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1 Journal of Topics & Issues Official publication of the American Medical Technologists Continuing Education April 2013 Volume 15 Number 2 Inside This Issue Quality Control: Part 3 Case Twenty Five: A Disseminated Fungal Infection The Role of Animal Models in Determining the Genetic Bases of Osteosarcoma Safely Storing Laboratory Chemicals

2 AMT 75th Educational Program & National Meeting July 8 12, 2013 PITTSBURGH, PENNSYLVANIA o know Pittsburgh, you have to see it for yourself. Come and see a city that has had a remarkable environmental renaissance, a top- 10 city for certified green building space, a city ripe with natural and cultural amenities. Pittsburgh International Airport is nation s third largest airport. In a statement to the New York Times, Prince Phillip said that Pittsburgh is the only city he has ever seen that has an entrance. The first glimpse of the Golden Triangle upon exiting the Fort Pitt Tunnel, on the way in from the airport, is absolutely incredible! There are 50 museums located in and around the Pittsburgh area. Pittsburgh, the City of Champions, is a sports fan s paradise with a new football stadium and new baseball park. Located just a short drive from Pittsburgh is one of the most famous private homes ever built, Fallingwater, Frank Lloyd Wright s architectural masterpiece. Omni William Penn Hotel FEATURES: Downtown location many restaurants and shopping within walking distance Located just 18 miles from airport Self parking $13.75 weekdays, $5.00 weekends Directly across the street from the T, Pittsburgh s free underground rail system Each guestroom has coffeemaker, hair dryer, iron and ironing board When a guest joins the free Omni loyalty program, he/she will receive many complimentary benefits during his/her stay, such as complimentary Wi-Fi service, morning beverage delivery, pressing of clothing items, bottled water, shoe shine, newspaper. AMT attendees will receive 15% discount in all hotel restaurants. Omni William Penn Hotel 530 William Penn Place, Pittsburgh, PA Phone (412) Website: FindAHotel/ PittsburghWilliamPenn.aspx AMT Convention room rate: $ plus 14% taxes (rate valid from July 2 to July 15, 2013) For additional Information: Contact AMT: West Higgins Road, Suite 150 Rosemont, IL Phone 847/ Fax: 847/ Website:

3 Journal of Continuing Education April 2013 Volume 15 Number 2 Contents 34 AMTIE President s Report 36 Cases in Clinical Microbiology 38 Article 398 Quality Control: Part 3 David Plaut and Deena Davis 41 Questions for Article Crossword Puzzle 44 Article 399 Case Twenty Five: A Disseminated Fungal Infection Irmeen Siddiqui, Carlos Teran, Katie Ruger and Joel Mortensen 48 Questions for Article Article 400 The Role of Animal Models in Determining the Genetic Bases of Osteosarcoma Haider Saddam Qasim Center Pullout Section Pittsburgh Convention Preliminary Program 63 Questions for Article Article 401 Safely Storing Laboratory Chemicals Karen Appold Topics &Issues Editor Gerard P. Boe, PhD Associate Editor Diane Powell 69 Questions for Article AMT Directory 72 Abstracts From the Current Literature Business Office American Medical Technologists W. Higgins Rd., Suite 150 Rosemont, IL address: Web Site: Journal of Continuing Education Topics & Issues (ISSN ) is published in January, April, and August under the sponsorship of the American Medical Technologists, W. Higgins Rd., Suite 150, Rosemont, Illinois Copyright 2013 by American Medical Technologists. Subscriptions include three issues of Journal of CE Topics & Issues and four issues of AMT Events: $50.00/year + $10 postage for foreign countries. Members may not deduct subscription price from dues. Postmaster: Please send change of address to AMT, W. Higgins Rd., Suite 150, Rosemont, Illinois Moving? Be sure AMT publications move with you. Send your new address and old mailing label from an AMT publication to AMT six weeks before you move. Cover photo: Hydrocortisone photomicrograph, Eric Clark, National High Magnetic Field Laboratory, Florida State University, Tallahassee.

4 American Medical Technologists Institute for Excellence (AMTIE) PRESIDENT S REPORT AMTIE s New Direction Recently I received a copy of AMT's new Annual Report, entitled American Medical Technologists October September 2012, A Year of Progress. It is an exciting overview of the growth and improvements of the American Medical Technologists organization and included information about the American Medical Technologists Institute for Excellence (AMTIE). AMT has grown in membership not only in the US but also to include members in 56 countries. Because of this growth and the need to provide educational opportunities to its members, the role of AMTIE has changed. Linda Jones, MT, AMTIE President AMTIE is a 501(3)(c) [tax exempt] educational support corporation charged with the administration of scholarships and grants associated with enhancing educational and competency opportunities for current and future allied health professionals. AMTIE solicits contributions from its members and is in the process of getting its strategic initiatives underway to solicit donations from businesses, philanthropic organizations, and non-amt members who have expressed the desire to support our worthy cause. In 2012, AMTIE gave seven scholarships, totaling $6,500, and awarded $1,000 in educational grants/awards. AMTIE Board of Trustees Election Two open positions are available in The June issue of AMT EVENTS will publish candidates' notice of intent and photos. This information must be submitted to Diane Powell at the AMT Home Office immediately. The final deadline to submit your application to the AMT office staff and have it posted on the bulletin board in the AMT Registration area of the convention is Monday, July 8th, by 10am. NO EXCEPTIONS. The voting will take place on Wednesday, July 10th, and all AMT members can vote for the two candidates of their choice. You do not have to be a delegate to vote in the AMTIE election. All applicants MUST present themselves to the membership at "Meet the Candidates" on Tuesday, July 9th. AMT Presents the 75th Educational and National Meeting The Omni William Penn Hotel, Pittsburgh, PA, is the location for the national convention. The dates are July 8-12, This year the meeting will be a day shorter, but nonetheless filled with educational opportunities for your continuing education to meet recertification requirements. The Welcome Reception will be held Monday night with music, dancing, and a lot of fun. The Awards Banquet will be on Wednesday night. At this time, we honor outstanding AMT members. 34 April 2013 Continuing Education Topics & Issues

5 The week is filled with committee meetings, town hall, district meetings, the seating of the delegates with voting for bylaws changes and national board members. It is a jam-packed meeting to include the AMT family reunion. There will be lots of hugs from old friends and the opportunity to make new acquaintances. and lastly, but most important AMTIE is sponsoring the Boasting Arts and Crafts Show. We are asking AMT members to donate one of their crafts to be sold at auction. The money from the sale of the items will be donated to AMTIE to help sponsor the scholarships and grants awarded by AMTIE. Taffy Durfee, our AMTIE Trustee from Texas, is heading up the sale. Please let her know if you plan to contribute to the Arts and Crafts Show. or call Thank you for allowing me to serve you as I am most proud of our organization and profession. Best regards, Linda Jones, BS, MT Continuing Education Topics & Issues April

6 Cases in Clinical Microbiology The case description on this page and its follow-up discussion presented elsewhere in this issue is the 25th in a series of articles presenting clinical microbiology cases that will appear in this journal. Readers should study the case description below and formulate their own answers to the questions posed. After coming up with a solution to the problem, turn to page 44 in this issue and read the Case Follow-up and Discussion. This is followed by Questions for STEP Participants on page 48. Joel E. Mortensen, PhD, MLT(AMT), Series Editor Case Description: An11-year-old male, who previously had a bone marrow transplant (April 2012) secondary to X linked hyper-igm syndrome, developed skin Graft-versus-Host Disease shortly after bone marrow transplant and was placed on azithromycin and acyclovir. Due to persistent gastrointestinal symptoms including hematemesis (blood in his vomit), he was readmitted in June Because of the immunosuppression, history of histoplasmosis lymphadenitis, severe giardiasis and CMV viremia in the past, he was placed on broad-spectrum antibacterial agents (ciprofloxacin, meropenem, metronidazole, and vancomycin), antifungal agents (caspofungin and voriconazole) along with a prophylactic antiviral agent (gancyclovir). During this stay, he started developing respiratory distress and fever. Multiple blood cultures were performed, but all remained negative after 5 days. CT scan of the chest showed the presence of multiple pulmonary nodules and effusion. Bronchoalveolar lavage specimens demonstrating lipid and hemosiderin laden macrophages and respiratory cultures showed few epithelial cells and white blood cells. No organisms were seen. Fungal work-up was also negative including urine antigen testing for Histoplasma Antigen performed by quantitative sandwich enzyme immunoassay at Mira Vista Diagnostics, Indiana, and serum Cryptococcal antigen performed using semiquantitative enzyme immunoassay at ARUP laboratories, Utah. Endoscopic studies (August 2012) were performed because of continuing gastrointestinal symptoms including diarrhea, nausea, vomiting showed the presence of fungal hyphae on periodic acid-schiff stained sections of gastric mucosa. The sample was not cultured at that time. Figure 1(a).Gastric mucosa (thick arrow) with fungal hyphae (thin arrow) (X20 Periodic acid-schiff stain) Figure 1(b). Broad, ribbon-like aseptate fungal hyphae (X40 Periodic acid-schiff stain) 36 April 2013 Continuing Education Topics & Issues

7 Figure 2(a): Head CT scan showing sub periosteal abscess in the inferior medial left orbit (yellow arrow) and sphenoidal sinusitis (red arrow). Figure 2(b): Brain MRI showing the exenterated left eye without intracranial extension. Figure 3. Wide branching, aseptate fungal hyphae (X40 hematoxylin and eosin stain) Figure 4(a). Fungal organism on Sabouraud dextrose with brain heart infusion agar at day 5 and 30 C. Figure 4(b). Globose sporangia (long arrow) with rhizoids (thick arrow) directly under unbranched sporangiophores (short arrow). (Katie Ruger, 2012). Hematoxylin and Eosin stained section of the tissue from the maxillary sinus showed abundant invasive fungi with broad aseptate hyphae. In the laboratory, maxillary sinus contents were inoculated onto two Sabouraud dextrose with Brain Heart Infusion agar plates (SABHI) for the isolation of fungi. On day five, a wooly-dark mould grew on both SABHI plates. Lactophenol blue tape preparations revealed globose sporangia with rhizoids directly under unbranched short sporangiophore. The patient was placed on amphotericin B liposomal but was persistently febrile and developed seizures. As part of the search for a focus, a head CT scan was performed, showing the presence of acute sinusitis of the sphenoid, ethmoid and maxillary sinuses with new subperiosteal abscess inferior medial left orbit. CNS infiltration was also considered due to the seizures. The patient was taken to the operating room every few days for surveillance endoscopy and debridement of the advancing sinusitis. What is the most likely identification of this mold? See page 44 for case followup and discussion. Continuing Education Topics & Issues April

8 Article Clock Hour Quality Control: Part 3 David Plaut and Deena Davis David Plaut, Plano, Texas, Consultant, AMT s Book Reviewer, and frequent speaker at AMT national conventions and regional meetings; Deena Davis, MLS, Point of Care Coordinator for Bozeman Deaconess Hospital in Bozeman, Montana. Welcome to the third installment of our series on Quality Control. In this installment we will discuss two sets of QC rules that will allow you to monitor and respond quickly to legitimate out of control situations as opposed to the false rejects that are so frustrating, not to mention time consuming and expensive. In this session we will take the mean and SD that we discussed in the last installment and use them with a QC chart (also called a Levey- Jennings or L-J chart). We will illustrate two ways to plot the two controls: 1) using one piece of paper or one worksheet in Excel and 2) using a single sheet for both controls. We leave it to you to choose the one you prefer. Our choice is the single sheet as it is easier to see both controls concurrently. Figure 1 is a chart for a single control over 30 runs. There is nothing magic about the 30 runs, although most interlaboratory programs report data each month (30 days in a month with one run of QC per day equals 30 runs total). The chart for the second level would be similar. Figure 2 shows both controls on one sheet. We have omitted the SD lines for clarity. You would want them on yours. We have plotted the mean and the + and 2, and 3 SD limits on the chart in Fig. 1. We use these limits to aid us in determining whether to label a run in or out. These are indeed labels as we are never 100% certain whether our label is correct. You may recall in school sometimes hoping the teacher would grade on the curve. It is this curve (often called a bell or normal curve) we use to label a run. Figure 3 is a drawing of the curve. Note the shape of the curve. Although it appears that the curve touches the x-axis (the horizontal line), it only comes extremely close to it, but never really touches it. Most of the area (68%) lies within the ±1 SD from the mean (0 in Figure 3), 95% of the area lies within ±2 SD and 99.7% lies within ± 3 SD of the mean. This is true of any of the measures we make repeatedly on the control material (or a patient sample) while the system is stable. Stable in the sense that the instrument is performing as it should and no changes are made in reagent or calibration during a given period. There will always be some variation (measured by the SD) even when the instrument is performing well. This is why there are limits rather than expecting all the data to be on the mean. (You may want to plot a histogram of data from one or more of your controls say on glucose or hemoglobin to see how closely your data fit the curve. It works best to use a dot plot with at least 70 points.) We use the probabilities from the curve to determine whether to label a run in or out, knowing that it is a probability and not a certainty. For example when we label a value that is more than 3 SD from the mean "out," we are saying we are more than 99% sure that there is a problem somewhere in the system. It could be the control or the reagents or the calibration or the instrument. Until we stop to ponder why the value(s) exceeded our limits, we don't know what is needed to fix the problem. We use these probabilities with the two or three controls to make our decisions about the run. We will illustrate each of the rules we recommend and discuss in some detail what a rule Figure 1 38 April 2013 Continuing Education Topics & Issues

9 Figure 2 Figure 3 failure can tell us about the source of the problem, in other words, knowing which rule was broken (the run labeled out). In our next installment, we discuss a bit more about trouble shooting when we have data from an instrument that measures more than one constituent at the "same" time. The flow chart in Figure 4 is an easy way to implement the rules we recommend. These rules are a combination of rules suggested in 1974 by the CAP and in 1981 by Westgard et al. It is worth noting that these rules have been validated to detect virtually all of the errors that would cause a proficiency failure or lead to a clinician making a wrong Figure 4 Figure 5 Figure 6 decision (based on laboratory data). If, and only if, you are doing your QC manually charting the controls on paper by hand the first rule or flag to consider is the 1 2SD flag. If there is no control value greater than 2 SDs from the mean, the run is labeled 'in' and the patient data are accepted. If there is a control value outside the 2 SD limits (a value on the 2 SD line is NOT out.), you need to look further. As the flow chart indicates, the next question is whether there is a control outside 3 SD. Figure 5 shows an example of a single control outside 3 SD. If so, the run is put on hold, all patient results should be held and trouble shooting is begun. Trouble shooting does NOT begin by rerunning the control. Rerunning the control when one of these rules is broken is simply a waste of money and time. A violation of a rule in the flow chart is not an error that will simply go away, no matter how hard you wish for it to or how many times you rerun the control. Some good old fashioned problem solving is the only answer. If neither control is outside 3 SD, continue along the flow chart to see if a second control is outside 2 SD on the same side of the mean. Figure 6 illustrates this 2 2 SD failure within a run. If a 2 2SD failure occurs, stop and begin trouble shooting. Continuing Education Topics & Issues April

10 Figure 7 Figure 8 If the second control is not outside the same (+ or ) 2 SD limit as the first control, then look at the previous run to see if the control that is out on this run was out on the previous run. If that is the case, stop and trouble shoot. Figure 7 illustrates this 2 2 SD failure across runs. If there are not consecutive values outside the same 2 SD limits (2 sequential results out by 2SD on the same side of the mean), on the current run where one control is outside 2 SD, look to see if the other control is also outside the other 2 SD limit. Figure 8 illustrates this. If this rule, the R 4SD rule, is not violated, all that has happened is one control is outside 2 SD which is NOT cause to stop. Report the data, no troubleshooting is necessary. As we mentioned, we will discuss trouble shooting in the next installment and we will also discuss ways to deal with repeating certain patient samples. If a run is rejected as out, do not include the control data in the good file. Do not discard it completely, but do not include it with the data used to calculate the mean and SD. Simply keep it so you may refer back to it in case this error occurs again and/or becomes a persistent problem. If you use three controls, the only rule that changes is the 2 2 SD within a run which becomes the 2 of 3 2 SD rule. This is illustrated in Figure 9. The reasons we recommend these rules, aside from the fact that they have been recommended by others, is that they are very sensitive to significant errors, those errors that could lead to harm to Figure 9 the patient or proficiency failures. They have about one-tenth of the false alarms that the 1 2 SD error has (rejecting a run with a single value outside 2 SD). They are simple to use manually and they can aid in trouble shooting. We can have greater faith in our analyzers and thus provide our patients with safe and accurate lab results. References 1. CAP Today, J O Westgard and T Groth Design and evaluation of statistical control procedures: applications of a computer "quality control simulator" program.clinical Chemistry 1981; v. 27, p D D Koch, J J Oryall, E F Quam, et al. Selection of medically useful quality-control procedures for individual tests done in a multitest analytical system.clinical Chemistry 1990; v. 36, p J O Westgard, P L Barry, M R Hunt, et al. A multi-rule Shewhart chart for quality control in clinical chemistry.clinical Chemistry 1981; v. 27, p April 2013 Continuing Education Topics & Issues

11 Questions for STEP Participants AMT strongly encourages you to submit your answers online so that the CE credits can be automatically transferred into your AMTrax account. To do so, go to click on the AMT Store on the top navigation bar. Click on STEP Online, then select the article number and purchase the test. Don t forget to log in to receive the discounted member price of $5 (nonmembers pay $15/test). If you wish to submit answers manually (only available to AMT members), the fee is $10/test. Please submit a copy of this page with your answers marked, along with a completed order form located elsewhere in this publication. Don t forget to include payment. Article Clock Hour 1. QC rules exist to a run. a. Assign b. Label c. Identify d. Allocate 2. A QC chart uses these statistics: a. Mean and CV b. CV and SD c. Mean and SD d. Mean, SD and CV 3. Runs are called in or out based on the QC. A. True B False 4. If a run is out, first rerun the control that was out. A. True B False 5. When the system in working as best it can, values will be outside 2 SD. a. 0.3% b. 5.0% c. 16% d. 95% 6. The QC rules suggested in this article date from a. Landsteiner early 1920s b. Levey and Jennings mid 1950s c. CAP and Westgard d. CLIA The normal or bell or Gaussian curve illustrates a. Systematic shifts b. Random error c. Both a and b d. Neither a nor b 8. Two values outside the same 2SD limit points to a a. Random error b. Systematic error c. Either random or systematic error d. No error 9. A single value outside 3 SD points to a a. Random error b. Systematic error c. Either random or systematic error d. No error 10. If QC is done manually, controls outside 2 SD should be rerun. A. True B False Continuing Education Topics & Issues April

12 Crossword Puzzle Answers on page April 2013 Continuing Education Topics & Issues

13

14 Article Clock Hour CASES IN CLINICAL MICROBIOLOGY Case Twenty Five: A Disseminated Fungal Infection Irmeen Siddiqui, Carlos Teran, Katie Ruger and Joel Mortensen Dr. Siddiqui is a Pathology Resident in the Department of Pathology and Laboratory Medicine of the University of Cincinnati. Dr. Teran is a Fellow in the Division of Infectious Diseases at Cincinnati Children s Hospital. Katie Ruger is Medical Technologist in the Diagnostic Infectious Diseases Testing Laboratory in the Department of Pathology and Laboratory Medicine at Cincinnati Children s Hospital. Dr. Mortensen is the Director of Diagnostic Infectious Diseases Testing Laboratory in the Department of Pathology and Laboratory Medicine at Cincinnati Children s Hospital, and Professor in the Department of Pathology and Laboratory Medicine of the University of Cincinnati, Ohio. EDITOR S NOTE: BEFORE reading the Case Follow-up and Discussion below, study the Case Description on page 36 of this issue, and formulate your own answers to the questions posed. Case Follow up The organism was presumptively identified as Rhizopus species based on the morphology of sporangiophore and sporangia. The Fungus Testing Laboratory, University of Texas Health Science Center later confirmed the identification as Rhizopus microsporus using growth characteristics and DNA sequencing. Of serval varieties of Rhizopus microsporus, the closest variety that resembled was R. microsporus variety chinensis. The subperiosteal abscess spread into the orbit and eye tissue and subsequent follow up MRIs and CT showed central nervous system spread of the lesions, as well. The Ophthalmology service performed a exenteration of the involved left eye because of the advancing infiltration. Because of the central nervous system involvement and mental status deterioration, he was intubated and placed on cardiorespiratory support. His clinical status continued to deteriorate, requiring more respiratory support with higher setting of the ventilator and finally died almost two months after admission. Background Zygomycosis infections have been reported worldwide and are the third most common invasive fungal infection after candidiasis and aspergillosis 3. Rhizopus, together with Mucor, Rhizomucor, Absidia, Apophysomyces, Cunninghamella, Syncephalastrum and Saksenaea are placed in the order of Mucorales, class of Zygomycetes 1. The incidence of zygomycosis is rising due to multiple factors including the hematological malignancies, immunosuppression, stem cell and organ transplants 1. Mucorales are ubiquitous moulds, widely distributed in the environment including soil, plants, decaying organic matter 4. They are frequent contaminants of food and grow well on fruits, cereal and bread 3. Airborne spores are thought to be the infectious particles responsible for disease, particularly in immunocompramised individuals and this explains the frequent localization in skin, sinuses and lungs. These molds are often found as laboratory contaminants and may cause nosocomial infection 5. The genus Rhizopus is characterized by rapid production of white fluffy colonies which turn brownish to black with time due to the presence of pigmented sporangiophores and sporangia 5. Rhizopus microsporus and Rhizopus oryzae are the most common species involved in zygomycosis 5. Rhizopus microsporus is a thermophilic zygomycete and can be isolated from soil or wood products. Different varieties of Rhizopus microsporus include Rhizopus microsporus var microsporus, Rhizopus microsporus var chinensis, Rhizopus microsporus var oligosporus and Rhizopus microsporus var rhizopodiformis. These can be differentiated on the basis of their sporangiospores morphology and the growth at different temperatures 5. Among these known four varieties, only Rhizopus microsporus var microsporus and Rhizopus microsporus var have been reported to cause infections in humans April 2013 Continuing Education Topics & Issues

15 Clinical Presentation Localized and disseminated forms of the disease need to be differentiated as the two most common initial presentations are rhinocerebral or pulmonary infection which rapidly progresses and involve the other viscera 8. Other common forms recognized are orbital, cutaneous, gastrointestinal and disseminated 3. Disseminated rates vary from 3% to more than 50% for patients with hematological malignancies (depending to some extent on the underlying diseases and the site of infection) 7, 8, 9. Sinus involvement is the most common presentation in the patients with diabetes and intravenous drug abusers and the pulmonary infection is the second most common while the reverse is true for hematology patients 7, 10. Infection causes necrosis and hemorrhage, localized or disseminated, which can have both clinical and radiological similarity to invasive aspergillosis 16. Cerebral infection may complicate sinusitis or can be the only presentation, especially in IV drug abusers; usually the patients present with lethargy, confusion or focal neurological deficits. Gastrointestinal involvement has been described in 7% of cases especially in low birth weight premature infants or malnourished individuals which can present with abdominal pain, perforation, peritonitis and dissemination to the liver 7. Pathogenesis There are several factors responsible for the pathogenicity of different fungi. Macrophages and neutrophils play an important role in protecting against zygomycosis. Prolonged neutropenia or impaired function of neutrophils and macrophages induced by any drug (corticosteroids) or underlying disease like diabetes are important risk factors for zygomycosis 18. Studies have also pointed an important role for iron in these infections. Iron is essential for the virulence and growth of Mucorales so the conditions associated with iron overload like hematologic malignancies or hemodialysis with deferroxamine therapy can be predisposing factors for the infection 19. Adhesion to endothelial cells and internalization of fungus facilitates the process of angioinvasion causing infarction of surrounding tissues and dissemination into other organs 20. Recently, a study has been done which demonstrated a novel host receptor (the glucose-regulated protein 78 [GPR78]), which facilitates the invasion of human endothelial cells, by Rhizopus oryzae 25. They found that in patients with iron overload and increase blood glucose (diabetes), there is increased expression of GPR78 receptor and blood vessel destruction which is also the mechanism to gain access to central nervous system from direct extension and vessel invasion from paranasal sinuses 25 Lab identification Direct examination and histopathology: Demonstration of hyphae in clinical samples is important for the diagnosis of zygomycosis 11. Wet mounts of clinical samples can be observed directly by adding a few drops of potassium hydroxide. Tissue samples can also be processed in the histopathology laboratory and hyphae can be visualized by staining sections by Gomori-methenamine-silver (GMS) or periodic acid-schiff (PAS) staining. The specific morphological characteristics suggestive of Mucorales are thin, hyaline, non or pauciseptate walls, ribbon like hyphae with large diameter and wide branching angles (>=90 ) 5. Culture is of prime importance for the diagnosis of zygomycosis because differentiating it from other mucorales and hyaline hyphomycetes can be difficult based on the morphology of hyphae in the tissue alone and also culture is needed for antibiotic susceptibility testing 7. Mucorales are not fastidious organisms and can grow on common microbiological agar media, but mycological media like Sabouraud dextrose agar containing antibiotics are preferred because it inhibits the bacterial growth and enables the isolation of some opportunistic fungi which are sensitive to cycloheximide, included is some selective fungal media 5. Culture should be incubated at 37 C for optimal yields but for incubation of a second tube at 25 to 30 C is recommended because some species have an optimal temperature of growth below 37 C 6. Historically, identification of Mucorales fungi to the species level is based mainly on the examination of their macroscopic and asexual microscopic characteristics or maximum growth temperature 6. Genus Rhizopus produces pale to brownish cottony colonies. The sporangiophores are unbranched; arise singly or in groups with well-developed rhizoids at the base. Rhizopus microsporus have sporangiophores arising from stolons and measuring up to 400 micrometer in length. Sporangia are dark brown, colu- Continuing Education Topics & Issues April

16 mellae are conical and sporangiospores are striate and angular to ellipsoidal. Rhizopus microsporus var chinensis have angular sporangiospores with growth occurring at temperature from 30 to 45 C 5, 17. There are currently no specific antigen detection methods and there are no commercially available molecular detection techniques 13. Different approaches have been tried. Most studies have used PCR based techniques. A real time PCR assay targeting a conserved region of the Mucorales cytochrome b gene had a sensitivity and specificity of 56 and 100% respectively 14. An in situ hybridization technique using Mucorales-specific DNA probes targeting 18S rrna subunit also showed promising results 15. Chromosomal sequencing of selected genes is becoming more common and probably represents the future of mould identification. In addition, the use of mass spectral analysis is being applied to the identification of moulds including zygomcetes. Antifungal and antifungal susceptibility testing Antifungal susceptibility can be evaluated both invitrio and in vivo. In vitro antifungal susceptibility can be evaluated by microdilution broth technique developed by Clinical and Laboratory Standards Institute 21 or European Committee on antimicrobial susceptibility testing 22 or by commercially available E test 23. Amphotericin B is the most active drug against Mucorales. Among the azoles, voriconazole has poor activity whereas posaconazole has better activity with low minimum inhibitory concentration values 5. Capsofungin has also shown efficacy in treating zygomycosis infection specially if combined with amphotericin B 24. Conclusion Zygomycosis represents a fulminant fungal infection especially in the immunocompramised patients or with diabetes. Rhizopus microsporus and Rhizopus oryzae are the most common causative agents of zygomycosis. The disease typically involves the rhino-orbital-cerebral area, lungs, gastrointestinal system, skin and less commonly other organs too. Timely diagnosis of zygomycosis by culture and histology followed by surgery and correction of underlying condition is the key for successful treatment. Posaconazole and amphotericin B are usually preferred as a first line of therapy. References 1. Uckay I, Chalandon Y, Sartoretti P, Rohner P, Berney T, Hadaya K and van Delden C. Invasive zygomycosis in transplant recipients. Clin Transplant 2007: 21: Cheng VCC, Chan JFW, Ngan AHY, To KKW, Leung SY, Tsoi HW, Yam WC, Tai WM, Wong SSY, Tse H, Li IWS, Lau SKP, Woo PCY, Leung AYH, Lie AKW, Liang RHS, Que TL, and Yuen KY. Outbreak of Intestinal infection due to rhizopus microsporus. Journal of Clinical Microbiology. 2009:47: De Mol P and Meis JFGM. Disseminated Rhizopus microsporus infection in a patient on oral corticosteroid treatment: a case report. The Journal of Medicine. 2009:67: Ribes JA, Vanover-Sams and Baker DJ. Zygomycetes in human disease. Clin. Microbiol. 2000: 13: Gracia-Hermoso D, Dannaoui E, Lortholary O and Dromer F. Agent of systemic and subcutaneous mucormycosis and entomophthoromycosis. Manual of Clinical Microbiology. 20--Chapter 119: Schwartz P, Lortholary O, Dromer F and Dannui E.Carbon assimilation profiles as a tool for identification of zygomycetes. J. Clin. Microbiol. 2007: 45: Roden MM, Zaoutis TE, Buchanan WL, Knudsen TA, Sarkisova TA, Schaufele RL, Sein M, Sein T, Chiou CC, Chu JH, Kontoyiannis DP and Walsh TJ. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin. Infect. Dis. 2005:41: Nosari A, Oreste P, Montillo M, Carrafiello G, Draisci M, Muti G, Molteni A and Morra E. Mucormycosis in hematologic malignancies: an emerging fungal infection. Hematologica. 2005:85: Pagano L, Offidani M, Fianchi L, Nosari A, Candoni A, Picardi M, Corvatta L, D'Antonio D, Girmenia C, Martino P and De Favero A. Mucormycosis in hematologic patients. Hematologica. 2004: 89: Kontoyiannis DP, Lionakis MS, Lewis RE, Chamilos G, Healy M, Perego C, Safdar A, Kantarjian H, Champlin R, Walsh TJ, and Raad II. Zygomycosis in a tertiary care cancer center in the era of Aspergillus-active antifungal therapy: a case control observational study of 27 recent cases. J. Infect. Dis. 2005:191: Torres-Narbona M, Guinea J, Martinez-Alarcon J, Munoz P, Pelaez T and Bouza E. Workload and clinical significance of the isolation of zygomycetes in a tertiary hospital. Med. Mycol. 2008: 46: Ruchel R and Schaffrinski M. Versatile fluorescent staining of fungi in clinical specimens by using the optical brightener Blankophor. J. Clin. Microbiol. 1999: 37: Dannoui E. Molecular tools for identification of zygomycetes and diagnosis of zygomycosis. Clin. Microbiol. Infect. 2009:15 (suppl.5): Hata D, Buckwalter SP, Pritt BS, Roberts GD and Wengenack NL. Real-time PCR method for detection of Zygomycetes. J. Clin. Microbiol.2008:46: Hayden RT, Qian X, Procop GW, Roberts GD and Lloyd RV. Insitu hybridization for the identification of filamentous fungi in the tissue section. Diagn. Mol. Pathol. 2002:11: Sun HY, Aguado JM, Bonnati H, Forrest G, Gupta KL, Safdar N, John GT, Pursell KJ, Munor P, Patel R, Fortun J, Martin-Davila P,Philippe B, Philit F, Tabah A, Terzi N, Chatelet V, Kusne S, Clark N, Blumberg E, Julia MB, Humar A, Houston C, Lass-Florl C, Johnson L, Dubberke ER, Barron MA, Lortholary O and Singh Pulmonary zygomycosis in solid organ transplant recipients in the current era. Am. J. Transplant. 2009:9: Schipper MAA and Stalpers JA. A revision of genus Rhizopus. II. The Rhizopus microsporus group. Stud. Mycol. 1984: 25: April 2013 Continuing Education Topics & Issues

17 18. Morace G and Borghi Invasive Mold Infections: Virulence and Pathogenesis of Mucorales.International journal of microbiology Symeonidis AS. The role of iron and iron chelators in zygomycosis. Clinical Microbiology and Infection. 2009: 19: Ibrahim AS, Spellberg B, Avanessian V, Fu Y, and Edwards JE. Rhizopus oryzae adheres to, is phagocytosed by, and damages endothelial cells in vitro. Infection and Immunity. 2005:73: Clinical and Laboratory Standards Institute (CLSI).Reference method for broth dilution antifungal susceptibility testing of filamentous fungi: Approved standard. Document M-38A. CLSI, Wayne PA 22. Rodriguez-Tudela JL, Donelly JP, Arendrup MC, Arikan S, Barchiesi F, Bille J, Chryssanthou E, Cuenca-Estrella M, Dannoui E, Denning D, Fegeler W, Gaustad P, Lass-Florl C, Moore C, Richardson M, Schmalreck A, Velegraki A and Verweij PE.EUCAST technical note on the method for the determination of broth dilution minimum inhibitory concentrations of antifungal agents for conidia forming moulds. Clin. Micobiol. Infect. 2008:14: Espinel-Ingroff A. Comparison of three commercial assays and a modified disk diffusion assay with two broth microdilution reference assays for testing zygomycetes, Aspergillus spp., Candida spp., and Cryptococcus neoformans with posaconazole and amphotericin B. J. Clin. Microbiol. 2006:44: Reed C, Bryant R, Ibrahim AS, Edwards Jr. J, Filler SG, Goldberg R, and Spellberg B. Combination polyene-capsofungin treatment of rhino-orbital-cerebral mucormycosis. Clin. Infect. Dis.2008: 47: Liu M, Spellberg B, Phan QT et al. The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice. Journal of Clinical Investigation. 2010: 120: AMTrax Online Recording System AMTrax is a member service designed to help you keep track of earned continuing education (CE) credit. The system: Provides an effective means of validating and organizing participation in CE activities Provides a convenient means for documenting certification-related activities for employers and licensing agencies Helps self-assess progress in complying with the Certification Continuation Program (CCP) Entering your CE data online is simple! Visit and click on AMTrax under the CE tab. You must be logged in as a member to take advantage of this service. AMTrax For more information please visit: Continuing Education Topics & Issues April

18 Article Clock Hour Questions for STEP Participants AMT strongly encourages you to submit your answers online so that the CE credits can be automatically transferred into your AMTrax account. To do so, go to click on the AMT Store on the top navigation bar. Click on STEP Online, then select the article number and purchase the test. Don t forget to log in to receive the discounted member price of $5 (nonmembers pay $15/test). If you wish to submit answers manually (only available to AMT members), the fee is $10/test. Please submit a copy of this page with your answers marked, along with a completed order form located elsewhere in this publication. Don t forget to include payment. 1. Which of the following genera do not belong to the order Mucorales? A. Mucor B. Rhizomucor C. Absidia D. Aspergillus 2. Which of the following clinical conditions represents the most common clinical presentation of zygomycosis? A. Pulmonary and gastrointestinal B. Rhinocerebral and pulmonary C. Rhinocerebral and skin D. Disseminated 3. Which of the following mechanisms is not attributed to the pathogenesis of zygomycosis? A. Impaired function of neutrophils and macrophages B. Iron overload C. Lymphatic permeation and spread D. Angioinvasion and destruction 4. Which is considered as the most effective antifungal drug against Mucorales? A. Amphotericin B B. Voriconazole C. Fluconazole D. Nystatin 5. Which of the following is a characteristic of Rhizopus species? A. Narrow, septate hyphae with right angle branching B. Broad based budding yeast C. Budding yeast with a halo around it. D. Broad, aseptate hyphae with wide angle branching 6. The temperature of incubation is important for the isolation and identification of Zygomyctes. Media should be incubated at 37 C. and a second set at which of the following temperatures? A. 35 C. B C. C C. D C. 7. Which of the following represents the most common mode of transmission of Rhizopus infection? A. Feco-oral B. Airborne C. Sexually transmitted D. Water borne 8. Which of the following statements best describe Rhizopus microsporus and Rhizopus oryzae? A. the most common species involved in zygomycosis B. always susceptible to amphotericin B C. cause diseases in children D. All of the above 9. Which of the following terms is not associated with Rhizopus microsporus? A. Oligosporus B. Chinensis C. Fumigatus D. Rhizopodiformis 10. When stained with hematoxylin and eosin, which of the following statements best describes a Zygomycetes in tissue? A. Narrow, septate hyphae with right angle branching B. Broad based budding yeast C. Budding yeast with a halo around it. D. Broad, aseptate hyphae with wide angle branching 48 April 2013 Continuing Education Topics & Issues

19 STEP Order Form To submit STEP answers manually (only available to AMT members), you must complete this form and attach the appropriate quiz(es) with your payment and mail to American Medical Technologists. The fee for manual submission is $10 per quiz. AMT will record your results in your AMTrax account. NOTE: Florida state licensed MT or MLT members, if you would like AMT to record STEP article to CE broker please fill in your Florida state license number below. STEP Article Number Title Member Cost ($10 per Article) Payment Information: Name Member ID # Address FL License # City State Zip Visa Master Card American Express Discover Check (US funds only) payable to: American Medical Technologists W. Higgins Road, Suite 150 Rosemont, Illinois Total amount of order Total Fees Enclosed Account Number Exp Date Billing Address City State Zip Signature Daytime # You can also order Continuing Education Modules online at Rev. 8/12

20 Article Clock Hours The Role of Animal Models in Determining the Genetic Bases of Osteosarcoma Haider Saddam Qasim Haider Saddam Qasim, MT(AMT), Clinical Laboratory Consultant/Medical Scientist (Anatomical Pathology) B.M.L.Sc., L.I.B.M.S., P.M.I.A.C., F.A.S.C.P., C.L.C (NCA). M.L.S. (NZ) Abstract Osteosarcoma is a highly malignant tumor of bone, mostly affecting children and adolescent age groups. This tumor is characterized by complex genetic changes, which are supposed to be involved in osteosarcoma tumorigenesis. Secondary osteosarcoma also can develop as sequences of bone abnormalities such as fibrous dysplasia, Paget s disease, and osteomyelitis. The peak incidence of osteosarcoma occurs between 1-22 years old groups with a smaller peak after age 50. Osteosarcoma typically arises at the growth plate (Metaphysis) of the long bones, and it is mostly high grade and tends to develop pulmonary metastasis. In spite of clinical management, the patients with metastasis or even with local disease have a poor prognosis. In addition, there is no advance treatment for osteosarcoma, only cytotoxic therapy and limb amputation. This review focuses on the existing data which indicate that osteosarcoma tumors display a broad range of genetic alterations, including loss, deletion, and rearrangements of chromosomal regions. There has evolved some inactivation of tumor suppressor genes and deregulation of some signalling pathways. Certain studies found that p53 and prb mutations are most commonly reported in osteosarcoma patients and also reported in the animal model cell lines. This review focuses on the importance of animal models because of the difficulty to obtain human samples with different classifications of the disease, and also a limited number of clinically related with biological insights. Furthermore, human tissue is often taken from chemotherapy patients who then have the problems of a cellular tumor stroma and tumor necrosis induced by the chemotherapy. For these reasons, relevant animal models are essential to provide an investigational tool for the study of osteosarcoma. This review provides the comparison of human, canine, and murine models in particular, and feline and rabbit in general including incidence, risk factors, clinical presentation and diagnosis, genetic abnormalities, biological behaviors and prognostic factors. Finally, this review suggests osteosarcoma should be considered as a dedifferentiated disease caused by genetic changes that interrupted osteoblast differentiation from mesenchymal stem cells. Thus, understanding the molecular pathology of osteosarcoma could lead to the development of better diagnosis and prognostic markers, as well as therapeutic agents for osteosarcoma patients. Introduction Osteosarcoma (OS) is the most primary malignant tumor of bone. It occurs most often in adolescence and affects the long bones most commonly. While relatively rare, with approximately 170 cases of bone cancer per annum in Australia (Australasian Association of Cancer Registries 2006), and approximately 600 patients developing OS each year in the United States 1, it is still the most common pediatric non-hematological sarcoma of bone and the 5th most common malignancy of adolescence. Over the past two decades, even with significant advances in oncology fields, little has changed in the management of this disease. Treatment still involves the use of high-dose cytotoxic chemotherapy and tumor resection, with 5-year survival rate between 65% - 75% for localized disease and 20% with metastasis patients 2. Cure rates for patients with metastatic or relapsed disease are poor (<20% survival). With such statistics, studies addressing the mechanisms associated with the initiation and maintenance of OS may provide valuable insights into cancer biology and may provide new avenues for therapeutic targeting. Furthermore, identifying the oncogenes which induce the aggressive behavior of OS will poten- 50 April 2013 Continuing Education Topics & Issues

21 tially assist the development of valuable diagnostic indicators and therapeutic agents. Extensive researches over the years have analysed genes in primary human OS and metastatic lung lesions and identified genes involved in metastatic potency 3. Studies have indicated that genetic profiling may assist to understand the pathogenesis of OS and whether or not it is related to familial syndromes. There are four known causes of OS: genetic mutations, chemical compounds, radiation, and environmental agents 2. Some genes are identified by mutated or over expressed in tumor cells and metastasis. However, the contribution of these mutated genes to initiate in OS is still unclear 4. This review will focus on the genetic profiling of OS, especially that involved with human, canine and murine models. The importance of canine and murine models of OS has been demonstrated by a number of genetic similarities found in humans. The similarities between canine and human OS are in biological behavior. Further, distribution in the tibial and knee joints occurs naturally in both species 4. Comparisons have been established of human and murine models of the genetic mutations (deletions or overexpressed genes), and similarities noted in tumorigenesis, aggressiveness and metastatic behavior 4. The treatment of OS is unchanged over the last 30 years, with only surgical resection and adjuvant chemotherapy being the two available treatments 5. The successful treatment of OS will depend on the identification of genes responsible to induce the OS. This will allow the development of gene therapy and immunotherapy against the tumor aggressiveness. 5. Incidence of OS OS is highly prevalent in children and in young adults ages up to 21 years old 6, 5 (see table 1). There have been reported cases of OS in elderly individuals (56-80 years old) in association with Paget s disease of the bone 7. Paget s disease is a disorder of the normal bone structure, formation and remodelling process, leading to the development of various complications including bone pain, deformity, pathological fracture and arthritis 8. There is no evidence of gender preference in OS 9. However, overall male predominance in gender predilection with male: female ratio 1.5: In all cases of OS, the sites affected by the primary malignant tumor are the long bones such as the Femur, Tibia and Humerus 11. In 10% - 20% of cases, the tumor occurs in head, and neck and most are located in the mandible or maxilla and extragnathic bones. 12 (See table 1). OS Animal Models To investigate the pathogenesis of human OS requires an analysis of clinically relevant animal models. The ideal animal model should provide varying degrees of tumor growth at the primary site and of metastatic potential of human OS. Such models should be valuable as tools to investigate factors (chemical, radiation, and genetic factors) that promote or inhibit OS growth and/or metastasis. For example, one method is to investigate the differential gene expression patterns resulting in promotion of cell proliferation and inhibition of differentiation, and which genes could potentially promote or inhibit metastasis. Animal models can also be used to test potential new therapeutics such as anti-tumor small molecules or other targeted therapies 13, 14. The best experimental models for preclinical cancer studies must meet several criteria: (1) determine methods which are used to induce the tumor; (2) clinical and pathological similarity with the corresponding human tumors (see table 1 and 2). Tibial Injection Model In general, the mouse model aimed to replicate many factors of human disease behavior, especially in tumor biology, genetic expressions, causes, and response to the therapeutic agents. It reflects some of the most prominent features of the human OS, such as lung metastasis (see table 1 and 2). Moreover, the model may provide some understanding of the complex process of development and pathogenesis of OS 15, and also can be tested for many kinds of therapeutic agents in vivo, at primary sites, to determine the terms of development of metastasis. This model is very helpful to image and monitor the tumor progression in living mice 16. The advantages of the mouse model to understand the behaviors of OS are the following 17 : The OS will develop after inoculation in bone, and within a short period time allow for tumor progression analysis. It has the ability to spread within a short time. This model demonstrates the several marker expressions characteristic of OS in vivo (but not all in vitro), such as alkaline phosphatase (ALP), pro-b 1-collagen (COL), osteopontin (OPN), matrix Gla protein (MGP) and osteocalcin (OSN) 18. OS in the mouse model displays the characteristics of osteoid matrix and spontaneously provides development of pulmonary metastasis, Continuing Education Topics & Issues April

22 which is the most common feature of humans OS. A study explaining the principal injection of mouse by tumor cells, must follow different criteria: (1) cell lines must be extracted and prepared; the cancer cells are to be grown in culture and harvested when sub confluent; cell suspension needs to be prepared in phosphate buffered saline and placed on ice. OS cells were obtained from the primary culture of a spontaneous OS which arose from the distal femur of an 894-day-old female Balb/c mouse. 19. (2) Mouse preparation usually uses inhaled isoflurane to anesthetize the mouse. Other methods can use anesthetic injection to achieve the same effect. The efficiency of anesthesia is assessed by using toe pinch. There should be no reflex when the toe is pinched. Properly position the anesthetized mouse, which was already shaved. Then, the cells must be injected into the long bone. The abdomen is readied with a betadine solution. The abdomen and surgical site are covered in a sterile fashion 20. Recently, the development of a novel bioluminescence in vivo imaging technique (IVIS) allowed to monitor in real-time the labeled substances in experimental animals. This technology was successfully used to study tumor progression Table 1. Genetic Abnormalities Associated with Osteosarcoma in Human and Animal Models Osteosarcoma Human Dog Genetic abnormalities including inherited genes Sporadic genetic mutation P53, Rb, MDM2, RECQ helicases, Telomere maintenance (96, 97). Inherited diseases: Li- Fraumeni (p53), Rothmund-Thomos (RTS (RecQL4)), Werner Syndromes (WRN (RecQ2)), Bloom Syndrome (BLM (RecQL3)) (53) TWIST, MYC, CDKN2A, CDKN2B, BUB3, FGFR2, PRIM1, MDM2, TSPAN31, GLI1, Rb1, TOPS3A, MAPK7, COPS3, PMP22, TP53, DCC, CHK2 (53) P53, Rb, MDM2, RECQ helicases, Telomere maintenance (2) Tibial injected mouse model Frequency of p53 mutation 15%-30% (78) 16%-29% (2) Not applicable p53 mutation pathway Double conditional knockout mouse model Conditional knock out p53 and Rb. (4) Cat Inactivate p53 (46) Rabbit Not identified Not reported Not reported Not reported Not reported Not reported 100% completely floxed p53, and 30%-77.8% of heterozygous floxed p53 (4) 3.4% (46) Not reported Rearrangement and Not reported Deleted Knock out Alteration (46) Not reported deletion gene reported (98) Rb gene Disrupted Disrupted Normal Not applicable Not reported Not reported RECQ helicases pathway PTEN gene pathway HER-2/erbB2 oncogene IGF and IGF-1 Mutation been identified with patients of Rothmund- Thomason syndrome and correlated with OS risk (99) Not been evaluated Not reported Not reported Not reported Not reported Mutation in other human cancers but not examined in human OS (2) Over expressed (100) Over expression and antiapoptotic, and play a role of OS proliferation and invasiveness (102) HGF and its receptor c-met Over expression (103) Other oncogenes Metastasis related genes c-myc, c-fos, MET, SAS, GLI are all over expressed (105) Ezrin (106), Annexin-2 (3), CXCR4 (107), Fas-ligand (95), COX-2 (108) Overexpression reported in canine OS cell lines (37) Over expressed in cell lines and only expressed in dog tissue samples (101) Over expression and antiapoptotic, and play a role of OS proliferation and invasiveness (102) Over expression in cell lines (104) ch-ras, c-sis, c-myc are all over expressed (2) Ezrin (106), COX-2 (108) Not reported Not reported Not reported Not reported Not reported but it would same as double conditional model Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Do not use this model to monitor the metastases activities Not reported Not reported Not reported 52 April 2013 Continuing Education Topics & Issues continued after center spread

23 continued from page 52 and verify the advantages of new therapies. 21, 22. A Luciferase labeled metastatic OS model has been established in vivo. Highly and poorly metastatic cell lines were originally established from an OS, spontaneously arising in a Balb/c mouse 19. Metastatic cells were selected and engineered in vivo to express the reporter gene (Luciferase). Upon orthotopic injection, the IVIS technique allows monitoring tumor growth and metastases. IVIS analysis and gene expression showed that the metastatic OS cells phenotype was maintained after propagation in culture and gene marking. 16 (see table 1). Transgenic Mouse Model A transgenic mouse contains additional or artificially introduced genetic material into other cells. There are two main methods to produce transgenic mouse model. The first method is pronuclear microinjection (which is isolated). After fertilization, use a fine needle to inject the foreign DNA into the large male pronucleus derived from sperm, then is implanted in a foster mother and develops into an embryo. Then the DNA tends to integrate to a random position in the genome. Therefore, the resulting mouse may be partially transgenic. 23. The second method to producing the Table 2. Clinical and Pathological Features of Osteosarcoma in Human and Animal Models Osteosarcoma Human Dog Tibial injected mouse model Double conditional knockout mouse model Grade High grade primary (2) High grade primary (109) Variable grade High grade DKO model (4) High grade (43) Incidence 1-3 cases/ mill worldwide (110) > 8000 cases/ year registered (USA only) (109, Artificial induces OS 111) Not recorded Cat Rabbit High grade induced by radiation (42) Rare, but few cases Uncommon, have been reported cases/100,000 (44, 45) (42) Gender (1.5male:1 female) (2) Equal (2) Not reported No significance (4) Not reported Not reported Age Location in bone Distribution Occur commonly middle-age OS can induced artificially 75% of cases between to older ages, with median 7 Best to inject as young by chemical injection with Average age between 8-10 Median age reported years of age. 10%over years, however, many cases as possible (4-5 weeks 18 months old mice and 21 years (27, 48) 6 years old (42) 50s with secondary OS (2) reported OS between age) days OS detected after months (30) injection (4) Metaphysis of the long bone Metaphysis of long bone (2) Not reported (2) 75% occur in appendicular 50% knee joint (10), 25% skeleton (14-15), forelimbs femur, 15% tibia, 10% predominantly. Distal radius Only in tibia humerus 18%, proximal humerus 7% (112) Metaphysis of long bone (after injection) Metaphysis of long bone Metaphysis of long (46) bone (42) Jaw, head, followed by the Appendicular, axial & Distal scapula to the hind leg and hind hip, and extraskeletal sites (O6), diaphysis of humerus ribs and vertebra (4) and subcutaneous OS (47) (42) Location of metastases Lung (2) Lung (2) Lung Lung (4) Adjacent soft tissue (48) Aetiology Unknown Unknown Injected OS cell lines Unknown Unknown Unknown Experimental induced OS Clinical features Radiological Diagnosis Histology Spread through adjacent bone and there is no evidence of metastasis to the lung (42) Chemical agents: Beryllium, Mutagenic effects of ionizing Genetic manipulation, Injected OS cell lines Viruses: FBJ-virus, Irradiation radiation (113) Multiple double conditional knockout from double conditional induces: secondary OS, minor trauma (114), and of p53, prb genes Not reported Radiation (42) knockout model cell Electrical burn, and Trauma Genetic alterations (87) Chemical agents: lines (96) Radiation agents (4) Intermittent pain. Swelling at involved site (2) Acute to chronic lameness, swelling of the affected limb Same Same (24) Same (48) Same (42) (2) Destructive lesion at Aggressive destructive the bone from distal Aggressive, metaphyseal Aggressive, metaphyseal Aggressive, destruct the growth toward the joint with scapula to the lesions of the long bone, and lesions of the long bone, and Using luciferare imaging cortex of the bone and periosteal new bone diaphysis of the the tumour ranged from lytic the tumour ranged from lytic and micro CT involve surrounding soft formation at the site of humerus (no to blastic OS (115) to blastic (2) tissues (48) injection (24) surrounding tissue involved) (42, 116) Round to polyhedral neoplastic cells, round Osteoid, fibroblastic tumour, Malignant spindle cells, Malignant spindle cells, Malignant mesenchymal to oval nuclei, high similar with double malignant spindle cells, production of osteoid matrix production of osteoid matrix spindle cells, which c e l l u l a r, conditional model abnormal mitotic, multinucleated giant cells (4) by tumour cells (117) by the tumour cells (2) produced osteoid (48) pleomorphism, large number of multinucleated giant (116) Continuing Education Topics & Issues April

24 transgenic mouse is by introducing the DNA into embryonic stem cells; then the embryonic stem cells need a host embryo to develop and are isolated from a mouse with different color fur. The implanted embryonic stem cells will colonize a host embryo, and the resultant mouse in the first generation being chimera (mixture brown and black colors) the resulting sperms will carry the features of the original injected DNA. Then when these transgenic sperms fertilize a normal egg, a transgenic mouse will produce with the same foreign DNA in whole body cells 23. The most modern model was a genetically engineered technique performed on the mouse based on osteoblast-restricted deletion of p53 and prb. As a result, the OS development is dependent on loss of p53 and Rb, revealing a dominance of p53 mutation in the development of OS. This model is a crucial to addressing the molecular genetics of OS comparable with human, and valuable for developing therapeutic agents. 4 (see table 2). A study was done in Koch Institute for Integrative Cancer Research in MIT to successfully generate a double conditional knockout model (Osx-Cre+p53fl/flpRbfl/fl double conditional knockout mice). The combined deletion of both genes (p35 and prb) gave completely penetrant OS model and developed many defining characters similar to human OS, such as gene expression signatures, histological characters and metastatic potential 1. To generate the double conditional knockout model, the same study used mice that carried three alleles, which are the conditional allele of prb, p53 and Osx1-GFP-Cre transgene 24. Cre recombinase expression is controlled by Osterix1 (Osx1) promoter (Osx is a gene which differentially expresses at the earlier stages of osteoblast) 25. Crossing Rb+/c, Cre+, p53+/c, Cre+ or Rb+/cp53+/c, Cre+ males with Rbc/c, p53c/c or Rbc/c, p53c/c females will generate animals with all possibilities of combination between p53 and prb with or without Cre. It was confirmed that Cre only expressed in specific osteoblast and not other mesenchymal cells, and also confirmed that Cre catalytic activity only to the conditional prb and p53 alleles in bone. The breeding between fluxed p53 and prb with presence of Cre expression will develop a genotype highly predisposed to develop OS with short latency and complete penetrance, and the metastases are commonly seen in lung and liver 24. The double conditional knockout model (DKO) displayed typical characters of human OS such as histological features which showed destruction of the bone cortex, ossified spicules in the tumor which will be arised outside the periosteum (4). In addition, DKO model provides similarities in X-ray analysis with human OS by revealed sunburst pattern which indicate osteoid tissue (osseous before calcification stage) 24. Similarities Between Double Conditional Knockout Model (fluxed p53 and prb) and Tibial Injected Model A study 24 addressed a number of similarity characters between DKO model and tibial injected model by doing the following: (1) Harvested the OS tumor from the DKO mouse model. (2) Mechanically disaggregated tumor cells. (3) Placed those cells into the tissue culture. (4) After the tumor cells were grown in tissue culture, the cultured cells were injected into the nude immuno-compromised mouse intravenously and subcutaneously. (5) After days, the tumor arised. (6) A biopsy was taken from the arised lesion. H & E staining, Sirius Red stain, and Alizarin Red stain indicated that the arised lesion tumor closely resembled the parental OS which was poorly differentiated to undifferentiated. Furthermore, the subcutaneous injected tumor was highly invasive and metastasized into the lung and liver 24. Canine Model The clinicopathologic features of the canine OS closely approximates the morphology and biology behaviors of human OSs 26 (see table 1). Furthermore, the clinical staging system of OS in canine is highly similar in human OS, and because of the short life span of the dog, it is very easy to manifest the neoplasm within a short period. On the other hand, canine model clearly demonstrates that therapeutic results can be made within a shorter period time than human. For example, one year in OS survival in the dog is roughly equivalent to 4-5 years in human 27, 28 (Table 1). The epidemiological studies in the USA (Alabama and San Francisco universities) show the rate incidence of bone tumor is 7.9/100,000 dogs, whereas the incidence of bone tumors is 1.1/100,000 human 29. The fibrosarcomatous subtype is associated with a relatively favorable prognosis in both species 30. The best comparison in age incidence between human and dog OS, formulated by Lebeau, is 12 years old in human is equivalent to 1 year in dog; that is mean. With the OS diagnosed in a April 2013 Continuing Education Topics & Issues

25 old human, it will be equivalent to 2 years of OS diagnosed in dog 28. Age and site predilection are different. Most of the affected dogs are older animals, whereas mainly adolescents are affected in human. This feature represents the most difference between dog and human of age incidence 29. The dog limb bones and the knee region in the human are the sites involved. The varying localizations in man and dog, cat, cow, horse, and rodent might be associated with the stress of weight burden (radius, humerus, tibia and femur) 30. Males have slightly more incidence than females in man and dog 31, % of canine OS arises in the long bones, and only 23% involve flat bones 33. The majority sites of OS affected the dog forelimbs specifically in the proximal humerus and distal radius. Human OSs are arising in irradiated bone, in bone affected by Paget s disease, and in skeletal tumors (multiple enchondromas, multiple osteochondromas, fibrous dysplasia, and chondorsarcomas) 34, 35. The majority of clinical findings in canine OS are lameness and swelling, and have been observed within six months. The affected areas include a hard fusiform and painless swelling, with a severe case lymphedema at the distal side of tumor. The clinical pulmonary symptoms are not initially metastatic, but commonly develop the hypertrophic pulmonary osteoarthropathy at the late stage of OS metastasis 33 (see table 1). The histological features of canine OS are highly identical with human OS, which is character finding of osteoid by the sarcoma cells and varying amount of chondroid and collagen 33, 36. A study of 144 untreated dogs with OS indicated 49 dogs diagnose with metastasis, and 44 involve the lungs. The measurement of metastasis correlated with the tumor diameter, volume, and extension from the original site 30 (see table 1). Canine OS (OS) cell lines arise from mutations that directly inactivate the tumor suppressor genes p53 and retinoblastoma. Another gene such as PTEN gene (phosphatase and tensin homolog consider as a tumor suppressor gene through the action of its phosphatase protein product) is mutated in many human cancers 37. PTEN is mutated or down regulated in a high percentage of canine OS tumor cells 37 (see table 2). Mutations of the p53 gene in canine OS were screened for mutations of the complete p53 gene using PCR. The mutated gene was analyzed by single-strand conformational polymorphism. The clinical outcome of dogs with p53-mutated OS was compared to dog OS without a mutation. After complete surgical excision of the primary tumor, which is demonstrated by the p53 mutation common in canine OS, there may be may prognostic value that suggests the mutations of the p53 gene might be influenced by survival rate and it should be considered when evaluating the canine OS 38. Some case reports diagnosed the metastasis of appendicular OS. The appendicular OS metastasis extended to the anterior limbs. Some clinical findings showed detectable metastases to the eye before systemic organ metastases 39 (see table 1). However, there are no specific oncogenes that contribute to the pathogenesis of canine OS (OS). The over expresses the sis oncogene that encodes the platelet-derived growth factor (PDGF)-B. All of canine OS cell lines tested contained PDGF receptors. These cell lines are capable of responding to PDGF given the importance of PDGF in promoting cell proliferation, migration, and cell survival. Therefore, the activation of the sis oncogene potentially contributes to the pathogenesis of a subset of canine OS0 40 (see table 2). The study of isolated and characterized cancer stem cells from canine OS suggests that cancer is a stem cell disease 37. One of human OS cell line and three canine cell lines were cultivated in non-adherent media by used serum-starved and semi-solid medias. The grower colonies from all cell lines were identified under these conditions and were characterized by using molecular and cytochemical techniques for embryonic stem cell markers. Similarities between human and canine OS cell lines support the dog as a model for human disease. 41. A comparative study of OS may lead to new etiologic and pathogenetic concepts. Advantages of Canine Model For OS OS in canine 28 is more common than human. The clinical and diagnosis of canine OS is very easily recognized. Both humans and dogs share the same environment and similar causative agents; that should help to determine the environmental factors that might induce OS. The large size of dogs allows enough sample collection of blood and tissue samples. However, this characteristic does not present in the murine model. Unlike in dogs and humans, the murine model has no osteonal contexture, for example, a harversian canal; that is mean. The development of OS in dog osteonal bones is more closely aligned to human OS. Close similarity in the clinical, radiological and histological features of dog OS with human OS may give invaluable informa- Continuing Education Topics & Issues April

26 tion about the etiological, epidemiological, immunological, and therapeutic features of human OS. Rabbit Model Osteosarcoma occurring in domestic rabbit is rare, but a few cases have been reported 42, and it is highly induced by radiation. The median age reported is 6 years (see table 1). The clinical features of the rabbit are swelling at the site of lesion, with fever and lameness, and increase in the ALP 42. Many cases reported marked proliferative and destructive lesions of bone at the diaphysis of the humerus and involve joint space (see the table 1). Histological finding are similar among human, dog and rabbit which are round-to-polyhedral neoplastic cells that resembled histocytes; round-oval-nuclei, highly mitosis, pleomorphism; atypical nuclei and cytoplasm are predominant; and a large number of muti-nucleated giant cells (see table 1). Radiological diagnosis demonstrates the destructive lesion at the bone from distal scapula to the diaphysis of the humerus and no surrounding tissue involved (see table 1). However, no classification of osteosarcoma has been established. Furthermore, there are no reports of osteosarcoma metastasis to the lung in rabbit 42. In addition, it is seldom that osteosarcoma involves the joint spaces or surrounding soft tissues 42. Finally, there are no reports referring to the genetic involvement in rabbit osteosarcoma 42. Feline Model Feline osteosarcoma is relatively infrequent, but it is the most common malignancy of the bone tumors in the cat 43. The incidence has been reported of per cases 44, 45. The average age occurrence is between 8-10 years 27 (see table 1). There is no report that recognizes the gender preference of osteosarcoma in feline model 46. Feline osteosarcoma, located in the appendicular, axial of the long bones and extraskeletal sites, accounted for 40% of all feline osteosarcoma 47. Also, the extraskeletal osteosarcoma can be induced by injection sites. However, it has a poorer prognosis than the skeletal osteosarcoma 46, 47. Low metastasis rate of only 5-10% is reported in adjacent soft tissues 46 (see table 1). The histological characteristics of feline skeletal osteosarcoma are not significantly different from the canine osteosarcoma model 46, 48. The X-ray diagnos revealed the aggressiveness, destruction in the cortex of the bone and involved surrounding soft tissue 46. Genetically, the mutation of p53 in feline cases of osteosarcoma has been identified (see table 2). Data confirmed that osteosarcoma in the feline model is caused by the mutation in the coding regions of p53 gene 46, 49. A study used the IHC (Immunohistochemistry) analysis of p53 in feline neoplasia (46). The IHC staining analysis demonstrate p53 mutation in four cases of osteosarcoma out of 77 cases from different tumors, and also found the p53 inactivate mutation in lymphoma, mammary carcinoma and osteosarcoma, and the p53 mutated overexpressed in squamous cell carcinoma 46. This study suggests the mechanism of tumorigenesis may be similar in both human and feline.e. Furthermore, all the 77 feline tumour samples demonstrate the immunostaning only appear at the nucleus and no signals at the cytoplasm, which is provide strong evidence to support p53 abnormalities in the pathogenesis of different types feline neoplasia 46. Summary of animal models Mouse, dog, cat and rabbit are considered as mammalian animal models, serving in use for research and investigation of human disease, for the purposes of better understanding of the diseases without added any risk to humans during the process. OS is more common in the canine model than in the human model. Unlike the murine model, the OS is spontaneously induced in the canine model without genetic manipulation. Murine and canine models share many similarities in clinical and diagnostic features, histologically and in aggressiveness, as well as some oncogenes overexpressed in OS. The genetic engineering techniques had been performed on osteoblast - knockout of p53 and prb with using Osx1 - Cre, which is called double conditional knockout (DKO). The transgenic model has early developed OS with high penetrance and short latency. In contrast, the interrupted overexpression of p35 and prb pathways results the canine OS tumorigenesis. The osteosarcoma in the feline model reported by mutation in the coding regions of p53 gene. However, there are no data reported on genes expressed in rabbit osteosarcoma. Therefore, the animal models replicate many facts of human OS mechanism behavior, metastasis and pathogenesis; in addition, these models are helpful to monitor the progression of disease. 56 April 2013 Continuing Education Topics & Issues

27 The Genetic Basis Of Osteosarcoma (see table 1) No specific translocations or genetic abnormalities in humans have been identified to cause OS; 14, However, approximately 70% of OS tumor cells display the contribution of some genetic variation, which leads to cytogenic abnormalities 54, 55. Retinoblastoma All OS cell line results indicate that they are deficient of Rb pathways 56 ; retinoblastoma is a tumor suppressor gene. Rb family consists of Rb, P107, and P130, and they produce proteins which regulate cell proliferation and differentiation Normally, the prb gene regulates the cell cycle by controlling the activities of a number of E2F family. A group of activator and suppressor coding genes of transcriptional factors in high eukaryotic cells participate in cell cycle regulation and DNA synthesis 60. Many reports recognize the absence of Rb pathways, the Rb mrna levels will increase to compensate the loss or inactivation of Rb protein. 61, 62. The patients exhibitory prb mutations have approximate 500 folds higher incidence of OS than the general population. Furthermore, the prb mutations have been detected in 70% of all adolescent diagnosed with primary OS Moreover, the prb protein interacts with Runx2, which results the complex transcriptional activities involved the late stage of osteoblast marker osteocalcin 73 Thus, the loss of prb can suppress the terminal stage of osteogenic differentiation in vitro 74. However, a heterozygous Rb mutation produces a different type of tumour, but no OS 73. p53 P53 is a tumor suppressor protein which is encoded via TP53 gene. This gene plays a major role in osteoblast differentiation and bone development. P53 rearrangement and/or deletion of both alleles are common in human OS. P53 is activated in response of various stimuli which including DNA damage or promote nucleotide imbalance. A study by A.J. Levine was found the P21 and mdm2 inductive are considered to be one of defective properties of canine OS cell lines. 75 In another study was found the loss of heterozygosity at the Rb1 locus is present in approximately 60% to 70% of OS tumors 67. An absence of the p53 oncogene has been found in the early and metastatic stages of OS 76. Other reports identified the chromosomal location of 17p13, as abnormal in OS, and that is where p53 is located 55, 77. However, p53 mutation status is not associated with the stage of OS tumor and/or metastasis 78. Many studies demonstrate the p53 has ability to modulate the differentiation of osteoblasts, as well as play an important role in the bone development. Thus, the p53 deficient mice has accelerated osteoblast differentiation and increased bone density 79. The hyperactivation of p53 is induced by deleting mdm2 (p53 inhibitor), which leads to suppressed osteoblast differentiation by inhibited Runx2 (a bone specific transcriptional factor 80. The deletion of p53 from mesenchymal stem cells or from osteoblast precursors in vitro, that promotes transcriptional changes associated with early stages of osteogenesis but stops or impair at the end stage of differentiation to mature osteocyte 76. In addition, the reduced levels of p53 mrna are possibly resulted from inhibition of transcription or alteration of mrna degradation, which is lead to compromised p53 activities in tumour cells 56, 81. Many researches indicate the p53 is overexpressed in 84% from tumour cells derived from appendicular bones location, and in 56% from tumour cells derived from axial bones location 75, 81. The Relation Mechanism Between p53 and prb Genes Through studies performed by Nigg and Weinberg, it was found that any mutation or inactivation of Rb protein or response of growth inhibitory signals, the cyclin-dependant kinases (cdk) 4 and 6 inhibitors block the prb pathway by decrease the inhibitory activities of prb or deregulate cyclin D 60, 2. On the other hand, a study found that the p53 activity induced during any cell stress or DNA damage; by transcript mdm2 and cki p21 (is a protein encoded by CDK inhibitors and mdm2 is a negative regulator of p53 protein stability), both block of Rb phosphorylation 61, 62, 74, 83. In addition, the p53 participate in programmed apoptosis program of the cell in response to DNA damage, hypoxia, or chemotherapeutic agents 84, 85 and because of the tumour cells have activated oncogenes, the p53 and prb pathways are already inactivated, these features give more resistance against apoptosis and give a chance to accumulate additional mutations which contribute to tumour progression and aggressiveness 86. A study used IHC techniques to demonstrate the p53 is overexpressed in high percentage in canine OS cell lines 87, 88, and conse- Continuing Education Topics & Issues April

28 quently there are missing specific fragments in the prb, for example missing 3.7kb Rb specific sites which are presented in the control bone. Inactivation p53 and prb in murine OS cell lines The mutation of prb and p53 tumour suppressors is associated with OS development, using the transgenic mouse strain with inactivated p53 and prb in osteoblast precursors. The result of double conditional knockout mouse (DKO) of p53 and Rb has early developed onset of OS with complete penetrance 24, DKO (prb c/c; p53c/c) with the Osx1-Cre transgene (Cre recombinase is an enzyme that delete a gene between the two targeted sequences called loxp. Osx1 is a gene which only expressed in earlier stages of osteoblast development), produces a transgenic mice with complete OS penetrance and short latency, whereas die as early as 4 months age 89. DKO OS cell line in mice share many characters of human OS such as 90 ; predisposition to develop the tumour within femur, knee joint and lower femur and upper tibia, when are considered to be active bone growth and repair sites. Cellular composition is similar to human and both species and share high incidence of pulmonary metastases is a major cause of death. Both sporadic and familiar OS predispose the inactivation of p53 and prb play a key role in development of OS and other tumours such as neuroendocrine tumours, and 53, 91 hibernomas Inactivation p53 and prb in canine OS cell lines Canine model of OS has been used to study the cancer biology and treatment; however the pathogenesis of canine OS is still unknown 92, the similarity characteristics between human and canine OS are the same aggressiveness 93, highly metastatic tumour, similar histology 94, difficult to manage clinically, because the aggressive biological behaviour of this tumour, and same location tumour distributed of the long bones. Furthermore, both species are associated with abnormalities of p53 and prb genes in the OS. On the other hand, there are different characters between human and Canine OS including that it is a common tumour in dogs but rare with human 95. OS generally occur in older age in dogs whereas OS occur in adolescent age group in human 95. The Comparison Between p53 and prb of Murine and Canine OS Cell Lines All the results obtained from the canine OS cell lines underscored the inactivation of p53 and prb in canine OS tumorigenesis 92. The p53 mrna is either overexpressed or not expressed in canine cell lines OS 2. The prb mrna is overexpressed with high levels in all canine cell lines OS. P53 and Rb proteins are overexpressed in high percentage of canine OS 2, whereas in all DKO mouse OS cell lines, the p53 and prb genes are absolutely knockout 24. Common Methods are Used for Osteosarcoma Research A number of developing technologies continue to provide us a comprehensive assessment to understand more about the tumor behaviors. Recently, massive studies have been done of the molecular genomic sequences of osteosarcoma by using techniques of genomic array, FISH, and ISH. To understand the mrna expression of osteosarcoma and also in many tumors, the RT-PCR is the best way for these purposes. Western blot (WB) experiments have been used for more understanding of protein expression which resulted from the gene or oncogene expression. Flow Cytometry (FC) is a very widely used method to understand the tumor cell surface expression and to determine which CDs or markers would differentiate a tumor from others. It is a very valuable method to understand the tumor cell expressions in metastasis stages in vitro. Remarkably, Immunohistochemistry (IHC) is the best method to localize the proteins expression in the tumor tissue sample and it will provide important information of OS tumorogenesis and aggressiveness. Finally, the PCNA (Proliferating Cell Nuclear Antigen) is a valuable method to measure the invasiveness and aggressiveness of malignancies including all kinds of osteosarcoma. Summary of Genetic Bases of OS Genes expression profiles will provide valuable information about cancer biology and behaviors. It can be used for developing biomarkers to identify consequent genes and be involved in a specific function of tumor molecular biology. On the other 58 April 2013 Continuing Education Topics & Issues

29 hand, the initial mutations have been linked to activate oncogenes or inactivate the tumour suppressor genes, which can trigger certain subsequent events leading to cellular transformation and tumor formation. Finally, the identification of these genes might increase the understanding of how osteosarcoma develops and progresses to malignancy as well as the tumorigenesis and metastasis behaviors. Conclusions This review describes the importance of submissive animal models of human disease which will offer many opportunities to advance our knowledge and understanding of cancer biology and genetics of human cancer. The modern genetic engineered mouse (DKO) model provides many similarities to human OS characteristics. On the other side, a number of studies demonstrate the similarity between the tibial injected model and DKO model. In comparative oncology, canine model of OS has great potential with characteristics of human OS, especially in histology, clinical relevant, biological advances, pre- and post- clinical treatment evaluations. Interestingly, many genes are expressed and/or overexpressed in OS common among human, mouse, and canine models. Therefore, the study of genes expression and the mechanisms are involved to initiate OS are very important to understanding the tumorigenesis, invasiveness and aggressiveness of this tumor. In other words, the development and utilization of murine and canine models faithfully reflect the OS behaviors in humans, which is considered a significant promise to enhance our understanding of OS genetic basis. Finally, the advance in diagnostic methods and therapeutic agents will be enhanced by identifying the genes that contribute to OS aggressiveness, and identifying the genes involved in primary OS and other genes that contribute to potential metastasis. References 1. 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Tissue-specific tumor suppressor activity of retinoblastoma gene homologs p107 and p130. Genes Dev Dec 1;18(23): Clark JC, Dass CR, Choong PF. A review of clinical and molecular prognostic factors in osteosarcoma. J Cancer Res Clin Oncol Mar;134(3): Levine RA, Fleischli MA. Inactivation of p53 and retinoblastoma family pathways in canine osteosarcoma cell lines. Vet Pathol Jan;37(1): Mertens WC, Bramwell V. Osteosarcoma and other tumors of bone. Curr Opin Oncol Jul;6(4): Theilen GH, Leighton R, Pool R, Park RD. Treatment of canine osteosarcoma for limb preservation using osteotomy, adjuvant radiotherapy and chemotherapy (a case report). Vet Med Small Anim Clin Feb;72(2): Ru G, Terracini B, Glickman LT. Host related risk factors for canine osteosarcoma. Vet J Jul;156(1): Fuchs B, Pritchard DJ. Etiology of osteosarcoma. Clin Orthop Relat Res Apr(397): Wang LL. Biology of osteogenic sarcoma. Cancer J Jul- Aug;11(4): Mendoza S, Konishi T, Dernell WS, Withrow SJ, Miller CW. Status of the p53, Rb and MDM2 genes in canine osteosarcoma. Anticancer Res Nov-Dec;18(6A): Wang LL, Gannavarapu A, Kozinetz CA, Levy ML, Lewis RA, Chintagumpala MM, et al. Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. J Natl Cancer Inst May 7;95(9): Continuing Education Topics & Issues April

32 100. Zhou H, Randall RL, Brothman AR, Maxwell T, Coffin CM, Goldsby RE. Her-2/neu expression in osteosarcoma increases risk of lung metastasis and can be associated with gene amplification. J Pediatr Hematol Oncol Jan;25(1): Flint AF, U Ren L, Legare ME, Withrow SJ, Dernell W, Hanneman WH. Overexpression of the erbb-2 proto-oncogene in canine osteosarcoma cell lines and tumors. Vet Pathol May;41(3): Kappel CC, Velez-Yanguas MC, Hirschfeld S, Helman LJ. Human osteosarcoma cell lines are dependent on insulin-like growth factor I for in vitro growth. Cancer Res May 15;54(10): MacEwen EG, Kutzke J, Carew J, Pastor J, Schmidt JA, Tsan R, et al. c-met tyrosine kinase receptor expression and function in human and canine osteosarcoma cells. Clin Exp Metastasis. 2003;20(5): Coltella N, Manara MC, Cerisano V, Trusolino L, Di Renzo MF, Scotlandi K, et al. Role of the MET/HGF receptor in proliferation and invasive behavior of osteosarcoma. Faseb J Jun;17(9): Ladanyi M, Park CK, Lewis R, Jhanwar SC, Healey JH, Huvos AG. Sporadic amplification of the MYC gene in human osteosarcomas. Diagn Mol Pathol Sep;2(3): Khanna C, Wan X, Bose S, Cassaday R, Olomu O, Mendoza A, et al. The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat Med Feb;10(2): Laverdiere C, Hoang BH, Yang R, Sowers R, Qin J, Meyers PA, et al. Messenger RNA expression levels of CXCR4 correlate with metastatic behavior and outcome in patients with osteosarcoma. Clin Cancer Res Apr 1;11(7): Dickens DS, Kozielski R, Khan J, Forus A, Cripe TP. Cyclooxygenase-2 expression in pediatric sarcomas. Pediatr Dev Pathol Jul-Aug;5(4): Priester WA, McKay FW. The occurrence of tumors in domestic animals. Natl Cancer Inst Monogr Nov(54): Goorin AM, Abelson HT, Frei E, 3rd. Osteosarcoma: fifteen years later. N Engl J Med Dec 26;313(26): Withrow SJ, Powers BE, Straw RC, Wilkins RM. Comparative aspects of osteosarcoma. Dog versus man. Clin Orthop Relat Res Sep(270): Knecht CD, Priester WA. Musculoskeletal tumors in dogs. J Am Vet Med Assoc Jan 1;172(1): Gillette SM, Gillette EL, Powers BE, Withrow SJ. Radiation-induced osteosarcoma in dogs after external beam or intraoperative radiation therapy. Cancer Res Jan 1;50(1): Bennett D, Campbell JR, Brown P. Osteosarcoma associated with healed fractures. J Small Anim Pract Jan;20(1): Wrigley RH. Malignant versus nonmalignant bone disease. Vet Clin North Am Small Anim Pract Mar;30(2):315-47, vivii Renfrew H, Rest JR, Holden AR. Extraskeletal fibroblastic osteosarcoma in a rabbit (Oryctolagus cuniculus). J Small Anim Pract Sep;42(9): Powers BE, LaRue SM, Withrow SJ, Straw RC, Richter SL. Jamshidi needle biopsy for diagnosis of bone lesions in small animals. J Am Vet Med Assoc Jul 15;193(2): LABORATORY TRAINING FROM THE EXPERTS The Association of Public Health Laboratories (APHL) sponsors educational programs on critical issues in laboratory science, some of which are in conjunction with other professional laboratory organizations such as the Clinical and Laboratory Standards Institute (CLSI) and the American Society for Clinical Laboratory Science (ASCLS). Below are only a few of the courses available. All courses provide P.A.C.E. credits. For a complete listing of upcoming, pre-recorded, and on demand programs, visit MARK YOUR CALENDARS (for these upcoming webinars) May 7 On Slippery Slopes: Principles, Problems and Cases in Lab Ethics May 14 The Impact of Global Warming on Vector-Borne Diseases June 4 Determining Clinical Relevance of Fungal Isolates June 20 Transport Systems and CLSI Document M40: It s Not Just Swabs (cosponsor CLSI) June 27 CLSI s Guide to Planning Laboratory Operations during a Disaster (cosponsor CLSI) Above are just a few of the upcoming webinars. Registration fee for webinars includes the live webinar for ALL of your staff PLUS unlimited access to the archived webinar (and CEUs) for your staff for 6 months! What a bargain! Don t worry if you can t participate on that day; all are available as on-demand courses AFTER the course same great deal of unlimited access (and CEUs). AND MANY MORE! Log on to and see why thousands of your colleagues attend APHL-sponsored courses each year! REGISTRATION NOW OPEN: 2013 APHL Annual Meeting & 7 th Government Environmental Laboratory Conference June 2-5, 2013 Raleigh, NC Pre-Conference Workshops (June 2): FBI s Joint Criminal & Epidemiological Investigation & Informatics & Meaningful Use April 2013 Continuing Education Topics & Issues

33 Questions for STEP Participants AMT strongly encourages you to submit your answers online so that the CE credits can be automatically transferred into your AMTrax account. To do so, go to click on the AMT Store on the top navigation bar. Click on STEP Online, then select the article number and purchase the test. Don t forget to log in to receive the discounted member price of $5 (nonmembers pay $15/test). If you wish to submit answers manually (only available to AMT members), the fee is $10/test. Please submit a copy of this page with your answers marked, along with a completed order form located elsewhere in this publication. Don t forget to include payment. Article Clock Hours 1. Treatment for Osteosarcoma has not changed in the last 30 years. A. True B. False 2. Why have researchers selected the tibial injected model of OS in mouse? A. Because of the similarity in oncogenic behaviors between human & mouse model B. Because of the similarity in clinical diagnosis between human & mouse models C. Because the similarity in tumorogenesis & metastasis behavior between human & mouse model D. Because the similarity in environmental factors between human & mouse models 3. Bioluminescence, an in vivo imaging technique, enables real-time monitoring of the labeled substances in experimental animals. A. True B. False 4. Cure rates for patients with metastatic or relapsed disease are poor, around 50% survival. A. True B. False 5. Osteosarcoma metastases (tumor invasiveness) by blood vessels A. True B. False 6. Osteosarcoma has high invasiveness and metastasis into the A. brain and CNS B. lower limbs C. lung and liver D. adrenal gland & kidney 7. The cellular similarity between double conditional knockout mouse model and tibial injected mouse model of Osteosarcoma is: A. Both models of Osteosarcoma cells are difficult to culture in vivo B. Both cells are mechanically disaggregated C. Both cells show the invasiveness to the kidney tissue in the immunecompromizing node mice D. Both cells are highly differentiated 8. The genetic engineering techniques had been performed on osteoblast - knockout of p53 and prb using Osx1 - Cre, which is called double conditional knockout (DKO). The transgenic model has early developed OS with A. High penetrance and short latency. B. High penetrance and long latency C. Low penetrance and short latency D. Low penetrance and long latency 9. In bone malignancies, the loss of prb can suppress the terminal stage of: A. Osteogenic differentiation B. Chondogenic differentiation C. Embryonic Stem cell differentiation D. Hematopoietic cells differentiation 10. p53 gene has unrecognized ability to modulate the differentiation of osteoblasts, and bone development. A. True B. False Continuing Education Topics & Issues April

34 HOME STUDY UNITS FOR AMT MEMBERS Offered by Association for Continuing Education, LLC, (ACE) The self-instructional units listed below have been reviewed and approved for Continuing Education for AMT members by the American Medical Technologists Institute for Education (AMTIE). To participate in home study programs: 1) Order the units desired directly from Association for Continuing Education (ACE) using the form below (photocopy accepted); 2) Complete unit and AMTIE post test enclosed with unit; 3) Send completed post test to ACE, P.O. Box 573, Beaufort, SC with $6.00 per test for grading and score reporting. Results of your participation will be recorded in your AMT continuing education file. ORDER FORM The following self-instructional units are AMTIE approved for AMT Continuing Education. PROGRAM CLOCK UNIT QUANTITY TOTAL HOURS COST ORDERED COST Basic Laboratory Techniques #100 Performing a Capillary Puncture 1.5 $ 9.50 #101 Venipuncture: The Art of Drawing Blood 3.0 $13.50 #102 The Making of a Blood Film 1.5 $ 9.50 Chemistry #206 Quality Control Overview for Clinical Chemistry 3.0 $13.50 #207 Laboratory Evaluation of Cardiac Markers 3.0 $13.50 #208 Kidney Function Tests 3.0 $13.50 #209 Total and Ionized Calcium in Serum 2.0 $11.50 Chemistry #400-1 Intro to Hematopoiesis - booklet and CD w/35 photo images 4.0 $37.50 #400-2 Intro to Hematopoiesis - booklet only (no CD) 2.0 $12.50 #404 Hematology Indices 2.0 $12.50 #409-1 Cerebrospinal Fluid - booklet and CD w/37 photo images 5.0 $44.50 #409-2 Cerebrospinal Fluid - booklet only (no CD) 3.0 $13.50 #410-1 Reticulocyte Counts - booklet and CD w/35 photo images 4.0 $37.50 #410-2 Reticulocyte Counts - booklet only (no CD) 2.0 $12.50 #411 Erythrocyte Sedimentation Rates 1.0 $ 8.50 #414 Hemoglobin H Disease 2.0 $12.50 #415 Iron Metabolism 3.0 $13.50 #418 Hemolysis Testing 4.0 $14.50 #450 Coagulation Phase of Hemostasis 2.0 $12.50 Immunology #500 Intro to ABO Blood Group System 2.0 $12.50 #501 Reading and Grading Agglutination Reactions 1.0 $ 8.50 #502 Solving Blood Bank Problems 3.0 $14.50 #503 Problems in Antibody Identification 3.0 $14.50 #550 Antigens and Antibodies 2.0 $12.50 #551 Principles of Antigen-Antibody Reactions Used in the Lab 3.0 $14.50 #552 Complement Cascade 2.0 $12.50 Microbology #606 Overview of TB Infection and Disease 2.0 $12.50 Mycology #650 Introduction to Medical Mycology 1.0 $ 8.50 Statistics #762 Descriptive Statistics 2.0 $12.50 Urinalysis #800 Chemical Screening of Urine by Reagent Strip 2.5 $13.00 Name Address City, State, Zip MT MLT RMA RDA AMT ID # Total Shipping $4.75 Amount Enclosed Return this form with check or money order to: ACE P.O. Box 573, Beaufort, SC April 2013 Continuing Education Topics & Issues

35 Continuing Education Opportunities AMT strongly advocates lifelong learning as a part of your personal and professional growth. Take a look at the great CE opportunities that AMT has to offer! STEP Online STEP Online consists of short scholarly articles on a variety of topics and a 10-question quiz. While the articles and quizzes are available online, they also appear in the Journal of Continuing Education Topics & Issues. A nominal fee is assessed for the quiz, taken either online or manually. Topics On-Demand Courses On-demand courses are offered on timely topics and are available 24/7. Each course consists of an audio-presentation synched with PowerPoint slides. To receive credit, the participant must successfully pass a 10-question quiz. A nominal member fee applies. Prevention Assistants Webinars available 24/7. To receive credit, the participant must successfully pass a 10-question quiz. A nominal member fee applies. Topics

36 Article Clock Hour Safely Storing Laboratory Chemicals Karen Appold Karen Appold is a medical writer. Visit www. WriteNowServices. com. When looking to learn about proper chemical storage in your laboratory, consult officials who can advise you. These might include your facility s safety officer, the local fire marshal, a radiation safety officer (if you handle radioactive material), an Occupational Safety and Health Administration representative and/or an Environmental Protection Agency official (if you re disposing of unused chemicals). Become friends with these people, they can help you, advised Peggy A. Wenk, HTL(ASCP)SLS, Beaumont Health System, Beaumont Laboratory, Royal Oak, MI, who recently presented an audio conference on this topic for the National Society for Histotechnology. When consulting with these individuals, tell them what chemicals you have, where they are located, the room s layout, where fire extinguishers are placed and where chemicals are being stored. You don t want safety personnel to be surprised during a fire or evacuation, Wenk said. Invite them to come in and to look around. Ask them for advice and to train you on how you can do things better. They can t cite or fine you if you invited them in, Wenk continued. That is much better than them coming in unannounced and finding violations and fining you. That can be very expensive. Preparing a Chemical Inventory Create an inventory sheet of all chemicals in stock prior to a consultant s visit. Indicate details such as the quantity on hand and its physical state (e.g., solid, liquid or gas). This will save a significant amount of time and should be easy to revise. New employees can access this form to determine what type of gloves to wear, how to store chemicals, how to dispose of chemicals and so forth. If you need a safety data sheet, ask your safety officer or google MSDS and the chemical s full name in quotes. Enter vendor information and any other relevant information such as correct chemical, correct percent and concentration. You can also obtain a lot of MSDS from the web site Safety Information Resources, Inc., available at On the chemical inventory sheet, be sure to record the chemical s exact name. This might require writing more than one name, such as sodium borate, borax or sodium tetraborate decahydrate. If you re listing dye powders, include the digital number from the Biological Stain Commission. If using pre-made solution, you don t have to list every single dye, Wenk noted. Your inventory sheet should also include where each chemical is stored, how to dispose of it, if any personal protective equipment needs to be worn when handling it, what engineering controls need to be used, if a splash guard is required, if it needs to be used in a hood, and so forth. Properly Placing Containers Chemicals should be stored at or below countertop level. They should not be stored on the floor (they can be kicked over and break) or a top shelf (they could fall and break). Don t store too many chemicals in a cupboard. Having to move around containers to find the correct chemical could lead to a container being dropped. Don t store chemicals underneath a sink, either. Hot water passing through pipes can warm 66 April 2013 Continuing Education Topics & Issues

37 an area, heat up chemicals and cause them to break down. Also be wary of storing too many bottles in a hood--this can impair ventilation. Chemicals also shouldn t be stored on the countertop. Here, they can be knocked over and exposed to light, exposing employees to additional dangers. Wenk advised against storing chemicals alphabetically, because some chemicals aren t compatible. Store chemicals according to their hazard, she said. You ll also want to avoid placing chemicals in sunlight or direct light. Bulbs that illuminate counters make the counters hotter, lighter and brighter, Wenk said. Pay attention to light and heat sources. Put chemicals in cupboards away from heat, including the undercounter lights that warm up the bottom shelf in the cupboard. Wenk also suggested that laboratorians examine shelves and racks. Make sure they are strong enough to support the weight of chemicals. Don t store bottles on their sides if they don t fit upright in a cupboard--they could roll off and break. Don t store bottles on top of each other, either. Securely anchor shelves, cupboards and racks to a permanent structure. Put a bar or lip on the front of a shelf in case of an earthquake or other unsuspecting motion occurs. And don t think that something couldn t happen to you, Wenk said. People in Washington, DC, were totally taken off guard with the earthquake in Clean out cupboards periodically. If you don t use a chemical for one year, throw it out. Same goes if the expiration date occurs, a container rusts or bulges, or the color changes, Wenk said. Purchasing large quantities isn t always wise if you have to toss unused expired chemicals. Choosing Containers As far as the type of material used to store chemicals, plastic is ideal. Metal containers can rust and/or the label might fall off. Spills and splashes could result. Glass can break. But if glass is necessary, Wenk advised buying glass coated with polyethylene that is impact resistant. Always check for leaks and spills when storing chemicals. Ideally, chemicals should be stored in their original containers. You can pour a chemical into another container, but be sure to properly label it, Wenk said. Check that lids and caps are on tightly. Chemicals can outgas and they can interact and create new chemicals, Wenk noted. Signs and Labels Some dangers can be avoided by properly identifying hazardous chemicals and areas. For instance, make large signs to indicate the oxidizer cabinet and note where the flammable cabinet is. Post a note on a refrigerator if food shouldn t be stored in it. Many companies sell safety signs, one of which is Lab Safety Supply, available at www. lss.com. Label chemicals with the dates they arrived and when they expire. If you make chemicals, you need to say exactly what chemicals are in the solution, Wenk reminded listeners. Specific Chemical Storage Tips Wenk also provided specific advice for the storage of all types of chemicals, from acids to reactive/explosive chemicals. Here s a partial summary of tips she offered. Store acids in a corrosive cabinet that has the word acid written across it. Certain acids should not be stored together. For example, nitric acid should be stored separately from organic and inorganic acids. Bases/alkalis, the opposite of acids, need to be stored separately in a corrosive-resistant cabinet. They can destroy tissue and/or metals. An oxidizer, a chemical that releases oxygen, will increase a fire hazard. Don t store them near paper. Contact your safety department and/or fire marshal to figure out where flammables/combustibles can be stored, and at what quantity. Reactive/explosive chemicals, i.e., those that will have a sudden release of pressure, gas or heat, should be stored in places where minimal damage would occur. Toxic chemicals, those that will act upon life processes, and cause death, temporary incapacitation, or permanent harm to humans or animals, should be stored in a cool, well-ventilated area, away from heat and light. Controlled substances, i.e., drugs or other substances that have a potential for abuse or for causing dependence, should be in a double locked metal box, bolted to a permanent structure. Continuing Education Topics & Issues April

38 Final Thoughts Wenk advised laboratorians to walk around their lab with chemical eyes looking for chemical risks. Consult safety experts to determine the risk assessment, create a chemical inventory sheet, implement appropriate storage techniques, and identify hazards and plan to minimize them. This article is based upon an audio conference presented by the National Society for Histotechnology titled, "Safe Storage of Laboratory Chemicals, given by Peggy A. Wenk, HTL(ASCP)SLS, Beaumont Health System, Beaumont Laboratory, Royal Oak, MI. Crossword solution from page April 2013 Continuing Education Topics & Issues

39 Questions for STEP Participants AMT strongly encourages you to submit your answers online so that the CE credits can be automatically transferred into your AMTrax account. To do so, go to click on the AMT Store on the top navigation bar. Click on STEP Online, then select the article number and purchase the test. Don t forget to log in to receive the discounted member price of $5 (nonmembers pay $15/test). If you wish to submit answers manually (only available to AMT members), the fee is $10/test. Please submit a copy of this page with your answers marked, along with a completed order form located elsewhere in this publication. Don t forget to include payment. Article Clock Hour 1. Which personnel can provide information on how to properly store chemicals in your laboratory? A. Your facility's safety officer B. The local fire marshal C. A radiation safety officer D. All of the above 2. If you invite safety personnel into your lab, they can cite or fine you for a violation. A. True B. False 3. Chemicals can be stored anywhere in the lab, as long as they are stored properly. A. True B. False 4. You shouldn't store chemicals underneath a sink because hot water going through pipes can heat up chemicals and cause them to break down. A. True B. False 5. It's a good idea to store chemicals alphabetically, because they will be easier to find. A. True B. False 6. Which one is not a good reason to throw away a chemical: A. It just expired. B. You haven't used it for six months. C. The container is bulging. D. A chemical's color changed. 7. What is the best type of material to store most chemicals in? A. Metal B. Glass C. Plastic D. Cardboard 8. Certain types of acids should never be stored together. A. True B. False 9. Which type of chemical should not be stored close to paper? A. Acid B. Oxidizer C. Bases D. Alkalis 10. What are some guidelines regarding storing toxic chemicals? A. Store in a cool place B. Store in a well-ventilated area C. Store in a well-lit area D. Only A and B are correct. Continuing Education Topics & Issues April

40 American Medical Technologists AMT National Officers, 2013 (Terms of Office) President: Mary Burden, MT, 1041 Kings Road, Moore, OK ( ) Vice-President: Everett Bloodworth, MT, 930 Pine St., Benton, KY ( ) secretary: Jeff Lavender, MT, Blue Haven Dr. NE, Kalkaska, MI ( ) Treasurer: Janet Sesser, RMA, 2815 East Windrose Dr., Phoenix, AZ ( ) Board of Directors (Terms of Office) Nancy B. Barrow, MT, 715 Beverly Way, Martinsville, VA ( ) Dr. Paul C. Brown, MT, 2506 South Cobb Loop, Millbrook, AL ( ) Heather Herring, MT, RMA, E. Eaves Way, Farmington, MN ( ) Jeannie Hobson, RMA, RPT, CMAS, AHI, 2323 E. Robinson, Fresno, CA 93726, ( ) Carole Aston, 716 Ontario St. #3, Oak Park, IL (Public Member) (Appointed annually) Immediate Past-President Roxann Clifton, MT, 409 E. Mississipi, Sayre, OK ( ) Judiciary Councillor (Appointed annually) Kim Cheuvront, PhD, 100 Fair Oaks Dr., Fairmont, WV EXECUTIVE COUNCILLOR (Appointed annually) Edna Anderson, MT, 1397 Redwood St., NW, Salem, OR Eastern District (Maine, New Hampshire, Vermont, Massachusetts, New York, Connecticut, Rhode Island, New Jersey, Pennsylvania, Delaware, District of Columbia, Maryland, West Virginia, Canada) Janet Crigler, MT, 23 Pheasant Dr., Fairmont, WV DISTRICT COUNCILLORS (Appointed annually) Great Lakes District (Michigan, Wisconsin, Illinois, Indiana, Ohio, Iowa, Minnesota, North Dakota, South Dakota) Clara Boykin, MT 1023 Dayton Ave., St. Paul, MN Southern District (Alabama, Florida, Georgia, South Carolina, Kentucky, North Carolina, Tennessee, Virginia, Caribbean) Shannon Newman, MT 249 Willie Craig Rd. Bassett, VA Central District (Texas, Oklahoma, Arkansas, Louisiana, Nebraska, Kansas, Missouri, Mississippi) Randall Swopes, MT 2691 Whittington Westlake, LA Western District (Washington, Oregon, Idaho, Montana, Nevada, California, Wyoming, Utah, Colorado, Arizona, New Mexico, Alaska, Hawaii) Kenneth Hawker, MT 6631 W. Sunrise Oak Dr. West Jordon, UT AMTIE BOARD OF TRUSTEES, 2013 (Terms of Office) President: Linda Jones, MT, 4673 Lambsburg Rd., Lambsburg, VA ( ) Vice-President: Art Contino, RMA, 3117 South Horizon Pl., Oviedo, FL ( ) SecRETARY Marty Hinkel, MT, 2204 Peggy Dr., Worland, WY ( ) Treasurer: David P. Yocom, Jr., th St. SE, Everett, WA (Public member - appointed annually) Executive Director: Gerard P. Boe, PhD, MT, 7 Sussex Ct., Beaufort, SC (Appointed annually) TRUSTEES: Everett Bloodworth, MT, 930 Pine St., Benton, KY (AMT Board appointment)(appointed annually) Norma (Taffy) Durfee, MT, PO Box 432, Iola, TX ( ) Kay Fergason, MT, 3712 Arava Dr., Green Cove Springs, FL (Immediate Past President) ( ) Zenaida Maraggun, MT, 1602 Amour Drive, Leesville, LA ( ) AMT OFFICE Christopher A. Damon, J.D., Executive Director W. Higgins Road, Suite 150 Rosemont, Illinois Telephone: (847) or (800) Fax: (847) Web Site: AMT, established in 1939, is a national, non-profit certification agency for: Medical Technologist, MT Medical Laboratory Technician, MLT Registered Medical Assistant, RMA Registered Dental Assistant, RDA Certified Medical Laboratory Assistant, CMLA Registered Phlebotomy Technician, RPT Certified Laboratory Consultant, CLC Certified Allied Health Instructor, CAHI Certified Medical Administrative Specialist, CMAS For information on qualifications necessary for each certification, contact: AMT, Higgins Rd., Suite 150, Rosemont, IL Phone: 847/ April 2013 Continuing Education Topics & Issues

41 Directory Alabama Rikki Packer, RMA, Virginia Col, Dailey Lane, Foley, AL 36535, Arizona Fred Morley, MT, 5700 East El Camino Quinto, Apache Junction, AZ 85119, Arkansas Tonda Ellis, CMLA, RPT, 1160 Midway Rd., Monticello, AR 71655, California Sheryl Rounsivill, RMA, RPT, CMAS, AHI, 2078 S. Hayston, Fresno, CA 93702, CENTRAL PLAINS (Kansas/Nebraska) Tera Benefiel, MT, 622 S. McPherson Ave., Burrton, KS 67020, COLORADO (See Rocky Mountain) CONNECTICUT (See Tri-State) DC/DELAWARE/MARYLAND Robin Miliner, MT, 9695 Halstead Ave., Laurel, MD 20723, Florida Kay Fergason, MT, 3712 Arava Dr., Green Cove Springs, FL 32043, Georgia Marvin Matthews, MT, 5565 La Fleur Trail, Lithonia, GA 30038, Hawaii Minelva B. Manuel, RMA, Koauka LP Unit 10F, Aiea, HI IDAHO (See Northwest) Illinois Nancy Gabl, RMA, AHI, 1768 Coach Drive, Naperville, IL 60565, Indiana L.E. Vern Hein, MT, 6060 E. 141st Ave., Crown Point IN Iowa Beverly Christiansen, RMA, 1096 Grouse Ave., Hampton, IA 50441, Kansas (See Central Plains) KENTUCKY Christina Huff, RPT, RMA, 597 Morehead Rd., Bowling Green, KY 42101, huffcggclinic.com LOUISIANA Zenaida Maraggun, MT, 1602 Amour Drive, Leesville, LA 71446, maine/new Hampshire Susan Constable, MT, 257 Heywood Rd., Winslow, ME 04901, MASSACHUSETTS (See Tri-State) Maryland (See DC/Delaware) michigan Sieglinde Wildie, MLT, 25 Rural St., Port Huron, MI minnesota Edith Tefft, MT, 317 Frenn Ave., Red Wing, MN 55066, mississippi Cecil Hunt, MT, 4040 Colton Dr., Olive Branch, MS 38654, missouri Alberta Smith, RMA, AHI, 1997 Ridgeway, Arnold, MO 63010, MONTANA (See Northwest) NEBRASKA (See Central Plains) NEVADA Juanita Stocke, MT, 1812 Cambridge Hills Ct., Reno, NV 89523, NEW HAMPSHIRE (See Maine) NEw jersey Elizabeth Suarez, RMA, Lincoln Tech Inst, 3 Silvercolt Dr., Colts Neck, NJ 07722, new mexico Virgil E. 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Durfee, MT, PO Box 432, Iola, TX 77861, Tri-State (Connecticut, Massachusetts, Rhode Island) Phyllis Nordby, RMA, Porter & Chester Inst., 166 Davis St., Oakville, CT 06779, UTAH Michelle Tew, RMA, 1158 Lafayette Drive, Salt Lake City, UT 84116, Virginia Patricia Harris, MT, P.O. Box 262, Independence, VA Washington state (See Northwest) West Virginia Tonya Brown, MT, 333 Baldwin St., Fairmont, WV 26554, wisconsin Julie Lent, MT, 610 Fremont St., Algoma, WI 54201, WYOMING (See Rocky Mountain) Caribbean Assn. (CASMET) Grant Lambert, AHI, PO Box 2293, Lagoon Rd., St. George s, Grenada, West Indies, Committees Executive Mary Burden, MT, President Everett Bloodworth, MT, Vice President Jeffrey Lavender, MT, Secretary Jan Sesser, RMA, Treasurer Roxann Clifton, MT, Immediate Past President Edna Anderson, Executive Councillor Kim Cheuvront, PhD, Judiciary Councillor Christopher A. Damon, J.D., Executive Director (ex-officio) Audit & Budget Janet Sesser, RMA, Chair Everett Bloodworth, MT Mary Burden, MT Luther Ray Dean, MT Cynthia Kukenberger, MT Miriam Mia Rutkiewicz, RMA Nicole Weiss-Lopez, RMA, RPT Christopher A. Damon, J.D., Executive Director (ex-officio) Federal Government/Legislative John Sherer, MT, Chair Pat Westbrook, MT, Vice Chair Mary Burden, MT George Cook, MT Bill Dettwyler, MT Linda Jones, MT Mary Midkiff, MT Bob Newberry, MT Barbara Ware, MT Kimberly Cheuvront, PhD (ex-officio) Michael McCarty (ex-officio) Judiciary Kim Cheuvront, PhD, Chair Everett Bloodworth, MT Sheryl Rounsivill, RMA, RPT, CMAS, AHI Michael McCarty, Legal Counsel Bylaws Kimberly Cheuvront, PhD, Chair Joyce Lybrand, MT Linda Raven, RMA, RPT, COLT Michael McCarty (ex-officio) Examinations, Qualifications and Standards David McCullough, MT, Chair Roxann Clifton, MT Ronald Lepoff, MD Janet Sesser, RMA James Fidler, PhD (ex-officio) Laboratory Certification Examination Development Teams General Laboratory Charles Baker, MT, Team Leader Fred Morley, MT Norma (Taffy) Durfee, MT Clinical Chemistry Mary Midkiff, MT, Team Leader Roxann Clifton, MT Hematology, Hemostasis, and Urinalysis Dr. Georgia McCauley, Team Leader Carlo Ledesma, MT Yvonne Spade, MT Blood Banking, Immunohematology, and Immunology Judy Smith, MT, Team Leader Michele Gillies, MT Cynthia Kukenberger, MT Microbiology Dr. Terry Else, Team Leader Dr. Joel Mortensen Kathy Sutton, MT Certified Medical Laboratory Assistant (CMLA) Exam Team Barbara Ware, CLC, Chair Ann Bachman Chris Pontious, AHI, COLT, RMA, RPT Bob Newberry, MT Linda Jones, MT James Fidler, Ph.D. (ex-officio) RMA EQS Clinical Team Deborah Westervelt, COLT, RMA, Committee Co-Chair, Clinical Team Leader Arthur Contino, AHI, RMA Heather Herring, MT, RMA Jeannie Hobson, RMA, RPT, CMAS, AHI Tracy Mixdorf, D.O. James Fidler, PhD (ex-officio) Administrative Team Jill Carlson, RMA, Committee Co-Chair, Administrative Team Leader Beverly Christiansen, RMA Marilyn Johnson-Gilliam, RMA, RPT Donna Nelson, RMA Patricia Poitier-Sands, RMA Angela Davis-Woodson, RMA James Fidler, PhD (ex-officio) RPT EQS Richard Crowner, MT, RPT, Chair Marty Hinkel, MT Alice Macomber, RMA, AHI, RPT Linda Raven, RMA, RPT, COLT Dorothy Roush, MT (Emeritus) Anna Seals, RPT James Fidler, PhD (ex-officio) RDA EQS Judith Dry, RDA, Chair Vivian Koistinen Glinda Otoki-Garrett Lisa Theodore Althea Wynn James Fidler, PhD (ex-officio) CMAS EQS Sharon Paff, RMA, Chair Barbara Garrido, RMA Kathleene Hardy, RMA Donna Hiatt, RMA, CMAS Diana Kendrick, RMA James Fidler, PhD (ex-officio) State Legislative Bob Newberry, MT, Chair Everett Bloodworth, MT George Cook, MT All State Legislative Chairs Terri Breitwieser, MT, AHI Carletha Durham, MT Webb Gray, MT Linda Raven, RMA, RPT, COLT Diane Robbins, MT John Sherer, MT Barbara Ware, MT Pat Westbrook, MT Deborah Westervelt, RMA, COLT Tommie Williams, MT Michael McCarty (ex-officio) Kimberly Cheuvront, PhD (ex-officio) CASMET Liaison Chris Seay, MT Credentials Jeff Lavender, MT, Chair Jeannie Hobson, RMA, RPT, CMAS, AHI Janet Crigler, MT Cecil Hunt, MT Marilyn Johnson-Gilliam, RMA Christopher Seay, MT Future Planning/Membership Mary Midkiff, MT, Chair Taffy Durfee, MT, Co-Chair Edna Anderson, MT Nancy Barrow, MT Alicia Gregorio, MT Josephine Harden, MT Debra Janeczko, RMA Jeffrey Lavender, MT Lucy Leyva, RPT Brett Merkle, RMA Francine Oran, RMA Ann Roby, COLT Linda Witte, RMA Carol Yankovich, MT Christopher Damon, JD (ex-officio) Kathy Cilia, MT (ex-officio) Proctoring Everett Bloodworth, MT, Chair All State Society Proctor Chairs Kathy Cilia (ex-officio) Nominating Louise Isbell, RMA Melissa Martin, RMA Kim Meshell, RMA, RPT, AHI Sueollen Schobert, MLT Dave McCullouth, MT Nominating Alternates Charles Baker, MT Leann Bart, RMA Vernell Boyd, MT John Sherer, MT Barbara Ware, MT Convention Peggy Oiler, MT, Chair Janet Crigler, MT Gloria Culla, MT Lynn Dunlop, MLT Carla Filles, RPT Heather Herring, MT, RMA Marty Hinkel, MT Alicia Houston, MLT Jerry Hudgins, MT Elizabeth Sarchet, MLT Lia Kaye Spears, MT Diane Powell, CMP (ex-officio) Scientific/Speakers Kay Fergason, MT, Chair Michelle Jenkins, MT, Vice Chair Jeri Bond, RMA, AHI Don Bouchelle, MT Clara Boykin, MT Tereyo Cop, MT Sujana De Almeida, RMA Arlene DeCarli, MT Roxanne Erskine, MT Hattie Gallon, MT Lt. Calvina Glover, MT Solomon Goldberg, RMA Patty Harris, MT Vern Hein, MT Pam Kriegel, MT Dorothy Marks, MT Melissa Martin, RMA Naomi Melvin, MT Fred Morley, MT Jean Palmer, RMA, AHI Patricia Poitier-Sands, RMA Delores Lola Rosalis, RMA Mimi Roush, MT Alberta Smith, RMA, AHI Sieglinde Wildie, MLT Felicia Williams, MT Diane Powell, CMP (ex-officio) Mentor Barbara Ware, MT, Chair Tera Benefiel, MT Nathalie Dixon, MT Betty Geary, MT Alice Macomber, AHI, RPT Juanita Stocke, MT Audrienne Whitley, MT Virgil Marchand, RMA Student Activities Julie Hardcastle, MT, Chair Ivette Rivera, RMA, AHI, Vice Chair Vanessa Austin, AHI, RMA Lisa Marie Bromley, RMA Jamie Horn, RMA, RPT Elizabeth Hurd, MT Amber Huskinson, MLT Karina Ibarra, RMA, RPT Alaine Johnson, RMA, AHI Cynthia Jones, MT Kody Karas, RPT Grant Lambert, MT Fred Morley, MT Shannon Newman, MT Rikki Packer, RMA Chris Pontious, RMA Faith Robeson, MA Student Ozzie Skinner, MT Leonila Sumarsono, RMA, RPT Lynette Thomson, MT Nicole Weiss, RMA, RPT Kathy Cilia, MT (ex-officio) Publications Nancy Gabi, RMA, Chair Maria Chevy-Newham, MT Carole Fecteau, MT Maria Guzman, MT Ken Hawker, MT Teresita Hacuman, AHI Kim Meshell, RMA, RPT, AHI Robin Miliner, MT Donna Nelson, RMA Suellen Schobert, MLT Edith Tefft, MT Kaye Tschop, MT Diane Powell, CMP (ex-officio) Armed Services Calvina Jordan, MT, Chair Sarah Hanaway, MLT Gerald Simi, MLT, AHI Randy Swopes, MT Felicia Williams, MT Viviana Vera, RMA Christopher Damon, JD (ex-officio) CLC Evaluation Committee Gerard P. Boe, PhD, Chair Ann Bachman, CLC Joel E. Mortensen, PhD Ann M. Steele, PhD Dianne B. Zielinski, PhD Christopher A. Damon, J.D. (ex-officio) Career Education Advisory Committee Bradley Moore, Chair Janice Donnelly Judith Dry, RDA Sandy Ock Tammy Renner Marylou de-roma-ragaza Janet Sesser, RMA John Smith, Ed.D. Christopher A. Damon, J.D. (ex-officio) Kathy Cilia (ex-officio) Continuing Education Topics & Issues April

42 ABSTRACTS FROM THE CURRENT LITERATURE None of us can read all the medical literature, even that that pertains particularly to medical technology. Presented below are short abstracts from current literature presented with the hope that they will answer some of your questions and lead you to a better understanding of what is happening. You are encouraged to send copies of articles you have found in journals or on the Internet to AMT and we will abstract them for an upcoming issue. We encourage and welcome future contributors from readers of this journal. Please send your abstracts to Editor, Journal of Continuing Education Topics & Issues, W. Higgins Rd., Suite 150, Rosemont, IL The following abstracts were contributed by David Plaut, Plano, TX, who is AMT s book reviewer and a frequent speaker at AMT annual conventions. Your hospital librarian or your public librarian can help obtain copies of the full text of these articles. Iron deficiency and overload. Implications in oxidative stress and cardiovascular health. Nutr Hosp May-Jun;25(3): Toxqui L. De Piero A. Courtois V. et al. Although iron is an essential mineral for maintaining good health, excessive amounts are toxic. Nowadays, much interest is focused on the mechanisms and regtulation of iron metabolism by downregulation of the hormone hepcidin. Disorders of iron metabolism could lead to iron overload, mainly causing the rare disease hereditary hemochromatosis, or on the other hand, iron deficiency may cause anemia. Currently, these alterations constitute an important problem of public health. Iron overload causes lipid peroxidation and increases cardiovascular risk. Recently, a relationship between iron metabolism and insulin resistance and obesity has been described. In contrast, regarding a possible relationship between iron deficiency anemia and cardiovascular disease, many aspects remain controversial. Clustering and risk factors of methicillin-resistant Staphylococcus aureus carriage in two Italian long-term care facilities. Infection Jun;37(3): Brugnaro P, Fedeli U, Pellizzer G Methicillin-resistant Staphylococcus aureus (MRSA) is a well-recognized agent of health care-associated infections in long-term care facilities, but few data about the circulation of MRSA in this setting in Italy are available. The aim of the study is to determine the prevalence and risk factors for MRSA carriage in nursing home residents in Vicenza (northeastern Italy). A point prevalence survey was conducted in two long-term care facilities (subdivided into 15 wards) from 12 June 2006 to 6 July Anterior nasal swabs were obtained from residents and laboratory screening for MRSA was performed; full antibiotic susceptibility was assessed in MRSA isolates. Macrorestriction analysis of chromosomal DNA was carried out by pulsed field gel electrophoresis (PFGE). For each subject, demographic data, length of stay, dependency, cognitive function, presence of medical devices, comorbidities, current and previous antibiotic treatment, previous hospital admission and presence of infection were assessed on the day of sample collection. Nasal swabs were obtained in 551 subjects; overall 43 MRSA carriers were detected. The rate of nasal carriers was very similar in the two institutions, and varied from 0% (0/36) to 18% (7/39) between wards. Only two out of 15 wards were found to have no MRSA carriers; overall, three pairs of colonized roommates were detected. Upon multilevel logistic regression, the risk of MRSA carriage was increased in patients with cancer in those that had undergone recent hospitalization and it reached an outcome ratio of 4.0 in those with three or more antibiotic treatments in the previous year; about 10% of the variability in MRSA carriage could be attributed to differences between wards. Pulsed field gel electrophoresis analysis permitted the definition of six clusters; two of these comprised 78.6% of the studied isolates and were quite similar, with one being more strongly represented among subjects hospitalized in the previous 12 months. All of the MRSA strains were resistant to ciprofloxacine; nevertheless, the majority were susceptible to most other non-betalactam antibiotics. The study suggests that nursing homes are a significant reservoir for MRSA. Statistical and PFGE analyses indicate a scenario where MRSA seems to be endemic and individual risk factors, namely recent hospitalizations and repeated antibiotic treatments, playa major role in the selection of drugresistant organisms. Infection control measures should be coordinated among different health care settings, and the appropriate use of antibiotics has emerged as an important issue for improving the quality of care. 72 April January Continuing Education Topics & Issues & Issues

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