RESUMO
BACKGROUND & AIMS: Esophageal adenocarcinoma (EA) is increasingly common among patients with Barrett's esophagus (BE). We aimed to provide consensus recommendations based on the medical literature that clinicians could use to manage patients with BE and low-grade dysplasia, high-grade dysplasia (HGD), or early-stage EA. METHODS: We performed an international, multidisciplinary, systematic, evidence-based review of different management strategies for patients with BE and dysplasia or early-stage EA. We used a Delphi process to develop consensus statements. The results of literature searches were screened using a unique, interactive, Web-based data-sifting platform; we used 11,904 papers to inform the choice of statements selected. An a priori threshold of 80% agreement was used to establish consensus for each statement. RESULTS: Eighty-one of the 91 statements achieved consensus despite generally low quality of evidence, including 8 clinical statements: (1) specimens from endoscopic resection are better than biopsies for staging lesions, (2) it is important to carefully map the size of the dysplastic areas, (3) patients that receive ablative or surgical therapy require endoscopic follow-up, (4) high-resolution endoscopy is necessary for accurate diagnosis, (5) endoscopic therapy for HGD is preferred to surveillance, (6) endoscopic therapy for HGD is preferred to surgery, (7) the combination of endoscopic resection and radiofrequency ablation is the most effective therapy, and (8) after endoscopic removal of lesions from patients with HGD, all areas of BE should be ablated. CONCLUSIONS: We developed a data-sifting platform and used the Delphi process to create evidence-based consensus statements for the management of patients with BE and early-stage EA. This approach identified important clinical features of the diseases and areas for future studies.
Assuntos
Adenocarcinoma/terapia , Esôfago de Barrett/terapia , Ablação por Cateter , Neoplasias Esofágicas/terapia , Esofagectomia , Esofagoscopia , Adenocarcinoma/diagnóstico , Adenocarcinoma/etiologia , Adenocarcinoma/mortalidade , Esôfago de Barrett/complicações , Esôfago de Barrett/diagnóstico , Esôfago de Barrett/mortalidade , Técnica Delphi , Progressão da Doença , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/etiologia , Neoplasias Esofágicas/mortalidade , Esofagectomia/mortalidade , Humanos , RiscoRESUMO
BACKGROUND: Barrett's epithelial dysplasia, the direct precursor to esophageal adenocarcinoma, is often unapparent and frequently missed during surveillance of Barrett's esophagus with four-quadrant forceps biopsy protocol. AIM: To determine whether the detection of dysplasia is improved by adding computer-assisted brush biopsy (EndoCDx©) to four-quadrant biopsy protocol. METHODS: Patients with a history of Barrett's esophagus with dysplasia scheduled for endoscopic surveillance were recruited from four academic medical centers. Patients underwent brush biopsy followed by four-quadrant biopsy every 1-2 cm. The results from brush and forceps biopsy were reviewed independently by pathologists blinded to the other's results. RESULTS: Among 151 patients enrolled (124 men, 27 women; mean age: 65), 117 (77.5%) had forceps and brush-biopsy specimens adequate for interpretation. The mean number of forceps biopsies was 11.9 (median 10, range 2-40) and brush biopsies was 2.0 (median 2, range 1-4). The overall yield of forceps alone was 25.2% (n = 38). Brush biopsy added an additional 16 positive cases increasing the yield of dysplasia detection by 42% (95% CI: 20.7-72.7). The number needed to test (NNT) to detect one additional case of dysplasia was 9.4 (95% CI: 6.4-17.7). There were no significant differences in results among different centers, between standard versus jumbo forceps, or between forceps biopsies taken every 1 cm versus every 2 cm. CONCLUSIONS: These data suggest that computer-assisted brush biopsy is a useful adjunct to standard endoscopic surveillance regimens for the identification of dysplasia in Barrett's esophagus.
Assuntos
Adenocarcinoma/patologia , Esôfago de Barrett/patologia , Esôfago/patologia , Interpretação de Imagem Assistida por Computador/métodos , Lesões Pré-Cancerosas/patologia , Idoso , Idoso de 80 Anos ou mais , Biópsia/instrumentação , Biópsia/métodos , Neoplasias Esofágicas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Instrumentos CirúrgicosRESUMO
Polyphenon E (Poly E) is a green tea polyphenol preparation whose most active component is epigallocatechin gallate (EGCG). We studied the cancer preventive efficacy and safety of Poly E in subjects with rectal aberrant crypt foci (ACF), which represent putative precursors of colorectal cancers. Eligible subjects had prior colorectal advanced adenomas or cancers, and had ≥5 rectal ACF at a preregistration chromoendoscopy. Subjects (N = 39) were randomized to 6 months of oral Poly E (780 mg EGCG) daily or placebo. Baseline characteristics were similar by treatment arm (all P >0.41); 32 of 39 (82%) subjects completed 6 months of treatment. The primary endpoint was percent reduction in rectal ACF at chromoendoscopy comparing before and after treatment. Among 32 subjects (15 Poly E, 17 placebo), percent change in rectal ACF number (baseline vs. 6 months) did not differ significantly between study arms (3.7% difference of means; P = 0.28); total ACF burden was also similar (-2.3% difference of means; P = 0.83). Adenoma recurrence rates at 6 months were similar by arm (P > 0.35). Total drug received did not differ significantly by study arm; 31 (79%) subjects received ≥70% of prescribed Poly E. Poly E was well tolerated and adverse events (AE) did not differ significantly by arm. One subject on placebo had two grade 3 AEs; one subject had grade 2 hepatic transaminase elevations attributed to treatment. In conclusion, Poly E for 6 months did not significantly reduce rectal ACF number relative to placebo. Poly E was well tolerated and without significant toxicity at the dose studied. PREVENTION RELEVANCE: We report a chemoprevention trial of polyphenon E in subjects at high risk of colorectal cancer. The results show that polyphenon E was well tolerated, but did not significantly reduce the number of rectal aberrant crypt foci, a surrogate endpoint biomarker of colorectal cancer.
Assuntos
Focos de Criptas Aberrantes/tratamento farmacológico , Catequina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Recidiva Local de Neoplasia/prevenção & controle , Focos de Criptas Aberrantes/diagnóstico , Focos de Criptas Aberrantes/patologia , Idoso , Catequina/administração & dosagem , Catequina/efeitos adversos , Colo/diagnóstico por imagem , Colo/efeitos dos fármacos , Colo/patologia , Colonoscopia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Humanos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/patologia , Placebos/administração & dosagem , Placebos/efeitos adversos , Reto/diagnóstico por imagem , Reto/efeitos dos fármacos , Reto/patologia , Resultado do TratamentoRESUMO
OBJECTIVES: The source of most cases of non-cardiac chest pain (NCCP) is thought to be the esophagus. We reasoned that if the origin of NCCP is truly esophageal and not cardiac, the characteristics and survival of individuals with NCCP should be similar to those of individuals with benign esophageal disease, such as gastroesophageal reflux disease (GERD). The aim of this study was to compare the characteristics, natural history, and long-term survival of two well-defined groups, NCCP patients and GERD patients. METHODS: From 1984 to 1996, patients with NCCP were referred for endoscopy by the cardiology service after a coronary angiography done for chest pain was reported by the cardiologist as negative. Patients with GERD were referred for endoscopy for one of the usual symptoms of acid reflux. The baseline endoscopy and referrals occurred in the pre-proton pump inhibitor (PPI) era, before and during the availability of only the histamine receptor antagonists (HRAs). Thus, the endoscopic findings reflected the untreated natural state of the gastrointestinal mucosa. Endoscopic exams, esophageal biopsy, endoscopic anatomy mapping, and data verification were carried out in the endoscopy lab by one of three endoscopists using predefined criteria. All results were recorded both by hand and by entry into a database storage program. Patients were followed by their primary care providers in their usual outpatient general medicine clinics. The Veterans Affairs Decentralized Hospital Computer Program (VA DHCP) storage system provided access to mortality data as well as details of all prescriptions filled since 1985. RESULTS: During the 12-year enrollment period, 1,218 patients in the GERD group and 161 in the NCCP group were referred for endoscopy. The follow-up period ranged from 1-22 years (mean 9.8 years). The groups were similar in age, gender, smoking and alcohol habits, and use of aspirin and NSAIDs (non-steroidal anti-inflammatory drugs) (P=NS), but there was a greater proportion of blacks in the NCCP group (P<0.003). In every parameter, NCCP patients had a significantly lower prevalence of GERD-related findings such as endoscopic esophagitis (P<0.0001), Barrett's metaplasia (P=0.02), the development of esophageal adenocarcinoma, and hiatal hernia presence (P=0.0001). In patients with hiatal hernia, the size of the hernia was similar in both groups (P=0.94). In the NCCP group compared with the GERD group, there was a significantly higher prevalence of cardiac factors, such as coronary artery disease (P=0.03), and there was a trend toward greater cardiac clinic enrollment (P=0.08) and cardiac medication usage (P=0.06). The amount and duration of anti-GERD therapy, such as HRAs and PPIs, were significantly less in the NCCP group (P=0.0001 for PPIs and P=0.0002 for HRAs). The diagnosis of NCCP disappeared from the electronic hospital record in 96% of patients within 2 years of follow-up. There was no significant difference in survival between the GERD and NCCP groups (hazard ratio=1.1; CI=0.8-1.5); however, longer duration of follow-up in those with a greater number of events may make a difference in survival. CONCLUSIONS: NCCP in most patients seems to be a short-lived event requiring extensive medical evaluation and having clinical characteristics significantly different from those associated with GERD. Patients with NCCP, confirmed by the absence of angiogram-documented coronary artery disease, who are referred for diagnostic endoscopy, have an excellent long-term benign prognosis, similar to patients with GERD.
Assuntos
Dor no Peito/mortalidade , Refluxo Gastroesofágico/mortalidade , Dor no Peito/etiologia , Progressão da Doença , Endoscopia do Sistema Digestório , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/diagnóstico , Humanos , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
BACKGROUND: As a noninvasive colorectal cancer (CRC) screening test, a multi-marker first generation stool DNA (sDNA V 1.0) test is superior to guaiac-based fecal occult blood tests. An improved sDNA assay (version 2), utilizing only two markers, hypermethylated vimentin gene (hV) and a two site DNA integrity assay (DY), demonstrated in a training set (phase 1a) an even higher sensitivity (88%) for CRC with a specificity of 82%. AIM: To validate in an independent set of patients (phase 1b) the sensitivity and specificity of sDNA version 2 for CRC. METHODS: Forty-two patients with CRC and 241 subjects with normal colonoscopy (NC) provided stool samples, to which they immediately added DNA stabilizing buffer, and mailed their specimen to the laboratory. DNA was purified using gel-based capture, and analyzed for hV and DY using methods identical to those previously published. RESULTS: Using the same cutpoints as the 1a training set (N = 162; 40 CRCs, 122 normals), hV demonstrated a higher and DY a slightly lower sensitivity, for a combined sensitivity of hV + DY of 86%. Optimal cutpoints based on the combined phase 1a + 1b dataset (N = 445; 82 CRCs, 363 normals) yielded a CRC sensitivity of 83%. The vast majority of cancers were detected regardless of tumor stage, tumor location, or patient age. Assay specificity in the phase 1b dataset for hV, DY, and hV + DY was 82%, 85%, and 73%, respectively, using the phase 1a cutpoints. Optimal cutpoints based on the combined phase 1a + 1b dataset yield a specificity of 82%. CONCLUSIONS: This study provides validation of a simplified, improved sDNA test that incorporates only two markers and that demonstrates high sensitivity (83%) and specificity (82%) for CRC. Test performance is highly reproducible in a large set of patients. The use of only two markers will make the test easier to perform, reduce the cost, and facilitate distribution to local laboratories.
Assuntos
Neoplasias Colorretais/diagnóstico , DNA/isolamento & purificação , Fezes/química , HumanosRESUMO
The Chemoprevention for Barrett's Esophagus Trial (CBET) was a phase IIb, multicenter, randomized, placebo-controlled trial of celecoxib in patients with Barrett's esophagus. The overall outcome of the study was that there were no significant differences in primary, secondary, or tertiary outcomes. The purpose of the current study is to focus on results related to the method of measuring lesion size called quantitative endoscopy (QE). The design includes a review of a total number of studies and then restricts analyses to the four clinics that enrolled more than four patients each for whom a baseline and 1-year QE study was performed, comparing intra- and inter-patient and clinic differences in Barrett's esophagus. Measurements include the number of total QEs and adverse events, changes in areas from baseline to 1 year and other intervals, classification of Barrett's lesion type with respect to patients, clinics, and treatment. A total of 309 QE studies were completed with no adverse events. Differences in surface area measurements over time for a particular patient are smaller than the differences for randomly selected patients. The complexity mix (as defined by the mix of circumferential, tongues, and islands) of the Barrett's lesions varied with different clinics. In conclusion, QE is an efficient, safe, and accurate way to measure the area of Barrett's lesions variation between different clinical sites may be attributable to a subtle type of selection bias at the individual clinics rather than to regional differences.
Assuntos
Esôfago de Barrett/patologia , Esôfago de Barrett/prevenção & controle , Inibidores de Ciclo-Oxigenase/uso terapêutico , Endoscopia , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Celecoxib , Estudos de Coortes , Humanos , Reprodutibilidade dos Testes , Estudos Retrospectivos , Viés de Seleção , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: Fecal DNA testing has shown greater sensitivity than guaiac-based occult blood tests for noninvasive colorectal cancer (CRC) screening. The prototype assay (version 1), which analyzed 22 gene mutations and DNA integrity assay (DIA), showed a sensitivity of 52% for CRC detection and a specificity of 94% in average-risk individuals. The present study was conducted to determine the sensitivity and specificity of a second-generation assay (version 2) that uses improved DNA stabilization/isolation techniques and a new promoter methylation marker. METHODS: Forty patients with CRC and 122 subjects with normal colonoscopy provided stool samples to which DNA preservation buffer was added immediately. DNA was purified using gel-based capture, and analyzed for the original panel of 22 mutations, DIA, and 2 new promoter methylation markers. RESULTS: By using DNA that was optimally preserved and purified from stool, the sensitivity of the prototype version 1 assay increased to 72.5% because of enhanced performance of DIA. Vimentin gene methylation alone provided sensitivity and specificity of 72.5% and 86.9%, respectively. The optimal combination of vimentin methylation plus DIA resulted in 87.5% sensitivity and 82% specificity; cancers were detected regardless of stage or location. False-positive vimentin methylation was associated with older age. CONCLUSIONS: An improved fecal DNA test that incorporates only 2 markers shows much higher sensitivity for CRC. The new assay is easier to perform and should be less costly, thereby facilitating its use for noninvasive CRC screening.
Assuntos
Neoplasias Colorretais/genética , DNA de Neoplasias/análise , Fezes/química , Programas de Rastreamento/métodos , Fatores Etários , Idoso , Colonoscopia , Neoplasias Colorretais/diagnóstico , Fragmentação do DNA , Metilação de DNA , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Reação em Cadeia da Polimerase , Sensibilidade e Especificidade , Fatores de Transcrição/genética , Vimentina/genéticaRESUMO
Most asthmatics have GER, and the evidence is strong that GER plays an important role in some patients who have asthma. Despite sophisticated study methods and technologically advanced diagnostic tests, the results of published studies on mechanisms have failed to provide a diagnostic test with a degree of certainty great enough to identify which patients have GER-induced or GER-exacerbated asthma and which patients will respond to antireflux therapy. The difficulties involved in establishing a definite cause-and-effect relationship between GER and asthma are real. Even positive results on such direct tests as sputum inspection and scintigraphic monitoring, both of which establish reflux into the tracheobronchial tree, do not necessarily establish cause or effect and cannot be used to predict outcomes. Ambulatory esophageal pH testing can suggest, but cannot prove, the diagnosis of GER-induced asthma, and pH testing cannot be relied on safely to make clinical decisions. A trial of a proton pump inhibitor (PPI) is indicated to assess if asthma improves subjectively and objectively, but the dose must be high enough to prevent even silent esophageal acid exposure, and the duration must be long enough to allow for detection of even subtle trends in subjective and objective respiratory improvement. Antireflux surgery remains a therapeutic option and should not be withheld if GER is a reasonable suspect in asthma exacerbations. Although strong opinions have been voiced as to whether or not a good response to PPI therapy predicts a good response to antireflux surgery, the opinions, although logical, are based on personal experience and gut feelings; a good PPI response may not necessarily predict a good surgery response. Opinions suggesting that a poor response to PPI predicts a poor response to antireflux surgery also may seem logical but are not based on clinical data; a poor PPI response may not necessarily predict a poor antireflux surgery response. When the method is found that predicts which patients who have GER and asthma will respond to antireflux treatment, the results could be profound: fewer hospitalizations for respiratory complications, less pulmonary morbidity and mortality, less need for pulmonary medications, less time lost from work, fewer visits to physicians' offices, and less illness associated with corticosteroid therapy. For the present, however, clinical judgment and good sense still are our best friends. It is not unreasonable to urge patients to alter their lifestyle: the huge volume, calorie-dense, high-fat meals eaten before bedtime are not likely to prevent GER or add to their life expectancy.
Assuntos
Asma/diagnóstico , Bronquite/diagnóstico , Refluxo Gastroesofágico/diagnóstico , Hérnia Hiatal/diagnóstico , Adulto , Distribuição por Idade , Asma/epidemiologia , Bronquite/epidemiologia , Criança , Pré-Escolar , Doença Crônica , Tosse/diagnóstico , Tosse/epidemiologia , Diagnóstico Diferencial , Esofagoscopia/métodos , Feminino , Determinação da Acidez Gástrica , Refluxo Gastroesofágico/epidemiologia , Hérnia Hiatal/epidemiologia , Humanos , Masculino , Manometria , Pessoa de Meia-Idade , Faringite/diagnóstico , Faringite/epidemiologia , Prevalência , Prognóstico , Índice de Gravidade de Doença , Distribuição por SexoRESUMO
The following on the natural history of Barrett's esophagus (BE) includes commentary on histological sequences of the development of Barrett mucosa; the transformation of esophageal cells from squamous to columnar phenotype; the stages of natural history of dysplasia; the difficulties of predicting progression of dysplasia to adenocarcinoma; the preferable biopsy protocols; the role of Helicobacter pylori infection and gastric atrophy in the risk of BE; the value of decrease of proton pump inhibitor efficacy following eradication of H. pylori; the place of antireflux surgery in the natural history of BE; the newest procedures for the endoscopic detection of early neoplasia; and the essential importance of a good understanding of the natural history for the best management of high-grade dysplasia.
Assuntos
Esôfago de Barrett/patologia , Adenocarcinoma/patologia , Esôfago de Barrett/microbiologia , Progressão da Doença , Neoplasias Esofágicas/patologia , Refluxo Gastroesofágico/patologia , Helicobacter pylori/isolamento & purificação , Humanos , Fatores de RiscoRESUMO
The following on endoscopic treatments of Barrett's esophagus includes commentaries on animal experiments on cryotherapy; indications for cryotherapy, choice of dosimetry, number of sessions, and role in Barrett's esophagus and adenocarcinoma; recent technical developments of RFA technology and long-term effects; the comparative effects of diverse ablation procedures and the rate of recurrence following treatment; and the indications for treatment of dysplasia and the role of radiofrequency ablation.
Assuntos
Esôfago de Barrett/terapia , Animais , Crioterapia , Modelos Animais de Doenças , Humanos , Cuidados PaliativosRESUMO
Sulindac, atorvastatin, or prebiotic dietary fiber may reduce colorectal cancer (CRC) risk. However, clinical trial data are currently limited. We conducted a randomized, phase II chemoprevention trial involving subjects 40 years or older, with previously resected colon cancer or multiple/advanced colorectal adenomas. Magnification chromoendoscopy (MCE) was performed to identify and characterize rectal aberrant crypt foci (ACF); eligibility criteria required five or more rectal ACFs at baseline. Intervention assignments were as follows: (a) atorvastatin 20 mg qd; (b) sulindac 150 mg bid; (c) oligofructose-enriched inulin (as ORAFTI®Synergy1) 6 gm bid; or (d) control (maltodextrin) 6 gm bid, for 6 months. Percent change in rectal ACF number (%ΔACF) within arm was the primary endpoint. Secondary endpoints included changes in proliferation (Ki67) and apoptosis (caspase-3), as measured from normal mucosa biopsy samples. Among 85 eligible randomized subjects, 76 (86%) completed the trial per protocol. The median (range) of rectal ACF was 9 (5-34) and 8 (0-37) at baseline and postintervention, respectively. The median (SD) for %ΔACF was 5.6 (-69% to 143%), -18.6 (-83% to 160%), -3.6 (-88% to 83%), and -10.0 (-100% to 117%) in the atorvastatin, sulindac, ORAFTI®Synergy1 and control arms, respectively. Neither within-arm (P = 0.12-0.59) nor between-arm (P = 0.30-0.92) comparisons of %ΔACF were statistically significant. The active and control interventions also seemed to have similar effects on mucosal proliferation and apoptosis (P > 0.05 for each comparison). Data from this multicenter, phase II trial do not provide convincing evidence of CRC risk reduction from 6-month interventions with atorvastatin, sulindac, or ORAFTI®Synergy1, although statistical power was limited by the relatively small sample size.
Assuntos
Focos de Criptas Aberrantes/prevenção & controle , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/prevenção & controle , Fibras na Dieta/uso terapêutico , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pirróis/uso terapêutico , Sulindaco/uso terapêutico , Focos de Criptas Aberrantes/patologia , Idoso , Atorvastatina , Neoplasias Colorretais/patologia , Feminino , Humanos , Mucosa Intestinal/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Although the prevalence of Barrett's esophagus (BE) is rising no data exist for racial minorities on prevalence in the general population. Minorities have a lower prevalence than Caucasians, and yet age, smoking, abdominal obesity, and Helicobacter pylori are all risk factors. Metabolic changes induced by adipocytokines and the apparently strong association between obesity, central adiposity, and BE may lead to reconsideration of some aspects of the natural history of BE. There is lack of experimental evidence on acid sensitivity and BE, which is hyposensitive compared to esophageal reflux disease. Reactive nitrogen and oxygen species lead to impaired expression of tumor suppressor genes, which can lead to cancer development; thus, antioxidants may be protective. Gastroesophageal reflux disease may be considered an immune-mediated disease starting at the submucosal layer; the cytokine profile of the mucosal immune response may explain the different outcome of gastroesophageal reflux.
Assuntos
Esôfago de Barrett/epidemiologia , Esôfago de Barrett/etiologia , Humanos , Incidência , PrevalênciaRESUMO
The following topics are explored in this collection of commentaries on treatments of adenocarcinomas related to Barrett's esophagus: the importance of intraoperative frozen sections of the margins for the detection of high dysplasia; the preferable way for sentinel node dissection; the current role of robotic surgery and of video-endoscopic approach; the value of the Siewert's classification of adenocarcinomas; the indications of two-step esophagectomy; the evaluation of pathological complete response; the role of PET scan in staging and response assessment; the role of p53 in the selection of adenocarcinomas patients; chemotherapy regimens for adenocarcinomas; the use of monoclonal antibodies in the control of cell proliferation; he attempt to define a stage-specific strategy, and the possible indications of selective therapy; and changes in mortality rates from esophageal cancer.
Assuntos
Adenocarcinoma/terapia , Esôfago de Barrett/patologia , Neoplasias Esofágicas/terapia , Adenocarcinoma/patologia , Terapia Combinada , Neoplasias Esofágicas/patologia , Humanos , Biópsia de Linfonodo Sentinela , Análise de SobrevidaRESUMO
OBJECTIVE: Utilizing data obtained during a multicenter investigation, this paper illustrates how the use of covariates and careful modeling techniques can be useful in assessing whether a negative outcome from a small multicenter clinical trial could be due to imbalance in baseline characteristics. The Chemoprevention for Barrett's Esophagus Trial (CBET) was a phase IIb, multicenter, randomized, placebo-controlled trial of celecoxib in patients with Barrett's esophagus. The primary outcomes for the original study were the proportion of biopsy samples exhibiting dysplasia in the celecoxib and placebo groups. The secondary and tertiary outcomes included histologic change and measurements of biologically relevant markers, including COX-1 and -2 mRNA, prostanoid levels, and methylation of tumor suppressor genes p16, APC, and E-cadherin. The original study reported no significant differences in primary, secondary or tertiary outcomes. In this paper, we focus on the results of one of the secondary measures, quantitative endoscopy (QE). DESIGN: The study utilizes data from 56 patients in the CBET for whom baseline (BL) QE and one-year follow-up QE (F04) studies were performed. Of these, 29 were treated with celecoxib (200 mg twice daily for a minimum of 48 weeks) and 27 received the placebo. These patients are segmented as to the presence or absence of circumferential, tongues or islands of Barrett's. MEASUREMENTS: The response of interest is total affected area at one year (Total F04); affected area at baseline (Total BL) is used as a covariate. RESULTS: Controlling for complexity and clinic, there is a significant treatment effect. In addition, there is significant evidence that the area of Barrett's involvement decreased for patients in the treatment group. CONCLUSIONS: That there was a decrease for the celecoxib over the placebo group adds to the body of evidence that relates COX-2 specific inhibitors and cancer incidence.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Esôfago de Barrett/prevenção & controle , Modelos Estatísticos , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Pirazóis/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Sulfonamidas/uso terapêutico , Celecoxib , Interpretação Estatística de Dados , Esofagoscopia , HumanosRESUMO
Aberrant crypt foci (ACF) are the earliest visible neoplastic lesions in the colorectum. The natural history of these lesions and their role in the adenoma-carcinoma sequence are unknown. We studied ACF in a subset of patients randomized to placebo (n = 17), celecoxib (200 mg twice daily; n = 15), or celecoxib (400 mg twice daily; n = 13) in the Adenoma Prevention with Celecoxib (APC) trial. Magnification chromoendoscopy was done to identify, count, and biopsy ACF within the rectum at baseline and after 8 to 12 months of treatment. A total of 655 ACF were identified in 45 patients. We examined 70 of these ACF histologically, and all 70 were nondysplastic. Cohort characteristics and APC trial treatment results for substudy patients were similar to those of the overall APC trial. There was no significant modulation of ACF by celecoxib (versus placebo; P = 0.77). Immunohistochemical comparison of ACF with adjacent normal mucosa showed that ACF had an increased proliferative index as determined by Ki-67 (P < 0.0001), but lacked other features of neoplasia such as increased cyclooxygenase-2 expression and microvessel density, nuclear localization of beta-catenin, or decreased expression of the tumor suppressors SMAD4, Estrogen Receptor alpha, or MGMT. Only baseline SMAD4 expression in ACF correlated with posttreatment adenoma recurrence (independent of treatment arm; P = 0.01). The presence or number of nondysplastic ACF did not correlate with a higher risk of synchronous advanced or recurrent adenomas. Our overall results indicated that nondysplastic ACF were not accurate surrogate endpoint biomarkers of recurrent colorectal adenomas in the APC trial.
Assuntos
Adenoma/prevenção & controle , Mucosa Intestinal/patologia , Neoplasias Intestinais/prevenção & controle , Lesões Pré-Cancerosas/patologia , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Adenoma/diagnóstico , Adenoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Biomarcadores/análise , Celecoxib , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Neoplasias Intestinais/diagnóstico , Neoplasias Intestinais/patologia , Pólipos Intestinais/patologia , Masculino , Pessoa de Meia-Idade , Placebos , Pirazóis/administração & dosagem , Sulfonamidas/administração & dosagemRESUMO
BACKGROUND & AIMS: Outcomes of colon surveillance after colorectal cancer screening with colonoscopy are uncertain. We conducted a prospective study to measure incidence of advanced neoplasia in patients within 5.5 years of screening colonoscopy. METHODS: Three thousand one hundred twenty-one asymptomatic subjects, age 50 to 75 years, had screening colonoscopy between 1994 and 1997 in the Department of Veterans Affairs. One thousand one hundred seventy-one subjects with neoplasia and 501 neoplasia-free controls were assigned to colonoscopic surveillance over 5 years. Cohorts were defined by baseline findings. Relative risks for advanced neoplasia within 5.5 years were calculated. Advanced neoplasia was defined as tubular adenoma greater than > or =10 mm, adenoma with villous histology, adenoma with high-grade dysplasia, or invasive cancer. RESULTS: Eight hundred ninety-five (76.4%) patients with neoplasia and 298 subjects (59.5%) without neoplasia at baseline had colonoscopy within 5.5 years; 2.4% of patients with no neoplasia had interval advanced neoplasia. The relative risk in patients with baseline neoplasia was 1.92 (95% CI: 0.83-4.42) with 1 or 2 tubular adenomas <10 mm, 5.01 (95% CI: 2.10-11.96) with 3 or more tubular adenomas <10 mm, 6.40 (95% CI: 2.74-14.94) with tubular adenoma > or =10 mm, 6.05 (95% CI: 2.48-14.71) for villous adenoma, and 6.87 (95% CI: 2.61-18.07) for adenoma with high-grade dysplasia. CONCLUSIONS: There is a strong association between results of baseline screening colonoscopy and rate of serious incident lesions during 5.5 years of surveillance. Patients with 1 or 2 tubular adenomas less than 10 mm represent a low-risk group compared with other patients with colon neoplasia.
Assuntos
Adenoma/diagnóstico , Colonoscopia , Neoplasias Colorretais/diagnóstico , Programas de Rastreamento/métodos , Adenoma/epidemiologia , Adenoma/patologia , Adenoma/cirurgia , Idoso , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Progressão da Doença , Seguimentos , Hospitais de Veteranos , Humanos , Incidência , Pessoa de Meia-Idade , Invasividade Neoplásica , Guias de Prática Clínica como Assunto , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Recidiva , Medição de Risco , Fatores de Risco , Fatores de Tempo , Estados Unidos/epidemiologiaRESUMO
BACKGROUND & AIMS: Common treatment practices in patients who continue to be symptomatic on proton pump inhibitor once-daily treatment include either increasing the dosage or the use of supplemental medication. This trial's purpose was to compare 2 therapeutic strategies, increasing the proton pump inhibitor dosage to twice daily versus switching to another proton pump inhibitor, in patients with persistent heartburn while receiving standard-dose proton pump inhibitor therapy. METHODS: This multicenter, randomized, double-blind, double-dummy trial included patients with persistent heartburn symptoms while receiving therapy with lansoprazole 30 mg once daily. Patients were randomly assigned to treatment for 8 weeks with either single-dose esomeprazole (40 mg once daily) (n = 138) or lansoprazole 30 mg twice daily (n = 144). The primary efficacy variable was the percentage of heartburn-free days from day 8 to the end of treatment. RESULTS: Single-dose esomeprazole was at least as effective as twice-daily lansoprazole for the primary end point of percentage of heartburn-free days during the study period (54.4% and 57.5%, respectively). Symptom scores improved from baseline in similar numbers of patients for heartburn (83.3% of patients in each group), acid regurgitation (76.8% vs 72.9%, P = .58), and epigastric pain (67.4% vs 61.1%, P = .32), and rescue antacid use was also similar (0.4 tablets/day vs 0.5 tablets/day, P = .50). CONCLUSIONS: Switching patients with persistent heartburn on a standard-dose proton pump inhibitor to a different proton pump inhibitor was as effective as increasing the proton pump inhibitor dosage to twice daily for controlling heartburn symptoms.
Assuntos
Inibidores Enzimáticos/uso terapêutico , Esomeprazol/análogos & derivados , Esomeprazol/uso terapêutico , Azia/tratamento farmacológico , Inibidores da Bomba de Prótons , 2-Piridinilmetilsulfinilbenzimidazóis , Adulto , Idoso , Método Duplo-Cego , Inibidores Enzimáticos/administração & dosagem , Esomeprazol/administração & dosagem , Feminino , Humanos , Lansoprazol , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Long-term gastric acid suppression has been suggested as a means to prevent complications of reflux esophagitis. We report on the 20-year follow-up of 2,306 patients with at least two endoscopic examinations who were taking no antisecretory medication before baseline endoscopy and whose long-term treatment was determined by reflux symptoms. METHODS: From 1979 through 1998, endoscopy and biopsy were performed in the Hines Veterans Affairs Hospital endoscopy clinic by three endoscopists. Antireflux treatment was symptom-driven, and endoscopies were repeated mostly for symptomatic recurrence due to cessation of therapy. RESULTS: Of 4,633 patients undergoing endoscopy for reflux symptoms, 2,306 had at least one follow-up endoscopy and biopsy. Over a mean follow-up period of 7.6 years (range, 1-20 years), the esophageal mucosa of 67% of patients remained unchanged, that of 21% improved, and that of 11% worsened. Esophageal stricture requiring dilation developed from a normal baseline mucosa in one of 1,313 patients (0.08%) and from an erosive baseline mucosa in 18 of 957 patients (1.9%). The overall incidence of stricture in patients with gastroesophageal reflux (GER) disease was <1/1,000 per year. Nonsteroidal anti-inflammatory drug (NSAID) consumption was associated with less mucosal improvement (odds ration [OR] = 0.67; confidence interval [CI] = 0.46-0.98). Use of histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) was associated with mucosal improvement (OR for PPIs = 1.49; CI = 1.14-2.17). Cohn's kappa was 42%, confirming the results that demonstrate stability of esophageal mucosal disease in the majority of patients. CONCLUSIONS: Symptom-driven treatment of GER disease after a thorough endoscopic examination to exclude premalignant or malignant esophageal mucosal disease is practical and safe for the vast majority of patients with uncomplicated GER symptoms.
Assuntos
Esofagoscopia , Refluxo Gastroesofágico/diagnóstico , Refluxo Gastroesofágico/fisiopatologia , Anti-Inflamatórios não Esteroides/efeitos adversos , Distribuição de Qui-Quadrado , Doença Crônica , Progressão da Doença , Neoplasias Esofágicas/patologia , Feminino , Refluxo Gastroesofágico/tratamento farmacológico , Antagonistas dos Receptores H2 da Histamina/uso terapêutico , Humanos , Masculino , Índice de Gravidade de DoençaRESUMO
Several studies suggest veterans have a higher prevalence of hepatitis C virus infection than nonveterans, possibly because of military exposures. The purpose of this study was to estimate the prevalence of anti-hepatitis C antibody and evaluate factors associated with infection among users of Department of Veterans Affairs medical centers. Using a two-staged cluster sample, 1288 of 3863 randomly selected veterans completed a survey and underwent home-based phlebotomy for serological testing. Administrative and clinical data were used to correct the prevalence estimate for nonparticipation. The prevalence of antihepatitis C antibody among serology participants was 4.0% (95% CI, 2.6%-5.5%). The estimated prevalence in the population of Veterans Affairs medical center users was 5.4% (95% CI, 3.3%-7.5%) after correction for sociodemographic and clinical differences between participants and nonparticipants. Significant predictors of seropositivity included demographic factors, period of military service (e.g., Vietnam era), prior diagnoses, health care use, and lifestyle factors. At least one traditional risk factor (transfusion or intravenous drug use) was reported by 30.2% of all subjects. Among those testing positive for hepatitis C antibody, 78% either had a transfusion or had used injection drugs. Adjusting for injection drug use and nonparticipation, seropositivity was associated with tattoos and incarceration. Military-related exposures were not found to be associated with infection in the adjusted analysis. In conclusion, the prevalence of hepatitis C in these subjects exceeds the estimate from the general US population by more than 2-fold, likely reflecting more exposure to traditional risk factors among these veterans.
Assuntos
Hepatite C/epidemiologia , Hospitais , United States Department of Veterans Affairs , Veteranos/estatística & dados numéricos , Adulto , Idoso , Transfusão de Sangue , Estudos Transversais , Feminino , Hepatite C/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Prisões , Fatores de Risco , Abuso de Substâncias por Via Intravenosa , Inquéritos e Questionários , Tatuagem , Estados Unidos/epidemiologiaRESUMO
Eight patients with refractory GERD symptoms were controlled over a mean of 15.4 years only by the addition of a benzodiazepine to once-daily or twice-daily PPI therapy. In selected patients with refractory GERD, as defined by continued reflux symptoms despite twice-daily PPIs, the addition of a benzodiazepine to the PPI regimen may provide additional control of GERD symptoms.