The National Bioethics Advisory Commission met in May, July, and September to discuss the use of human biological materials in research. They will be meeting monthly for the rest of 1998. The Commission is in the process of preparing a report that will be available at some time in the future (probably in one or two months) for public viewing and comment on the web (http://bioethics.gov). Currently, a working draft can be accessed, but the Commission has not formally voted to accept many of the statements and conclusions in the current draft, and is still in the deliberating stage. However, the Commission has, at least for the time being, made some decisions that will have a significant impact on the use of human biological materials. These include:

(1) A strict definition of "unidentifiable" and a very broad definition of "identifiable samples". In other words, if anyone, anywhere (even on another continent), has a key to a list of coded samples, the coded samples will be considered as identifiable and their use will be subject to the full range of federal regulations.

(2) Investigators and IRBs will be encouraged to consult with community, racial, and ethnic groups when research studies are proposed, however there will not be a formal requirement for such interaction and the community groups will not have veto power.

(3) Recognizing that there is a constant tension between acquisition of scientific knowledge and respecting personal rights, the default position is to respect personal rights as the primary mission. The Commission is still discussing the appropriateness of some of the current exemptions to the federal regulations, especially the meaning of "publicly available" and whether the current definition of "minimal risk" is too broad. The implications of these discussions are that the Commission is leaning toward decisions that may result in the need to recontact individuals for use of their archived stored tissue samples and obtain specific informed consent for each research project. The concept of a blanket consent has been discussed, but has not yet been approved by the Commission.

Several of the Commissioners stated that they were waiting for responses from professionals to determine how serious the impact of these decisions would be. It will therefore be necessary to follow this issue closely and to be prepared to quickly respond to the official draft report when it is available on the web. The expected time frame for accepting public response will only be 30 days. AMP, in conjunction with other pathology societies including ASIP and CAP, will be prepared to respond. However I encourage you to access the web page and look at Chapter 5 of the current working document, to get an idea of where the Commission is headed in its deliberations. It will be important to document examples of types of research that will be impeded should the strict recontact provisions be recommended. In addition, an assessment, based on data, of the total impact on how much research may be impeded by these decision will be helpful. If you believe you can provide any useful data, please contact Mark Sobel.

Contributed by: Mark E. Sobel, MD, PhD

The Nominations Committee, with the invaluable assistance of Maricel Herrera, sent out the ballot for elections on September 11. The final date for RECEIPT of ballots in the AMP office is October 15. Your participation in the election will guarantee that your voice is heard and will strengthen our society. If you have not received a ballot (and included membership directory), please contact the AMP office immediately.

Last year, we announced a new AMP Award for Excellence in Molecular Diagnostics, co-sponsored by AMP and Visible Genetics, Inc. This award, created under the leadership and efforts of Past-President (and current Chair, Training and Education Committee), Dr. Jeffrey Kant, will be awarded to a noted individual at each annual AMP meeting. The award will be presented yearly to a U.S. or international investigator whose work has provided the scientific rationale for, or led to the development of, novel technologies for molecular diagnostics, or whose scientific contributions have significantly advanced the clinical practice of molecular diagnostics in the fields of molecular medicine, particularly pathology and genetics. The first awardee for 1998 is Dr. Francis Collins (see pg. 20).

Nominations are currently being solicited from the AMP membership for the 1999 awardee. We ask that you please provide the names of individuals for consideration for this award and return it with your ballots. In addition, you may contact Mark Sobel directly with suggestions.

Contributed by Mark E. Sobel, MD, PhD

Your AMP clinical practice committee has been working on the following issues, recently:

As detailed on page 3, we have received over 100 submissions for the soon-to-be compiled 1998 AMP test directory. This exceeds the participation in the 1996 first edition test directory. We hope that our attempt to standardize entry input and nomenclature, by providing pre-made table templates with recommended test names, will enable easier and more comprehensive indexing to increase the utility of the test directory for you, the users. Our plan is now to close the entry process - sorry, its too late if you’re just now reminded that you forgot to submit your entry. Indexing will proceed immediately, including an index of test names, and perhaps (depending on complexity and cost), an index of laboratory directors. The hard copy of the test directory will be distributed at the AMP meeting; yet another reason to attend. The hard copy directory will NOT be available to those who are not AMP members, at this time. However, discussions are underway to investigate the possibility of making these data available on the web. Should someone with better web-based skills than our committee members be willing to volunteer some of their time, we could make this information much more widely available, link it to individual member laboratory web sites, and generally increase its utility both to us and, perhaps more importantly, to our prospective client base. Anyone willing to volunteer for this very worthwhile project should contact me or one of the CP committee members while the thought is still fresh in mind.

In response to Smith-Kline Beecham’s proposal to enforce their patent and significantly restrict the number of labs performing DNA-based testing for hemochromatosis gene mutations, AMP has recently voiced their concerns in a reply letter. The letter is duplicated here:

The Association for Molecular Pathology (AMP) is a professional medical society of pathologists and clinical laboratory scientists whose mission is to promote clinical practice, research, and education in the field of molecular pathology. Our members represent a significant fraction of the laboratory medicine professionals with whom clinicians consult about genetic testing and from whose labs clinical specimens for HFE (hemochromatosis) mutation testing originate. Recently, SmithKline Beecham Clinical Laboratories (SBCL) sent letters to some of our members, who are performing HFE testing, making clear SBCL’s intention to significantly restrict the number of laboratories that can perform clinical testing for the hemochromatosis mutation. We are concerned that this action is not likely to be in the best interest of the patient and might even be counter-productive to the business interests of SBCL. We foresee several potential drawbacks to restriction of sublicensing for performance of this test.

1) The demand for HFE gene testing continues to be highly dependent on the consultative recommendations of local clinical laboratory professionals and expert recommendations from medical specialty societies. Should HFE gene testing be restricted to a few facilities, local laboratory-based expertise will be unavailable, local clinician "awareness" of this test will be low, decision makers within medical specialty societies (like ours) may feel disenfranchised, and test demand will then inevitably fail to meet its potential.

2) More widespread clinical utilization of HFE gene testing awaits more definitive clinical research findings confirming the medical, economic, and public health benefits of this diagnostic approach. Should HFE gene testing be limited to only a few clinical testing facilities, the generation of these much-needed clinical research findings will be prevented or significantly delayed. Widespread sublicensing of this test will, to the contrary, rapidly (and without additional cost to SBCL) promote the accomplishment of the many clinical research studies that will be necessary for FDA-, HCFA-, CAP-, and CLIA-mandated documentation of the clinical utility of this test.

3) Significant restriction of sublicensing might also prove counter-productive to some of SBCL’s business interests. A restrictive licensing policy is bound to be very disappointing to a laboratory that has already invested time and resources validating its assay for HFE gene testing, and whose staff has developed a high level of clinical expertise with this disease. As the professionals directing these labs are often the same individuals who determine to which contract laboratories the organization’s routine or esoteric laboratory work is outsourced, such feelings of disappointment might translate into a lack of enthusiasm for utilizing SBCL as an outsourcing partner.

4) A restrictive licensing policy may actually increase the cost of patent ownership as SBCL will need to expend resources to monitor patent violations and enforce cease & desist orders. Contrast this with the example of Roche Molecular Systems who currently enjoy significant revenue from non-restrictive sublicensure of PCR technology.

5) Another disadvantage of restrictive licensing, which may not be immediately apparent to SBCL, is that in the absence of competition, SBCL can establish whatever price is required to cover costs and profit margins, as well as set the standards for test methodology, turnaround time, and quality control. The inability of other labs to perform this test would likely prevent or delay future technical, fiscal, or temporal improvements in the assay and may ultimately adversely affect the cost or quality of patient care.

We hope that following further consideration of these matters, SBCL will reconsider its proposed restrictive licensing policy for HFE testing. We realize, of course, that license holders of patents have the right to enforce their exclusivity options. The proposal by SBCL of a large up-front sublicense fee (or an equivalent value in referral business or clinical correlative data) would certainly accomplish that aim, and would be prohibitive for all but a few labs. In contrast, we propose that sublicensure be tied to only a reasonable per-test royalty payment (and no up-front licensing fee) that would allow SBCL to initiate an immediate revenue stream while still collaborating with the clinical laboratory community to promote more widespread testing.

In summary, we strongly believe that the sublicensing policy that SBCL finally adopts must make rational and efficient use of current health care resources and ultimately provide improved outcomes to patients. To do otherwise in the current era of restrictive reimbursement invites failure. Based on the considerations outlined above, we believe that an affordable, non-restrictive sublicensing policy for clinical HFE gene testing would be a true win-win scenario for both patients and SBCL. The AMP council and our membership would be happy to provide feedback to SBCL as you formulate a sublicensing policy. Toward this goal, AMP would like to suggest establishment of a committee of interested AMP members who would work with SBCL to design and implement an outcomes study with the goal of making recommendations on cost-effective testing and screening for hereditary hemochromatosis. Specific objectives would be to develop optimum methods for HFE mutation detection using cost analysis strategies, identify clinical indications and optimum sample types for the assay, and recommend interpretation and report formats. The study would be conducted at SBCL and in authorized AMP-member laboratories. We believe that such a joint venture would be mutually productive, benefit the public health, and provide a model of cooperativity for the diagnostic community at large.

We look forward to your response and to working with you on this important issue.

Sincerely, AMP President & Clinical Practice Committee chair

To voice your individual concerns regarding this matter, please contact:

Dr. David O'Bryan or Ms. Rose Tricoski

Smith-Kline Beecham Clinical Labs

1201 South Collegeville St.

Collegeville, PA 19426

Although we are all obviously reluctant to pay additional fees to perform clinical tests, my decidedly non-legal opinion is that the real solution to these types of problems lies, not with the individual patent-enforcer, but in re-evaluating the patent laws that permit these activities. I am looking forward to the stimulating presentation of this controversial topic which is scheduled to take place next month at a special topics session of the Crystal City AMP meeting. Stay tuned for more lively debate.

We have recently become aware that that the FDA may soon be investigating the utilization, by some labs, of molecular testing reagents newly classified by FDA as class III "analyte specific reagents", specifically those analytes (as quoted from the Federal Register): "intended as a component in a test intended for use in the diagnosis of a contagious condition that is highly likely to result in a fatal outcome and prompt, accurate diagnosis offers the opportunity to mitigate the public health impact of the condition (e.g., human immunodeficiency virus (HIV/AIDS) or tuberculosis (TB)."

According to the recent ASR final rule (www.access.gpo.gov/nara/index.html), labs utilizing these class III ASRs may be required to show proof of (as quoted from the Federal Register): "Date of 510(k), or date of Pre-Market Approval or notice of completion of a product development protocol is required. (1) Preamendments ASRs; No effective date has been established for the requirement for premarket approval for the device described in paragraph (b)(3) of this section."

Labs using in-house-developed reagents (i.e., not kits) for assays to detect HIV, MTb (and perhaps even CMV, HCV, or other "fatal" agents) may fall under the jurisdiction of these regulations. AMP is currently investigating these matters and planning, in collaboration with ASM and other professional medical societies, an appropriate response [Ed. Note: see the article by Dr. Schifreen and Mr. Schwarz on pages 12-13.]

As promised, in an attempt to collect data regarding real-world costs for the performance of the new molecular CPT codes recently approved by the AMA, the CP committee (primarily Rick Nolte) has devised a cost survey for AMP members. The data collected from this survey will be presented to HCFA in an attempt to influence the assignment of more reasonable reimbursement levels for these new codes. Many of you have probably also recently received a very similar cost survey from the American College of Medical Genetics (under the guidance of Mike Watson). Your participation in completing these forms will determine the quality of the data presented to HCFA, and will then ultimately determine how much you get paid to do your work. Need I say any more about your incentive to contribute to this effort. The survey that is pasted below has been (or will soon be) posted on CHAMP. I urge that you take a few minutes to send in your cost estimates, making sure to include "indirect" cost centers outside of typical reagent and personnel costs. If the timing is right, we would like to submit AMP and ACMG data to HCFA at the same time as a 1-2 punch. You'll notice that the survey is intentionally short to increase compliance. If possible, to enhance the uniformity of the data, we ask that you consider some (or all) of the 9 "common" tests listed below for your cost estimates. Responses can be sent to me (press_richard_d@lilly.com) or to Rick Nolte

Test name:

Source: (home brew or manufacturer's name)

Analyte/target: (DNA, or RNA/target sequence identifier)

Specimen types:

Analytical methods:

No. tests/year:

Batch size:

Run frequency:

CPT codes:

Cost/patient result*:

*Please indicate (X) which of the items below were considered in the cost analysis.

1. Reagents ( )
2. Equipment ( )
3. Labor (technical) ( )
4. Administration (director, technical supervisors, managers) ( )
5. Overhead (rent, utilities, corporate mark-ups) ( )
6. Miscellaneous costs (test development, pro-ficiency testing, marketing) ( )
7. PCR license fees ( )
8. Ancillary costs (clinic staff, counselors, office staff) ( )
9. Other costs (specify) ( )
10. All of the above ( )

We specifically recommend the following 9 tests for cost data collection:

Genetics: fragile X, CF (specifying how many mutations tested), Factor V R506Q Leiden.

ID: HIV viral load, C. trachomatis (qual), HCV (qual).

Hematopathology: B/T gene rearrangements, t(9;22) (qual), t(14;18) (qual).

The clinical practice committee welcomes your input on these and other practice-related issues. We look forward to your comments and suggestions.

Contributed by: Rick Press, MD, PhD

Clinical Practice Committee Chair

Clinical Laboratory Medicine, Lilly Research Labs

(press_richard_d@lilly.com)

for the 1998 AMP Clinical Practice Committee:

• Andrea Ferreira-Gonzalez, PhD (Genetics)

Medical College of Virginia

• Linda Wasserman, MD (Solid Tumors)

U California, San Diego

• Rita Braziel, MD (Heme-Path)

Oregon Health Sciences University

• Rick Nolte, PhD (ID)

Emory University

The sample exchange program is continuing apace; initial exchanges occurred for t(11; 14), t(14; 18) and PCR-based immunoglobulin heavy chain and T cell receptor rearrangements. The first exchanges dealing with the translocations are essentially complete (I believe), and the first samples for gene rearrangements have also gone out. I still have one Southern blot sample left, and one sample for PCR-based rearrangements. If somehow I forgot you, or you just didn’t get around to sending me your protocol, just e-mail me at oleary@afip.osd.mil and tjo@imsnet.net, and I will rectify the situation if I can.

I am hoping to send out a second group of samples (provided by Rita Braziel) to those who return answers for the first set, but I haven't quite taken care of all the logistical details, so it may be the end of September when this happens.

For folks that haven’t yet sent me either protocols or results for the PCR-based rearrangements, please do it soon! I need to forward the information off to Adam Bagg and Rita Braziel, and the workshops are just around the corner! We need to give them a chance to digest the information. If you've misplaced the information, results should be faxed to me at 202.782.7623, and protocols may be e-mailed, faxed, or sent snail mail to Timothy J. O’Leary, Department of Cellular Pathology, Armed Forces Instit. of Pathol., Washington, DC 20306-6000.

We hope the hemepath workshops will be the highlight of the AMP meeting, but they are getting stiff competition from all the plenary sessions, and the other workshops. The first workshop will be a follow-on to last year; the second will introduce a new group of assays - coordinators will be announced soon over CHAMP.

Finally, the hemepath business meeting gives us a chance to discuss some of our issues and pass them on to the AMP Council. Please fax or e-mail agenda items, so the business session will be a productive part of our meeting.

Finally, WELCOME to the incoming Hematopathology Chair, Jeff Madeiros.

Contributed by: Timothy J. O’Leary, MD, PhD

Armed Forces Institute of Pathology

AMP Fall Meeting, ID Program: The Infectious Disease program for the fall meeting is progressing. We had planned one workshop to address validation and troubleshooting issues dependent on member submissions. Since we have not received any, we have scheduled this workshop with at least three speakers, from different types of labs who will present their validation protocols on home-brew and manufacturers’ kits. Curt Gleaves will be moderating this workshop. Our second workshop will address issues related to outcomes research and the justification of molecular tests in medical care. Karen Kaul is moderating this workshop and examples of outcomes research as well as some pointers on conducting those important studies will be presented. We hope that these workshops will provide useful information towards the implementation of molecular tests. Please come prepared with questions and challenges.

Standards: Though this area seems to be moving at a snail’s pace for those of us who have desired materials and programs, things are starting to gain momentum. In the area of standard reference materials, the WHO has filed an HCV standard which is derived from patient plasma. This lyophilized material was distributed and tested a year ago in a global study with at least 23 different laboratories using home-brew and manufacturers’ tests. It was primarily designed as a standard reference material to qualify blood plasma manufacturers’ quality control labs for their PCR tests of pooled plasma. Because of this, it is a single point standard characterized at 105 IU. A current study to understand the correlation of IU to genome equivalents and to characterize other international HCV standards (i.e., Paul Erlich Institute’s standard, the FDA’s standard) in relation to the WHO material is underway. WHO is also in the process of testing candidates for HIV-1 and HBV standards.

Proficiency programs have also started to add molecular infectious disease targets to their offerings. CDC has an HIV performance evaluation panel which is sent twice yearly. CAP has two molecular panels: an ID panel which has analytes such as Borrelia burgdorferi, CMV, Herpes, HCV (qual and quant), Mtb and HIV-DNA sent in different combinations three times per year, and an HIV-1 viral load panel (HIV/HIV2) which contains 5 challenges, three times per year. In Europe, the newly granted Quality Control Concerted Action group, which seeks to provide pan-European proficiency and standardization, is beginning with an Enterovirus panel this fall and has started a working group to provide "blood-borne virus panels" (HIV, HCV, CMV, HBV).

Control manufacturers are also taking an interest and now many of them offer long range controls, panels with target values for product evaluation or comparison and sero-conversion panels with nucleic acid quantification values as well as antibody and antigen status. (Boston Biomedica, Bio-logical Partners and NABI are three of the companies which have ventured into this area.)

This area is growing rapidly, but is still in a learning phase. Not all panels and controls are appropriate for all tests and lab directors still have to do a bit of digging to try and find appropriate, reliable materials. At least this is a beginning; one in which growth and improvement is the expected outcome. If you need further information, contact either the organizations mentioned above or Roberta Madej

(roberta_madej@cc.chiron.com).

Contributed by Roberta Madej, MS

Update on Solid Tumor Activities at Annual Meeting: 23 abstracts will be presented in the Solid Tumor subdivision, including 3 on breast cancer, 10 on other specific tumors, 5 on methods to detect circulating malignant cells, and 5 on other methodologies. Four of the abstracts are in consideration for the AMP trainee award. A study of a method to detect circulating tumor cells in breast cancer patients by Drs. Linda Wasserman and Anne Wallace of the University of California, San Diego has been selected for a platform presentation.

The Solid Tumor plenary sessions will be held November 7. The first session will be presented by Dr. Fred Barr (Penn): "Translocations In Solid Tumors." The second session will be presented by Dr. Sean Lee (Harvard), replacing his colleague Dr. Dan Haber (who had a schedule conflict with his upcoming wedding). Dr. Lee’s topic is: "Evolving Definitions of Tumor Suppressor Genes."

The first Solid Tumor workshop will be on Nov. 7^th and will address "p53 Analysis For Prognosis And Response To Chemotherapy." The workshop will be led by Drs. Syd Finkelstein of Redpath Genetics, (Philadelphia) and Ron Przygodzki of AFIP, Washington DC. Discussion will include clinical applications of p53 analysis as well as onsiderations of methodology, cost-effectiveness and quality control. The second Solid Tumor workshop will be held Nov. 8^th and will address "Gene Amplification in Solid Tumors." This workshop will be led by Drs. Marc Ladanyi (Memorial Sloan-Kettering Cancer Center, NY) and Irene Andrulis (Mt. Sinai Hospital, Toronto). Discussion will include utility and analysis of n-myc amplification in neuroblastoma, and analysis of amplification of the HER-2/neu and mdr1 genes by quantitative PCR.

An important topic to be covered in a special session of the annual meeting is the impact of gene patents on Molecular Diagnostics. Recent announcements regarding patents issued for BRCA1 have prompted many in the Molecular Diagnostics community to specifically request clarification of terms for testing for mutations in these genes. Myriad Genetics has been granted five US patents covering BRCA1 mutations as well as predisposition diagnostic testing for those mutations and diagnostic testing of tumor samples. (No U.S. patents related to BRCA2 have been issued at this time.) Laboratories based in universities, cancer centers and similar institutions may apply for a license to perform commercial BRCA1 testing. At present, the terms allow for analysis of single mutations and multiple mutation panels (up to four mutations) for a modest per-test fee. There is no up-front license fee or minimum annual royalty. Non-commercial research is excepted from any requirement to obtain a license. In contrast to commercial testing, which is reimbursed by a patient or third-party payer, research projects are generally supported by grants. Additional details on licensing for BRCA1 analysis can be obtained from Mr. William Hockett, Director of Corporate Communications, at 801-854-3504.

Contributed by: Tom S. Frank, MD

Medical Director, Myriad Genetic Laboratories

320 Wakara Way, Salt Lake City, UT 84108

Phone 801-584-3531/Fax 801-584-3515

e-mail: tfrank@myriad.com

The Genetics Subdivision has organized two exciting workshops for the November AMP meeting. Here, we describe these workshops in more detail. We also want you to think of case examples to bring to the meeting to discuss during the second part of each workshop.

Workshop I: Molec. Gen. Aspects of Biochemical Gen. Moderator: C. Vnencak-Jones

There will be 2 speakers during this workshop: Anthony Killeen, MD, PhD (U Mich): "Molecular Genetics of Congenital Adrenal Hyperplasia". Karen Snow, PhD (Mayo Clinic): "Hemoglobinopathies/Thalassemias".

Each will be speaking for about 30 minutes plus a few minutes for a question/answer session. Subsequently, we would like to open the floor for discussions of interesting cases of CAH or hemoglobinopathies/thalassemias from laboratories represented in the audience. So, please plan to bring your data for a brief case presentation and open discussion among the workshop attendees.

In addition, keeping with the theme of discussions on genetic disorders less commonly studied within the AMP laboratories, part of the remainder of this time can be used for a brief (3-5 minute) informal presentation of some unique test performed in your lab.

Alternatively, if you have a technical problem or difficult case in any area of genetic testing that you would like to discuss, this is your opportunity to discuss it with the experts in the audience.

The latter part of this workshop is designed to foster participation and will both educate and inform us about the activities of our AMP colleagues. We hope that this will be an active workshop and all in attendance will participate.

For logistical concerns, please notify Cindy Vnencak-Jones or Robert Jenkins (see below) if you wish to present a case/topic/technical problem and would require something other than a slide projector.

Genetics Workshop II: What’s in a name? Nomenclature in FISH and Molecular Genetics.

Presented by Wendy Golden, PhD & Mark Lovell, MD.

This presentation will focus on the current and evolving nomenclature practices for FISH and molecular genetics. The utility and limitations of these systems will be discussed and practical applications will be presented as case studies for discussion.

In addition, we want you to bring interesting or problem cases that you have so that we can discuss how to address specific nomenclature issues. The more the merrier!! If you want to give Mark Lovell or Wendy Golden some warning, they might appreciate it (see below). Otherwise, bring a difficult problem and surprise them.

Cindy L. Vnencak-Jones, PhD

Genetics Workshop I Moderator

Vanderbilt University Medical Center

P 615-343-9074/F 615-343-9563/

Mark Lovell, MD, and Wendy Golden PhD

Genetics Workshop II Presenters

University of Virginia Hospital

Ph. 804-982-0973/Fax, 804-924-8060

e-mail: mal3u@virginia.edu

Robert Jenkins, MD, PhD

Genetics Subdivision Chair

Department of Lab Medicine and Pathology

Mayo Clinic

Ph. 507-284-9617/Fax, 507-284-0043

e-mail: rjenkins@mayo.edu

Contributed by: Robert Jenkins, MD, PhD

I would like to share with all my colleagues in AMP our experience at William Beaumont Hospital in launching a research project (and hopefully a useful future clinical test) in cooperation with our Cardiology department. The project involves genotyping the ACE (angiotensin converting enzyme) gene in patients with coronary stents. A positive association between the insertion/deletion (I/D) polymorphism of the ACE gene and coronary artery disease (CAD) has been previously reported. Recently, the presence of the D allele of ACE has been shown to be a major risk factor for restenosis after coronary stent placement. Currently, coronary angioplasty is an established treatment for CAD; the incidence of angiographic restenosis, however, is high; up to 40-50%. The incidence of clinical restenosis may be as high as 30-40%. The mechanism of restenosis involves elastic recoil of the dilated vessel, thrombosis, neointimal hyperplasia and arterial remodeling. Intracoronary stent implantation is an effective therapy in treating acute and threatened coronary occlusions. Coronary stenting has been shown to reduce the incidence of angiographic restenosis compared to balloon angioplasty and also results in a reduction in the rate of clinical restenosis. Stents successfully resist elastic recoil and arterial remodeling, but may actually trigger development of neointimal hyperplasia. Therefore, stent implantation provides an ideal model in which restenosis is related primarily to neointimal hyperplasia. On the other hand, ACE plays a major role in the pathogenesis of neointimal hyperplasia. The ACE levels in plasma are under genetic control; DD homozygotes have higher levels of plasma ACE than II homozygotes, with ID heterozygotes having intermediate levels. It is therefore to be expected that patients with DD genotype will be at higher risk for restenosis after angioplasty and stent implantation. A study on 146 patients published in 1997 showed that the ACE genotype influences the level of late luminal loss after coronary stenting. With this background information and reported clinical data, we thought that a large patient study to confirm the association between dose of D allele and restenosis would be necessary. And the next step was to get our cardiologists interested. Dr. Dan Farkas (formerly of Beaumont Hospital and now with Clinical Micro Sensors where ACE research continues in collaboration with Dr. Wayne Grody at UCLA) and I met with Dr. William O’Neill, Chairman of the Cardiology Department at William Beaumont Hospital, and not only interest, but full cooperation was offered to us in launching the research project which will enroll approximately 1000 patients. A Cardiology fellow was given the responsibility of coordinating the clinical arm of the project and a nurse was designated to coordinate specimen collection and transport to our lab. In addition, Cardiology research reimburses our lab for actual costs of performing the ACE genotyping. To date, we have already performed over 120 genotypes.

The reasons to share this experience with you are certainly multiple; it is an interesting, challenging project and hopefully will result in a useful clinical test. But my main reason in submitting this note is to stress the fact that many of our clinician colleagues are not only well-informed in Molecular Pathology as related to their areas of expertise, but interested and fully cooperative, if we approach them with clinical Molecular Pathology research projects. In this day of financial constraints in the clinical labs and in research, their help is most valuable and may not be as difficult to get as one might think.

Contributed by: Domnita Crisan, MD, PhD, HCLD

Director, Molecular Probe Laboratory

Department of Clinical Pathology

William Beaumont Hospital

Ph., 248-551-7261

Last year, the FDA published a regulation creating analyte specific reagents (ASRs) as a new category of diagnostic device (21 CFR 864.4020). These reagents were defined as the assay components that react specifically with the analyte of interest, e.g. primers in PCR. Reagents used in conjunction with ASRs to perform an assay, e.g. taq and nucleotides in PCR, were defined as being part of the already established category of general purpose reagents (GPRs). GPRs are Class I, exempt devices (21 CFR 864.4010). Most ASRs , except for those used in blood screening and other assays specifically defined in the regulation, are classified as Class I, exempt devices; and, thus do not require submission of a 510(k) or PMA to the FDA. Examples of these products are expected to appear on the market shortly after the regulation becomes effective this November.

This regulation represents a thoughtful compromise between a number of conflicting issues brought before the FDA. In this case, groups like the AMP, AACC and CAP were active participants in representing the needs of their constituents. A number of constituencies lobbied FDA to make advanced tests more accessible to the citizens of the United States. They pointed to cancer marker tests that are widely used in Europe and Asia, but not available in the U.S. Other groups asked the FDA to be more stringent to prevent patients from making major life decisions based only on the results of a single laboratory test where the quality of the reagents are unknown and the clinical relevance of the test has not been rigorously proven. Genetic testing was a particular area of concern, especially where patients make decisions to avoid a possible future problem without any symptoms or other means of verifying the results of the lab tests. FDA also claimed the right to regulate providers of "home-brew" testing as medical device manufacturers, a claim hotly contested by these practitioners claiming that regulation under CLIA was sufficient. The final regulation does not regulate the design or implementation of "home-brew" assays but does define who can perform these tests, who can order them and disclaimers which must accompany the test result.

The regulation primarily impacts manufacturers and distributors of these products who wish to promote them to "home-brew" molecular diagnostic users. While manufacturers must meet certain requirements, users are not necessarily required to purchase products that have met these requirements. This provides an interesting dilemma for manufacturers who must decide whether or not to invest in the upgraded systems required to meet the ASR or GPR requirements. Another dilemma for manufacturers is that they are allowed to promote their products to diagnostic users, but are not allowed to make any clinical or diagnostic claims. For example, a manufacturer of nucleic acid purification reagents can claim that their product can be used to isolate a particular viral DNA from whole blood, but may not make any claim or provide the customer with any advice or assistance in using that product for detecting that virus in a diagnostic assay.

Customers, in fact, may have some trouble identifying products that meet these new requirements. The FDA prohibits advertising that states that a manufacturer has met FDA requirements or registered with the FDA. For GPRs, the only evidence is the label statement: "For Laboratory Use". For products that don't meet these standards the Industry convention of labeling "For Research Use" will continue. For customers, the "For Laboratory Use" label means that the manufacturer has upgraded their complaint management systems to FDA standards, is participating in the medical device reporting program, is meeting certain standards for documentation and has registered and listed products with the FDA. GPR manufacturers are also subject to inspection by the FDA.

The requirements for ASRs are far more complex and expensive for manufacturers in that they must meet all the requirements of the Quality System Regulation (21 CFR 820). Additionally, special controls are required of Class II ASRs and premarket approval is required for Class III ASRs. Class I exempt ASRs must include the label statement "Analyte Specific Reagent. Analytical and performance characteristics are not established". Class II or III ASRs must include the label statement "Analyte Specific Reagent. Except as a component of the approved/cleared test (name of approved/cleared test), analytical and performance characteristics are not established". No statement regarding analytical or clinical performance can be made. The manufacturer is responsible for restricting sales for diagnostic applications to CLIA High Complexity or equivalently licensed labs. However, manufacturers may also sell these products for bona fide academic, research, forensic, and other non-clinical uses. As with GPRs, the only certain way for a user to identify a product properly manufactured and sold as an ASR is through inspection of the label statement.

For molecular diagnostic laboratories, the predominant ASR product will be oligos for use as primers in PCR or labeled as probes. To date, we are not aware of any manufacturer who has announced plans to meet the FDA regulations to sell these products as ASRs. According to the regulation, it is the manufacturers’ responsibility to ensure that their products are sold and used consistent with their label claims; the users do not share this responsibility. It will be interesting to see to what lengths oligo manufacturers who chose not to meet ASR regulations will go to prevent molecular diagnostics customers from buying and using their products. Possible approaches range from written disclaimers on the product label to requiring customers to certify in writing that the oligos will not be used for diagnostic applications prior to shipment of product. Those companies who chose to label their products as ASRs must implement a plan to ensure they only sell to CLIA high complexity or equivalently certified labs. Again, approaches may range from written disclaimers to requiring a copy of the customer’s certification prior to shipment.

Meeting the requirements to label products as a GPR will require some investment by manufacturers, but only a fraction of that required to meet the ASR requirements. It is reasonable to expect that at least a portion of this cost will be passed on to users in the form of higher prices. Will the molecular diagnostics user voluntarily make the decision to purchase these products in preference to less expensive alternatives labeled "For Research Use" which don't meet the same quality standards? To what extent will manufacturers take steps to prevent molecular diagnostics customers from purchasing products not labeled as ASRs or GPRs? Will a sufficient number of manufacturers chose to list products with the FDA as GPRs and ASRs to provide for a reliable supply of all reagents required by "home-brew" laboratories? How closely will FDA monitor this area and how stringently will they enforce the regulation? We should find out shortly.

Contributed by: Richard S. Schifreen, PhD, DABCC, Business Unit Leader, Molecular Diagnostics and Joseph E. Schwarz MS, MBA,

Regulatory Affairs Manager

Promega Corporation.

ASTM (American Society for Testing and Materials) Committee E-48 on Biotechnology is currently developing two new (voluntary consensus) PCR guidelines. One is for the detection of HIV by PCR ("Standard Guide for Detection of Nucleic Acid Sequences of the Human Immunodeficiency Viruses HIV-1 and HIV-2 by the Polymerase Chain Reaction Technique"). The other is for the detection of Mycobacterium tuberculosis and other mycobacteria by PCR ("Standard Guide for Detection of Nucleic Acids of the Mycobacterium Tuberculosis Complex and Other Pathogenic Mycobacteria by the Polymerase Chain Reaction Technique"). Both standards are being developed in collaboration with DIN (German Institute for Standardization). An ASTM general PCR standard that should be used in association with these two organism-specific PCR standards has been published (E1873-97: "Standard Guide for Detection of Nucleic Acid Sequences by the Polymerase Chain Reaction Technique"). Our committee is also planning to develop a new standard for controls needed in the performance of DNA/RNA amplification-based and related procedures used in basic biological research and biotechnology and in the diagnosis of infectious and genetic diseases. The particular ASTM subcommittee (E-48.02) developing these standards is a small, dynamic group of individuals interested in molecular methods research and standardization. Our next meeting is very close in time (November 2-3) and location (Rockville, MD; near Washington, D.C.) to the next AMP meeting in Crystal City, VA. Our ASTM meeting shall be held in the Parklawn Building, 5600 Fishers Lane, Rockville, MD ("Twinbrook- Red Line" Metro subway stop). We are a friendly group and serve refreshments; we should enjoy having you pay us a visit, and if you should also like to volunteer for any of the above standards development, please contact Larry E. Bockstahler, PhD, Chair, ASTM Subcommittee E48.02 (address: FDA, HFZ-113, Rockville, Maryland 20857; Ph,: (301) 443-7287; e-mail: leb@cdrh.fda.gov).

Contributed by: Larry E. Bockstahler, PhD

Molecular Biology Branch, FDA

A panel of clinicians and scientists convened by the International AIDS Society-USA has concluded that plasma HIV RNA levels and CD4 cell counts, not the results of drug resistance or susceptibility assays, are the main laboratory analytes that should be utilized to determine when to start antiretroviral therapy and when subsequent changes in therapy should occur.

In addition to drug resistance as a cause of treatment failure, the panel said that patient adherence, drug potency, and pharmacokinetic issues should also be reviewed. After reviewing data from published reports and material presented at research conferences, the panel said genotypic and phenotypic testing for HIV resistance to antiretroviral drugs may also be beneficial in managing individual cases. In particular, emerging evidence indicates that in drug-experienced patients, genotypic and phenotypic signs of resistance to the drug in vitro implies poor virologic response in vivo. In these cases resistance assays may be beneficial in identifying drugs that will not be beneficial in some regimens. However, the lack of genotypic or phenotypic evidence of viral drug resistance does not necessarily mean that a patient will respond favorably to a particular drug. Furthermore, the panel concluded that the assays currently being developed and offered need validation, standardization, and a clearer definition of their specific clinical roles. The article contains concise, readable explanations of the development of drug resistance, of interactive effects of mutations, and of current genotypic and phenotypic assays.

Routine testing for certain patients, e.g., antiretroviral drug-naïve pregnant women, or individuals with primary HIV infection, may be considered when the prevalence of drug resistance in that population is increased. In conclusion, although technologic advances have now made drug resistance assays possible, and although resistance assessment will likely someday be useful clinically for identifying drugs that will not be optimally active in a treatment regimen, a confirmed significant change in HIV RNA level together with changes in CD4 cell levels should remain the main trigger for considering a change in drug therapy.

Reference: "Antiretroviral Drug Resistance Testing in Adults with HIV Infection-Implications for Clinical Management", M. Hirsch et al., June 24, 1998 issue, J. Amer. Med. Assn., 279 (24): 1984-1991.

Contributed by: Bill Paxton, MD, PhD

Associate Director, Medical Research

Agouron Pharmaceuticals, Inc.

e mail: bill.paxton@agouron.com

Former Clinical Practice Committee Chairperson and current President-elect nominee, Dr. Debra Leonard of the University of Pennsylvania has been appointed Sr. Associate Editor of Molecular Diagnosis. Congratula-tions Debra!

Former AMP Program Chair Dr. Tony Killeen of the University of Michigan, has been elected the chairperson of the AACC Molecular Pathology Division for 1999, a post held previously by among others, AMP members Domnita Crisan, Patrick Hess, Gregory Tsongalis and Daniel H. Farkas. One of Tony’s aims will be developing further collaboration between AMP and AACC on issues of mutual concern including representation at legislative and regulatory bodies, and continuing education. Tony welcomes any input into these issues and can be reached at <akilleen@umich.edu>. Congratulations Tony!

This year’s Training and Education Committee set as an objective the establishment of a "bank" of training and education resources for molecular pathology and clinical molecular diagnostics.

The Committee has prepared broad topical themes from the four subdivisions and a miscellaneous group - see below; most contain a few non-exhaustive examples. We are asking AMP members to submit names of resources you find most useful in training residents or fellows or in the daily practice of molecular pathology. We are NOT looking for a Medline search of particular topics. Resources can include, but are not limited to:

• journal articles, e.g., important historical papers, original articles, reviews)
• books (or specific chapters)
• audiotapes or videotapes
• CD-ROM, software programs, or instructional web sites

To enable us to standardize the collection and listing (hopefully eventually online) of these, please use the following format for EACH submission:

1. Topic area (as broad or specific as you wish):
2. Resource title (journal article/book/chapter title if known, title of videotape, etc.):
3. Literature citation (journal or book citation if applicable, web URL, source to purchase):
4. Annotated comment (why do you like/how do you use this resource): VERY USEFUL
5. Appropriate for what level (novice, intermediate, advanced, all):
6. Other remarks:
7. Person submitting

This will of course be an ongoing and evolving bank of resource materials; a long-range goal is to add case-based educational resources with on-line images accessible via the AMP web site. For now, with a helpful initial bolus of submissions over the next month, we hope to have this underway for presentation at the annual meeting in Washington. Thanks for your cooperation. We hope to be buried with great submissions.

Send your best stuff to:

A) CHAMP (champ@champ.pathology.pitt.edu) - these will not be posted. On this you have special dispensation to hit the reply button!!

B) Training and Education Committee Members

CHAIR

Jeffrey A. Kant: kant@np.awing.upmc.edu or

kantja@msx.upmc.edu /412-383-9594 fax

GENETICS

Gregory J. Tsongalis: gtsonga@Harthosp.org

860-545-5206 fax

HEMATOPATHOLOGY

Ethel Cesarman: ecesarm@mail.med.cornell.edu

212-746-8302 fax

INFECTIOUS DISEASES

JS Dumler: sdumler@pathlan.path.jhu.edu

410-614-8087 fax

SOLID TUMORS

Jack H. Lichy: lichy@email.afip.osd.mil

202-782-7263 fax

AD HOC: Vivianna Van Deerlin: Fax: 215.662.7529

vivianna@mail.med.upenn.edu

Jeffrey Ross: jeffrey_ross@ccgateway.amc.edu

518-262-3663 fax

Resources In Molecular Pathology

GENETICS

1. Basic genetic principles
2. Genetic counseling, predisposition testing, risk analysis, and ethical issues - see also miscellaneous below
3. Trinucleotide repeat disorders (fragile X, myotonic dystrophy, SCA, HD)
4. Coagulation and blood disorders (factors II/V, thalassemia, hemophilia, sickle cell, porphyria)
5. Inherited cancers (RB, BRCA, COLON, XP - see also Solid Tumors below
6. Muscle diseases (DMD, BMD, CMT)
7. Identity testing (forensic, paternity, tissue typing)
8. Molecular assays for inborn errors of metabolism (with biochemical correlations) and other single gene disorders (HFE, PKU, Tay-Sachs, CF, NF)
9. Skeletal abnormalities (OI, Achondroplasia, Marfan’s)
10. Chromosomal Abnormalities and diseases of imprinting (Down Syndrome, Angelman/Prader-Willi)
11. Mitochondrial Diseases (MERRF, MELAS, LHON)
12. Multigenic disorders (diabetes, cardiovascular)
13. Histocompatibility testing
14. Molecular cytogenetic applications in genetic disorders

HEMATOPATHOLOGY

1. General principles of molecular hematopathology (antigen receptor gene structure and rearrangements, mechanisms of chromosomal translocation)
2. Molecular assays for detection of clonality (gene rearrangements, EBV terminal repeat analysis, chromosomal translocations)
3. Molecular assays for diagnosis, prognosis, or detection of residual disease in:

1. Lymphoid neoplasms (BCL-2, BCL-1, Bcr-abl, ALK/NPM, E2A/PBX1
2. Myeloid neoplasms (Bcr-abl, PML/RARalpha, ETO/AML1, CBFb/MYH11)

1. Association/detection of organisms in hematologic neoplasms (EBV, KSHV/HHV 8, HTLV-I)
2. Molecular assays for allogeneic transplantation engraftment (mini and microsatellite polymorphisms)
3. Molecular cytogenetic applications in hematologic disorders

INFECTIOUS DISEASES

1. Qualitative detection of infectious agent nucleic acids (e.g. viruses, bacteria, other)
2. Quantitative detection of infectious agent nucleic acids
3. Genotyping of infectious agents (e.g. direct sequence, RFLPs, hybridization)
4. Genetic analysis of antimicrobial resistance and virulence gene identification (methicillin, vancomycin, in CMV, HIV, staph, strep, E. coli, Helicobacter)
5. Classification based upon phylogenetic positions (ribosomal RNA and eubacterial species)
6. Molecular epidemiologic investigation for common point exposures and outbreaks (ribotyping, pulsed-field gel electrophoresis, RAPD, sequence analysis)
7. In situ hybridization for localization and morphologic evaluation of infectious agent in tissues and cytologic preparations.

SOLID TUMORS

1. Oncogene and Tumor Suppressor Gene Biology

1. Signal Transduction
2. Cell Cycle Regulation
3. Viral Oncogenesis
4. DNA Replication and Repair

1. Molecular assays for tumor diagnosis, prognosis, or detection of minimal disease (translocations like t(X;18), t(11;22); mutations in oncogenes or tumor suppressor genes [ras, p53]; oncogene amplification)
2. Solid Tumor Genetics

1. Inherited predisposition to cancer (RB, p53, BRCA1/BRCA2)
2. Acquired genetic changes associated with cancer (LOH, point mutations, translocations)

MISCELLANEOUS

1. Basic science background resources for Molecular Pathology (to include principles of molecular biology. molecular genetics)
2. Technology/Equipment

1. General (sample collection, preservation, etc.) - some of this best in subdivisions
2. Established technologies (Southern blot, PCR, RT-PCR, other)
3. Newer technologies (chips, arrays, real-time PCR, quantitative assays, sequencing)

1. Regulatory issues (licensing, QA, proficiency testing)
2. Economic issues in molecular pathology (reimbursement, patents, licensing proprietary technologies)
3. Informatics in molecular pathology/molecular biology
4. Design/structure of molecular pathology laboratories
5. Training in molecular pathology (curricula, guidelines, approaches)
6. Biomedical ethics in molecular pathology (confidentiality, archival material use, informed consent)

Contributed by Jeffrey Kant, MD, PhD

kant@np.awing.upmc.edu OR kantja@msx.upmc.edu

AACC’s 1998 Clinical Chemistry Forum, "Issues in Genetic Testing", will be held on November 3-4, 1998, at the Washington National Airport Hilton in Crystal City, VA (across the street from the AMP Hotel, the Hyatt Regency). This year’s Forum, which was developed in cooperation with the Association for Molecular Pathology (AMP), is an intensive, two-day examination of all the key legislative, regulatory, scientific, reimbursement and professional matters affecting genetic testing and molecular diagnostics. You will learn about the current and pending regulations affecting genetic testing, their impact on the laboratory and what you need to do today to comply.

The advance registration fee for the Forum is $325 for AACC and AMP members and $465 for nonmembers. The advance registration deadline is October 16, 1998. After that date, you must pay the on-site fee, which is $375 for AACC and AMP members and $515 for nonmembers. For a Forum brochure, please call AACC's Allison Colombel at 1-800-892-1400, ext. 757 or 202-835-8757, or view it on the internet, by visiting AACC's home page at http://www.aacc.org - look under What's New. This program is made possible by a generous educational grant from Roche Diagnostics (Boehringer Mannheim Corporation) to the Van Slyke Society.

The AMP Program Committee is putting the finishing touches on the program for the 1998 Annual Meeting to be held November 6-8 (2 1/2 days, Friday through Sunday) at the Hyatt Regency Hotel in Crystal City, Virginia. The Program Committee has been meeting regularly through its monthly conference calls to develop and monitor progress. For those of you still making plans to attend, do not forget that we are continuing the practice begun last year in San Diego and are scheduling a day of Pre-meeting Workshops that are sponsored and staffed by a number of our exhibitors. These have been organized by AMP Past President, Dr. Peggy Gulley and by AMP’s meeting coordinator Ms. Maricel Herrera. Currently nine companies have scheduled workshops for the afternoon and evening of November 5^th.

Five Plenary Sessions will be held. We are delighted that AMP President, Dr. Cheryl Willman, will be one of the featured speakers in the Hematopathology Plenary Session and will present exciting new findings in the monitoring of minimal residual disease. Each of the other plenary speakers likewise will be addressing topics of equal interest and importance to AMP members. A particularly timely topic is the potential impact of gene patenting in molecular diagnostics. Dr. Debra Leonard has organized an excellent panel to discuss this issue in the General Topics Plenary Session.

Planning for the Meeting Workshops is essentially complete and formats will vary from the less structured type used in the Hematopathology Workshops to address their sample-exchange program to the more traditional approach with speakers addressing specific topics. Workshop topics were chosen with special emphasis on the practical utility of the subject matter for the molecular diagnostics field. Regardless of format, Workshop Moderators have been encouraged to facilitate information exchange between speakers and members in the audience and encourage discussion.

The Program this year will see the expansion and integration of sessions focusing on technical issues which was begun at last year’s meeting. Cathie Leiendecker-Foster, MS, CLSp(MB) and W. Kent Williams, MT, have developed an excellent set of Workshops to address basic issues encountered at the bench which should prove especially helpful to those preparing for the certifying examination given by the NCA for Certified Laboratory Specialist in Molecular Biology. Comprehensive handouts are planned to assist the participants.

This year the Program Committee received and accepted 101 abstracts for presentation at the Annual Meeting. This represents an approximately 35% increase in comparison to the number received and presented last year. The Committee selected four of the abstracts deemed to be of special interest for platform presentation at the Abstracts Plenary Session. This year AMP will begin recognizing trainees whose poster presentations are judged to be especially meritorious. Committee Members will review posters of trainees during regular poster presentations on Friday and Saturday and announce the two awardees whose work was judged to be most meritorious on Sunday morning at the beginning of the General Topics Plenary Session. The Trainee Awards are due in large part to the efforts of Dr. Jeffery Kant, former AMP president and current Training Committee chairperson, who obtained support for the awards from prior exhibitors.

Work on this year’s program was significantly facilitated by use of a common Program Committee e-mail address. The Committee thanks former Program Chair, Dr. Anthony Killeen for establishing and maintaining this resource. Inevitably, some last minute changes are bound to occur. However, this year’s program should continue the Society’s tradition of compressing a maximum of useful information into a minimum of time and space.

Section Chairs/Chairs-Elect:

Hemepathol.: Tim O’Leary (tjo@afip.mil)

Jeff Medeiros: (Jeffrey_Medeiros@notes.mdacc.tmc.edu)

Genetics: Bob Jenkins (rjenkins@mayo.edu)

Mark Lovell (mal3u@virginia.edu)

Infectious Disease: Roberta Madej

Karen Kaul (k-kaul@nwu.edu)

Solid Tumors: Tom Frank (tfrank@myriad.com)

Mark Ladanyi

Program Chair/Chair-Elect:

Carleton Garrett (ctgarret@hsc.vcu.edu)

Karl Voelkerding

Submitted by

Carleton T. Garrett, MD, PhD, Program Chair

Karl V. Voelkerding, MD, Program Chair-Elect

A highlight of this year’s annual meeting in Crystal City will be the inaugural presentation of the AMP Award for Excellence in Molecular Diagnostics on November 6, 1998 from 5-6 PM. The first recipient is Francis S. Collins MD, PhD, Director of the National Human Genome Research Institute at the National Institutes of Health in Bethesda, Maryland. The Award lecture, sponsored for an initial 3 year period by Visible Genetics, Inc. of Toronto, honors an individual whose work has significantly advanced the development or application of clinical molecular diagnostics.

During his genetics fellowship at Yale University and first faculty job at the University of Michigan, Dr. Collins pioneered revolutionary positional cloning approaches to gene identification during the 1980s and co-discovered with Drs. Lap-Chee Tsui and Jack Riordan the gene responsible for cystic fibrosis. Dr. Collins’ laboratory has also identified or participated in significant work with a host of other important molecular diagnostic applications in cancer and inherited disease, including neurofibromatosis, Huntington Disease, hereditary breast and prostate cancer, and translocations associated with acute leukemia. Today these form the basis for hundreds of assays performed daily on patient samples. On top of an active and productive research effort, Dr. Collins’ major responsibility these days is oversight of the Human Genome Project, a 15 year effort to sequence the human genome which is currently ahead of schedule and under budget.

The winner of numerous national and international awards, Dr. Collins has also been elected to the National Academy of Sciences and the Institute of Medicine. A truly Renaissance man and motorcycle model of some renown, Dr. Collins is also a gifted lecturer and occasional guitar player. Please join AMP and Visible Genetics in honoring this outstanding physician-scientist who has done so much for molecular diagnostics.

The Selected Technical Topics sessions are intended to serve a dual purpose. The first purpose is a perceived need to provide some assistance to AMP members who wish to become NCA certified by taking the Molecular Biology specialty examination. The second purpose is to provide a forum for networking and the exchange of ideas by AMP members who perform molecular testing.

With regard to the first purpose, because of time constraints and an extremely active meeting schedule, it is impossible for this year to find enough time to provide a complete and comprehensive "review" session within the AMP Annual Meeting. This year, these sessions will run concurrently with the afternoon break times on both Friday and Saturday.

It was decided that we could best serve the members by providing a comprehensive review handout with an overview and discussion of a few selected topics, thus the session’s title. The three topics that have been chosen for this year's annual meeting are:

1. Sample handling, preparation, & extraction. Prepared & presented by W. Kent Williams, BS, St. Jude Children’s Res. Hosp.

2. PCR. Prepared and presented by Barbara Griffith, MS, U. New Mexico.

3. Probe labeling and hybridization techniques for Southern blotting. Prepared and presented by David Olson, B.S., Fairview-University Medical Center.

Each presenter has prepared a comprehensive handout for their topic that is intended to help review that topic in preparation for taking the NCA certification exam.

With regard to the second purpose, each presenter will provide an overview of their topic largely from their own experience within each of their laboratories and time will be allowed for audience participation. This is where we will be able to exchange ideas, put faces to names, and begin a network of colleagues who can become a rich source of information, support, and assistance with the technical problems and hurdles faced by every molecular technologist.

At the end of the session, there will be an evaluation form/survey where everyone will have an opportunity to provide ideas on how to improve this session for future meetings and suggest other topics to be discussed. We look forward to meeting many of you at these sessions. Please plan to attend and bring your questions, problems, and good ideas.

Contributed by: Cathie Leiendecker Foster, MS

Senior Scientist, University of Minnesota

Department of Lab Medicine & Pathology

Box 609 Mayo, 420 Delaware St. SE

Minneapolis, MN 55455

Ph, (612) 626-2305/FAX, (612) 625-6994

e-mail: foste011@maroon.tc.umn.edu

5-8 pm Registration

7:30-10:30 pm AMP Committee Meetings

7:30-9 pm Clinical Practice Committee Meeting

Training & Education Comm. Meeting

9-10:30 pm Nominating Committee Meeting

Program Committee Meeting

Publications Committee Meeting

7-7:50 am Registration/Continental Breakfast

7:30-7:50 Put Up Posters/Exhibits (1^st day)

7:50-8 am Opening Remarks

Carleton Garrett, MD, PhD

Medical College of Virginia

8-9:45 am Plenary Session I-Genetics

Moderator-Robert Jenkins, MD, PhD, Mayo Clin

Joan Knoll, PhD, Mass General Hospital

William McGinnis, PhD, Yale University

Moderator-Timothy O’Leary, MD, PhD, AFIP

Cheryl Willman, MD, University of New Mexico

Jerry Shay, PhD, University of Texas, Dallas

NOON-1 pm Lunch; visit poster/exhibits

NOON-1 pm Hemepath. subdiv. business mtg.

Genetics subdiv. business mtg.

1-2:30 pm Workshops-Session A

HEMATOPATHOLOGY-WORKSHOP I

Moderator-Jeffrey Medeiros, MD, University Texas MD Anderson Cancer Center

GENETICS-WORKSHOP I

Moderator-Cindy Vnencak-Jones, PhD

Vanderbilt University Medical Center

Anthony Killeen, MD, PhD, Univ. of Michigan

Hemoglobinopathies/Thalassemias

Karen Snow, PhD, Mayo Medical School

2:30-4 pm Visit Posters/Exhibits.

(Posters Attended 2:30- 3:15 pm)

2:30-4 pm Selected Technical Topics-Review & Discussion (parts 1 and 2)

Moderator-Cathie Leiendecker-Foster, MS, CLSp(MB)

This session is intended to present review information on 3 laboratory related topics with time for participatory discussion by the audience. An in-depth review handout with references for each topic will be available. In addition, information regarding the NCA Molecular Biology exam will be available, e.g., Applications, Content Outline, Reference List.

W. Kent Williams, MT, St Jude Children’s Research Hospital

PCR. Barbara Griffith, MS, Univ New Mexico

4-5 pm AMP Business Meeting

5-6 pm AMP Award of Excellence in Molecular Diagnostics Lecture

Francis Collins, MD, PhD

6:30-7:30 pm Welcome Reception

7-7:55 am Registration/Continental Breakfast

7:30-7:55 Put Up Posters/Exhibits (2^nd day)

8-9:45 am Plenary Session III-Inf. Disease

Moderator-Roberta Madej, MS, MBA, Chiron Diagnostics

Elizabeth Unger, MD, PhD, Center for Disease Control and Prevention

Jan Nowak, MD, PhD, Ill Masonic Med. Center

10:15-Noon Plenary Session IV-Solid Tumors

Moderators-Tom Frank, MD, Myriad Genetic Laboratories and Marc Ladanyi, MD, Memorial Sloan Kettering

Fred Barr, MD, PhD, University of Pennsylvania

Sean Lee, PhD, Mass General Hospital

NOON-1 pm Lunch; visit poster/exhibits

NOON-1 pm Inf. disease subdiv. business mtg.

Solid Tumor subdiv. bus. mtg.

INFECTIOUS DISEASES-WORKSHOP I

Moderator-Karen Kaul, MD, PhD, Evanston Hospital

John Ticehurst, MD, Johns Hopkins

Rob Lloyd, Applied Sciences, Inc.

SOLID TUMORS-WORKSHOP I

Moderators-Sydney Finkelstein, MD, Redpath Genetics & Ron Przygodzki, MD, AFIP

2:30-3:30 pm Visit Posters/Exhibits.

(Posters Attended 2:30- 3:15 pm)

2:30-3:30 pm Selected Technical Topics-Review & Discussion (part 3)

Moderator-C. Leiendecker-Foster, MS, CLSp(MB)

David Olson, BS, Fairview Univ Medical Center

INFECTIOUS DISEASES WORKSHOP II

Moderator-Curt Gleaves, MS F(AAM), Portland Providence Medical Center

Rick Hodinka, PhD, Children’s Hosp of Phila.

Andrea Ferreira-Gonzalez, PhD, Medical College of Virginia Hospital

Lynette Sawyer, Dr PH, Chiron Reference Testing Laboratory

GENETICS WORKSHOP II

Moderators-Mark Lovell, MD and Wendy Golden, PhD, University of Virginia

5:00-5:15 pm Break

5:15-6:15 pm Abstract Plenary Session

Detection of Circulating Tumor Cells in Breast Cancer Patients: Preliminary Validation of a Semi-Nested Rt PCR Assay for HER2/neu . L.M.Wasserman, University of California at San Diego, CA

Chracterization of a Familial Neurodegenerative Disorder Associated with Neurosepin Inclusion Bodies. A. E. Shrimpton, SUNY Health Science Center, Syracuse, NY

Detection, Quantatitation and Characterization of HBV DNA in Serum Using the Invader^TM Assay. J.G. Hall, Third Wave Technologies, Inc., Madison, WI.

Infrared-mediated PCR on Microchips for Immunoglobulin Gene Rearrangement Analysis . J.Landers, University of Pittsburgh, PA

7-8 am Continental Breakfast

8-10 am Plenary Session V-Special Topics

Moderators-Carlton Garrett, MD, PhD, Medical College of Virginia/VCU & Karl Voelkerding, MD, University Wisconsin Hospital and Clinic

Panel Moderator-Debra Leonard, MD, PhD, Univ Penn Molecular Pathology Laboratory

Speakers: John Doll, US Pat. & TM Office

David O’Bryan, PhD, SKBCL

Jon Merz, JD, PhD, U Penn Center for Bioethics

Doug Dolginow, MD, OncorMed, Inc.

10:30-Noon Workshops Session D

HEMATOPATHOLOGY-WORKSHOP II

Moderator-Jeffrey Medeiros, MD, Univ Texas MD Anderson Cancer Center

SOLID TUMORS-WORKSHOP II

Moderators-Marc Ladanyi, MD, Memorial Sloan Kettering Cancer Center & Irene Andrulis, PhD, Mount Sinai Hospital

NOON Conference Adjourns

There will be an excellent selection of pre-meeting workshops available on Thursday, November 5 as part of the AMP meeting. These workshops will cover a diversity of topics of interest in molecular diagnostics. The workshops promise a wealth of background, practical and new information from companies with a leadership position in this discipline. AND THEY ARE FREE! To accommodate the level of corporate interest, workshops will run simultaneously in several rooms. Thus, it will not be possible to attend all sessions, so bring two colleagues, tape recorders or video cameras if you want to sample everything! The workshops will range in length. Walk-ins are welcome and should be able to be accommodated at almost all workshops

Arlington Room

3-5 PM DiaSorin

Gentra Systems, Inc.

Kennedy/Jefferson Room

PE/Applied Biosystems

Arlington Room

7-9 PM Innogenetics, Inc. (7-8 PM)

Kennedy/Jefferson Room

Qiagen, Inc.

Prince William Room

(in alphabetical order))

CHIRON DIAGNOSTICS, INC- Ultrasensitive HIV Viral Load and PromptChart Data Management Software

Topics: (1) The next generation of Ultrasensitive HIV viral load assays and laboratory automation. Chiron recently launched this type of product, HIV-1 RNA 3.0

(2) PromptChart (tm), a web based care management software tool.

Chiron has recently launched an ultrasensitive 50 copy HIV viral load assay that is quickly becoming the class of diagnostic tests that are standard of care for monitoring HIV + patients. We would like to review this new product, the chemistry, performance, and automation that labs are beginning to adopt.

In addition to the benefits of new diagnostic HIV viral load tests Chiron has also developed a web based software program, PromptChart to help physicians manage their HIV+ patients more closely. This tool provides HIV care givers and patients easier access to the most relevant information critical for developing effective treatment strategies in today's increasingly complex therapeutic arena. Using HIV PromptChart can decrease the time required to review critical lab values by providing concise visual tools that track longitudinal changes in relevant markers, such as viral load and CD4 counts. This program provides patient specific reminders and alerts based on physician treatment guidelines. We would like to explain this product, its utility and provide examples of the visual tools found within the program.

CLINICAL MICRO SENSORS, INC - Point of Care DNA Diagnostics

DNA chips are new tools being formulated to decrease the turnaround time and costs associated with molecular diagnostics. DNA chips are solid supports onto which numerous DNA probes are attached, forming arrays. The number of probes can be varied depending on the application and will likely be small for diagnostics applications. The probes are synthetic oligonucleotides with complementarity to disease genes and infectious agents of interest. Sufficient space exists within the array to include controls important to the practitioners of molecular diagnostics.

Clinical Micro Sensors, Inc. (CMS) has developed approaches for the design of clinically relevant DNA chips combining organometallic chemistry and nanotechnology, resulting in DNA chips with built-in sensor capabilities. These chips and CMS’ proprietary AMBER technology (AMperommetric Bio-Electronic Reporter) allow the rapid and convenient detection of specific nucleic acid sequences using a very low-cost chip reader.

Electronic detection is relatively independent of interfering substances potentially obviating the need for washing steps and extensive DNA purification. Efforts are underway at CMS to refine and improve the technology to the point where rapid, direct diagnostics can be performed without target amplification.

This workshop will be an opportunity for attendees to learn about the technology which will be developed not only for point of care applications, but also for the larger test volumes of molecular diagnostics laboratories. Participants will be encouraged to examine CMS prototype instrumentation, suggest appropriate assays, offer collaborative support and define useful controls that they would like to see in the technology CMS plans to supply to AMP members.

DIASORIN - Simplified Detection of infections and Genetic Diseases Using the DiaSorin DnaEIA

The DiaSorin DNA enzyme immunoassay (DEIA) will be presented, to introduce the following new developments: 1) formation of a strong new partnership to improve the ease-of-use of DEIA in clinical laboratories, by emerging extraction, amplification and detection approaches; 2) dramatic improvement in the sensitivity and timing of the DEIA; and 3) new applications of DEIA, including batched probes and multiplexed assays.

GENTRA SYSTEMS, INC.- Advancements in Nucleic Acid Sample Preparation

Human Genetics and Clinical Molecular Diagnostic Laboratories require reliable DNA sample preparation methods. The wide variety of clinical specimens and DNA analysis procedures presents a problem in choosing the optimal sample preparation method. We have developed a selection database, available at our web site, to assist in choosing the optimal purification method for a given sample and application. The database contains links to detailed protocols, technical reports, literature references and product information. In a workshop format, we will demonstrate the use of this selection database for several specimens commonly encountered in clinical laboratories. Data will be presented with specimens such as 0.2 -10 ml whole blood samples, buffy coat preparations, paraffin-embedded tissues and buccal swabs, as used in applications such as amplification, sequencing, Southern blotting, and high throughput screening.

INNOGENETICS, INC. - Line Probe Assay (LIPA) Technology-Applications in Human Health and Disease

LiPA is a multiprobe, strip-based detection system for DNA. A large number of targeted genetic characteristics, located in one or more genes, can simultaneously be processed using a single patient sample. Specific oligonucleotide probes are immobilized as parallel lines on membrane strips. The patient's sample is amplified, using biotinylated primers, and the DNA amplicons are then hybridized to the probes on the strip. Streptavidin, labeled with alkaline phosphatase, is added, followed by incubation with NBT/BCIP chromogen. The banding pattern on the strip can then be interpreted. Current LiPA products include a genotyping assay for hepatitis C virus, an assay for the detection of mutations in the reverse transcriptase gene of HIV-1 virus associated with drug resistance, and assays for human leukocyte antigen (HLA) typing.

PE APPLIED BIOSYSTEMS - A Systems Approach to Molecular Diagnostics

Description: "As our understanding of the genetics of human disease grows, so does the need for nucleic analysis in the management of human disease. Systems are available to automate many of the applications used for the analysis of nucleic acids. This workshop will focus specifically on systems developed by PE Biosystems for automated DNA sequencing and DNA fragment sizing applications."

QIAGEN, INC. - Critical Factors for Successful PCR Troubleshooting/Primer Design

Discussion will focus on the dependence of specific annealing between primers and nucleic acid templates for successful PCR. The effect of cations in PCR buffers and other optimization reagents will be discussed as well as the effects of template quality as it relates to PCR. Using general guidelines to design primers for specific PCR scenarios; includes gel pictures demonstrating the results of various primer designs in PCR and a discussion of strategies to design effective primers using gel pictures and hypothetical experimental scenarios, participants will work to determine the potential causes of unsuccessful PCR results, and design experiments to test for and optimize reaction conditions.

THIRD WAVE TECHNOLOGIES, INC - Invader ™ and CFLP ^® technologies

This technical seminar will feature information and results of: The Invader ™ technology - our compelling new method for quantitative and qualitative analysis of specific DNA or RNA species in complex mixtures, without the need for performing PCR. Final readout is performed in standard microdilution plate formats, employing FRET or capture detection methods. The Invader assay platform is based on target-dependent, structure-specific recognition by the Cleavase® enzymes for direct detection of specific sequences. Examples of successful applications include hemostasis (factor V Leiden), bacteria (methicillin resistant Staphylococcus aureus), virus (HBV resistance and load, CMV load), cancer and other inherited disease targets as well as specific cytokine targets.

Participants will receive an in-depth foundation and practical understanding of the technology and its many applications for the clinical molecular laboratory, including preliminary alpha-site results.

CFLP® analysis - learn about the latest advances in scanning for changes in DNA sequences

CFLP analysis is based on the observation that denatured single strands of DNA can assume defined conformations, which can be detected and cleaved by the structure-specific Cleavase I enzyme. The cleavage patterns produced are characteristic of the sequence analyzed. Sequence differences as subtle as point mutations are reflected as changes in this fingerprint.

Participants will learn the principles of the CFLP technology as well as participate in the sharing of new and expanded applications for the molecular diagnostic laboratory.

VYSIS, INC. - Fluorescence in situ hybridization (FISH) based assessment of HER-2/neu gene amplification for prognosis and predictive response to therapy in breast cancer.

The latest information on the amplification of the HER-2/neu gene in breast cancer and its role as a marker of prognosis, predictive response to therapy and as a potential aid in the selection of patients for immunotherapy will be presented. A review of the molecular technique of FISH and interpretation of breast cancer tissue sections will be discussed. Prehybridized FISH slides will be available for review on the Quips imaging workstation.

President: Cheryl L. Willman, MD; 505 272-5622

Pres-elect: Mark E. Sobel, MD, PhD; 301 496-7999

Past President: Margaret L. Gulley, MD; 210 567-3100

Secretary-Treasurer (NEWSLETTER EDITOR):

Daniel H. Farkas, PhD, 626 584-5900 x35

Program Committee Chair:

Carleton T. Garrett, MD, PhD, 804 828-9564

Program Committee Chair-elect:

Karl V. Voelkerding MD, 608 263-8368

Clinical Practice Committee Chair:

Richard D. Press MD, PhD, 317 277-6478

Training & Education Committee Chair

Jeffrey A. Kant, MD, PhD, 412 648-8519

Exec Officer: Frances A. Pitlick, PhD; 301 571-1880

SUBDIVISION CHAIRS

Genetics Subdivision Chair:

Robert Jenkins MD, PhD, 507 284-9617

Hematopathology Subdivision Chair:

Tim O'Leary MD PhD, 202 782-2560

Infectious Diseases Subdivision Chair:

Roberta Madej MS, MBA, 510 923-4005

Solid Tumors Subdivision Chair:

Tom Frank MD, 801 584-3531