Donald L Weaver

University of Vermont Medical Center, Burlington, Vermont, United States

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Publications (120)921.11 Total impact

  • American Journal of Clinical Pathology 12/2015; 144(6):916-922. DOI:10.1309/AJCP80LYIMOOUJIF · 2.51 Impact Factor
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    BMC Cancer 12/2015; 15(1). DOI:10.1186/s12885-015-1860-2 · 3.36 Impact Factor
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    ABSTRACT: Long non-coding RNAs (lncRNAs) are potential biomarkers for breast cancer risk stratification. LncRNA expression has been investigated primarily by RNA sequencing, quantitative reverse transcription PCR or microarray techniques. In this study, six breast cancer-implicated lncRNAs were investigated by chromogenic in situ hybridisation (CISH). Invasive breast carcinoma (IBC), ductal carcinoma in situ (DCIS) and normal adjacent (NA) breast tissues from 52 patients were screened by CISH. Staining was graded by modified Allred scoring. HOTAIR, H19 and KCNQ1OT1 had significantly higher expression levels in IBC and DCIS than NA (p<0.05), and HOTAIR and H19 were expressed more strongly in IBC than in DCIS tissues (p<0.05). HOTAIR and KCNQ101T were expressed in tumour cells; H19 and MEG3 were expressed in stromal microenvironment cells; MALAT1 was expressed in all cells strongly and ZFAS1 was negative or weakly expressed in all specimens. These data corroborate the involvement of three lncRNAs (HOTAIR, H19 and KCNQ1OT1) in breast tumourigenesis and support lncRNA CISH as a potential clinical assay. Importantly, CISH allows identification of the tissue compartment expressing lncRNA. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to
    Journal of clinical pathology 08/2015; DOI:10.1136/jclinpath-2015-203275 · 2.92 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):2768-2768. DOI:10.1158/1538-7445.AM2015-2768 · 9.33 Impact Factor
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    ABSTRACT: Margin status is important in guiding decisions to re-excise following breast-conserving surgery (BCS) for breast cancer. The College of American Pathologists (CAP) developed guidelines to standardize pathology reporting; however, compliance with margin documentation guidelines has been shown to vary. The aim of this retrospective study was to determine whether compliance with CAP guidelines affects re-excision and mastectomy rates. We identified 1423 patients diagnosed with breast cancer between 1998 and 2006 who underwent BCS with negative margins. CAP compliance was categorized as maximal, minimal, or non-compliant. Statistical analyses were performed comparing the frequency of re-excision and mastectomy after initial BCS according to CAP margin reporting guideline compliance. Data were adjusted for provider facility by including a clustering variable within the regression model. Patients with non-compliant margin reporting were 1.7 times more likely to undergo re-excision and/or mastectomy than those with maximally compliant reporting. Level of compliance was most strongly associated with the frequency of mastectomy; non-compliant margin reporting was associated with a 2.5-fold increase in mastectomy rates compared to maximally compliant reporting. The results did not substantially change when the analyses accounted for clustering at the provider facility level. Our findings suggest that compliance with CAP guidelines in pathology reporting may be associated with variation in re-excision and mastectomy rates following BCS. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Breast (Edinburgh, Scotland) 07/2015; DOI:10.1016/j.breast.2015.06.007 · 2.38 Impact Factor
  • Joann G Elmore · Margaret S Pepe · Donald L Weaver ·

    JAMA The Journal of the American Medical Association 07/2015; 314(1):83-84. DOI:10.1001/jama.2015.6239 · 35.29 Impact Factor
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    ABSTRACT: General frameworks of the cancer screening process are available, but none directly compare the process in detail across different organ sites. This limits the ability of medical and public health professionals to develop and evaluate coordinated screening programs that apply resources and population management strategies available for one cancer site to other sites. We present a trans-organ conceptual model that incorporates a single screening episode for breast, cervical, and colorectal cancers into a unified framework based on clinical guidelines and protocols; the model concepts could be expanded to other organ sites. The model covers four types of care in the screening process: risk assessment, detection, diagnosis, and treatment. Interfaces between different provider teams (eg, primary care and specialty care), including communication and transfer of responsibility, may occur when transitioning between types of care. Our model highlights across each organ site similarities and differences in steps, interfaces, and transitions in the screening process and documents the conclusion of a screening episode. This model was developed within the National Cancer Institute-funded consortium Population-based Research Optimizing Screening through Personalized Regimens (PROSPR). PROSPR aims to optimize the screening process for breast, cervical, and colorectal cancer and includes seven research centers and a statistical coordinating center. Given current health care reform initiatives in the United States, this conceptual model can facilitate the development of comprehensive quality metrics for cancer screening and promote trans-organ comparative cancer screening research. PROSPR findings will support the design of interventions that improve screening outcomes across multiple cancer sites. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail:
    Journal of the National Cancer Institute 06/2015; 107(6). DOI:10.1093/jnci/djv120 · 12.58 Impact Factor
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    ABSTRACT: A breast pathology diagnosis provides the basis for clinical treatment and management decisions; however, its accuracy is inadequately understood. To quantify the magnitude of diagnostic disagreement among pathologists compared with a consensus panel reference diagnosis and to evaluate associated patient and pathologist characteristics. Study of pathologists who interpret breast biopsies in clinical practices in 8 US states. Participants independently interpreted slides between November 2011 and May 2014 from test sets of 60 breast biopsies (240 total cases, 1 slide per case), including 23 cases of invasive breast cancer, 73 ductal carcinoma in situ (DCIS), 72 with atypical hyperplasia (atypia), and 72 benign cases without atypia. Participants were blinded to the interpretations of other study pathologists and consensus panel members. Among the 3 consensus panel members, unanimous agreement of their independent diagnoses was 75%, and concordance with the consensus-derived reference diagnoses was 90.3%. The proportions of diagnoses overinterpreted and underinterpreted relative to the consensus-derived reference diagnoses were assessed. Sixty-five percent of invited, responding pathologists were eligible and consented to participate. Of these, 91% (N = 115) completed the study, providing 6900 individual case diagnoses. Compared with the consensus-derived reference diagnosis, the overall concordance rate of diagnostic interpretations of participating pathologists was 75.3% (95% CI, 73.4%-77.0%; 5194 of 6900 interpretations). Among invasive carcinoma cases (663 interpretations), 96% (95% CI, 94%-97%) were concordant, and 4% (95% CI, 3%-6%) were underinterpreted; among DCIS cases (2097 interpretations), 84% (95% CI, 82%-86%) were concordant, 3% (95% CI, 2%-4%) were overinterpreted, and 13% (95% CI, 12%-15%) were underinterpreted; among atypia cases (2070 interpretations), 48% (95% CI, 44%-52%) were concordant, 17% (95% CI, 15%-21%) were overinterpreted, and 35% (95% CI, 31%-39%) were underinterpreted; and among benign cases without atypia (2070 interpretations), 87% (95% CI, 85%-89%) were concordant and 13% (95% CI, 11%-15%) were overinterpreted. Disagreement with the reference diagnosis was statistically significantly higher among biopsies from women with higher (n = 122) vs lower (n = 118) breast density on prior mammograms (overall concordance rate, 73% [95% CI, 71%-75%] for higher vs 77% [95% CI, 75%-80%] for lower, P < .001), and among pathologists who interpreted lower weekly case volumes (P < .001) or worked in smaller practices (P = .034) or nonacademic settings (P = .007). In this study of pathologists, in which diagnostic interpretation was based on a single breast biopsy slide, overall agreement between the individual pathologists' interpretations and the expert consensus-derived reference diagnoses was 75.3%, with the highest level of concordance for invasive carcinoma and lower levels of concordance for DCIS and atypia. Further research is needed to understand the relationship of these findings with patient management.
    JAMA The Journal of the American Medical Association 03/2015; 313(11):1122-1132. DOI:10.1001/jama.2015.1405 · 35.29 Impact Factor
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    ABSTRACT: Elevated mammographic density is a breast cancer risk factor, which has a suggestive, but unproven, relationship with increased exposure to sex steroid hormones. We examined associations of serum estrogens and estrogen metabolites with area and novel volume mammographic density measures among 187 women, ages 40–65, undergoing diagnostic breast biopsies at an academic facility in Vermont. Serum parent estrogens, estrone and estradiol, and their 2-, 4-, and 16-hydroxylated metabolites were measured using liquid chromatography-tandem mass spectrometry. Area mammographic density was measured in the breast contralateral to the biopsy using thresholding software; volume mammographic density was quantified using a density phantom. Linear regression was used to estimate associations of estrogens with mammographic densities, adjusted for age and body mass index, and stratified by menopausal status and menstrual cycle phase. Weak, positive associations between estrogens, estrogen metabolites, and mammographic density were observed, primarily among postmenopausal women. Among premenopausal luteal phase women, the 16-pathway metabolite estriol was associated with percent area (p = 0.04) and volume (p = 0.05) mammographic densities and absolute area (p = 0.02) and volume (p = 0.05) densities. Among postmenopausal women, levels of total estrogens, the sum of parent estrogens, and 2-, 4- and 16-hydroxylation pathway metabolites were positively associated with area density measures (percent: p = 0.03, p = 0.04, p = 0.01, p = 0.02, p = 0.07; absolute: p = 0.02, p = 0.02, p = 0.01, p = 0.02, p = 0.03, respectively) but not volume density measures. Our data suggest that serum estrogen profiles are weak determinants of mammographic density and that analysis of different density metrics may provide complementary information about relationships of estrogen exposure to breast tissue composition.
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    ABSTRACT: BACKGROUND Current data on the pathologic diagnoses of breast biopsy after mammography can inform patients, clinicians, and researchers about important population trends.METHODS Breast Cancer Surveillance Consortium data on 4,020,140 mammograms between 1996 and 2008 were linked to 76,567 pathology specimens. Trends in diagnoses in biopsies by time and risk factors (patient age, breast density, and family history of breast cancer) were examined for screening and diagnostic mammography (performed for a breast symptom or short-interval follow-up).RESULTSOf the total mammograms, 88.5% were screening and 11.5% diagnostic; 1.2% of screening and 6.8% of diagnostic mammograms were followed by biopsies. The frequency of biopsies over time was stable after screening mammograms, but increased after diagnostic mammograms. For biopsies obtained after screening, frequencies of invasive carcinoma increased over time for women ages 40-49 and 60-69, Ductal carcinoma in situ (DCIS) increased for those ages 40-69, whereas benign diagnoses decreased for all ages. No trends in pathology diagnoses were found following diagnostic mammograms. Dense breast tissue was associated with high-risk lesions and DCIS relative to nondense breast tissue. Family history of breast cancer was associated with DCIS and invasive cancer.CONCLUSIONS Although the frequency of breast biopsy after screening mammography has not changed over time, the percentages of biopsies with DCIS and invasive cancer diagnoses have increased. Among biopsies following mammography, women with dense breasts or family history of breast cancer were more likely to have high-risk lesions or invasive cancer. These findings are relevant to breast cancer screening and diagnostic practices. Cancer 2015. © 2015 American Cancer Society.
    Cancer 01/2015; 121(9). DOI:10.1002/cncr.29199 · 4.89 Impact Factor
  • L. Samples · M. Rendi · D. Weaver · P. Frederick · T. Morgan · J. Elmore ·

    Journal of Investigative Medicine 01/2015; 63(1):91-91. · 1.69 Impact Factor
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    ABSTRACT: Physician attributes, job satisfaction and confidence in clinical skills are associated with enhanced performance and better patient outcomes. We surveyed 252 pathologists to evaluate associations between enjoyment of breast pathology, demographic/clinical characteristics and diagnostic performance. Diagnostic performance was determined by comparing pathologist assessments of a set of 60 cases with consensus assessments of the same cases made by a panel of experienced pathologists. Eighty-three percent of study participants reported enjoying breast pathology. Pathologists who enjoy breast interpretation were more likely to review ≥10 cases/week (p = 0.003), report breast interpretation expertise (p = 0.013) and have high levels of confidence interpreting breast pathology (p < 0.001). These pathologists were less likely to report that the field was challenging (p < 0.001) and that breast cases make them more nervous than other types of pathology (p < 0.001). Enjoyment was not associated with diagnostic performance. Millions of women undergo breast biopsy annually, thus it is reassuring that although nearly a fifth of practicing pathologists who interpret breast tissue report not enjoying the field, precision is not impacted. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Breast (Edinburgh, Scotland) 12/2014; 24(2). DOI:10.1016/j.breast.2014.10.003 · 2.38 Impact Factor
  • Zhouwei Zhang · Zhihua Peng · Daniel Olsen · James deKay · Donald L. Weaver · Mark F. Evans ·

    Cancer Research 10/2014; 74(19 Supplement):1498-1498. DOI:10.1158/1538-7445.AM2014-1498 · 9.33 Impact Factor
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    ABSTRACT: Breast cancer screening holds a prominent place in public health, health care delivery, policy, and women's health care decisions. Several factors are driving shifts in how population-based breast cancer screening is approached, including advanced imaging technologies, health system performance measures, health care reform, concern for “overdiagnosis,” and improved understanding of risk. Maximizing benefits while minimizing the harms of screening requires moving from a “1-size-fits-all” guideline paradigm to more personalized strategies. A refined conceptual model for breast cancer screening is needed to align women's risks and preferences with screening regimens. A conceptual model of personalized breast cancer screening is presented herein that emphasizes key domains and transitions throughout the screening process, as well as multilevel perspectives. The key domains of screening awareness, detection, diagnosis, and treatment and survivorship are conceptualized to function at the level of the patient, provider, facility, health care system, and population/policy arena. Personalized breast cancer screening can be assessed across these domains with both process and outcome measures. Identifying, evaluating, and monitoring process measures in screening is a focus of a National Cancer Institute initiative entitled PROSPR (Population-based Research Optimizing Screening through Personalized Regimens), which will provide generalizable evidence for a risk-based model of breast cancer screening, The model presented builds on prior breast cancer screening models and may serve to identify new measures to optimize benefits-to-harms tradeoffs in population-based screening, which is a timely goal in the era of health care reform. Cancer 2014. © 2014 American Cancer Society.
    Cancer 10/2014; 120(19). DOI:10.1002/cncr.28771 · 4.89 Impact Factor
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    Journal of Clinical Oncology 09/2014; 32(34). DOI:10.1200/JCO.2014.57.7361 · 18.43 Impact Factor
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    ABSTRACT: Background: Mammographic density (MD), the area of non-fatty appearing tissue divided by total breast area, is a strong breast cancer risk factor. Most MD analyses have employed visual categorizations or computer-assisted quantification, which ignore breast thickness. We explored MD volume and area, using a volumetric approach previously validated as predictive of breast cancer risk, in relation to risk factors among women undergoing breast biopsy. Methods: Among 413 primarily white women, ages 40-65, undergoing diagnostic breast biopsies between 2007-2010 at an academic facility in Vermont, MD volume (cm3) was quantified in cranio-caudal views of the breast contralateral to the biopsy target using a density phantom, while MD area (cm2) was measured on the same digital mammograms using thresholding software. Risk factor associations with continuous MD measurements were evaluated using linear regression. Results: Percent MD volume and area were correlated (r=0.81) and strongly and inversely associated with age, body mass index (BMI), and menopause. Both measures were inversely associated with smoking and positively associated with breast biopsy history. Absolute MD measures were correlated (r=0.46) and inversely related to age and menopause. Whereas absolute dense area was inversely associated with BMI, absolute dense volume was positively associated. Conclusions: Volume and area MD measures exhibit some overlap in risk factor associations, but divergence as well, particularly for BMI. Impact: Findings suggest that volume and area density measures differ in subsets of women; notably, among obese women, absolute density was higher with volumetric methods, suggesting that breast cancer risk assessments may vary for these techniques.
    Cancer Epidemiology Biomarkers & Prevention 08/2014; 23(11). DOI:10.1158/1055-9965.EPI-14-0257 · 4.13 Impact Factor
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    ABSTRACT: A pilot study examined the extent to which eye movements occurring during interpretation of digitized breast biopsy whole slide images (WSI) can distinguish novice interpreters from experts, informing assessments of competency progression during training and across the physician-learning continuum. A pathologist with fellowship training in breast pathology interpreted digital WSI of breast tissue and marked the region of highest diagnostic relevance (dROI). These same images were then evaluated using computer vision techniques to identify visually salient regions of interest (vROI) without diagnostic relevance. A non-invasive eye tracking system recorded pathologists' (N = 7) visual behavior during image interpretation, and we measured differential viewing of vROIs versus dROIs according to their level of expertise. Pathologists with relatively low expertise in interpreting breast pathology were more likely to fixate on, and subsequently return to, diagnostically irrelevant vROIs relative to experts. Repeatedly fixating on the distracting vROI showed limited value in predicting diagnostic failure. These preliminary results suggest that eye movements occurring during digital slide interpretation can characterize expertise development by demonstrating differential attraction to diagnostically relevant versus visually distracting image regions. These results carry both theoretical implications and potential for monitoring and evaluating student progress and providing automated feedback and scanning guidance in educational settings.
    PLoS ONE 08/2014; 9(8):e103447. DOI:10.1371/journal.pone.0103447 · 3.23 Impact Factor
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    ABSTRACT: Background: Screening mammography utilization in Vermont has declined since 2009 during a time of changing screening guidelines and increased interest in personalized screening regimens. This study evaluates whether the breast cancer risk distribution of the state's screened population changed during the observed decline. Methods: We examined the breast cancer risk distribution among screened women between 2001 and 2012 using data from the Vermont Breast Cancer Surveillance System. We estimated each screened woman's 5-year risk of breast cancer using the Breast Cancer Surveillance Consortium risk calculator. Annual screening counts by risk group were normalized and age-adjusted to the Vermont female population by direct standardization. Results: The normalized rate of low-risk (5-year breast cancer risk of <1%) women screened increased 8.3% per year (95% confidence interval [CI] = 4.8 to 11.9) between 2003 and 2008 and then declined by -5.4% per year (95% CI = -8.1 to -2.6) until 2012. When stratified by age group, the rate of low-risk women screened declined -4.4% per year (95% CI = -8.8 to 0.1; not statistically significant) for ages 40 to 49 years and declined a statistically significant -7.1% per year (95% CI = -12.1 to -2.0) for ages 50 to 74 years during 2008 to 2012. These declines represented the bulk of overall decreases in screening after 2008, with rates for women categorized in higher risk levels generally exhibiting small annual changes. Conclusions: The observed decline in women screened in Vermont in recent years is largely attributable to reductions in screening visits by women who are at low risk of developing breast cancer.
    JNCI Journal of the National Cancer Institute 08/2014; 106(8). DOI:10.1093/jnci/dju157 · 12.58 Impact Factor
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    ABSTRACT: Aims To assess the laboratory policies, pathologists’ clinical practice and perceptions about the value of second opinions for breast pathology cases among pathologists practising in the USA. Methods Cross-sectional data were collected from 252 pathologists who interpret breast specimens in eight states using a web-based survey. Descriptive statistics were used to characterise findings. Results Most participants had >10 years of experience interpreting breast specimens (64%), were not affiliated with academic centres (73%) and were not considered experts by their peers (79%). Laboratory policies mandating second opinions varied by diagnosis: invasive cancer 65%; ductal carcinoma in situ (DCIS) 56%; atypical ductal hyperplasia 36% and other benign cases 33%. 81% obtained second opinions in the absence of policies. Participants believed they improve diagnostic accuracy (96%) and protect from malpractice suits (83%), and were easy to obtain, did not take too much time and did not make them look less adequate. The most common (60%) approach to resolving differences between the first and second opinion is to ask for a third opinion, followed by reaching a consensus. Conclusions Laboratory-based second opinion policies vary for breast pathology but are most common for invasive cancer and DCIS cases. Pathologists have favourable attitudes towards second opinions, adhere to policies and obtain them even when policies are absent. Those without a formal policy may benefit from supportive clinical practices and systems that help obtain second opinions.
    Journal of Clinical Pathology 07/2014; 67(11). DOI:10.1136/jclinpath-2014-202290 · 2.92 Impact Factor
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    ABSTRACT: Context.-Little is known about the frequency of discordant diagnoses identified during research. Objective.-To describe diagnostic discordance identified during research and apply a newly designed research framework for investigating discordance. Design.-Breast biopsy cases (N = 407) from registries in Vermont and New Hampshire were independently reviewed by a breast pathology expert. The following research framework was developed to assess those cases: (1) compare the expert review and study database diagnoses, (2) determine the clinical significance of diagnostic discordance, (3) identify and correct data errors and verify the existence of true diagnostic discrepancies, (4) consider the impact of borderline cases, and (5) determine the notification approach for verified disagreements. Results.-Initial overall discordance between the original diagnosis recorded in our research database and a breast pathology expert was 32.2% (131 of 407). This was reduced to less than 10% after following the 5-step research framework. Detailed review identified 12 cases (2.9%) with data errors (2 in the underlying pathology registry, 3 with incomplete slides sent for expert review, and 7 with data abstraction errors). After excluding the cases with data errors, 38 cases (9.6%) among the remaining 395 had clinically meaningful discordant diagnoses (κ = 0.82; SE, 0.04; 95% confidence interval, 0.76-0.87). Among these 38 cases, 20 (53%) were considered borderline between 2 diagnoses by either the original pathologist or the expert. We elected to notify the pathology registries and facilities regarding discordant diagnoses. Conclusions.-Understanding the types and sources of diagnostic discordance uncovered in research studies may lead to improved scientific data and better patient care.
    Archives of pathology & laboratory medicine 07/2014; 138(7):955-961. DOI:10.5858/arpa.2013-0263-OA · 2.84 Impact Factor

Publication Stats

10k Citations
921.11 Total Impact Points


  • 1995-2015
    • University of Vermont Medical Center
      Burlington, Vermont, United States
  • 1993-2015
    • University of Vermont
      • • Department of Pathology
      • • College of Medicine
      • • Department of Surgery
      Burlington, Vermont, United States
  • 2002-2013
    • University of California, San Francisco
      • • Division of General Internal Medicine
      • • Division of Hospital Medicine
      San Francisco, California, United States
  • 2012
    • Tufts University
      • Department of Psychology
      Бостон, Georgia, United States
  • 2009
    • Brigham and Women's Hospital
      • Department of Pathology
      Boston, MA, United States
  • 1998-2009
    • Fletcher Allen Health Care
      Burlington, Vermont, United States