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ABSTRACT: Patients with multiple colorectal adenomas may carry germline mutations in the APC or MUTYH genes.
To determine the prevalence of pathogenic APC and MUTYH mutations in patients with multiple colorectal adenomas who had undergone genetic testing and to compare the prevalence and clinical characteristics of APC and MUTYH mutation carriers.
Cross-sectional study conducted among 8676 individuals who had undergone full gene sequencing and large rearrangement analysis of the APC gene and targeted sequence analysis for the 2 most common MUTYH mutations (Y179C and G396D) between 2004 and 2011. Individuals with either mutation underwent full MUTYH gene sequencing. APC and MUTYH mutation prevalence was evaluated by polyp burden; the clinical characteristics associated with a pathogenic mutation were evaluated using logistic regression analyses.
Prevalence of pathogenic mutations in APC and MUTYH genes.
Colorectal adenomas were reported in 7225 individuals; 1457 with classic polyposis (≥100 adenomas) and 3253 with attenuated polyposis (20-99 adenomas). The prevalence of pathogenic APC and biallelic MUTYH mutations was 95 of 119 (80% [95% CI, 71%-87%]) and 2 of 119 (2% [95% CI, 0.2%-6%]), respectively, among individuals with 1000 or more adenomas, 756 of 1338 (56% [95% CI, 54%-59%]) and 94 of 1338 (7% [95% CI, 6%-8%]) among those with 100 to 999 adenomas, 326 of 3253 (10% [95% CI, 9%-11%]) and 233 of 3253 (7% [95% CI, 6%-8%]) among those with 20 to 99 adenomas, and 50 of 970 (5% [95% CI, 4%-7%]) and 37 of 970 (4% [95% CI, 3%-5%]) among those with 10 to 19 adenomas. Adenoma count was strongly associated with a pathogenic mutation in multivariable analyses.
Among patients with multiple colorectal adenomas, pathogenic APC and MUTYH mutation prevalence varied considerably by adenoma count, including within those with a classic polyposis phenotype. APC mutations predominated in patients with classic polyposis, whereas prevalence of APC and MUTYH mutations was similar in attenuated polyposis. These findings require external validation.
JAMA The Journal of the American Medical Association 08/2012; 308(5):485-92. · 30.03 Impact Factor
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ABSTRACT: To review the contemporary management of gastrointestinal stromal tumor (GIST), including endoscopy, surgery, and systemic therapy, highlighting the aspects unique to small intestinal tumors.
Tumor size, mitotic count, and site of origin are the three key prognostic factors, with mitotic count being the single strongest predictor of recurrence. Tumors arising in the small bowel have worse prognosis than those of comparable size and mitotic count arising in other organs. Endoscopy and endoscopic ultrasound-guided, fine-needle aspiration are key components in the diagnosis of GIST. The role of endoscopy in surveillance and resection remain investigational. Surgery, either open or laparoscopic, remains the only curative option, but recurrence rates are high. Adjuvant therapy with imatinib mesylate improves recurrence-free survival rates and may improve overall survival (OS) with longer duration of treatment. Neoadjuvant imatinib may play an important role in the management of patients with locally advanced disease. For patients with advanced disease, first-line imatinib and second-line sunitinib malate have improved progression-free and OS rates. Systemic treatment should be continued life-long or until treatment failure.
Advances in the last decade have dramatically changed the management and prognosis of patients with primary and advanced GIST.
Current opinion in gastroenterology 12/2011; 28(2):113-23. · 4.33 Impact Factor
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ABSTRACT: Procedural skill is predicated on knowledge. We used a previously validated test to evaluate the impact of a web-based education program on medical residents' knowledge of 2 advanced medical procedures.
We enrolled 210 internal medicine residents at 3 residency programs in a randomized, controlled, educational trial. Study participants completed a 20-item, validated online test of their knowledge of central venous and arterial line (CVL and AL, respectively) placement at baseline and after performing their next 2 procedures (test 1 and test 2). Between test 1 and test 2, participants were randomized to online educational material for CVL insertion, AL insertion, both, or neither. The primary outcome of the study was the difference in test scores between test 1 and test 2 by randomization group.
Though residents in the baseline cohort were confident about their knowledge of procedural technique, their mean test scores were low (62% and 58% in the CVL and AL tests, respectively). Baseline test score correlated with the number of prior procedures performed. Sixty-five residents completed all 3 CVL tests, and 85 residents completed all 3 AL tests. Access to the web-based procedure education was associated with a significant improvement in scores for both the CVL test (effect size, d = 0.25, P = .01) and AL test (d = 0.52, P < .001).
Web-based procedure training improves knowledge of procedures to a significantly greater extent than performing the procedure alone. Web-based curricula can effectively supplement other methods of skill development.
Journal of graduate medical education. 12/2010; 2(4):548-54.
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Gastroenterology 10/2010; 139(4):1076-80, 1080.e1-2. · 11.68 Impact Factor
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Elena M Stoffel,
Rowena C Mercado,
Wendy Kohlmann,
Beth Ford, Shilpa Grover,
Peggy Conrad,
Amie Blanco,
Kristen M Shannon,
Mark Powell,
Daniel C Chung,
Jonathan Terdiman,
Stephen B Gruber,
Sapna Syngal
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ABSTRACT: OBJECTIVES: Lynch syndrome (LS) is a hereditary cancer syndrome that conveys a high risk of colorectal cancer (CRC). Guidelines recommend colonoscopy every 1 to 2 years. There is limited information about screening compliance in this high-risk group.
The American Journal of Gastroenterology 03/2010; · 7.28 Impact Factor
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Elena M Stoffel,
Rowena C Mercado,
Wendy Kohlmann,
Beth Ford, Shilpa Grover,
Peggy Conrad,
Amie Blanco,
Kristen M Shannon,
Mark Powell,
Daniel C Chung,
Jonathan Terdiman,
Stephen B Gruber,
Sapna Syngal
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ABSTRACT: Lynch syndrome (LS) is a hereditary cancer syndrome that conveys a high risk of colorectal cancer (CRC). Guidelines recommend colonoscopy every 1 to 2 years. There is limited information about screening compliance in this high-risk group.
Data about cancer screening behaviors were obtained from subjects recruited through four US cancer genetics clinics. The main outcome was prevalence of appropriate CRC surveillance for LS.
A total of 181 individuals had a family history that met the Amsterdam criteria for LS (n=154) and/or had an identified mutation in a mismatch repair (MMR) gene (n=105). Of these 181 individuals, 131 (73%) had appropriate LS surveillance with colonoscopies at least every 2 years for their age >25 years. Of those with inadequate surveillance, 26/49 (53%) had colonoscopies at 3- to 5-year intervals. There were no significant differences in health-care setting, perceived risk of CRC, or compliance with screening for other cancers. Rates of appropriate surveillance were higher among individuals who had been referred for genetic evaluation for LS compared with those who had not (109/136 (80%) vs. 23/45 (51%), respectively, P=0.0004). In multivariate analysis, personal history of CRC (odds ratio (OR) 2.81), having a first-degree relative with CRC at age <50 years (OR 2.61), and having undergone a genetic evaluation (OR 4.62) were associated with appropriate CRC surveillance for LS.
The time between colonoscopic exams in patients with LS is often longer than recommended by current guidelines and may place them at risk for interval cancers. Recognizing clinical features of LS and providing genetic counseling, evaluation, and intensive surveillance may improve cancer prevention for those at the highest risk for CRC.
The American Journal of Gastroenterology 03/2010; 105(8):1851-60. · 7.28 Impact Factor
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ABSTRACT: Of the estimated 150,000 colorectal cancer (CRC) cases diagnosed annually, approximately 30% have a familial basis and 3% to 5% are from high-penetrance inherited cancer syndromes. Lynch syndrome, or hereditary nonpolyposis colorectal cancer, caused by inherited germline mutations in mismatch repair (MMR) genes, is the most commonly inherited CRC syndrome. It is characterized by young-onset CRC and an increased risk for extracolonic tumors, including gynecologic, urinary tract, and other gastrointestinal cancers. Commercial testing is available for mutations in the MMR genes, but testing all patients with CRC would be economically prohibitive. Therefore, a comprehensive evaluation of a multigenerational family cancer history is essential for the identification of at-risk individuals. The presence of tumors diagnosed at a young age, multiple first- and second-degree relatives with cancer, or 2 or more primary cancers may be indicative of an inherited cancer syndrome and these individuals should undergo genetic evaluation. Genetic test results, when conclusive, can guide management for patients and their families. However, indeterminate test results may provide false reassurance to patients who should be managed as being at higher-than-average risk. Online risk assessment tools and commercial genetic testing offer the potential to identify a greater number of at-risk individuals at an earlier age. However, for these measures to improve outcomes, patients must receive screening recommendations and counseling appropriate for their cancer risk.
Journal of the National Comprehensive Cancer Network: JNCCN 01/2010; 8(1):98-105. · 4.41 Impact Factor
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ABSTRACT: Knowledge of core medical procedures is required by the American Board of Internal Medicine (ABIM) for certification. Efforts to improve the training of residents in these procedures have been limited by the absence of a validated tool for the assessment of knowledge. In this study we aimed to develop a standardized test of procedural knowledge in 3 medical procedures associated with potentially serious complications.
Placement of an arterial line, central venous catheter, and thoracentesis were selected for test development. Learning objectives and multiple-choice questions were constructed for each topic. Content evidence was evaluated by critical care subspecialists. Item test characteristics were evaluated by administering the test to students, residents and specialty clinicians. Reliability of the 32-item instrument was established through its administration to 192 medical residents in 4 hospitals.
Reliability of the instrument as measured by Cronbach's alpha was 0.79 and its test-retest reliability was 0.82. Median score was 53% on a test comprising elements deemed important by critical care subspecialists. Increasing number of procedures attempted, higher self-reported confidence, and increasing seniority were predictors of overall test scores. Procedural confidence correlated significantly with increasing seniority and experience. Residents performed few procedures.
We have successfully developed a standardized instrument to assess residents' cognitive competency for 3 common procedures. Residents' overall knowledge about procedures is poor. Experiential learning is the dominant source for knowledge improvement, but these experiences are increasingly rare.
Journal of Hospital Medicine 09/2009; 4(7):430-2. · 1.40 Impact Factor
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Shilpa Grover,
Elena M Stoffel,
Rowena C Mercado,
Beth M Ford,
Wendy K Kohlman,
Kristen M Shannon,
Peggy G Conrad,
Amie M Blanco,
Jonathan P Terdiman,
Stephen B Gruber,
Daniel C Chung,
Sapna Syngal
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ABSTRACT: Lynch syndrome is associated with inherited germline mutations in mismatch repair (MMR) genes. Genetic testing in high-risk individuals may yield indeterminate results if no mutation is found or if a mutation of unclear pathogenic significance is observed. There are limited data regarding how well patients with Lynch syndrome understand the clinical implications of genetic test results. This study examines colorectal cancer (CRC) risk perception in individuals tested for MMR mutations and identifies the factors associated with an appropriate interpretation of their cancer risk.
A total of 159 individuals who met the Revised Bethesda Guidelines and had previously undergone genetic testing completed a questionnaire eliciting demographic data, cancer history, genetic test results, and an estimate of their CRC risk. Associations between clinical factors, genetic test results, and CRC risk perception were explored using multivariable analyses.
Of the 100 individuals with a pathogenic mutation (true positive), 90 (90%) correctly estimated their CRC risk as "high" or "very high" compared with other individuals their age. However, only 23 (62%) of 37 individuals with an indeterminate genetic test result correctly estimated their risk. Individuals with a history of Lynch syndrome-associated cancer (odds ratio [OR], 0.1; 95% CI, 0.1 to 0.6) or indeterminate genetic test results (OR, 0.2; 95% CI, 0.1 to 0.6) were significantly less likely to estimate their CRC risk as increased.
Patients at risk for Lynch syndrome with an indeterminate genetic test result may be falsely reassured. It is important that health care providers continue to discuss the implications of uninformative results on lifetime cancer risk.
Journal of Clinical Oncology 08/2009; 27(24):3981-6. · 18.37 Impact Factor
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ABSTRACT: Lynch syndrome/Hereditary non-polyposis colorectal cancer is caused by inherited germline mutations in mismatch repair (MMR) genes, and accounts for 2-5% of colorectal cancers (CRC) . It is characterized by young onset CRC and an increased risk for gynaecologic, urinary tract and gastrointestinal cancers. Family history evaluation is crucial in the early identification of individuals at risk for Lynch syndrome. Individuals whose family history includes multiple relatives with cancer, two or more primary cancers, or component tumours diagnosed at a young age, should undergo genetic evaluation for Lynch syndrome. Guidelines recommend initial evaluation of the tumour with immunohistochemistry or microsatellite instability testing followed by germline testing for mutations in MMR genes in those with abnormal results. Genetic test results can guide screening recommendations for patients and their families. However, results are not always conclusive and in such cases recommendations for cancer screening should be individualized on the basis of personal and family history.
Best practice & research. Clinical gastroenterology 02/2009; 23(2):185-96. · 2.48 Impact Factor
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MedGenMed: Medscape general medicine 02/2007; 9(1):28.
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MedGenMed: Medscape general medicine 02/2007; 9(2):46.
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ABSTRACT: An accurate family history is an essential component of cancer risk assessment. Our aim was to determine the concordance of family history assessments made by physicians with patients' self-reports and the frequency of referral for genetic evaluation in high-risk colorectal cancer (CRC) patients.
A self-administered family cancer history questionnaire was completed by 387 consecutive CRC patients at their first visit to a gastroenterology cancer clinic. Physician notes from the first visit were reviewed to determine the concordance of the family cancer history with patients' self-reported history. Prevalence of individuals that satisfied the Bethesda guidelines for hereditary colon cancer were compared with actual rates of referral. Regression analyses were used to determine factors associated with a comprehensive physician evaluation of family history.
Oncologists documented a comprehensive family history in 59% (184 of 311) of patients with a first- or second-degree relative with cancer. Young age at diagnosis and a first-degree relative with CRC were not associated with a more comprehensive family history assessment. An increasing number of cancers per family was a strong predictor of a less comprehensive family history assessment (odds ratio = 0.63; P < 0.0001). Seventy-five of 387 (19%) CRC patients met Bethesda guidelines for genetics assessment, however, only 13 of 75 (17%) were referred.
Increased complexity in family cancer history leads to a decrease in accuracy of family history, suggesting the need for systematic approaches to facilitate family history assessment. Familial cancer risk remains largely unrecognized and referral rates for genetic evaluation for CRC syndromes are low.
Clinical Gastroenterology and Hepatology 09/2004; 2(9):813-9. · 5.63 Impact Factor
