Michael Harbut

Karmanos Cancer Institute, Detroit, Michigan, United States

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Publications (13)163.14 Total impact

  • Cancer Research 10/2014; 74(19 Supplement):1921-1921. DOI:10.1158/1538-7445.AM2014-1921 · 9.28 Impact Factor
  • Michael Harbut
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    ABSTRACT: Occupational and environmental medicine education is offered minimally, if at all, in the curriculum of U.S. medical schools & residency training programs. In 2012, there are only 28 occupational medicine residency/fellowship programs in North America. With the growing scientific cognizance that environmental insult plays an important role in human disease, it is imperative that more physicians be trained either in continuing medical education programs or other alternative routes. We describe a novel approach to physician training which has had impressive positive results. In cooperation with the ATSDR, Blue Cross Blue Shield of Michigan (BCBSM), and St John Providence Healthcare system, the Karmanos Cancer Institute has established a mechanism which allows for online CME credits and financial incentives for physician participation. Working with BCBSM we identified 3 leading causes of lung cancer in Michigan--asbestos, radon and arsenic---and after agreeing on the use of the ATSDR Case Studies in Environmental Medicine as the appropriate educational vehicle, we offered these CME credit-carrying on-line modules at no charge. Upon completion of required course work, an honorarium was paid to participating physicians. Over the past 2.5 years, more than 500 Michigan primary care physicians (including pediatricians) successfully completed the Environmental Cancer Program. Based on participant feedback, we expanded the program in 2012 to include educational modules specific for neurologists, obstetrician-gynecologists, and additional modules for pediatricians.
    140st APHA Annual Meeting and Exposition 2012; 10/2012
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    ABSTRACT: New biomarkers are needed to detect pleural mesothelioma at an earlier stage and to individualize treatment strategies. We investigated whether fibulin-3 in plasma and pleural effusions could meet sensitivity and specificity criteria for a robust biomarker. We measured fibulin-3 levels in plasma (from 92 patients with mesothelioma, 136 asbestos-exposed persons without cancer, 93 patients with effusions not due to mesothelioma, and 43 healthy controls), effusions (from 74 patients with mesothelioma, 39 with benign effusions, and 54 with malignant effusions not due to mesothelioma), or both. A blinded validation was subsequently performed. Tumor tissue was examined for fibulin-3 by immunohistochemical analysis, and levels of fibulin-3 in plasma and effusions were measured with an enzyme-linked immunosorbent assay. Plasma fibulin-3 levels did not vary according to age, sex, duration of asbestos exposure, or degree of radiographic changes and were significantly higher in patients with pleural mesothelioma (105±7 ng per milliliter in the Detroit cohort and 113±8 ng per milliliter in the New York cohort) than in asbestos-exposed persons without mesothelioma (14±1 ng per milliliter and 24±1 ng per milliliter, respectively; P<0.001). Effusion fibulin-3 levels were significantly higher in patients with pleural mesothelioma (694±37 ng per milliliter in the Detroit cohort and 636±92 ng per milliliter in the New York cohort) than in patients with effusions not due to mesothelioma (212±25 and 151±23 ng per milliliter, respectively; P<0.001). Fibulin-3 preferentially stained tumor cells in 26 of 26 samples. In an overall comparison of patients with and those without mesothelioma, the receiver-operating-characteristic curve for plasma fibulin-3 levels had a sensitivity of 96.7% and a specificity of 95.5% at a cutoff value of 52.8 ng of fibulin-3 per milliliter. In a comparison of patients with early-stage mesothelioma with asbestos-exposed persons, the sensitivity was 100% and the specificity was 94.1% at a cutoff value of 46.0 ng of fibulin-3 per milliliter. Blinded validation revealed an area under the curve of 0.87 for plasma specimens from 96 asbestos-exposed persons as compared with 48 patients with mesothelioma. Plasma fibulin-3 levels can distinguish healthy persons with exposure to asbestos from patients with mesothelioma. In conjunction with effusion fibulin-3 levels, plasma fibulin-3 levels can further differentiate mesothelioma effusions from other malignant and benign effusions. (Funded by the Early Detection Research Network, National Institutes of Health, and others.).
    New England Journal of Medicine 10/2012; 367(15):1417-27. DOI:10.1056/NEJMoa1115050 · 54.42 Impact Factor
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    ABSTRACT: Malignant pleural mesothelioma (MM) is an aggressive, asbestos-related pulmonary cancer that is increasing in incidence. Because diagnosis is difficult and the disease is relatively rare, most patients present at a clinically advanced stage where possibility of cure is minimal. To improve surveillance and detection of MM in the high-risk population, we completed a series of clinical studies to develop a noninvasive test for early detection. We conducted multi-center case-control studies in serum from 117 MM cases and 142 asbestos-exposed control individuals. Biomarker discovery, verification, and validation were performed using SOMAmer proteomic technology, which simultaneously measures over 1000 proteins in unfractionated biologic samples. Using univariate and multivariate approaches we discovered 64 candidate protein biomarkers and derived a 13-marker random forest classifier with an AUC of 0.99±0.01 in training, 0.98±0.04 in independent blinded verification and 0.95±0.04 in blinded validation studies. Sensitivity and specificity at our pre-specified decision threshold were 97%/92% in training and 90%/95% in blinded verification. This classifier accuracy was maintained in a second blinded validation set with a sensitivity/specificity of 90%/89% and combined accuracy of 92%. Sensitivity correlated with pathologic stage; 77% of Stage I, 93% of Stage II, 96% of Stage III and 96% of Stage IV cases were detected. An alternative decision threshold in the validation study yielding 98% specificity would still detect 60% of MM cases. In a paired sample set the classifier AUC of 0.99 and 91%/94% sensitivity/specificity was superior to that of mesothelin with an AUC of 0.82 and 66%/88% sensitivity/specificity. The candidate biomarker panel consists of both inflammatory and proliferative proteins, processes strongly associated with asbestos-induced malignancy. The SOMAmer biomarker panel discovered and validated in these studies provides a solid foundation for surveillance and diagnosis of MM in those at highest risk for this disease.
    PLoS ONE 10/2012; 7(10):e46091. DOI:10.1371/journal.pone.0046091 · 3.53 Impact Factor
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    ABSTRACT: Bisbenzimides, or Hoechst 33258 (H258), and its derivative Hoechst 33342 (H342) are archetypal molecules for designing minor groove binders, and widely used as tools for staining DNA and analyzing side population cells. They are supravital DNA minor groove binders with AT selectivity. H342 and H258 share similar biological effects based on the similarity of their chemical structures, but also have their unique biological effects. For example, H342, but not H258, is a potent apoptotic inducer and both H342 and H258 can induce transgene overexpression in in vitro studies. However, the molecular mechanisms by which Hoechst dyes induce apoptosis and enhance transgene overexpression are unclear. To determine the molecular mechanisms underlying different biological effects between H342 and H258, microarray technique coupled with bioinformatics analyses and multiple other techniques has been utilized to detect differential global gene expression profiles, Hoechst dye-specific gene expression signatures, and changes in cell morphology and levels of apoptosis-associated proteins in malignant mesothelioma cells. H342-induced apoptosis occurs in a dose-dependent fashion and is associated with morphological changes, caspase-3 activation, cytochrome c mitochondrial translocation, and cleavage of apoptosis-associated proteins. The antagonistic effect of H258 on H342-induced apoptosis indicates a pharmacokinetic basis for the two dyes' different biological effects. Differential global gene expression profiles induced by H258 and H342 are accompanied by unique gene expression signatures determined by DNA microarray and bioinformatics software, indicating a genetic basis for their different biological effects. A unique gene expression signature associated with H342-induced apoptosis provides a new avenue to predict and classify the therapeutic class of minor groove binders in the drug development process. Further analysis of H258-upregulated genes of transcription regulation may identify the genes that enhance transgene overexpression in gene therapy and promote recombinant protein products in biopharmaceutical companies. DATA DEPOSITION: The microarray data reported in this article have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no.GSE28616).
    PLoS ONE 10/2011; 6(10):e25822. DOI:10.1371/journal.pone.0025822 · 3.53 Impact Factor
  • Cancer Research 07/2011; 71(8 Supplement):2812-2812. DOI:10.1158/1538-7445.AM2011-2812 · 9.28 Impact Factor
  • Clinical Cancer Research 10/2010; 16(19 Supplement):A3-A3. DOI:10.1158/DIAG-10-A3 · 8.19 Impact Factor
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    ABSTRACT: Taconite, although not classified by the United States Government as asbestos or asbestiform material, has been associated with asbestos-related diseases. The mineral is used in the production of steel and as a road-patch material and is mined in Michigan and Minnesota. This report describes the case of a middle-aged Caucasian woman with exposure to taconite mining dust from her miner father's clothing in childhood with a resultant presentation consistent with asbestosis and intractable pleural pain. Intractable pleural pain has been described in asbestos-exposed patients with theorized etiologies. However, no in vivo reported mechanism has demonstrated a plausible, anatomically apparent mechanism for the pain. We utilize an application of the Vitrea software for enhancement of high-resolution computerized tomography which demonstrates at least one likely mechanism for intractable pleural pain.
    International journal of occupational and environmental health 07/2009; 15(3):269-73. DOI:10.1179/107735209799239124 · 1.10 Impact Factor
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    ABSTRACT: Soluble mesothelin-related peptide (SMRP) is a potential marker for malignant pleural mesothelioma (MPM), which may be useful for screening high-risk asbestos-exposed individuals. We evaluated SMRP in serum from MPM patients (n = 90), lung cancer patients (n = 170), age and tobacco-matched asbestos-exposed individuals (n = 66), and in MPM pleural effusions (n = 45), benign effusions (n = 30), and non-MPM effusions (n = 20) using the MesoMark enzyme-linked immunosorbent assay kit (Fujirebio Diagnostics, Malvern, PA). Receiver operating characteristic (ROC) curves were used to define true and false positive rates at various cutoffs. Mean serum SMRP levels were higher in MPM compared with lung cancer (5.67 +/- 0.82 nM [mean +/- standard error of the mean vs 1.99 +/- 0.43 nM, p < 0.001), and stage I MPM SMRP levels (n = 12; 2.09 +/- 0.41 nM) were significantly higher than those in asbestos-exposed individuals (0.99 +/- 0.09 nM, p = 0.02, respectively). Stage 2 to 4 SMRP serum levels were significantly higher than those for stage 1 MPM. The area under the ROC curve for serum SMRP was 0.81 for differentiating MPM and asbestos-exposed individuals; cutoff = 1.9 nM (sensitivity = 60%, specificity = 89%). The MPM pleural effusion SMRP was significantly higher than benign or other non-MPM pleural effusions (65.57 +/- 11.33 nM vs 27.46 +/- 11.25 nM [p = 0.003] and 18.99 +/- 7.48 nM [p = 0.044], respectively). These data support SMRP as a promising marker for MPM in both serum and pleural effusion fluid, and justify prospective screening studies of SMRP in combination with other markers for screening of asbestos-exposed cohorts.
    The Annals of thoracic surgery 02/2008; 85(1):265-72; discussion 272. DOI:10.1016/j.athoracsur.2007.07.042 · 3.65 Impact Factor
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    ABSTRACT: In September 2004 the American Thoracic Society released a revised set of guidelines for the clinical diagnosis of nonmalignant asbestos-related disease (Am J Resp Crit Care Med. 2004;170:691-715). The conditions of concern are asbestosis, pleural disorders, and chronic airways obstruction. The criteria are evidence of structural lesion consistent with asbestos-related disease, evidence of causation by asbestos, and exclusion of alternative diagnoses. Findings that satisfy each are described. These guidelines are an extension of the 1986 ATS criteria and expand on them by establishing three explicit criteria, accommodating newer diagnostic modalities, recommending evaluation of impairment appropriate to the diagnosis, and outlining initial management measures following diagnosis. A history of significant asbestos exposure obligates the responsible physician to provide a management plan for the patient that takes into consideration current disease, impairment, and future risk. Persons identified as having asbestos-related disease or having significant exposure histories may benefit from management directed at preserving lung function, preventing complications, reducing the risk of lung cancer, and screening for potentially treatable asbestos-related disease including malignancies. Various issues arising since the publication of the guidelines are addressed, including evidence for pleural plaques being a marker of risk for lung disease apart from history of asbestos exposure; evidence against smoking being associated with a greater frequency of pleural plaques; an association between asbestos exposure and colon cancer; the diagnostic sensitivity of the chest film in smokers; and affirming the adequacy of findings on plain chest films as sufficient for the diagnosis of nonmalignant asbestos-related disease but not always sufficient to rule it out.
    Clinical Pulmonary Medicine 02/2007; 14(2):82-92. DOI:10.1097/01.cpm.0000258388.64855.43
  • Lung Cancer 10/2006; 54. DOI:10.1016/S0169-5002(07)70084-3 · 3.74 Impact Factor
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    ABSTRACT: We investigated the presence of osteopontin in pleural mesothelioma and determined serum osteopontin levels in three populations: subjects without cancer who were exposed to asbestos, subjects without cancer who were not exposed to asbestos, and patients with pleural mesothelioma who were exposed to asbestos. A group of 69 subjects with asbestos-related nonmalignant pulmonary disease were compared with 45 subjects without exposure to asbestos and 76 patients with surgically staged pleural mesothelioma. Tumor tissue was examined for osteopontin by immunohistochemical analysis, and serum osteopontin levels were measured by an enzyme-linked immunosorbent assay. There were no significant differences in mean (+/-SE) serum osteopontin levels between age-matched subjects with exposure to asbestos and subjects without exposure to asbestos (30+/-3 ng per milliliter and 20+/-4 ng per milliliter, respectively; P=0.06). In the group with exposure to asbestos, elevated serum osteopontin levels were associated with pulmonary plaques and fibrosis (56+/-13 ng per milliliter) but not with normal radiographic findings (21+/-5 ng per milliliter), plaques alone (23+/-3 ng per milliliter), or fibrosis alone (32+/-7 ng per milliliter) (P=0.004). Serum osteopontin levels were significantly higher in the group with pleural mesothelioma than in the group with exposure to asbestos (133+/-10 ng per milliliter vs. 30+/-3 ng per milliliter, P<0.001). Immunohistochemical analysis revealed osteopontin staining of the tumor cells in 36 of 38 samples of pleural mesothelioma. An analysis of serum osteopontin levels comparing the receiver-operating-characteristic curve in the group exposed to asbestos with that of the group with mesothelioma had a sensitivity of 77.6 percent and a specificity of 85.5 percent at a cutoff value of 48.3 ng of osteopontin per milliliter. Subgroup analysis comparing patients with stage I mesothelioma with subjects with exposure to asbestos revealed a sensitivity of 84.6 percent and a specificity of 88.4 percent at a cutoff value of 62.4 ng of osteopontin per milliliter. Serum osteopontin levels can be used to distinguish persons with exposure to asbestos who do not have cancer from those with exposure to asbestos who have pleural mesothelioma.
    New England Journal of Medicine 10/2005; 353(15):1564-73. DOI:10.1056/NEJMoa051185 · 54.42 Impact Factor
  • American Journal of Respiratory and Critical Care Medicine 03/2005; 171(5):528-530. DOI:10.1164/ajrccm.171.5.952 · 11.99 Impact Factor

Publication Stats

380 Citations
163.14 Total Impact Points

Institutions

  • 2008–2012
    • Karmanos Cancer Institute
      • Division of Hematology and Oncology
      Detroit, Michigan, United States
  • 2011
    • Wayne State University
      • Department of Internal Medicine
      Detroit, Michigan, United States