News Story #16101

Urgent, emergency, stat and critical care are a few of the words that describe it best, but whatever the name, it’s the kind of care we all hope to never need. Critical care and the tests that go with it can encompass everything from heart attacks and trauma to acute asthma attacks and stomach pains. The common thread is the urgent nature of the symptoms.
The usual suspects that come to mind when you think of critical care testing are pH, PO2, PCO2, sodium, potassium, chloride, BUN, glucose, CBC, PT, APT and ACT, but it can be any clinical test that is urgently needed to make a diagnosis or start a treatment.
   In this month’s disease management section, we look at some usual and not so usual critical care issues.
   For example, point-of-care testing may be one of the fastest growing segments of the lab industry, but it presents a special challenge in data collection and data management. As our article, “Data management catches up with critical care point-of-care testing,” points out, many critical care tests have migrated from the central lab to the patient bedside. This puts point-of-care instruments in the hands of clinicians rather than labratorians, who are trained in the importance of documentation and regulatory requirements surrounding lab testing.
    Manually keeping track of quality control checks and calibrations, knowing which tests are done by whom and on which instrument is not something that Les Revier, lab supervisor at the University of San Diego Medical Center, would ever do again. After years of using a coag analyzer that required a manual log of entries, Revier says he would never purchase a POC instrument that did not incorporate data management.
   In a completely different arena of critical care is the American Journal of Nursing study on the beneficial effects of having a family member in the emergency department when a patient is undergoing invasive procedures, including cardiopulmonary resuscitation. The study found that family members felt it was their “right” to stay with loved ones during critical care procedures and that they experienced no psychological harm from doing so.
   Cancer diagnosis and treatment would not ordinarily fall under the heading of critical care, but when the debilitating side effects and complications of chemotherapy take hold, critical care is usually all that is left. Fortunately, a new HER-2 test that reliably characterizes tumors helps oncologists better target their chemotherapy dosage to a patient’s individual needs.
— Coleen Curran

Data management catches up with with critical care POC testing
As more critical care tests migrate away from the central lab and toward the patient bedside, the need for simple but effective data management solutions grows along with it. In the past, the competing interests of fast turnaround time on lab test results and thorough documentation of the process seemed difficult to resolve.
   Clinicians at the point of care were interested in rapid turnaround times on test results and cared little for process checks such as quality controls and calibration. On the other hand, the average clinical laboratory, in order to keep running, needs enough documentation process checks to satisfy CAP, JCAHO, CLIA and an alphabet soup of other regulatory and accrediting bodies that seem to add a regulation a day to their rule books.
   The good news is that point-of-care testing and data management have met and are co-existing nicely in many critical care units throughout the country. The University of California, San Diego Medical Center is one of those places.

Les Revier, a laboratory supervisor at UCSD, who also holds the titles of Quality Assurance Coordinator, Point-of-Care Coordinator, Safety Coordinator and Continuing Education Coordinator, is a strong proponent of data management in point-of-care settings. He played a key role in implementing point-of-care coagulation testing in the blood bank laboratory, and Revier wanted to be sure the chosen instrument came with the maximum amount of data management capabilities. His experience with an earlier coag analyzer, where everything had to be hand-written on log sheets, provided plenty of motivation.

   Revier chose the TAS (Thrombolytic Assessment System), which is manufactured by CardioVascular Diagnostics of San Diego and distributed by Bayer Diagnostics of Tarrytown, N.Y. Why the TAS? “It required you to do controls. It kept track of who did it, and it will lock you out if controls are not run,” Revier said. “The controls have to be in range. It stores the patient record, and I can download these things to my laptop. Previously, I was trying to rely on log sheets from the POC sites, and that was just not very effective.”
   The reason behind the TAS implementation was a desire on the part of the lab and the blood bank to save money on frozen blood products. Without a point-of-care system, surgeons and anesthesiologists would order blood products on the chance that they might need them. If a trauma patient was on the way in, they would place the order ahead of time rather than wait until the patient got in and central lab test results were available in an hour.
    In many cases, the blood products were being ordered but not used. Of course, once blood products have been thawed, they cannot be re-frozen. “It becomes an expense,” Revier said, “because once you take it out and have it ready, you have to use it within 24 hours or discard it.”
   The lab wanted to eliminate the waste, but first it had to eliminate surgeons’ fear of the unknown. In this case, the unknown was what was going on in the clotting pathways of trauma patients on the way to the hospital.
    “To do that, we needed to provide them with the appropriate coag testing methodologies and better turnaround times on test results,” Revier said. “If they’re going to have to wait 45 minutes to an hour to get a coag test, a PT or PTT, it’s not very productive to them. They’ll just go ahead and order the blood supplies any way, just to have them available. Because when they do want it, they do want it.”
   In July of 1999, UCSD Medical Center added a rapid turnaround point-of-care coag analyzer to its blood bank laboratory. “Our proposal was to do a PT or PTT right there and have the result back in 10 minutes as opposed to an hour,” Revier said. “Based on that value, the surgeon could make a quick determination on whether or not he or she needs those blood bank products. So that was our plan to reduce costs, meet our accreditation requirements and give good patient care.”
   Although the program is still in its trial period and more data needs to be collected, Revier believes it has proven to be quite a success.
   The TAS also is used for point-of-care coag testing at Doctor’s Hospital in Dallas.
   The TAS analyzer is simple to use, and results are returned within 10 minutes, according to Connie Conine, a medical technologist in the clinical lab at Doctor’s Hospital.
   The user pipettes 35 mL of whole blood onto a thin card, about the size and shape of a credit card, where the reagent is held. The card is then placed inside a slot in the front of the device and the blood is heated to 37 degrees Centigrade. This doesn’t take long because the card is thin and the volume of blood is so small. The TAS does three tests: PT, PTT and HMT (heparin management therapy). HMT is the same test as ACT (activated clotting time) on other analyzers. Revier notes that so-called rapid coag testing has been around for a few years, but the larger sample size and heating times required for older instruments can slow them down. None of the instruments he looked at, besides the TAS, had those all-important data management capabilities.
   Doctors at the hospital started using the TAS HMT test on cardiac cath and kidney dialysis patients in July 1997. The previous coag analyzer used 15 mL of sample and took several minutes to heat the sample to the correct temperature. “But the main reason we chose the TAS,” Conine said, “was that it had QC lock-out capabilities. You could not perform the test unless the QC had been run at the designated intervals. You also had to have operator and patient information input before running the test.”
   With data management capabilities catching up with point-of-care testing, labratorians may be more inclined to support future initiatives that propose to move their ultimate responsibility (safe, accurate lab testing) away from their traditional comfort zone (the central lab).
— Coleen Curran

New HER-2 test reliably characterizes tumors
Despite many advances, chemotherapy is still a formidable process that can include debilitating side effects and potentially severe complications that put patients into a critical care situation. One way to increase the effectiveness and avoid the pitfalls of chemo and other therapies is to better target the therapy to the causative agent or mechanism of the disease. In other words, to use a rational rather than an empiric approach to treatment.
   Until recently, the best method available for determining a cancer patient’s HER-2 status was immunohistochemistry (IHC). But a new test, utilizing Fluorescence in situ Hybridization (FISH) called PathVysion HER-2 DNA Probe Kit, made by Vysis Inc. of Downers Grove, Ill., and approved by the FDA just over a year ago, is challenging standard IHC testing.

The top row shows IHC staining results and interpretation on formalin-fixed, paraffin-embedded breast tissue showing membrane staining from left to right of 0, 1+, 2+ and 3+. The bottom row is representative HER-2 FISH results on formalin-fixed, paraffin-embedded breast tissue demonstrating unambiguous results (please note: not matched tissues). The FISH results exhibit orange signals representing copies of the HER-2 gene and green signals represent copies of chromosome 17 that can easily be quantified. The HER-2 FISH results from left to right are normal, normal, low amplification and high amplification.
Photo: Courtesy of Michael J. Kornstein, M.D., Medical College of Virginia/Virginia Commonwealth University, Richmond, Va.

  A familiar example of rational versus empiric treatment is the use of susceptibility testing to select the best antibiotic for treating a bacterial infection. Identifying the causative organism prior to treatment allows physicians to prescribe an antibiotic that is more likely to eradicate the organism, thereby reducing the likelihood that the patient will have to undergo additional treatment due to failed antibiotic therapy. Rational selection of chemotherapy has similar advantages for cancer patients. Not only does it help determine which chemotherapy will be most effective, but it reduces the risk that patients will be exposed to ineffective regimens, their side effects and the potential risk of complications. An example of this approach to cancer treatment is the use of tumor characterization to determine a patient’s HER-2 status.
   The HER-2/neu gene (or c-erbB2) is known to play a role in the regulation of cell growth. Although we all have a HER-2 gene, abnormally high quantities of the gene have been associated with rapid tumor cell growth, resistance to therapy, shorter disease-free periods and a lower overall survival rate among those suffering from several types of cancer including small cell lung, stomach, bladder, ovarian and breast.
   About 20 to 23 percent of patients with breast cancer have an amplified HER-2 gene resulting in over expression of the gene and its products. HER-2 amplification and over expression of the gene product are now generally considered important prognostic and therapeutic indicators for breast cancer. Breast cancer patients who have HER-2 amplification show improved response to intensified adriamycin-based chemotherapy. In contrast, patients who do not have HER-2 amplification do not benefit from dose intensified chemotherapy regimens. Thus, knowing a patient’s HER-2 status can help oncologists select an effective chemotherapy and avoid prescribing intensified therapy that may be ineffective, risky and difficult for the patient to tolerate.
   IHC is an antibody-based test that measures the amount of HER-2 protein on the surface of tumor cells. A slide of formalin-fixed, paraffin-embedded tumor tissue is prepared and stained with the protein-specific antibody. The slide is read under a white-light microscope, and the amount of staining is scored on a scale of 0 to 3+. Despite its widespread use; however, IHC does have some shortcomings. The formalin-fixation used to stabilize cell morphology can cause changes in the tumor tissue that are difficult to control and that influence how the staining is interpreted. For example, fixation can destroy the HER-2 epitope. This can result in a false-negative rate of 15 to 20 percent. Moreover, antigen-retrieval techniques used to overcome this problem can result in an increase in false positive readings. Finally, even under the best of circumstances, IHC testing only provides a subjective interpretation of the degree of staining that can vary from lab to lab, and even within labs.
   The PathVysion test uses an alternative method called fluorescence in situ hybridization (FISH). FISH tests also are performed on formalin-fixed, paraffin embedded tumor tissue. However, unlike the IHC test, the FISH test provides a straightforward, yes-or-no result. This is because rather than staining a gene product that is subject to degradation from slide preparation procedures, and then requiring a pathologist to make a judgment as to the intensity of the staining, the FISH test directly measures HER-2 status at the DNA level. DNA is very stable and so is less likely to be affected by the fixation and embedding processes. Thus, the false-negative rate for FISH tests is less than 5 percent.
Interpreting FISH test results also is more objective than interpreting IHC tests. The PathVysion kit uses molecular genetic technology to create a fluorescent DNA probe that produces a bright microscopic signal when it selectively attaches to the gene-specific complementary DNA. The kit also contains a different DNA probe that attaches to the chromosome 17 centromere. The signals appear as orange and green fluorescent colors for the HER-2 gene and chromosome 17, respectively. This makes it possible to calculate a ratio of HER-2 to chromosome 17 signals. To read the test results, the clinician counts the actual number of HER-2 genes present in the cell nucleus, using a fluorescent microscope. The count is objective because no judgment is required and tissue preparation has minimal effect on test results. “The probability you’ll get the same answer from different laboratories on different days is very high,” said Dr. Steven Seelig, Vysis’s chief medical officer. Reliable HER-2 testing is important because incorrect results could lead to patients receiving unnecessary therapy or not receiving potentially beneficial therapy.
   FISH testing is an emerging technology in clinical laboratories, but Vysis has been involved in its development for the past seven years. In that time, it has brought to market five FDA-cleared and/or approved clinical in vitro diagnostic products that use FISH technology. Three of those are for Leukemia indication, one is for HER-2 and one, AneuVysion, is for prenatal diagnostic use. All five products demonstrated 100 percent reproducibility in controlled, blinded clinical trial studies of multiple labs using “proficiency panels” of normal, weak, moderate and strong positive samples. After two years of marketing AneuVysion, the test accuracy remains at greater than 99.9 percent for informative cases.
   When compared to IHC in one study, for example, FISH tests were reported to take more technologist time and more interpretation time. And, FISH tests are more expensive. However, Dr. Seelig believes conflicting reports on ease of use and the time it takes to interpret test results are primarily due to a lack of familiarity with the technology. He also points out that other issues are involved in evaluating a test.
    “What is the quality of information that you are getting, and how do you compare the quality of that information and the cost of downstream consequences,” he asked. “The false positive rate is much lower with FISH than with IHC. Consequently, it may be possible to improve the economic model of cancer treatment cost with a more accurate diagnostic test. All diagnostic and treatment costs need to be analyzed before concluding a particular test is more or less expensive.”
   Two important benefits result from a more reliable test of any kind, one economic and one human. The economic picture is brightened any time a laboratory is able to better identify when a treatment is appropriate and when it is not. The advantage for patients occurs when they are able to receive the most appropriate treatment and avoid inappropriate or potentially risky treatment. As one part of an overall rational approach to cancer treatment, the more reliable tumor characterization provided by FISH technology may ultimately provide both these benefits.
— Jonathan Briggs