Publications by authors named "Scott M Weissman"

19 Publications

  • Page 1 of 1

At-home genetic testing in pediatrics.

Curr Opin Pediatr 2019 12;31(6):723-731

Geisinger National Precision Health - North Bethesda, Maryland, USA.

Purpose Of Review: This review discusses the state of at-home genetic testing, including both direct-to-consumer and consumer-directed genetic testing, for children.

Recent Findings: At-home genetic testing continues to increase in popularity and laboratories are starting to offer tests geared towards newborns and children. Available at-home genetic tests for children address ancestral descent, supplement newborn screening, or provide risks for childhood and adult-onset disorders as well as pharmacogenomic data. However, there are aspects of at-home testing that are unique to children that both providers and parents need to be aware of before considering this type of testing; these include issues related to motivations for testing; privacy concerns; result interpretation; ethical, legal and social implications; and impact on family relationships, among others.

Summary: This review addresses the challenges associated with at-home genetic testing in children and provides guidance for pediatricians and other health care providers who field inquiries about this type of testing or who are presented with at-home genetic test results for interpretation.
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http://dx.doi.org/10.1097/MOP.0000000000000824DOI Listing
December 2019

Coordinating an Oncology Precision Medicine Clinic Within an Integrated Health System: Lessons Learned in Year One.

J Patient Cent Res Rev 2019 28;6(1):36-45. Epub 2019 Jan 28.

Aurora Cancer Care, Aurora Health Care, Milwaukee, WI.

Precision medicine is a term describing strategies to promote health and prevent and treat disease based on an individual's genetic, molecular, and lifestyle characteristics. Oncology precision medicine (OPM) is a cancer treatment approach targeting cancer-specific genetic and molecular alterations. Implementation of an OPM clinical program optimally involves the support and collaboration of multiple departments, including administration, medical oncology, pathology, interventional radiology, genetics, research, and informatics. In this review, we briefly introduce the published evidence regarding OPM's potential effect on patient outcomes and discuss what we have learned over the first year of operating an OPM program within an integrated health care system (Aurora Health Care, Milwaukee, WI) comprised of multiple hospitals and clinics. We also report our experience implementing a specific OPM software platform used to embed molecular panel data into patients' electronic medical records.
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http://dx.doi.org/10.17294/2330-0698.1639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676755PMC
January 2019

The dawn of consumer-directed testing.

Am J Med Genet C Semin Med Genet 2018 03 7;178(1):89-97. Epub 2018 Mar 7.

Chicago Genetic Consultants, LLC, Northbrook, Illinois.

As the public's interest in genetics and genomics has increased, there has been corresponding and unprecedented growth in direct-to-consumer genetic testing (DTC-GT). Although regulatory concerns have limited true DTC-GT available without a physician order, the paradigm has shifted to a model of consumer-directed genetic testing (CD-GT) in which patients are researching testing options and requesting specific genetic testing from their health-care providers. However, many nongenetics health-care providers do not have the background, education, interest, or time to order and/or interpret typical clinical genetic testing, let alone DTC-GT. The lines between CD-GT, DTC-GT, and traditional clinical genetic testing are also blurring with the same types of tests available in different settings (e.g., carrier screening) and tests merging medical and nonmedical results, increasing the complexity for consumer decision-making and clinician management. The genetics community has the training to work with CD-GT, but there has been a hesitancy to commit to working with these results and questions about what to do when consumers have more complicated asks, like interpretation of raw data. Additionally, at the rate with which CD-GT is growing, there are questions about having sufficient genetics professionals to meet the potential genetic counseling demand. While there are many complex questions and challenges, this market represents a chance for the genetics community to address and unmet need. We will review the history of the CD-GT/DTC-GT market and outline the issues and opportunities our profession is facing.
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http://dx.doi.org/10.1002/ajmg.c.31603DOI Listing
March 2018

Implementing a Virtual Health Telemedicine Program in a Community Setting.

J Genet Couns 2018 04 4;27(2):323-325. Epub 2017 Dec 4.

Genomic Medicine Program, Aurora Health Care, 2900 W Oklahoma Ave, Milwaukee, WI, 53215, USA.

Aurora Health Care in eastern Wisconsin has a clinical genetics program driven by genetic counselors in the cancer/adult and prenatal genetics settings. In 2015, the workforce shortage of genetic counselors left us with 4 open positions for genetic counselors that we were unable to fill. We explored many models of alternative service delivery, and determined virtual health (VH) via telemedicine to be the best option for our system. Historically, telemedicine technologies have been used to provide access to healthcare services to patients in remote areas. We, however, were struggling to find genetics counselors to staff both our remote clinics and urban clinics. To solve this problem, we recruited genetic counselors from across the country to work remotely from their current home or home office utilizing VH to staff our clinics. We then created clinical workflows and an implementation process of virtual health for 9 prenatal and cancer clinics across the eastern Wisconsin footprint of our healthcare system over the course of 12 months. Here we provide our experience and process in establishing a VH program in order to help other institutions that have been affected by the workforce shortage of clinical genetics professionals.
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http://dx.doi.org/10.1007/s10897-017-0177-5DOI Listing
April 2018

Implementing an oncology precision medicine clinic in a large community health system.

Am J Manag Care 2017 08;23(10 Spec No.):SP425-SP427

Aurora Research Institute, 960 N 12th St, Room 4111, Milwaukee, WI 53233. E-mail:

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August 2017

FDA Approval of PARP Inhibitors and the Impact on Genetic Counseling and Genetic Testing Practices.

J Genet Couns 2018 02 5;27(1):131-139. Epub 2017 Aug 5.

GeneDx, Gaithersburg, MD, USA.

In December 2014, the FDA approved olaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi) for ovarian cancer patients who have failed three or more lines of chemotherapy and have a germline BRCA1/2 mutation identified through a companion diagnostic test (BRACAnalysis CDx™ (CDx™)) offered exclusively by Myriad Genetic Laboratories. This study explored the impact of PARPi/CDx™ on genetic counselors' (GCs) counseling and testing practices. One hundred twenty three GCs responded to an online survey regarding pre- and post-FDA approval referral patterns, testing strategies/influences, and anecdotal experiences with insurance coverage of PARPi for BRCA1/2 positive patients through a non-CDx™ platform. Following PARPi approval, 40% of respondents reported an increase in overall referrals of ovarian cancer patients and 20% had an increase in post-test counseling only referrals. The majority (61.9%) of respondents reported no change in genetic testing strategy, and there was no change in factors influencing choice of testing laboratory. Nearly all (98.1%) respondents who had experience with insurance covering PARPi indicated approval with mutations identified via non-CDx™ testing. Respondents indicated an increase in referral volume following FDA approval of PARPi/CDx™, but did not report changes in testing practices. Respondents were not aware of PARPi insurance coverage denial in the absence of CDx™.
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http://dx.doi.org/10.1007/s10897-017-0130-7DOI Listing
February 2018

Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant.

Am J Hum Genet 2016 05 14;98(5):830-842. Epub 2016 Apr 14.

Department of Genetics and Computational Biology, QIMR Berghofer, Herston, QLD 4029, Australia. Electronic address:

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal-dominant cancer-predisposition syndrome with a significant risk of gastric, but not colorectal, adenocarcinoma. We mapped the gene to 5q22 and found loss of the wild-type allele on 5q in fundic gland polyps from affected individuals. Whole-exome and -genome sequencing failed to find causal mutations but, through Sanger sequencing, we identified point mutations in APC promoter 1B that co-segregated with disease in all six families. The mutations reduced binding of the YY1 transcription factor and impaired activity of the APC promoter 1B in luciferase assays. Analysis of blood and saliva from carriers showed allelic imbalance of APC, suggesting that these mutations lead to decreased allele-specific expression in vivo. Similar mutations in APC promoter 1B occur in rare families with familial adenomatous polyposis (FAP). Promoter 1A is methylated in GAPPS and sporadic FGPs and in normal stomach, which suggests that 1B transcripts are more important than 1A in gastric mucosa. This might explain why all known GAPPS-affected families carry promoter 1B point mutations but only rare FAP-affected families carry similar mutations, the colonic cells usually being protected by the expression of the 1A isoform. Gastric polyposis and cancer have been previously described in some FAP-affected individuals with large deletions around promoter 1B. Our finding that GAPPS is caused by point mutations in the same promoter suggests that families with mutations affecting the promoter 1B are at risk of gastric adenocarcinoma, regardless of whether or not colorectal polyps are present.
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http://dx.doi.org/10.1016/j.ajhg.2016.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863475PMC
May 2016

Evaluation of laboratory perspectives on hereditary cancer panels.

Fam Cancer 2016 10;15(4):689-96

GeneDx, Gaithersburg, MD, USA.

Genetic counseling and testing for hereditary cancer susceptibility is a rapidly evolving field and partly a result of next-generation sequencing (NGS) allowing analysis of multiple cancer susceptibility genes simultaneously. This qualitative study explored laboratory perspectives on hereditary cancer panels. Semi-structured interviews were conducted with representatives of clinical laboratories offering hereditary cancer panels via NGS. Several themes emerged from the responses pertaining to hereditary cancer panel development, the importance of communication of panel properties with patients, variant reporting policies, and the future of hereditary cancer gene testing. Clinical utility was discussed as primary consideration during panel development. In addition, while participants indicated gene and syndrome overlap prompted panel development in general, laboratories differed in their opinions of whether phenotypic overlap warrants offering pan-cancer panels only versus cancer specific panels. Participants stressed the importance of patients understanding implications of panel testing, including what is tested for and limitations of testing. While all laboratories discussed the limitations of a variant of uncertain significance result, they differed significantly in their reporting methods. This study provides healthcare providers information on the laboratory approach to panel testing, highlighting both commonalities and differences in laboratory approaches, and may allow providers to make more informed decisions when ordering hereditary cancer panels.
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http://dx.doi.org/10.1007/s10689-016-9880-xDOI Listing
October 2016

Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.

Genet Med 2016 08 17;18(8):823-32. Epub 2015 Dec 17.

Department of Pediatrics and Medicine, Columbia University Medical Center, New York, New York, USA.

Purpose: Germ-line testing for panels of cancer genes using next-generation sequencing is becoming more common in clinical care. We report our experience as a clinical laboratory testing both well-established, high-risk cancer genes (e.g., BRCA1/2, MLH1, MSH2) as well as more recently identified cancer genes (e.g., PALB2, BRIP1), many of which have increased but less well-defined penetrance.

Methods: Clinical genetic testing was performed on over 10,000 consecutive cases referred for evaluation of germ-line cancer genes, and results were analyzed for frequency of pathogenic or likely pathogenic variants, and were stratified by testing panel, gene, and clinical history.

Results: Overall, a molecular diagnosis was made in 9.0% of patients tested, with the highest yield in the Lynch syndrome/colorectal cancer panel. In patients with breast, ovarian, or colon/stomach cancer, positive yields were 9.7, 13.4, and 14.8%, respectively. Approximately half of the pathogenic variants identified in patients with breast or ovarian cancer were in genes other than BRCA1/2.

Conclusion: The high frequency of positive results in a wide range of cancer genes, including those of high penetrance and with clinical care guidelines, underscores both the genetic heterogeneity of hereditary cancer and the usefulness of multigene panels over genetic tests of one or two genes.Genet Med 18 8, 823-832.
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http://dx.doi.org/10.1038/gim.2015.166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985612PMC
August 2016

Diagnostic Exome Sequencing Identifies a Novel Gene, EMILIN1, Associated with Autosomal-Dominant Hereditary Connective Tissue Disease.

Hum Mutat 2016 Jan 4;37(1):84-97. Epub 2015 Nov 4.

Department of Translational Research, CRO-IRCCS National Cancer Institute, Aviano, 33081, Italy.

Heritable connective tissue diseases are a highly heterogeneous family of over 200 disorders that affect the extracellular matrix. While the genetic basis of several disorders is established, the etiology has not been discovered for a large portion of patients, likely due to rare yet undiscovered disease genes. By performing trio-exome sequencing of a 55-year-old male proband presenting with multiple symptoms indicative of a connective disorder, we identified a heterozygous missense alteration in exon 1 of the Elastin Microfibril Interfacer 1 (EMILIN1) gene, c.64G>A (p.A22T). The proband presented with ascending and descending aortic aneurysms, bilateral lower leg and foot sensorimotor peripheral neuropathy, arthropathy, and increased skin elasticity. Sanger sequencing confirmed that the EMILIN1 alteration, which maps around the signal peptide cleavage site, segregated with disease in the affected proband, mother, and son. The impaired secretion of EMILIN-1 in cells transfected with the mutant p.A22T coincided with abnormal protein accumulation within the endoplasmic reticulum. In skin biopsy of the proband, we detected less EMILIN-1 with disorganized and abnormal coarse fibrils, aggregated deposits underneath the epidermis basal lamina, and dermal cells apoptosis. These findings collectively suggest that EMILIN1 may represent a new disease gene associated with an autosomal-dominant connective tissue disorder.
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http://dx.doi.org/10.1002/humu.22920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4738430PMC
January 2016

Cancer genetic testing panels for inherited cancer susceptibility: the clinical experience of a large adult genetics practice.

Fam Cancer 2014 Dec;13(4):527-36

Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA.

Next-generation sequencing genetic testing panels for cancer susceptibility (cancer panels) have recently become clinically available. At present, clinical utility is unknown and there are no set criteria or guidelines established for whom to offer such testing. Although it may be a cost-effective method to test multiple cancer susceptibility genes concurrently, the rate of finding variants of unknown significance (VUS) may be high and testing may yield mutations in genes with no established management recommendations. We describe our Center's experience over a 14-month period (April 2012-June 2013) for patient interest and uptake in cancer panel testing and whether there were predictors of pursuing testing or identifying mutations. Using a clinical ranking system, patients' family histories were ranked from 0 to 3 (low likelihood to high likelihood for underlying genetic susceptibility). The clinical ranking system was assessed to determine its predictability of finding mutations. Of the 689 patients who met inclusion criteria, the option of pursuing a cancer panel was discussed with 357 patients; 63 (17.6 %) patients pursued testing. Those who pursued testing were more likely to be older, male, affected with cancer, affected with multiple primary cancers, and had a higher clinical rank than non-pursuers. There were no significant predictors of finding a mutation on panel testing. Of the 61 patients who have received results, there was a 6.6 % mutation rate and 19.7 % VUS rate. The yield of cancer panels in clinical practice is low and the strength of family history alone may not predict likelihood of finding a mutation.
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http://dx.doi.org/10.1007/s10689-014-9741-4DOI Listing
December 2014

Physicians' preparedness for integration of genomic and pharmacogenetic testing into practice within a major healthcare system.

Genet Test Mol Biomarkers 2013 Mar 7;17(3):219-25. Epub 2013 Feb 7.

Department of Medicine, Center for Medical Genetics, NorthShore University HealthSystem, Evanston, Illinois 60201, USA.

Purpose: Physicians will play a large role in the delivery of genomic medicine, given the limited number of trained genetics professionals. The objective of this study was to assess physician preparedness for incorporating genomic testing (GT) and pharmacogenetic testing (PT) into practice by determining knowledge, experience, comfort level, and barriers, as well as their expectations for practice and educational needs.

Methods: A 30-question survey was distributed to physicians spanning all disciplines within our healthcare system.

Results: Perceived knowledge was poor; 40%-72% reported "no to minimal knowledge" for all genomics topics. Recent graduates or those with no patients who had undergone GT or PT had lower comfort levels. Participating physicians anticipate usage to increase; however, most were uncertain when and how to incorporate genomics into practice. Physicians perceived lack of knowledge and time to keep updated as their greatest barriers to incorporating GT and PT into practice.

Conclusion: Overall, physicians appear underprepared, perceiving they lack sufficient knowledge and confidence to incorporate GT and PT into practice. The majority of physicians expect their role in GT and PT to increase. The results underscore the importance of enhancing policies and initiatives to increase physician knowledge and comfort level.
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http://dx.doi.org/10.1089/gtmb.2012.0165DOI Listing
March 2013

Genetic testing by cancer site: ovary.

Cancer J 2012 Jul-Aug;18(4):320-7

NorthShore University HealthSystem, Center for Medical Genetics, Evanston, IL 60201, USA.

Approximately 1 in every 4 to 5 women with a diagnosis of ovarian cancer has a hereditary gene mutation that is responsible for the development of her cancer. Identifying women at increased risk of developing ovarian cancer due to a hereditary cancer syndrome can allow for early detection or prevention of not only ovarian cancer, but also other cancers, depending on the causative gene. This review focuses on 3 of the most common hereditary ovarian cancer syndromes, hereditary breast and ovarian cancer syndrome (the BRCA1 and BRCA2 genes), Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer syndrome), and Peutz-Jeghers syndrome, including key features, genetics, and management of these syndromes. In addition, newly discovered genes (eg, RAD51C and RAD51D) linked to ovarian cancer are discussed.
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http://dx.doi.org/10.1097/PPO.0b013e31826246c2DOI Listing
January 2013

Identification of individuals at risk for Lynch syndrome using targeted evaluations and genetic testing: National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Colorectal Cancer joint practice guideline.

J Genet Couns 2012 Aug 14;21(4):484-93. Epub 2011 Dec 14.

Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA.

Identifying individuals who have Lynch syndrome (LS) involves a complex diagnostic work up that includes taking a detailed family history and a combination of various genetic and immunohistochemical tests. The National Society of Genetic Counselors (NSGC) and the Collaborative Group of the Americas on Inherited Colorectal Cancer (CGA-ICC) have come together to publish this clinical practice testing guideline for the evaluation of LS. The purpose of this practice guideline is to provide guidance and a testing algorithm for LS as well as recommendations on when to offer testing. This guideline does not replace a consultation with a genetics professional. This guideline includes explanations in support of this and a summary of background data. While this guideline is not intended to serve as a review of LS, it includes a discussion of background information on LS, and cites a number of key publications which should be reviewed for a more in-depth understanding of LS. These guidelines are intended for genetic counselors, geneticists, gastroenterologists, surgeons, medical oncologists, obstetricians and gynecologists, nurses and other healthcare providers who evaluate patients for LS.
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http://dx.doi.org/10.1007/s10897-011-9465-7DOI Listing
August 2012

Genetic counseling considerations in the evaluation of families for Lynch syndrome--a review.

J Genet Couns 2011 Feb 8;20(1):5-19. Epub 2010 Oct 8.

Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA.

Lynch syndrome is the most common hereditary colorectal cancer syndrome and the most common cause of hereditary endometrial cancer. Identifying and evaluating families for Lynch syndrome is increasing in complexity due to the recognition that: family history-based clinical criteria lack sensitivity and specificity; genetic testing for Lynch syndrome continues to evolve as understanding of the molecular mechanisms underlying it evolves; and the Lynch syndrome phenotype encompasses multiple organ systems and demonstrates overlap with other hereditary cancer syndromes. This document is a summary of considerations when evaluating individuals and families for Lynch syndrome, including information on cancer risks, diagnostic criteria, tumor and genetic testing strategies, and the management of individuals with this condition.
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http://dx.doi.org/10.1007/s10897-010-9325-xDOI Listing
February 2011

Detection of BRCA1 and BRCA2 Ashkenazi Jewish founder mutations in formalin-fixed paraffin-embedded tissues using conventional PCR and heteroduplex/amplicon size differences.

J Mol Diagn 2010 Jan 3;12(1):20-6. Epub 2009 Dec 3.

Department of Pathology & Laboratory Medicine, NorthShore University HealthSystem, 2650 Ridge Avenue, Evanston, IL 60201, USA.

In many families with histories suggestive of BRCA1- or BRCA2-related disease, the proband is deceased. Reliable assessment of archived tissue blocks not amenable to full gene sequencing would be helpful. In this study, a polymerase chain reaction (PCR) assay using primers that bracket the BRCA mutation site and microfluidics-based detection of heteroduplex/amplicon size differences was developed to circumvent artifacts associated with low quality DNA from formalin-fixed paraffin-embedded (FFPE) tissue. Genomic DNA was extracted from 100 FFPE specimens from patients that had previously undergone BRCA gene sequence analysis on blood specimens. Conventional PCR amplification products were differentiated using the Agilent 2100 Bioanalyzer. One FFPE specimen failed to amplify the wild-type alleles for all three sites and was therefore called indeterminate. All 62 FFPE specimens with known Ashkenazi Jewish founder mutations had both the wild-type and the correct mutated allele amplified, including one specimen that failed to amplify the mutant allele in other real-time PCR assays. Appropriately, 21 FFPE specimens known to have other BRCA1/2 mutations and 16 without any mutation had only the wild-type allele correctly amplified for each target. Therefore, by changing the primer location and detecting amplicons via heteroduplexes formed by size differences, we identified mutations from FFPE tissues missed using real-time methods.
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http://dx.doi.org/10.2353/jmoldx.2010.090023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797714PMC
January 2010

Managing hereditary gastrointestinal cancer syndromes: the partnership between genetic counselors and gastroenterologists.

Nat Clin Pract Gastroenterol Hepatol 2008 Oct 16;5(10):569-82. Epub 2008 Sep 16.

Evanston Northwestern Healthcare Center for Medical Genetics, Evanston, IL 60201, USA.

A standard of care for the recognition and management of patients and families with hereditary gastrointestinal cancer syndromes is emerging, and both gastroenterologists and genetic counselors have an important role. This Review considers these roles and outlines the partnership needed between gastroenterologists and genetic counselors. The role of the gastroenterologist involves careful sampling of polyps and tumors, and requires a basic working knowledge of the features of hereditary gastrointestinal cancer syndromes. The role of the genetic counselor is to gather and synthesize family history and pathology information, formulate a genetic differential diagnosis, determine a genetic testing strategy, guide medical management and help patients communicate information to their relatives. Managing the complex logistics of testing the best candidate in the family, facilitating informed consent, outlining costs to patients and interpreting test results are also responsibilities assumed by genetic counselors. In addition, genetic counselors help physicians meet their ethical and medicolegal obligations with respect to patient management and family communication. Referral schemata for patients with polyposis and nonpolyposis features are presented in this Review, along with comprehensive tables that outline the features of well-known and rare syndromes that heighten the risk of gastrointestinal malignancy.
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http://dx.doi.org/10.1038/ncpgasthep1235DOI Listing
October 2008

Psychological impact of recall in high-risk breast MRI screening.

Breast Cancer Res Treat 2009 May 26;115(2):365-71. Epub 2008 Jul 26.

Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Purpose: To address the widespread concern that false-positive results during breast MRI screening may have adverse psychological effects.

Methods: Impact of Event Scale measurements in 103 high-risk women enrolled in a longitudinal MRI screening study and comparison of subjects with normal results vs. those with prior recall events.

Results: Of 189 MRI scans performed, 64 (34%) prompted further evaluation. Subjects with previously abnormal results had significantly higher Avoidance scores at the time of their second MRI. Multivariate analysis showed this was driven by the greater number of BRCA1/2 carriers in that group but was not related to screening recall.

Conclusions: Practitioners' concerns about the high false positive rate of breast MRI may not be matched by actual psychological effects in most high-risk women.
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http://dx.doi.org/10.1007/s10549-008-0140-0DOI Listing
May 2009

Hereditary nonpolyposis colorectal carcinoma (HNPCC) and HNPCC-like families: Problems in diagnosis, surveillance, and management.

Cancer 2004 Jan;100(1):53-64

Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, Nebraska 68178, USA.

Background: To the authors' knowledge, hereditary nonpolyposis colorectal carcinoma (HNPCC) is the most commonly occurring hereditary disorder that predisposes to colorectal carcinoma (CRC), accounting for approximately 2-7% of all CRC cases diagnosed in the U.S each year. Its diagnosis is wholly dependent on a meticulously obtained family history of cancer of all anatomic sites, with particular attention to the pattern of cancer distribution within the family.

Methods: The objective of the current study was to illustrate various vexing problems that can deter the diagnosis of HNPCC and, ultimately, its management. This was an observational cohort study. Sixteen HNPCC and HNPCC-like families were selected from a large resource of highly extended HNPCC families. High-risk patients were selected from these HNPCC families. An ascertainment bias was imposed by the lack of a population-based data set. Personal interviews and questionnaires were used for data collection.

Results: There was an array of difficulties highlighted by limitations in compliance, lack of a clinical or molecular basis for an HNPCC diagnosis, ambiguous DNA findings, problems in genetic counseling, failure to meet Amsterdam or Bethesda criteria, small families, lack of medical and pathologic documentation, poor cooperation of family members and/or their physicians, cultural barriers, economic stress, frequent patient fear and anxiety, perception of insurance discrimination, and limited patient and/or physician knowledge regarding hereditary cancer.

Conclusions: The diagnosis and management of HNPCC is predicated on physician knowledge of its phenotypic and genotypic heterogeneity, in concert with the multifaceted problems that impact on patient compliance.
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http://dx.doi.org/10.1002/cncr.11912DOI Listing
January 2004