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1.
Am J Gastroenterol ; 2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32483010

RESUMO

INTRODUCTION: Limited data inform the current postpolypectomy surveillance guidelines, which suggest a shortened interval to third colonoscopy after a negative second examination if high-risk adenomas (HRA) were present on the initial screening colonoscopy. Therefore, we examined the risk of HRA at third colonoscopy stratified by findings on 2 previous examinations in a prospective screening colonoscopy cohort of US veterans. METHODS: We identified participants who had 3 or more colonoscopies from CSP#380. We examined the risk of HRA on the third examination based on findings from the previous 2 examinations. Multivariate logistic regression was used to adjust for multiple covariates. RESULTS: HRA were found at the third examination in 114 (12.8%) of 891 participants. Those with HRA on both previous examinations had the greatest incidence of HRA at third examination (14/56, 25.0%). Compared with those with no adenomas on both previous examinations, participants with HRA on the first examination remained at significantly increased risk for HRA at the third examination at 3 years after a negative second examination (odds ratio [OR] 3.41, 95% confidence interval [CI] 1.28-9.08), 5 years (OR 3.14, 95% CI 1.49-6.61), and 7 years (OR 2.89, 95% CI 1.08-7.74). DISCUSSION: In a screening population, HRA on the first examination identified individuals who remained at increased risk for HRA at the third examination, even after a negative second examination. This finding supports current colorectal cancer surveillance guidelines, which suggest a shortened, 5-year time interval to third colonoscopy after a negative second examination if high-risk findings were present on the baseline examination.

2.
Am J Gastroenterol ; 2020 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-32496341

RESUMO

Advanced adenomas represent a subset of colorectal polyps that are known to confer an increased risk of colorectal neoplasia to the affected individual and their first-degree relatives (FDRs). Accordingly, professional guidelines suggest earlier and more intensive screening for FDRs of those with advanced adenomas similar to FDRs of those with colorectal cancer (CRC). Although the risk to family members is less clear among patients with advanced serrated polyps, they are often considered in the same category. Unfortunately, there is a growing concern that patients, endoscopists, and primary care providers are unaware of the familial risk associated with these polyps, leaving a wide gap in screening these high-risk individuals. Herein, we propose a standardized language around advanced colorectal polyps and present a detailed review of the literature on associated familial risk. We outline the challenges to implementing the current screening recommendations and suggest approaches to overcome these limitations, including a proposed new colonoscopy quality metric to capture communication of familial CRC risk. Improving screening in these high-risk groups has the potential to substantially reduce the burden of CRC.

3.
J Clin Gastroenterol ; 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32379085

RESUMO

BACKGROUND AND AIMS: Men are at a higher risk for Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), but little is known about BE progression to dysplasia and EAC in women. We performed a retrospective, multicenter cohort study to assess risk of BE progression to dysplasia and EAC in women compared with men. We also investigated comorbidities, medication use, and endoscopic features that contribute to sex differences in risk of BE progression. METHODS: We collected data from large cohort of patients with BE seen at 6 centers in the United States and Europe, followed for a median 5.7 years. We obtained demographic information (age, sex, ethnicity), clinical history (tobacco use, body mass index, comorbidities), endoscopy results (procedure date, BE segment length), and histopathology findings. Neoplasia was graded as low-grade dysplasia, high-grade dysplasia (HGD), or EAC. Rates of disease progression between women and men were compared using χ analysis and the Student t test. Multivariable logistic regression was used to assess the association between sex and disease progression after adjusting for possible confounding variables. RESULTS: Of the total 4263 patients in the cohort, 2145 met the inclusion criteria, including 324 (15%) women. There was a total of 34 (1.6%) incident EACs, with an overall annual incidence of 0.3% (95% confidence interval: 0.2%-0.4%). We found significant differences between women and men in annual incidence rates of EAC (0.05% for women vs. 0.3% in men; P=0.04) and in the combined endpoint of HGD or EAC (0.1% for women vs. 1.1% for men; P<0.001). Female gender was an independent predictor for reduced progression to HGD or EAC when rates of progression were adjusted for body mass index, smoking history, race, use of aspirin, nonsteroidal anti-inflammatory drugs, proton-pump inhibitors, or statins, hypertriglyceridemia, BE length, and histology findings at baseline (hazard ratio: 0.11; 95% confidence interval: 0.03-0.45; P=0.002). CONCLUSIONS: In a multicenter study of men versus women with BE, we found a significantly lower risk of disease progression to cancer and HGD in women. The extremely low risk of EAC in women with BE (0.05%/y) indicates that surveillance endoscopy may not be necessary for this subgroup of patients with BE.

5.
J Med Chem ; 63(8): 4334-4348, 2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-32271569

RESUMO

Dopamine-derived N6-substituents, compared to N6-(2-phenylethyl), in truncated (N)-methanocarba (bicyclo[3.1.0]hexyl) adenosines favored high A3 adenosine receptor (AR) affinity/selectivity, e.g., C2-phenylethynyl analogue 15 (MRS7591, Ki = 10.9/17.8 nM, at human/mouse A3AR). 15 was a partial agonist in vitro (hA3AR, cAMP inhibition, 31% Emax; mA3AR, [35S]GTP-γ-S binding, 16% Emax) and in vivo and also antagonized hA3AR in vitro. Distal H-bonding substitutions of the N6-(2-phenylethyl) moiety particularly enhanced mA3AR affinity by polar interactions with the extracellular loops, predicted using docking and molecular dynamics simulation with newly constructed mA3AR and hA3AR homology models. These hybrid models were based on an inactive antagonist-bound hA1AR structure for the upper part of TM2 and an agonist-bound hA2AAR structure for the remaining TM portions. These species-independent A3AR-selective nucleosides are low efficacy partial agonists and novel, nuanced modulators of the A3AR, a drug target of growing interest.

7.
Ann Intern Med ; 172(6): 441-442, 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32176908
17.
Gastroenterology ; 158(2): 436-440, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31614123

RESUMO

Colon polyp surveillance now accounts for 25% of all colonoscopies performed. The evidence that colonoscopy surveillance reduces colorectal cancer (CRC) incidence or mortality is weak. The biology of the baseline lesions and quality of the baseline exam are two primary factors contributing to post-colonoscopy CRC. Prior recommendations for surveillance were based largely on the likelihood that patients with adenomas would develop advanced adenomas, a surrogate for CRC. There is now evidence that baseline colonoscopy findings are strongly associated with the risk of incidence or death from CRC. This evidence provides a basis for updated evidence-based recommendations for surveillance. In addition, there is also growing evidence that the quality of the baseline exam is an important predictor of the likelihood of developing post-colonoscopy CRC.


Assuntos
Pólipos Adenomatosos/patologia , Pólipos do Colo/patologia , Colonoscopia , Neoplasias Colorretais/patologia , Detecção Precoce de Câncer/métodos , Pólipos Adenomatosos/epidemiologia , Pólipos Adenomatosos/cirurgia , Pólipos do Colo/epidemiologia , Pólipos do Colo/cirurgia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/prevenção & controle , Progressão da Doença , Humanos , Incidência , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Fatores de Risco , Fatores de Tempo
18.
Gastroenterology ; 158(4): 862-874.e8, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31376388

RESUMO

BACKGROUND & AIMS: Few studies have evaluated long-term outcomes of ongoing colonoscopic screening and surveillance in a screening population. We aimed to determine the 10-year risk for advanced neoplasia (defined as adenomas ≥10mm, adenomas with villous histology or high-grade dysplasia, or colorectal cancer [CRC]) and assessed whether baseline colonoscopy findings were associated with long-term outcomes. METHODS: We collected data from the Department of Veterans Affairs Cooperative Studies Program Study on 3121 asymptomatic veterans (50-75 years old) who underwent a screening colonoscopy from 1994 through 1997 at 13 medical centers and were then followed for 10 years or until death. We included 1915 subjects with at least 1 surveillance colonoscopy and estimated cumulative incidence of advanced neoplasia by Kaplan-Meier curves. We then fit a longitudinal joint model to estimate risk of advanced neoplasia at each subsequent examination after baseline, adjusting for multiple colonoscopies within individuals. RESULTS: Through 10 years of follow-up, there were 146 individuals among all baseline colonoscopy groups found to have at least 1 incident advanced neoplasia. The cumulative 10-year incidence of advanced neoplasia was highest among those with baseline CRC (43.7%; 95% CI 13.0%-74.4%), followed by those with baseline advanced adenoma (AA) (21.9%; 95% CI 15.7-28.1). The cumulative 10-year incidence of advanced neoplasia was 6.3% (95% CI 4.1%-8.5%) and 4.1% (95% CI 2.7%-5.4%) for baseline 1 to 2 small adenomas (<1cm, and without villous histology or high-grade dysplasia) and no neoplasia, respectively (log-rank P = .10). After adjusting for prior surveillance, the risk of advanced neoplasia at each subsequent examination was not significantly increased in veterans with 1 or 2 small adenomas at baseline (odds ratio 0.96; 95% CI 0.67-1.41) compared with veterans with no baseline neoplasia. CONCLUSIONS: Baseline screening colonoscopy findings associate with advanced neoplasia within 10 years. Individuals with only 1 or 2 small adenomas at baseline have a low risk of advanced neoplasia over 10 years. Alternative surveillance strategies, could be considered for these individuals.


Assuntos
Adenoma/patologia , Pólipos do Colo/patologia , Colonoscopia/estatística & dados numéricos , Neoplasias Colorretais/epidemiologia , Detecção Precoce de Câncer/estatística & dados numéricos , Adenoma/diagnóstico por imagem , Adenoma/cirurgia , Idoso , Colo/diagnóstico por imagem , Colo/patologia , Colo/cirurgia , Pólipos do Colo/diagnóstico por imagem , Pólipos do Colo/cirurgia , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Humanos , Incidência , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/patologia , Mucosa Intestinal/cirurgia , Estudos Longitudinais , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Estados Unidos/epidemiologia , United States Department of Veterans Affairs/estatística & dados numéricos , Veteranos/estatística & dados numéricos
19.
Arch Pathol Lab Med ; 144(1): 90-98, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31211614

RESUMO

CONTEXT.­: Next-generation sequencing is a high-throughput method for detecting genetic abnormalities and providing prognostic and therapeutic information for patients with cancer. Oncogenic fusion transcripts are among the various classifications of genetic abnormalities present in tumors and are typically detected clinically with fluorescence in situ hybridization (FISH). However, FISH probes only exist for a limited number of targets, do not provide any information about fusion partners, cannot be multiplex, and have been shown to be limited in specificity for common targets such as ALK. OBJECTIVE.­: To validate an anchored multiplex polymerase chain reaction-based panel for the detection of fusion transcripts in a university hospital-based clinical molecular diagnostics laboratory. DESIGN.­: We used 109 unique clinical specimens to validate a custom panel targeting 104 exon boundaries from 17 genes involved in fusions in solid tumors. The panel can accept as little as 100 ng of total nucleic acid from PreservCyt-fixed tissue, and formalin-fixed, paraffin-embedded specimens with as little as 10% tumor nuclei. RESULTS.­: Using FISH as the gold standard, this assay has a sensitivity of 88.46% and a specificity of 95.83% for the detection of fusion transcripts involving ALK, RET, and ROS1 in lung adenocarcinomas. Using a validated next-generation sequencing assay as the orthogonal gold standard for the detection of EGFR variant III (EGFRvIII) in glioblastomas, the assay is 92.31% sensitive and 100% specific. CONCLUSIONS.­: This multiplexed assay is tumor and fusion partner agnostic and will provide clinical utility in therapy selection for patients with solid tumors.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Proteínas de Fusão Oncogênica/análise , Análise de Sequência de RNA/métodos , Humanos , Reação em Cadeia da Polimerase Multiplex/métodos , Isoformas de Proteínas/análise
20.
J Clin Gastroenterol ; 54(4): 356-364, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30106836

RESUMO

BACKGROUND AND AIMS: National guidelines for colonoscopy screening and surveillance assume adequate bowel preparation. We used New Hampshire Colonoscopy Registry (NHCR) data to investigate the influence of bowel preparation quality on endoscopist recommendations for follow-up intervals in average-risk patients following normal screening colonoscopies. METHODS: The analysis included 9170 normal screening colonoscopies performed on average risk individuals aged 50 and above between February 2005 and September 2013. The NHCR Procedure Form instructs endoscopists to score based on the worst prepped segment after clearing all colon segments, using the following categories: excellent (essentially 100% visualization), good (very unlikely to impair visualization), fair (possibly impairing visualization), and poor (definitely impairing visualization). We categorized examinations into 3 preparation groups: optimal (excellent/good) (n=8453), fair (n=598), and poor (n=119). Recommendations other than 10 years for examinations with optimal preparation, and >1 year for examinations with poor preparation, were considered nonadherent. RESULTS: Of all examinations, 6.2% overall received nonadherent recommendations, including 5% of examinations with optimal preparation and 89.9% of examinations with poor preparation. Of normal examinations with fair preparation, 20.7% of recommendations were for an interval <10 years. Among those examinations with fair preparation, shorter-interval recommendations were associated with female sex, former/nonsmokers, and endoscopists with adenoma detection rate ≥20%. CONCLUSIONS: In 8453 colonoscopies with optimal preparations, most recommendations (95%) were guideline-adherent. No guideline recommendation currently exists for fair preparation, but in this investigation into community practice, the majority of the fair preparation group received 10-year follow-up recommendations. A strikingly high proportion of examinations with poor preparation received a follow-up recommendation greater than the 1-year guideline recommendation. Provider education is needed to ensure that patients with poor bowel preparation are followed appropriately to reduce the risk of missing important lesions.

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