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Patel R.,Laboratory Medicine and Pathology | Baddour L.M.,Mayo Medical School
Annals of Surgery | Year: 2013

OBJECTIVE:: To determine whether bacterial colonization of drains can be reduced by local antiseptic interventions. BACKGROUND:: Drains are a potential source of bacterial entry into surgical wounds and may contribute to surgical site infection after breast surgery. METHODS:: After institutional review board approval, patients undergoing total mastectomy and/or axillary lymph node dissection were randomized to standard drain care (control) or drain antisepsis (treated). Standard drain care comprised twice daily cleansing with alcohol swabs. Antisepsis drain care included (1) a chlorhexidine disc at the drain exit site and (2) irrigation of the drain bulb twice daily with dilute sodium hypochlorite (DakinÊs) solution. Culture results of drain fluid and tubing were compared between control and antisepsis groups. RESULTS:: Overall, 100 patients with 125 drains completed the study with 48 patients (58 drains) in the control group and 52 patients (67 drains) in the antisepsis group. Cultures of drain bulb fluid at 1 week were positive (1+ or greater growth) in 66% (38/58) of control drains compared with 21% (14/67) of antisepsis drains (P = 0.0001). Drain tubing cultures demonstrated more than 50 colony-forming units in 19% (8/43) of control drains versus 0% (0/53) of treated drains (P = 0.004). Surgical site infection was diagnosed in 6 patients (6%) - 5 patients in the control group and 1 patient in the antisepsis group (P = 0.06). CONCLUSIONS:: Simple and inexpensive local antiseptic interventions with a chlorhexidine disc and hypochlorite solution reduce bacterial colonization of drains. Based on these data, further study of drain antisepsis and its potential impact on surgical site infection rate is warranted (ClinicalTrials.gov Identifier: NCT01286168). Copyright © 2013 Lippincott Williams & Wilkins.


Borges S.,Mayo Clinic Comprehensive Cancer Center | Doppler H.,Mayo Clinic Comprehensive Cancer Center | Sun Z.,Mayo Medical School | Anastasiadis P.Z.,Mayo Clinic Comprehensive Cancer Center | And 3 more authors.
Breast Cancer Research | Year: 2013

Introduction: DNA methylation-induced silencing of genes encoding tumor suppressors is common in many types of cancer, but little is known about how such epigenetic silencing can contribute to tumor metastasis. The PRKD1 gene encodes protein kinase D1 (PKD1), a serine/threonine kinase that is expressed in cells of the normal mammary gland, where it maintains the epithelial phenotype by preventing epithelial-to-mesenchymal transition.Methods: The status of PRKD1 promoter methylation was analyzed by reduced representation bisulfite deep sequencing, methylation-specific PCR (MSP-PCR) and in situ MSP-PCR in invasive and noninvasive breast cancer lines, as well as in humans in 34 cases of " normal" tissue, 22 cases of ductal carcinoma in situ, 22 cases of estrogen receptor positive, HER2-negative (ER+/HER2-) invasive lobular carcinoma, 43 cases of ER+/HER2- invasive ductal carcinoma (IDC), 93 cases of HER2+ IDC and 96 cases of triple-negative IDC. A reexpression strategy using the DNA methyltransferase inhibitor decitabine was used in vitro in MDA-MB-231 cells as well as in vivo in a tumor xenograft model and measured by RT-PCR, immunoblotting and immunohistochemistry. The effect of PKD1 reexpression on cell invasion was analyzed in vitro by transwell invasion assay. Tumor growth and metastasis were monitored in vivo using the IVIS Spectrum Pre-clinical In Vivo Imaging System.Results: Herein we show that the gene promoter of PRKD1 is aberrantly methylated and silenced in its expression in invasive breast cancer cells and during breast tumor progression, increasing with the aggressiveness of tumors. Using an animal model, we show that reversion of PRKD1 promoter methylation with the DNA methyltransferase inhibitor decitabine restores PKD1 expression and blocks tumor spread and metastasis to the lung in a PKD1-dependent fashion.Conclusions: Our data suggest that the status of epigenetic regulation of the PRKD1 promoter can provide valid information on the invasiveness of breast tumors and therefore could serve as an early diagnostic marker. Moreover, targeted upregulation of PKD1 expression may be used as a therapeutic approach to reverse the invasive phenotype of breast cancer cells. © 2013 Borges et al.; licensee BioMed Central Ltd.


News Article | December 5, 2016
Site: www.eurekalert.org

SAN ANTONIO -- The American Association for Cancer Research (AACR) will honor two renowned researchers for their work in breast cancer at the 2016 San Antonio Breast Cancer Symposium, held Dec. 6-10. Fergus J. Couch, PhD, of the Mayo Clinic in Rochester, Minnesota, will receive the ninth annual AACR Outstanding Investigator Award for Breast Cancer Research, funded by Susan G. Komen, and Max S. Wicha, MD, of the University of Michigan Comprehensive Cancer Center in Ann Arbor, will receive the ninth annual AACR Distinguished Lectureship in Breast Cancer Research. The AACR Outstanding Investigator Award for Breast Cancer Research recognizes an investigator of no more than 50 years of age whose novel and significant work has had or may have a far-reaching impact on the etiology, detection, diagnosis, treatment, or prevention of breast cancer. Such work may involve any discipline across the continuum of biomedical research, including basic, translational, clinical, and epidemiological studies. Couch, who is the Zbigniew and Anna M. Scheller professor of medical research, and chair of the Division of Experimental Pathology and Laboratory Medicine in the Department of Laboratory Medicine and Pathology at the Mayo Clinic, is being honored for his seminal work in identifying the inherited genes and mutations that predispose to breast cancer. Much of his research has focused on determining the clinical relevance of inherited variants of uncertain significance (VUS) in breast cancer predisposition genes using genetic epidemiology and molecular biology approaches. Couch will present his Outstanding Investigator Award for Breast Cancer Research lecture, "Decoding Breast Cancer Predisposition Genes," Friday, Dec. 9, at 11:30 a.m. CT, in Hall 3 of the Henry B. Gonzalez Convention Center. A distinguished national leader in cancer genetics, Couch is a founder and member of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium, and a leader in the BRCA Challenge and the Prospective Registry of Multiplex Testing (PROMPT) initiatives aimed at understanding alterations in cancer predisposition genes. He is also a co-founder of the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a Triple Negative Breast Cancer Consortium (TNBCC), and is a long-term member of the Breast Cancer Association Consortium. Working with members of these consortia, Couch has led genome-wide association studies to identify common genetic variants that influence risk of estrogen receptor (ER) negative and triple negative breast cancer and modify risks of breast cancer among carriers of germline BRCA1 and BRCA2 mutations. In more recent research, Couch has been working to estimate risks of breast cancer associated with pathogenic variants identified by clinical genetic testing using multigene panels, and is leading an effort to identify genetic factors that account for the missing heritability of breast cancer. The AACR Distinguished Lectureship in Breast Cancer Research was established to recognize outstanding science that has inspired or has the potential to inspire new perspectives on the etiology, diagnosis, treatment, or prevention of breast cancer. Wicha, director emeritus of the University of Michigan Comprehensive Cancer Center, is being recognized for his leadership in breast cancer research and as a pioneer in the field of cancer stem cells (CSCs). Wicha is among the most highly cited investigators in the field. His group was part of the team that first identified CSCs in human breast cancers, the first in any solid tumor. His laboratory has developed many of the techniques and assays used to study these cells and to elucidate the pathways which regulate their behavior. These pathways have provided targets for the development of drugs aimed at targeting CSCs. He will present his Distinguished Lectureship in Breast Cancer Research award lecture, "Targeting Breast Cancer Stem Cells: Challenges and Opportunities," Thursday, Dec. 8, at 11:30 a.m. CT, in Hall 3 of the Henry B. Gonzalez Convention Center. Wicha is co-founder of OncoMed Pharmaceuticals, a company focused on developing CSC therapeutics, which has produced five agents currently in clinical testing. After training at the National Cancer Institute in clinical oncology and cancer biology, Wicha joined the faculty of the University of Michigan in 1980, where he served as chief in the Division of Hematology/Oncology in the Department of Internal Medicine. He served as director of the University of Michigan Comprehensive Cancer Center since its inception in 1986 until 2015, when he became director emeritus. He remains an active clinician, specializing in the treatment of patients with breast cancer. The mission of the 2016 San Antonio Breast Cancer Symposium is to produce a unique and comprehensive scientific meeting that encompasses the full spectrum of breast cancer research, facilitating the rapid translation of new knowledge into better care for patients with breast cancer. The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio, the American Association for Cancer Research (AACR), and Baylor College of Medicine are joint sponsors of the San Antonio Breast Cancer Symposium. This collaboration utilizes the clinical strengths of the CTRC and Baylor and the AACR's scientific prestige in basic, translational, and clinical cancer research to expedite the delivery of the latest scientific advances to the clinic. For more information about the symposium, please visit http://www. .


Diamond E.L.,Sloan Kettering Cancer Center | Dagna L.,San Raffaele Scientific Institute | Hyman D.M.,Sloan Kettering Cancer Center | Cavalli G.,San Raffaele Scientific Institute | And 13 more authors.
Blood | Year: 2014

Erdheim-Chester disease (ECD) is a rare, non-Langerhans histiocytosis. Recent findings suggest that ECD is a clonal disorder, marked by recurrent BRAFV600E mutations in >50% of patients, in which chronic uncontrolled inflammation is an important mediator of disease pathogenesis. Although ~500 to 550 cases have been describedin the literature todate, increased physician awareness has driven a dramatic increase in ECD diagnoses over the last decade. ECD frequently involves multiple organ systems and has historically lacked effective therapies. Given the protean clinical manifestations and the lack of a consensus-derived approach for the management of ECD, we provide here the first multidisciplinary consensus guidelines for the clinical management of ECD. These recommendationswere outlined at the First International Medical Symposium for ECD, comprised of a comprehensive group of international academicians with expertise in the pathophysiology and therapy of ECD. Detailed recommendations on the initial clinical, laboratory, and radiographic assessment of ECD patients are presented in addition to treatment recommendations based on critical appraisal of the literature and clinical experience. These formalized consensus descriptions will hopefully facilitate ongoing and future research efforts in this disorder. © 2014 by The American Society of Hematology.


ROCHESTER, Minn. -- Research from Mayo Clinic included in the November issue of JAMA Neurology identifies a new biomarker for brain and spinal cord inflammation, allowing for faster diagnosis and treatment of patients. Vanda Lennon, M.D., Ph.D., and colleagues identified the new biomarker in spinal fluid and blood serum of patients with a neurological disorder called autoimmune meningoencephalomyelitis. The biomarker is an antibody. Antibodies are molecules used by the immune system to fight infections or cancer. When an antibody is directed against healthy tissue by a misguided immune system, as it is in this disorder, it is called an autoantibody. In autoimmune meningoencephalomyelitis, the autoantibody targets a protein called glial fibrillary acidic protein within cells called astrocytes that are found in the brain and spinal cord. "Headache is a prominent symptom reported by the patients," says Dr. Lennon, who is senior author on the study. "It is accompanied by neurological findings of varying severity. Inflammatory cells in the spinal fluid and MRI images raise suspicion for brain infection, other inflammatory brain disease or a cancer spreading to the lining of the brain." Dr. Lennon notes that this disease rapidly reverses with therapy directed at the immune system, such as prednisone, in contrast to infections that need antibiotics and cancer that requires aggressive treatment. A positive test for glial fibrillary acidic protein autoantibody should bring the correct diagnosis earlier and hasten the most appropriate treatment. The glial fibrillary acidic protein antibody biomarker initially was identified in Mayo Clinic's Neuroimmunology Laboratory, which is within the Department of Laboratory Medicine and Pathology. The biomarker was identified using a test developed in the 1960s. The process involves applying a patient's serum or spinal fluid to thin sections of mouse tissues. If an autoantibody is present, it will stick to the targeted tissue. After the serum or spinal fluid is washed off, a probe in the form of another antibody is applied to the tissue to detect any human antibody that remains bound to the tissue. The probe antibody is tagged with a fluorescent dye. When viewed under a fluorescence microscope, the tagged antibody shows the location of the bound human autoantibody, revealing the cells targeted by the immune system. In this case, the pattern of binding to mouse brain tissue resembles the pattern of abnormalities seen in MRI images of the patients' brain and spinal cord. "That method has been a tremendous tool of discovery as well as a diagnostic tool for the last 35 years since I set up this lab," says Dr. Lennon. "It had fallen out of fashion about 20 years ago when we were encouraged to use modern molecular techniques. Well, we certainly do use molecular techniques, which are important validation steps, but we did not give up on the valuable older technology as a component of our 21st-century screening protocol to detect informative autoantibodies. In the process, we have continued to discover new autoantibodies of clinical importance." With the discovery of this biomarker, Dr. Lennon and the team expect that diagnosis and treatment for patients will improve in another important way. "At this stage, we've identified about 103 patients," says Dr. Lennon. "And about a third of them are turning out to have an unsuspected cancer in a remote part of the body." The research team suspects that, because cancer cells and the nervous system use some of the same mechanisms for communication, the immune response that is attacking a cancer is causing collateral damage to the nervous system in the process. "It appears from evidence to date that the antibody does not itself cause the brain inflammation," says Dr. Lennon. "It is a proxy marker of a more aggressive component of the immune system called killer T cells, which target the same brain protein." The next steps are to verify the glial fibrillary acidic protein autoantibody's diagnostic performance. At that point, Mayo Clinic's Neuroimmunology Laboratory anticipates offering this test for diagnostic purposes. This study was funded by the Mayo Clinic Foundation. Dr. Fang, a visiting associate professor of neurology, was supported by the China Scholarship Council Exchange. The authors and Mayo Clinic in general disclose conflicts of interest related to this research in the published paper. Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit mayoclinic.org/about-mayo-clinic or newsnetwork.mayoclinic.org.


News Article | November 14, 2016
Site: www.sciencedaily.com

Research from Mayo Clinic included in the November issue of JAMA Neurology identifies a new biomarker for brain and spinal cord inflammation, allowing for faster diagnosis and treatment of patients. Vanda Lennon, M.D., Ph.D., and colleagues identified the new biomarker in spinal fluid and blood serum of patients with a neurological disorder called autoimmune meningoencephalomyelitis. The biomarker is an antibody. Antibodies are molecules used by the immune system to fight infections or cancer. When an antibody is directed against healthy tissue by a misguided immune system, as it is in this disorder, it is called an autoantibody. In autoimmune meningoencephalomyelitis, the autoantibody targets a protein called glial fibrillary acidic protein within cells called astrocytes that are found in the brain and spinal cord. "Headache is a prominent symptom reported by the patients," says Dr. Lennon, who is senior author on the study. "It is accompanied by neurological findings of varying severity. Inflammatory cells in the spinal fluid and MRI images raise suspicion for brain infection, other inflammatory brain disease or a cancer spreading to the lining of the brain." Dr. Lennon notes that this disease rapidly reverses with therapy directed at the immune system, such as prednisone, in contrast to infections that need antibiotics and cancer that requires aggressive treatment. A positive test for glial fibrillary acidic protein autoantibody should bring the correct diagnosis earlier and hasten the most appropriate treatment. The glial fibrillary acidic protein antibody biomarker initially was identified in Mayo Clinic's Neuroimmunology Laboratory, which is within the Department of Laboratory Medicine and Pathology. The biomarker was identified using a test developed in the 1960s. The process involves applying a patient's serum or spinal fluid to thin sections of mouse tissues. If an autoantibody is present, it will stick to the targeted tissue. After the serum or spinal fluid is washed off, a probe in the form of another antibody is applied to the tissue to detect any human antibody that remains bound to the tissue. The probe antibody is tagged with a fluorescent dye. When viewed under a fluorescence microscope, the tagged antibody shows the location of the bound human autoantibody, revealing the cells targeted by the immune system. In this case, the pattern of binding to mouse brain tissue resembles the pattern of abnormalities seen in MRI images of the patients' brain and spinal cord. "That method has been a tremendous tool of discovery as well as a diagnostic tool for the last 35 years since I set up this lab," says Dr. Lennon. "It had fallen out of fashion about 20 years ago when we were encouraged to use modern molecular techniques. Well, we certainly do use molecular techniques, which are important validation steps, but we did not give up on the valuable older technology as a component of our 21st-century screening protocol to detect informative autoantibodies. In the process, we have continued to discover new autoantibodies of clinical importance." With the discovery of this biomarker, Dr. Lennon and the team expect that diagnosis and treatment for patients will improve in another important way. "At this stage, we've identified about 103 patients," says Dr. Lennon. "And about a third of them are turning out to have an unsuspected cancer in a remote part of the body." The research team suspects that, because cancer cells and the nervous system use some of the same mechanisms for communication, the immune response that is attacking a cancer is causing collateral damage to the nervous system in the process. "It appears from evidence to date that the antibody does not itself cause the brain inflammation," says Dr. Lennon. "It is a proxy marker of a more aggressive component of the immune system called killer T cells, which target the same brain protein." The next steps are to verify the glial fibrillary acidic protein autoantibody's diagnostic performance. At that point, Mayo Clinic's Neuroimmunology Laboratory anticipates offering this test for diagnostic purposes.


Song J.Y.,U.S. National Institutes of Health | Song J.Y.,City of Hope Medical Center | Pittaluga S.,U.S. National Institutes of Health | Dunleavy K.,U.S. National Institutes of Health | And 7 more authors.
American Journal of Surgical Pathology | Year: 2015

Lymphomatoid granulomatosis (LYG) is a rare angiocentric and angiodestructive Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorder. It is hypothesized that these patients have dysregulated immune surveillance of EBV. We reviewed the biopsies of 55 patients with LYG who were referred for a prospective trial at the National Cancer Institute (1995 to 2010) and evaluated the histologic, immunohistochemical, in situ hybridization, and molecular findings of these biopsies in conjunction with clinical information. Grading of the lesions was based on morphologic features and the number of EBV-positive B cells. The median age was 46 years (M:F 2.2:1). Clinically, all patients had lung involvement (100%), with the next most common site being the central nervous system (38%). No patient had nodal or bone marrow disease. All patients had past EBV exposure by serology but with a low median EBV viral load. We reviewed 122 biopsies; the most common site was lung (73%), followed by skin/subcutaneous tissue (17%); other sites included kidney, nasal cavity, gastrointestinal tract, conjunctiva, liver, and adrenal gland. Histologically, the lesions showed angiocentricity, were rich in T cells, had large atypical B cells, and were positive for EBV. Grading was performed predominantly on the lung biopsy at diagnosis; they were distributed as follows: LYG grade 1 (30%), grade 2 (22%), and grade 3 (48%). Necrosis was seen in all grades, with a greater degree in high-grade lesions. Immunoglobulin gene rearrangement studies were performed, and a higher percentage of clonal rearrangements were seen in LYG grade 2 (50%) and grade 3 (69%) as compared with grade 1 (8%). LYG is a distinct entity that can usually be differentiated from other EBV-associated B-cell lymphoproliferative disorders on the basis of the combination of clinical presentation, histology, and EBV studies. Grading of these lesions is important because it dictates the treatment choice. © 2014 Wolters Kluwer Health, Inc. All rights reserved.


Islam R.S.,Mayo Medical School | Patel N.C.,Mayo Medical School | Lam-Himlin D.,Laboratory Medicine and Pathology | Nguyen C.C.,Mayo Medical School
Gastroenterology and Hepatology | Year: 2013

The increasing use of endoscopy has led to more discernable abnormalities in the stomach, including polyps. Gastric polyps encompass a spectrum of pathologic conditions that can vary in histology, neoplastic potential, and management. Despite their high prevalence, there is a paucity of literature to support management and treatment decisions for endoscopists. The goal of this review is to summarize clinical, endoscopic, and histopathologic features of various polyps, review syndromes associated with such polyps, and provide management recommendations.


Smith M.,Laboratory Medicine and Pathology | Colby T.,Laboratory Medicine and Pathology
Turk Patoloji Dergisi/Turkish Journal of Pathology | Year: 2014

Pleural biopsies for the evaluation of malignant mesothelioma can be some of the most challenging cases faced by the practicing surgical pathologist. We review the epidemiology, clinical presentation, and imaging studies in patients with malignant mesothelioma, and then present a practical approach to the diagnosis using the cytologic features for malignancy and whether there is an epithelioid or spindled morphology; four main scenarios are discussed. The pertinent immunohistochemical work-up is reviewed for each scenario. Following this general overview, more unusual histologic patterns are compared and unusual presentations are discussed. Brief mention of grading systems for malignant mesothelioma and the use of electron microscopy and molecular studies is made. Practical considerations in the diagnosis of malignant mesothelioma are made throughout.


Borges S.,Mayo Medical School | Perez E.A.,Mayo Medical School | Thompson E.A.,Mayo Medical School | Radisky D.C.,Mayo Medical School | And 2 more authors.
Molecular Cancer Therapeutics | Year: 2015

Invasive ductal carcinomas (IDC) of the breast are associated with altered expression of hormone receptors (HR), amplification or overexpression of HER2, or a triple-negative phenotype. The most aggressive cases of IDC are characterized by a high proliferation rate, a great propensity to metastasize, and their ability to resist to standard chemotherapy, hormone therapy, or HER2-targeted therapy. Using progression tissue microarrays, we here demonstrate that the serine/threonine kinase protein kinase D3 (PKD3) is highly upregulated in estrogen receptor (ER)-negative (ER-) tumors. We identify direct binding of the ER to the PRKD3 gene promoter as a mechanism of inhibition of PKD3 expression. Loss of ER results in upregulation of PKD3, leading to all hallmarks of aggressive IDC, including increased cell proliferation, migration, and invasion. This identifies ER- breast cancers as ideal for treatment with the PKD inhibitor CRT0066101. We show that similar to a knockdown of PKD3, treatment with this inhibitor targets all tumorigenic processes in vitro and decreases growth of primary tumors and metastasis in vivo. Our data strongly support the development of PKD inhibitors for clinical use for ER- breast cancers, including the triplenegative phenotype. © 2015 American Association for Cancer Research.

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