays, respectively. With a false discovery rate (FDR)<5%, 1988 transcripts were found to be differentially expressed between primary and metastatic OSCC. Of these, 114 were found to have a significant correlation between DNA copy number and gene expression (FDR<0.01). Among these 114 correlated transcripts, the corresponding genomic regions of each of 95 transcripts had CNAs differences between primary and metastatic OSCC (FDR<0.01). Using an independent dataset of 133 patients, multivariable analysis showed that the OSCC-specific and overall mortality hazards ratio (HR) for patients carrying the 95-transcript signature were 4.75 (95% CI: 2.03-11.11) and 3.45 (95% CI: 1.84-6.50), respectively. To determine the degree by which these genes impact cell survival, we compared the growth of five OSCC cell lines before and after knockdown of over-amplified transcripts via a high-throughput siRNA-mediated screen. The expression-knockdown of 18 of the 26 genes tested showed a growth suppression ≥ 30% in at least one cell line (P<0.01). In particular, cell lines derived from late-stage OSCC were more sensitive to the knockdown of G3BP1 than cell lines derived from early-stage OSCC, and the growth suppression was likely caused by increase in apoptosis. Further investigation is warranted to examine the biological role of these genes in OSCC progression and their therapeutic potentials.


Assuntos
Carcinoma de Células Escamosas , Linfonodos , Metástase Linfática , Neoplasias Bucais , Prognóstico , Idoso , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Genômica , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Metástase Linfática/genética , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , RNA Interferente Pequeno/genética
8.
Cancer Causes Control ; 26(3): 467-73, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25618792

RESUMO

PURPOSE: Studies linking cholesterol levels to the development of colorectal neoplasia are inconsistent, and Mendelian randomization has been suggested as a way to help avoid problems with confounding and reverse causation. METHODS: We genotyped individuals who received a colonoscopy at Group Health (1998-2007) for 96 of 102 single-nucleotide polymorphisms identified by the Global Lipids Genetics Consortium. Participants included 139 advanced adenoma cases, 518 non-advanced adenoma cases, 380 non-adenomatous polyp cases, and 754 polyp-free controls. All had at least one available pre-colonoscopy lipid measurement from electronic records maintained by Group Health. RESULTS: Advanced adenoma cases were more likely than controls to have higher pre-colonoscopy zenith low-density lipoprotein (LDL), triglycerides (TG), and total cholesterol (TC) (odds ratio, OR per 20 mg/dL LDL increase: 1.16, 95 % confidence interval, CI 1.03-1.30; per 40 mg/dL TG increase: 1.09, 1.03-1.16; and per 20 mg/dL TC increase: 1.09, 1.02-1.18). For these traits, genotype-polyp ORs using weighted allele scores were not statistically significant (OR per increase in score scaled to a 20 mg/dL LDL increase: 1.17, 0.78-1.75; a 40 mg/dL TG increase: 1.12, 0.91-1.38; a 20 mg/dL TC increase: 0.99, 0.71-1.38). CONCLUSIONS: Cholesterol levels may be associated with advanced adenomas, but larger studies are warranted to determine whether this association can be attributed to genetics.


Assuntos
Adenoma/sangue , Colesterol/sangue , Pólipos do Colo/sangue , Pólipos do Colo/etiologia , Neoplasias Colorretais/sangue , Polimorfismo de Nucleotídeo Único , Triglicerídeos/sangue , Adenoma/etiologia , Adulto , Idoso , Biópsia , Pólipos do Colo/genética , Colonoscopia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/genética , Feminino , Genótipo , Humanos , Lipídeos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Razão de Chances , Fenótipo
9.
Am J Epidemiol ; 180(2): 223-32, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24875374

RESUMO

We conducted a case-control study of the association between subsets of colorectal polyps, including adenomas and serrated polyps, and single-nucleotide polymorphisms (SNPs) related to colorectal cancer through prior genome-wide association studies (GWAS). Participants were enrollees in the Group Health Cooperative (Seattle, Washington) aged 24-79 years who received a colonoscopy from 1998 to 2007, donated a buccal or blood sample, and completed a structured questionnaire. We performed genotyping of 13 colorectal cancer susceptibility SNPs. Polytomous logistic regression models were used to estimate odds ratios and 95% confidence intervals for associations between polyps and the colorectal cancer risk allele for each SNP under a log-additive model. Analyses included 781 controls, 489 cases with adenoma, 401 cases with serrated polyps, and 188 cases with both polyp types. The following SNPs were associated with advanced adenomas: rs10936599, rs10795668, rs16892766, and rs9929218 (P < 0.05). For nonadvanced adenomas and for serrated polyps overall, only rs961253 was statistically significant (P < 0.05). These associations were in the same directions as those in prior colorectal cancer GWAS. No SNP was significantly associated with hyperplastic polyps, and only rs6983267 was significantly associated with sessile serrated polyps, but this association was opposite of that found in colorectal cancer GWAS. Our results suggest that the association between colorectal cancer susceptibility SNPs and colorectal polyps varies by polyp type.


Assuntos
Adenoma/genética , Pólipos do Colo/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Adenoma/patologia , Adulto , Idoso , Estudos de Casos e Controles , Pólipos do Colo/classificação , Pólipos do Colo/patologia , Neoplasias Colorretais/patologia , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários
10.
Lab Med ; 2024 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-39159202

RESUMO

BACKGROUND: The United States notoriously has one of the highest rates of incarceration in the world, yet scant attention to the health care needs of those incarcerated exists within laboratory medicine and pathology training and education. This article explores health disparities among incarcerated and released individuals regarding diagnostic laboratory testing and pathology services. METHODS: A literature search was conducted for articles published between 2002 and 2023 using keywords including "healthcare," "incarcerated," "laboratory services," "pathology services," and "health insurance for prisoners." Central themes were extracted and discussed to reveal the realities of health care during and after release from incarceration. Excluded from the analysis were articles about the immediate or extended family of incarcerated persons. RESULTS: Incarcerated individuals have an increased risk for the development and exacerbation of communicable and noncommunicable diseases and mental health disorders, which results in exceedingly high morbidity and mortality rates. CONCLUSION: Policy changes are needed to mitigate disparities and improve health outcomes for incarcerated and released persons. Central to these disparities is decreased access to laboratory and pathology services, impeded by inadequate health care funding for these carceral institutions. Providing additional funding to the carceral system's health care budget is necessary to improve access to pathology and laboratory services.

11.
Am J Epidemiol ; 177(7): 625-37, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23459948

RESUMO

Using a case-control design, we evaluated differences in risk factors for colorectal polyps according to histological type, anatomical site, and severity. Participants were enrollees in the Group Health Cooperative aged 20-79 years who underwent colonoscopy in Seattle, Washington, between 1998 and 2007 and comprised 628 adenoma cases, 594 serrated polyp cases, 247 cases with both types of polyps, and 1,037 polyp-free controls. Participants completed a structured interview, and polyps were evaluated via standardized pathology review. We used multivariable polytomous logistic regression to compare case groups with controls and with the other case groups. Factors for which the strength of the association varied significantly between adenomas and serrated polyps were sex (P < 0.001), use of estrogen-only postmenopausal hormone therapy (P = 0.01), and smoking status (P < 0.001). For lesion severity, prior endoscopy (P < 0.001) and age (P = 0.05) had significantly stronger associations with advanced adenomas than with nonadvanced adenomas; and higher education was positively correlated with sessile serrated polyps but not with other serrated polyps (P = 0.02). Statistically significant, site-specific associations were observed for current cigarette smoking (P = 0.05 among adenomas and P < 0.001 among serrated polyps), postmenopausal estrogen-only therapy (P = 0.01 among adenomas), and obesity (P = 0.01 among serrated polyps). These findings further illustrate the epidemiologic heterogeneity of colorectal neoplasia and may help elucidate carcinogenic mechanisms for distinct pathways.


Assuntos
Adenoma/epidemiologia , Adenoma/patologia , Pólipos do Colo/epidemiologia , Pólipos do Colo/patologia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/patologia , Adulto , Idoso , Anti-Inflamatórios não Esteroides/administração & dosagem , Índice de Massa Corporal , Estudos de Casos e Controles , Colonoscopia , Terapia de Reposição de Estrogênios/estatística & dados numéricos , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Fatores de Risco , Índice de Gravidade de Doença , Sexo , Fumar/epidemiologia , Fatores Socioeconômicos
12.
Bioconjug Chem ; 24(2): 167-75, 2013 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-23273065

RESUMO

Molecular imaging, the visualization of molecular and cellular markers, is a promising method for detection of dysplasia and early cancer in the esophagus and can potentially be used to identify regions of interest for biopsy or tumor margins for resection. EGFR is a previously reported cell surface receptor with stepwise increases in expression during the progression from Barrett's metaplasia to adenocarcinoma. In this work, a 200 nm fluorescent nanoparticle contrast agent was synthesized for targeted imaging of EGFR through a series of surface modifications to dye-encapsulated polystyrene particles. Amino-functionalized polystyrene particles were PEGylated using a heterobifunctional PEG linker. Subsequently, thiolated M225 antibodies were conjugated to maleimide functional groups on attached PEGs for EGFR targeting. In vitro binding studies using flow cytometry demonstrated specific binding of M225-PEG-NP to EGFR-expressing cells with minimal nonspecific binding in EGFR(-) cells. Binding was shown to increase proportionally with the number of conjugated M225 antibodies. Adsorbed formulations with unmodified M225 antibodies, M225 + PEG-NP, were synthesized using the same antibody feeds used in M225-PEG-NP synthesis to determine the contribution of adsorbed antibodies to EGFR targeting. Adsorbed antibodies were less efficient at mediated nanoparticle targeting to EGFR than conjugated antibodies. Finally, M225-PEG-NP demonstrated binding to EGFR-expressing regions in human esophageal tissue sections.


Assuntos
Anticorpos , Receptores ErbB/análise , Corantes Fluorescentes , Nanopartículas , Neoplasias/diagnóstico , Imagem Óptica/métodos , Adenocarcinoma/diagnóstico , Anticorpos/química , Esôfago de Barrett/diagnóstico , Linhagem Celular Tumoral , Meios de Contraste/química , Neoplasias Esofágicas/diagnóstico , Esôfago/patologia , Corantes Fluorescentes/química , Humanos , Imagem Molecular/métodos , Nanopartículas/química , Polietilenoglicóis/química , Poliestirenos/química
13.
Genes Chromosomes Cancer ; 51(4): 384-93, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22170739

RESUMO

The aberrant DNA methylation of tumor suppressor genes occurs frequently in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) and likely affects the initiation and progression of BE to EAC. In the present study, we discovered PKP1 as a novel methylated gene in EAC and then investigated the role of loss of PKP1, a constituent of the desmosome complex found in stratified epithelial layers, on the behavior of Barrett's esophagus and esophageal adenocarcinoma cells. By using primary esophageal tissue samples we determined that PKP1 was rarely methylated in normal squamous esophagus (5/55; 9.1%) and BE (5/39; 12.8%) and more frequently methylated in Barrett's esophagus with high-grade dysplasia (HGD) or EAC (20/60; 33.3%; P < 0.05). Furthermore, PKP1 levels were decreased in BE and HGD/EAC cases compared to normal squamous esophagus cases. Knockdown of PKP1 in the BE cell lines CP-A and CP-D (both normally express PKP1) resulted in increased cell motility. Thus, PKP1 loss secondary to promoter methylation, as well as other mechanisms, may promote the progression of BE to EAC in a subset of patients via decreased desmosome assembly and increased cell motility.


Assuntos
Adenocarcinoma/genética , Esôfago de Barrett/genética , Metilação de DNA , Neoplasias Esofágicas/genética , Placofilinas/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Esôfago de Barrett/metabolismo , Esôfago de Barrett/patologia , Biomarcadores Tumorais/genética , Movimento Celular , Desmossomos/metabolismo , Progressão da Doença , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Humanos , Placofilinas/metabolismo , Regiões Promotoras Genéticas , Interferência de RNA , RNA Mensageiro/genética , RNA Interferente Pequeno , Células Tumorais Cultivadas
14.
Am J Gastroenterol ; 107(8): 1213-9, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22688851

RESUMO

OBJECTIVES: Colonoscopy is associated with a decreased risk of colorectal cancer but may be more effective in reducing the risk of distal than proximal malignancies. To gain insight into the differences between proximal and distal colon endoscopic performance, we conducted a case-control study of advanced adenomas, the primary targets of colorectal endoscopy screening, and sessile serrated polyps (SSPs), newly recognized precursor lesions for a colorectal cancer subset that occurs most often in the proximal colon. METHODS: The Group Health-based study population included 213 advanced adenoma cases, 172 SSP cases, and 1,704 controls aged 50-79 years, who received an index colonoscopy from 1998-2007. All participants completed a structured questionnaire covering endoscopy history. Participants with polyps underwent a standard pathology review to confirm the diagnosis and reclassify a subset as advanced adenomas or SSPs. Logistic regression analyses were conducted to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association between endoscopy and advanced adenomas and SSPs separately; site-specific analyses were completed. RESULTS: Previous endoscopy was inversely associated with advanced adenomas in both the rectum/distal colon (OR=0.38; 95% CI: 0.26-0.56) and proximal colon (OR=0.31; 95% CI: 0.19-0.52), but there was no statistically significant association between previous endoscopy and SSPs (OR=0.80; 95%CI: 0.56-1.13). CONCLUSIONS: Our results support the hypothesis that the effect of endoscopy differs between advanced adenomas and SSPs. This may have implications for proximal colon cancer prevention and be due to the failure of endoscopy to detect/remove SSPs, or the hypothesized rapid development of SSPs.


Assuntos
Adenoma/diagnóstico , Neoplasias do Colo/diagnóstico , Pólipos do Colo/diagnóstico , Colonoscopia , Adenoma/patologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Neoplasias do Colo/patologia , Pólipos do Colo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
15.
Nat Med ; 11(1): 95-101, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15619629

RESUMO

Molecular profiling of human biopsies and surgical specimens is frequently complicated by their inherent biological heterogeneity and by the need to conserve tissue for clinical diagnosis. We have developed a set of novel 'tissue print' and 'print-phoresis' technologies to facilitate tissue and tumor-marker profiling under these circumstances. Tissue printing transfers cells and extracellular matrix components from a tissue surface onto nitrocellulose membranes, generating a two-dimensional anatomical image on which molecular markers can be visualized by specific protein and RNA- and DNA-detection techniques. Print-phoresis is a complementary new electrophoresis method in which thin strips from the print are subjected to polyacrylamide gel electrophoresis, providing a straightforward interface between the tissue-print image and gel-based proteomic techniques. Here we have utilized these technologies to identify and characterize markers of tumor invasion of the prostate capsule, an event generally not apparent to the naked eye that may result in tumor at the surgical margins ('positive margins'). We have also shown that tissue-print technologies can provide a general platform for the generation of marker maps that can be superimposed directly onto histopathological and radiological images, permitting molecular identification and classification of individual malignant lesions.


Assuntos
Neoplasias da Próstata/diagnóstico , Proteínas , Biomarcadores , Humanos , Masculino , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Proteínas/metabolismo
16.
Virchows Arch ; 478(4): 805-809, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33025296

RESUMO

Our aims were to assess performance of duodenal intraepithelial lymphocyte counting for diagnosis of Helicobacter pylori (H. pylori) gastritis, and effects of eradication therapy on intraepithelial lymphocytosis. Paired duodenal and gastric biopsies from subjects with a pathologic diagnosis of H. pylori gastritis were reviewed. Higher duodenal intraepithelial lymphocyte counts were observed in 40 subjects with H. pylori gastritis (26 ± 5 per villus) than 52 subjects negative for H. pylori (12 ± 2 per villus). After successful eradication therapy, duodenal lymphocytes were indistinguishable from H. pylori-negative subjects, whereas they remained elevated after failed eradication therapy. This study confirms previous reports of increased duodenal intraepithelial lymphocytes in patients with concurrent Helicobacter pylori gastritis. Intraepithelial lymphocyte counts of > 15 per villus or > 10 per 100 enterocytes were predictive of infection. Duodenal lymphocytosis decreases significantly after successful eradication therapy but remains elevated when treatment fails.


Assuntos
Antibacterianos/uso terapêutico , Duodeno/patologia , Gastrite/diagnóstico , Infecções por Helicobacter/diagnóstico , Helicobacter pylori , Linfocitose/patologia , Estômago/patologia , Adulto , Biópsia , Gastrite/tratamento farmacológico , Gastrite/microbiologia , Gastrite/patologia , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/patologia , Humanos , Mucosa Intestinal/patologia , Modelos Lineares , Linfocitose/diagnóstico , Linfocitose/microbiologia , Sensibilidade e Especificidade , Estômago/microbiologia , Resultado do Tratamento
17.
Mol Cancer ; 9: 143, 2010 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-20537188

RESUMO

BACKGROUND: Lymphotropism in oral squamous cell carcinoma (OSCC) is one of the most important prognostic factors of 5-year survival. In an effort to identify genes that may be responsible for the initiation of OSCC lymphotropism, we examined DNA copy number gains and losses and corresponding gene expression changes from tumor cells in metastatic lymph nodes of patients with OSCC. RESULTS: We performed integrative analysis of DNA copy number alterations (CNA) and corresponding mRNA expression from OSCC cells isolated from metastatic lymph nodes of 20 patients using Affymetrix 250 K Nsp I SNP and U133 Plus 2.0 arrays, respectively. Overall, genome CNA accounted for expression changes in 31% of the transcripts studied. Genome region 11q13.2-11q13.3 shows the highest correlation between DNA CNA and expression. With a false discovery rate < 1%, 530 transcripts (461 genes) demonstrated a correlation between CNA and expression. Among these, we found two subsets that were significantly associated with OSCC (n = 122) when compared to controls, and with survival (n = 27), as tested using an independent dataset with genome-wide expression profiles for 148 primary OSCC and 45 normal oral mucosa. We fit Cox models to calculate a principal component analysis-derived risk-score for these two gene sets ('122-' or '27-transcript PC'). The models combining the 122- or 27-transcript PC with stage outperformed the model using stage alone in terms of the Area Under the Curve (AUC = 0.82 or 0.86 vs. 0.72, with p = 0.044 or 0.011, respectively). CONCLUSIONS: Genes exhibiting CNA-correlated expression may have biological impact on carcinogenesis and cancer progression in OSCC. Determination of copy number-associated transcripts associated with clinical outcomes in tumor cells with an aggressive phenotype (i.e., cells metastasized to the lymph nodes) can help prioritize candidate transcripts from high-throughput data for further studies.


Assuntos
Carcinoma de Células Escamosas/genética , Dosagem de Genes , Perfilação da Expressão Gênica , Neoplasias Bucais/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Feminino , Expressão Gênica , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/mortalidade , Neoplasias Bucais/patologia , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Modelos de Riscos Proporcionais , RNA Mensageiro , Curva ROC , Adulto Jovem
18.
Liver Transpl ; 16(7): 874-84, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20583086

RESUMO

To expand the donor liver pool, ways are sought to better define the limits of marginally transplantable organs. The Donor Risk Index (DRI) lists 7 donor characteristics, together with cold ischemia time and location of the donor, as risk factors for graft failure. We hypothesized that donor hepatic steatosis is an additional independent risk factor. We analyzed the Scientific Registry of Transplant Recipients for all adult liver transplants performed from October 1, 2003, through February 6, 2008, with grafts from deceased donors to identify donor characteristics and procurement logistics parameters predictive of decreased graft survival. A proportional hazard model of donor variables, including percent steatosis from higher-risk donors, was created with graft survival as the primary outcome. Of 21,777 transplants, 5051 donors had percent macrovesicular steatosis recorded on donor liver biopsy. Compared to the 16,726 donors with no recorded liver biopsy, the donors with biopsied livers had a higher DRI, were older and more obese, and a higher percentage died from anoxia or stroke than from head trauma. The donors whose livers were biopsied became our study group. Factors most strongly associated with graft failure at 1 year after transplantation with livers from this high-risk donor group were donor age, donor liver macrovesicular steatosis, cold ischemia time, and donation after cardiac death status. In conclusion, in a high-risk donor group, macrovesicular steatosis is an independent risk factor for graft survival, along with other factors of the DRI including donor age, donor race, donation after cardiac death status, and cold ischemia time.


Assuntos
Fígado Gorduroso/diagnóstico , Transplante de Fígado/normas , Fígado/patologia , Medição de Risco/tendências , Doadores de Tecidos , Obtenção de Tecidos e Órgãos/normas , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biópsia , Criança , Pré-Escolar , Isquemia Fria , Morte , Fígado Gorduroso/patologia , Feminino , Rejeição de Enxerto , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
19.
Gastrointest Endosc ; 71(2): 223-30, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19846077

RESUMO

BACKGROUND: Optical coherence tomography (OCT) is being developed as a potentially valuable method for high-resolution cross-sectional imaging of the esophageal mucosal and submucosal layers. One potential application of OCT imaging is to identify subsquamous Barrett's epithelium in patients who have undergone ablative therapy, which is not visible on standard endoscopic examination. However, histologic correlation confirming the ability of OCT to image subsquamous Barrett's epithelium has yet to be performed. DESIGN: Histologic correlation study. OBJECTIVE: To perform histologic correlation of ultrahigh-resolution optical coherence tomography (UHR-OCT) imaging for identification of subsquamous Barrett's epithelium. SETTING: Academic Medical Center (University of Washington, Seattle, WA). PATIENTS: Fourteen patients with pathologic biopsy specimens, proven to be high-grade dysplasia or adenocarcinoma underwent esophagectomy. INTERVENTIONS: UHR-OCT imaging was performed on ex vivo esophagectomy specimens immediately after resection. MAIN OUTCOME MEASUREMENTS: Correlation of UHR-OCT images with histologic images. RESULTS: Subsquamous Barrett's epithelium was clearly identified by using UHR-OCT images and was confirmed by corresponding histology. LIMITATIONS: Difficulty distinguishing some subsquamous Barrett's glands from blood vessels in ex vivo tissue (because of the lack of blood flow) in some cases. Imaging was performed with a bench-top system. CONCLUSIONS: Results from this study demonstrate that UHR-OCT imaging is capable of identifying subsquamous Barrett's epithelium.


Assuntos
Adenocarcinoma/patologia , Esôfago de Barrett/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Lesões Pré-Cancerosas/patologia , Tomografia de Coerência Óptica/métodos , Centros Médicos Acadêmicos , Adenocarcinoma/cirurgia , Esôfago de Barrett/cirurgia , Biópsia por Agulha , Carcinoma de Células Escamosas/cirurgia , Diagnóstico Diferencial , Educação Médica Continuada , Epitélio/patologia , Epitélio/cirurgia , Neoplasias Esofágicas/cirurgia , Esofagectomia/métodos , Esofagoscopia/métodos , Feminino , Humanos , Hiperplasia/patologia , Imuno-Histoquímica , Masculino , Estudos de Amostragem , Sensibilidade e Especificidade
20.
Clin Cancer Res ; 15(4): 1353-61, 2009 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-19228736

RESUMO

PURPOSE: To determine if gene expression signature of invasive oral squamous cell carcinoma (OSCC) can subclassify OSCC based on survival. EXPERIMENTAL DESIGN: We analyzed the expression of 131 genes in 119 OSCC, 35 normal, and 17 dysplastic mucosa to identify cluster-defined subgroups. Multivariate Cox regression was used to estimate the association between gene expression and survival. By stepwise Cox regression, the top predictive models of OSCC-specific survival were determined and compared by receiver operating characteristic analysis. RESULTS: The 3-year overall mean+/-SE survival for a cluster of 45 OSCC patients was 38.7+/-0.09% compared with 69.1+/-0.08% for the remaining patients. Multivariate analysis adjusted for age, sex, and stage showed that the 45 OSCC patient cluster had worse overall and OSCC-specific survival (hazard ratio, 3.31; 95% confidence interval, 1.66-6.58 and hazard ratio, 5.43; 95% confidence interval, 2.32-12.73, respectively). Stepwise Cox regression on the 131 probe sets revealed that a model with a term for LAMC2 (laminin gamma2) gene expression best identified patients with worst OSCC-specific survival. We fit a Cox model with a term for a principal component analysis-derived risk score marker and two other models that combined stage with either LAMC2 or PCA. The area under the curve for models combining stage with either LAMC2 or PCA was 0.80 or 0.82, respectively, compared with 0.70 for stage alone (P=0.013 and 0.008, respectively). CONCLUSIONS: Gene expression and stage combined predict survival of OSCC patients better than stage alone.


Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Perfilação da Expressão Gênica , Neoplasias Bucais/genética , Neoplasias Bucais/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Componente Principal , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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