Smear Campaign

Pap smears, unlike most other high-volume tests, are manual, subjecting them to human error and inexact judgments. To offset these deficiencies, scientists have been working for nearly three decades to develop automated screening systems, endeavors that until recently were littered with failures.

The marketing of the new automated Pap smear systems is getting ugly. Clinicians are concerned about the cost and confused about the value. The suppliers’ claims and counter-claims don’t help.

• The approval within a few months of three new overlapping technologies aimed at improving conventional Pap smears has aroused controversy among laboratory professionals and stirred a marketing war among companies.

• NeoPath and Neuromedical Systems (NSI) are taking very different approaches to marketing. NeoPath concentes on large laboratories while NSI tries to create demand among clinicians and consumers.

• Laboratories have been waiting for automated Pap smear systems for decades and are eager for any technology that improves the success of Pap smear screening. But many labs think the systems add to their costs, and are skeptical that third-party payers will reimburse for them.

Pap smears are the Jekyll and Hyde of cancer screening tests. Laboratorians cite them as one of the cheapest, most effective cancer screening tools. Critics decry what they call their high false negative rates and labs’ shoddy screening practices. Pap smears are a major reason why cancer of the cervix is no longer the number one killer of women, reducing deaths from the disease by more than 70%. Yet Pap smear misreading is one of the more common reasons medical malpractice suits are filed against laboratories.

The tests’ vulnerability to criticism stems in part from the fact that Pap smears, unlike most other high-volume tests, are manual, subjecting them to human error and inexact judgments, and in part from their success—they have been so effective that the public holds them to a higher standard of performance than is realistic. To offset these deficiencies, scientists have been working for nearly three decades to develop automated screening systems, endeavors that until recently were littered with failures.

But in the past eight months, the FDA approval of three new technologies for bringing automation to the Pap smear process has thrown the cytopathology community into a controversial whirl and shaken half-century old perspectives. While none of the technologies actually replaces manual screening and each has a different indication, all are aimed at reducing problems in the current approach. NeoPath Inc. received FDA approval for its AutoPap 300QC automated cervical cytology screening system in September as a replacement for the random slide selection portion of the manual quality control procedure; in March, the company got a further boost when HCFA affirmed that the system can be used by clinical laboratories to select slides for quality control review. Neuromedical Systems Inc. ’s Papnet slide reading system was approved in November as an adjunct to conventional Pap testing. And, last month, Cytyc Corp. gained FDA approval of its easier-to-read ThinPrep sample preparation technology as a replacement for the conventional method of Pap smear preparation.

Hype vs. Hope

The introduction of three technologies after years of waiting has aroused considerable attention both in the laboratory and financial communities. Excitement about these developments is evident on Wall Street, where the three manufacturers have raised substantial sums of money in separate public offerings. Most recently, Cytyc raised $44.6 million in an initial public offering, even before its product received the FDA approval. In January, NeoPath raised $62 million net proceeds in a follow-on offering, and competitor NSI raised more than $90 million in December.

But laboratory directors remain circumspect. On one hand, under intense competitive and pricing pressures, they welcome tools that help improve Pap smear results, reduce their liability exposure, and give them a marketing edge over other laboratories. On the other, they are concerned that these systems will raise the cost of screening substantially without significantly contributing to improving the overall process. The new products, as some see it, are interim steps that not only don’t advance but actually fly in the face of the true goal of automation: to reduce screening costs.

For suppliers, the stakes are high. Pap smear screening is perhaps the single highest volume testing still done manually; more than 50 million smears are screened a year in the US alone. While the manufacturers state that their technologies may be complementary rather than competitive, given the costs involved, laboratories aren’t likely to buy all three systems simultaneously. Since Pap smear screening, as with other kinds of diagnostic and screening tests, is increasingly centralized in a few large laboratories (the six largest laboratories, according to NeoPath, now do nearly 50% of all screening in the US), accessing the major accounts is likely to be critical to success.

A nasty marketing war has broken out, with NeoPath and NSI in particular accusing each other of misleading potential clients and creating confusion among the public and the clinicians who order the tests. The firms are vulnerable to such charges in part because their products, though aimed at the same goal of reducing false negative rates, take very different approaches and are approved for somewhat different indications. Furthermore, a number of issues in the field remain unresolved, allowing both sides to capitalize on uncertainty, notably the degree to which Pap smear reading errors are actually a problem in laboratories and the extent to which laboratories need to be concerned about exposure to malpractice suits.

For now, the two companies are positioning their products in the marketplace quite differently. NeoPath, with a small, four-person sales force, is pursuing the large laboratories; NSI is taking a more decentralized approach and trying to create demand from the ground up. It is targeting the several hundred laboratories, large and small, that do Pap smears in the US, as well as clinicians who order the tests, and patients who will be able to ask for the tests.

A Convoluted History

Conventional Pap smear screening has been a major success story. Taking a smear is a painless process in which a physician takes a scraping of cells from the outer portion of the cervix and lower uterus where precancerous cells usually begin to develop. The cells are stained and examined under a microscope for the presence of abnormal cells. When Pap smear screening was introduced after World War II, cervical cancer was the number one killer of women. Since screening has been made available, cervical cancer deaths have decreased by more than 70%, according to the College of American Pathologists (CAP). Studies show that 80-85% of women who die of cervical cancer today in the US have not had a Pap evaluation for five years or more, says CAP.

But Pap smear screening has come under intense criticism in recent years, largely because as a tedious, repetitive manual procedure it is prone to human error. Laboratories have been hit with a barrage of bad publicity about high false negative rates (the percentage of abnormal smears that are misclassified as normal) and the poor performance and shoddy work practices of some laboratories, where cytotechnologists were under pressure to read several hundred slides a day. These reports were, in fact, a major motivation for the passage of the Clinical Laboratory Improvement Act of 1988 (CLIA), which mandated strict quality control measures for laboratories that interpret cervical cytology smears, including random rescreening of 10% of all slides classified as negative, proficiency testing and the requirement that cytotechnologists meet certain skill levels and be limited to reading no more than 100 slides a day.

Efforts to improve the process by automating it have failed, until recently. Many companies, even the federal government, have attempted to automate methods of sample preparation and screening and most have given up. Those that remain in the field have overcome a series of setbacks. An FDA advisory panel, for example, recommended Cytyc’s original PMA for approval in the summer of 1993, but the FDA rejected it following a routine audit during which agency inspectors found that the company hadn’t adequately monitored its clinical trial investigators, leading to inconsistencies in data. Cytyc withdrew its PMA, and rather than revise the data, it began trials again from scratch. Likewise, in the course of its efforts NeoPath nearly ran out of cash at least twice and while its original goal was to automate the entire process of screening Pap smears it settled, at least initially, for seeking a quality control indication because of fluctuating FDA regulatory policies.

Until now, the biggest obstacles to automation have been technological: simply put, it is hard for existing computer systems to read the disorganized, overlapping cells on the typical Pap smear. They can measure individual cells and differentiate individual cells in clusters. But, like humans, they run into problems differentiating cells in dense clusters. And, when they do recognize cells they have trouble making judgments about whether the cells are normal.

As automation becomes more of a commercial reality, however, business issues come to light. The semi-automated systems now available are a double-edged sword commercially: They pave the way for fully automated systems, helping laboratories and regulatory bodies adjust to the concept. But they don’t offer the key advantage inherent in fully automated systems: the ability to directly save money.

Divergent Approaches

The strength of the new products lies rather in their ability to address quality improvement. All three target what some see as a major concern with the current Pap smear screening process: the unacceptably high false negative rates. They differ, however, in their approaches to tackling the problem. NeoPath and NSI are trying to improve the process of reading slides, while Cytyc is concentrating on making the samples easier to read.

NeoPath’s AutoPapQCsystem comes closest to being a “black box” system that cuts out the need for human intervention for a portion of the screening process. It is approved as a quality control device and meets guidelines mandated by CLIA. Under CLIA, laboratories must have experienced cytotechnologists rescreen a minimum of 10% of all Pap smears classified as normal in an initial review; currently these smears are based on a random sample. The AutoPap QC, when running in a quality control mode, rescreens all Pap smears classified as normal in the initial manual screening and designates for manual rescreen those Pap smears that are identified as indicating the highest potential for abnormality; in March, in something of a coup for NeoPath, HCFA, which oversees CLIA implementation, authorized the AutoPap’s use as a replacement for the random screening selection process. NeoPath claims that its trial data shows up to a five-fold improvement in the detection of all types of false negative slides over a standard 10% random selection method of quality control and an eight-fold improvement in the detection of biopsy-confirmed pre-cancerous and cancerous slides.

NSI’s Papnetsystem, on the other hand, takes an entirely different tack. Its system is designed to be used as a supplement to manual screening, rather than as a replacement for current quality control methods. If the AutoPap reduces reliance on human intervention, even slightly, the Papnet system doesn’t claim to and, in the opinion of some, requires more work than the conventional process. And rather than involving all smears that come into a laboratory, Papnet testing is performed on smears only at the request of physicians, patients, or third party payers. Laboratories subscribing to the Papnet system send the designated smears to an NSI center, where they are scanned for the 128 cells on the slide most likely to be abnormal. The 128 images are recorded on a digital tape and both the tape and slide are returned to the laboratory for further evaluation by a cytotechnologist using a Papnet review station

<Body>NSI does not claim that Papnetcan make a diagnosis of a slide or smear. But it does believe that Papnet can increase the detection of cervical abnormality by up to 30% when compared to manual screening alone. If manual screening detects 100 positives out of a total of 1100 slides, for example, Papnet can be expected to increase detection to 130 positives (30% of 100), says Mark Rutenberg, NSI’s chairman and CEO. COMPUTER-ASSISTED PAP SMEAR SCREENING MANUFACTURERS: FINANCIAL HIGHLIGHTS* ($millions)Fiscal Yr 95/ FY 94 Cytyc NeoPath Neuromedical SystemsRevenues $4.2/$2.9 0/0 $2.5 /$1.3Operating Expenses $8/ $4.8 $16/ $12.5 $31.7/$14.8Operating (Losses) ($6.2)/ ($4.2) ($16)/ ($12.5) ($29.2)/ ($13.6)Net Income (Loss) ($5.9)/ ($4.3) ($14.4)/ ($12.3) ($29.4)/ $13.8)Net Income (Loss) Per Share ($0.54)/ ($0.48) ($1.59)/ ($6.67) ($1.67)/ ($0.84)Sources: Company reports

An Alternative Approach: Easier to Read Slides

While NSI and NeoPath focus on screening deficiencies, Cytyc is trying to improve and simplify the sample preparation process on the theory that one major reason mistakes occur in conventional Pap smear testing is that slides often aren’t prepared properly. Even when they are, Cytyc and others say, they tend to contain an excess of obscuring debris, making them difficult to read. In addition, the conventional Pap smear produces inconsistent and non-uniform slides with extreme variability in quality. As a result, patients are sometimes asked to return to their doctors’ offices for repeat testing.

Cytyc relies on what cytopathol-ogists call a monolayer preparation, which is a sample that has been cleaned of debris and contains a thin layer of cells. The aim is to improve slide quality, reduce inconclusive readings, and enable a single sample to be used for additional diagnostic testing.

Cytyc’s ThinPrepsystem replaces the conventional method of manually smearing the sample on a microscope slide and immediately spraying the slide with a fixative agent. With ThinPrep, a physician takes a cervical sample using a special sampling device, which, rather than being smeared on a microscope slide, is immersed in a vial filled with a proprietary solution, PreservCyt. The vial is then sent to a laboratory, where it is run through a special processor, which cleans it and prepares it on a slide so that a cytotechnologist trained to read monolayers can review it manually.

Cytyc’s most direct competitor is likely to be the Roche Image Analysis Systemsunit of Roche Diagnostic Systems Inc. , a subsidiary of Roche Holding Ltd.

Roche has a monolayer sample preparation technology in development, including a collection device that is similar to Cytyc’s and a preparation instrument, CytoRich, that it claims is more automated than Cytyc’s filtering methodology. While Cytyc’s processor handles samples one by one, Roche’s system will be capable of batch preparation, says Ernest Knesel Jr., the unit’s president. Roche, however, is still in the midst of conducting clinical trials for its system and doesn’t expect to file a PMA until later this year, he says. This puts it behind Cytyc in terms of market introduction, but it also means that Cytyc has paved the way for Roche both with the FDA and potential customers, Knesel says. Furthermore, Roche is simultaneously conducting trials on an automated instrument, the AUTOcyte, which is capable of screening monolayers and classifying them as negative or abnormal, a capability that Roche believes makes it suitable for primary screening.

By focusing on screening as well as sample preparation Roche hopes to automate the entire process in a way that Cytyc hasn’t been able to do. “In our view, you need to address sample preparation then screening,” says Knesel. “Machines don’t have the sensitivity of human screeners. If cells are hard for people to see, machines won’t see them either. But if you improve the preparation of cells, you’ve made a dramatic step toward improving the quality upon which humans and machines can act.”

Furthermore, Roche will have additional resources to put into the technology if a proposed merger between its image analysis business unit and Becton Dickinson & Co. ’s image analysis unit is finalized. The new company, with Roche and BD as majority shareholders, would then take over development work, says Knesel.

Roche is also developing an automated microscope called AUTOcyte, which is designed to evaluate 300 monolayer slides per day and combines features of both Papnetand AutoPap systems. Like Papnet, the system is interactive, singling out the most abnormal looking cells from each slide and allowing the cytotechnologist to review and interpret selected cell images in a very high resolution true-color display. Like AutoPap, it supplies an independent machine-generated interpretation of what it views. For the AUTOcyte, Roche plans to seek both a quality control indication and, more importantly, a primary screening approval from the Food and Drug Administration.

Group Purchasing vs. Consumer Marketing

While the scientific community debates the merits of each technology, the manufacturers have very different marketing strategies. NeoPath has a small, four-person sales force focusing on convincing large laboratories that perform the bulk of testing to sign up for its program, for which it will charge on a per-slide basis. Getting even one of the three national laboratories to make a firm commitment to use the system would be a coup, since competitors would likely have to follow suit, if not for scientific reasons then to reduce liability exposure and improve their competitive positions. “We want to see reputable clinical laboratories and their medical directors leading the effort [to adopt our technology],” says Alan Nelson, PhD, NeoPath’s founder and CEO.

Already the company appears to have made some inroads. It has contracts with SmithKline Beecham Clinical Laboratories,Corning Clinical Laboratories, and several other major Pap smear screening facilities to use its products on a pilot basis and Nelson says it has placed 18 instruments in major laboratories, including eight in SBCL’s St. Louis facilities. It is in the middle of negotiating with the third major national laboratory, Laboratory Corp. of America Holdings . Corning is making the system available in its Chicago area facility, which services Chicago and parts of Wisconsin, upon physician request and says it is looking at all of the technologies very closely.

But the large laboratories remain cautious. SBCL, a unit of SmithKline Beecham PLC, isn’t sure what these technologies, when they are put into practice in large laboratory settings, do to the false negative rates, says Edward Kaufman, MD, the company’s national medical director. Furthermore, he notes that “as currently approved, these technologies must be used in a way that is supplemental to what we are doing now, so there is an added cost.”

NSI, rather than centralizing its efforts, is targeting the 400 laboratories that do most of the Pap smear screening in the country; already, it can process from 120 laboratories in the US, including LabCorp and CCL. In addition, it has launched a major campaign to educate 30,000 gynecologists and other physicians about the benefits of its service and plans to start marketing directly to consumers later this year.

NSI’s approach to the marketplace, it believes, protects it in case it has a hard time obtaining third-party reimbursement. The company thinks that women will be willing to pay the additional cost of approximately $35 for Papnetrescreening out-of-pocket in order to assure themselves of greater accuracy of test results, says Rutenberg. In addition it is in discussions with managed care organizations about plans to co-market Papnet testing. NSI’s message is that by offering Papnet, managed care organizations can demonstrate their commitment to women’s health. It’s too early to say how effective its appeal to consumers and clinicians will be; for the most part, laboratory directors say they receive occasional inquiries from clinicians and don’t think most consumers are yet aware of the alternative.

Changes and Counter Changes

The competition between NeoPath and NSI has taken a nasty turn at times, with both manufacturers accusing each other of making misleading comparisons between their products. NSI believes that NeoPath’s selection of slides for quality would result in an improved detection rate of 2-4%; while Papnetimproves the detection rate by up to 30%, claims Rutenberg. Nationwide trials involving rescreening of thousands of presumed negative smears found that the Papnet system detected 4.8% of these smears as abnormal smears; manual rescreening typically finds less than 1% and NeoPath’s approved claims is that AutoPap is half as sensitive as manual rescreening, he adds.

Nelson responds that these observations are based on misrepresented data. He complains that NSI has disseminated this and similar kinds of information to the investment community, at one point causing NeoPath’s stock to start to fall. Last winter, NeoPath went so far as to demand in a formal letter that NSI stop its tactics unless it could verify its accusations, but so far it hasn’t taken legal action against NSI. NSI attorneys in turn have complained to NeoPath about public statements NeoPath executives made regarding comparative trial data, but also took no legal action.

NSI in particular is seen by many in the industry as overly aggressive, its plan to appeal directly to patients is particularly controversial. In February, CAP sent a letter to the FDA expressing its concern about what it deemed the company’s misleading and inaccurate promotional claims. The organization was particularly concerned that NSI was exaggerating the problem of false negative Pap smear readings in order to scare women into asking for Papnetreviews. Such tactics, CAP said, might deter women from getting regular Pap smear tests because they would think the tests don’t work well when in fact they are highly effective.

The direct-to-consumer approach, in addition to catching the attention of professional organizations and regulatory agencies, poses other risks. Not only are laboratories unconvinced that such an approach will work or that patients will want to pay additional sums of money for the service, they are wary of the legal implications of offering a service that may discriminate against poor women who can’t afford the extra charge.

NeoPath faces a different problem: The company’s strength has been in its scientific and technical expertise rather than sales and marketing, says one consultant. But with a new technology like AutoPap, which eliminates the need for human intervention in a process that has been entirely manual, excellent marketing skills are critical to getting cytotechnologists to trust the “black box,” she adds. NeoPath plans to let its laboratory customers lead efforts to arouse interest in its technology, but laboratories aren’t noted for their marketing skills.

Cytyc, for its part, is beginning its promotional campaign by targeting the 350 cytology laboratories that already employ its system for non-gynecologic specimen preparation. The campaign is being conducted by the company’s 20-person sales force. Cytyc has mailed letters to the laboratories promoting ThinPrep’s newly approved use as an alternative to conventional Pap smear preparation. Cytyc’s processor costs $35,000, in addition to an $8 to $10 cost per test kit; those laboratories already using it for non-gynecologic applications can obtain a software card that modifies the processor’s computer capacity.

By many accounts, the rapid introduction of three overlapping technologies within a short time frame has led to confusion among investors, the public, and, to a lesser extent, laboratory directors.

Laboratory directors at major screening centers and hospital laboratories at least understand that there are differences among the approaches, even if they have yet to sort out the pros and cons of each. But clinicians and the public are likely to have more trouble distinguishing among the technologies and the claims made by manufacturers. “It’s tough to sort out the hype from the science,” says R. Marshall Austin, MD, PhD, staff pathologist at Roper Hospital in Charleston, SC, and co-chairman of a CAP-sponsored conference held earlier this month on liability and quality issues in cervicovaginal cytology. “There i s a lot of confusion among everyone at all levels.” Clinicians, he says, need more information, including prospective, controlled studies that assess the cost effectiveness of the technologies and compare them with each other and conventional screening. There is a substantial additional expense to these technologies and cost is a significant factor in access to Pap smear screening.”

Laboratories are having trouble comparing the different products based on existing data, largely because companies approached the trials so differently. Says one laboratory director at a major national lab: “Papnetpicks up some cases but I don’t know if it makes a big difference. In a good lab, I don’t know whether you’ll find a vast improvement in misses.” NeoPath, he notes, seems to have a higher yield in picking up abnormals. Both instruments do what they say they will do but they add what could be substantial costs to the system. And there is no way to compare the two companies because data was prepared totally differently. Simply put, he says, “people can’t make rational decisions about these products.”

Rising Liability Risks

To some extent the widespread confusion plays into the hands of companies, who can capitalize on unresolved disagreements within the cytopathology community and pressures placed on that community by the public. While most cytopathologists would agree that the instruments do reduce error rates, they aren’t sure of the extent to which the rates are reduced and they disagree about the degree to which error rates are a significant problem in the field. Says Austin: “There is an assumption that Pap smear screening should be perfect and anything less violates the official standard of care.” But perfection isn’t realistic, he notes.

No one knows the real rate of false negatives and positives in laboratories. The automation companies and some laboratorians believe that the false negative rate is as high as 25%, even 40% in certain kinds of smears. That is, one out of four women with abnormal smears are identified falsely as negative; out of a total population, of course, this number would be much smaller, since abnormal slides make up only about 5% of all smears.

But many professionals say those numbers are too high, particularly at large reference laboratories and academic centers with rigorous quality controls. These facilities are more likely to have false negative rates of 5-7% of abnormal smears, says Austin and others. A 5% false negative rate at a laboratory would mean that one out of 20 women with abnormal smears will be identified falsely as negative and most of the abnormals would involve atypical cells that aren’t pre-cancerous.

But Nelson and others dispute these figures. Studies show that even laboratory directors who think their labs are extremely accurate miss one of four abnormals, Nelson says. “Even people who think their quality is very high would be surprised.”

Nevertheless, given concerns about false negative slides, reduction of liability exposure may indeed become a major reason why laboratories adopt these technologies and the main way to justify the costs of their implementation, especially if third party reimbursement is hard to obtain.

As a result of high expectations, litigation in the field has increased. By some accounts, cytology, as a result of Pap smear screening concerns, has become one of the high-risk medical specialties and some attorneys are concerned that introduction of these new technologies, rather than helping to reduce exposure, will only raise the public’s expectations of Pap smear performance to even more unrealistic levels. Particularly frightening to many laboratory directors is a case last year in which criminal charges were brought against Chem-Bio Corp., a laboratory in Milwaukee, for allegedly misreading the Pap smears of two women with cervical cancer. The laboratory pleaded no contest and was fined $20,000; in addition, its medical director and the cytotechnologist responsible for reading the women’s slides agreed to limit their professional activities for six years without admitting wrongdoing.

The Bottom Line: Who Pays?

But ultimately, the big question for laboratories is likely to be who pays for these technologies. The cost argument is one that the companies have yet to make convincingly. NeoPath argues that although it charges labs $4-5 per test, this additional cost can be justified because the AutoPap QChelps to reduce the laboratory’s liability exposure and provides state of the art technology in a highly competitive field. Some laboratories calculate liability exposure to be $1-3 per slide, says Nelson.

So far, he says, laboratories that use AutoPaphaven’t passed on the additional costs to patients or payers, but they’d like to. To this end, NeoPath is talking to managed care payers. In addition, laboratories are themselves seeking higher reimbursement for Pap smear screens, an action that if successful would ultimately help to cover the additional costs associated with the process.

Palomar Pomerado Health System’s laboratory, for example, has been using AutoPapfor eight weeks, and charges $20 extra for it, says William Tench, MD, the laboratory’s associate director. But it isn’t sure whether it will be able to collect the money because it has a number of capitated contracts that won’t pay the additional expense. The $20 is billed directly to the patient, Tench says. He predicts, however, that the use of AutoPap will eventually result in a small savings from quality control rescreening.

The issue is even more pertinent for NSI because of the widespread perception that Papnetincreases costs significantly, is time consuming and of uncertain utility. “NSI says it finds 30% of missed cases and they do find cases, but you spend a fair amount of time doing so and incur great costs,” says Tench, who owns stock in both NSI and NeoPath. “There are scanning, shipping and clerical costs associated with the service. You have to log slides out of the laboratory, incurring additional administrative costs.” Tench’s laboratory has worked with Papnet, but ultimately elected to use the AutoPap QC because it could rescreen the entire negative population at half the cost of the Papnet system.

Given the cost concerns, the real coup in this field is likely to be reserved for the company that develops an automated primary screener, especially if the screener significantly reduces costs.

For this reason, the current technologies are viewed as dress rehearsals, both in terms of preparing the FDA to approve a screening replacement and getting laboratories used to automated technology. Indeed, NeoPath is starting trials that would enable it to seek FDA approval for use of the AutoPapas a primary screening technology; likewise, Roche is hoping that its AutoRich system will be FDA approved as a primary screening technology for monolayer samples. “I think demand for a primary screener will explode,” says Tench. “There is no way laboratories will be able to afford not to take advantage of an automated primary screener. No one has spent money on this in order for them to wind up as quality control devices. These are evolutionary in development of a primary device.”—WD

How the Automated Pap Smear Technologies Work

While all three Pap smear technologies now approved aim to decrease the number of misreadings, they approach the problem differently. The AutoPap QCworks as follows: Bar-coded, conventionally prepared Pap smears previously diagnosed as normal by manual screening are loaded into a slide tray and placed in the AutoPap QC system. A sensor notes the presence of the tray and each slide on the tray. A low power scan maps the slide and a high power scan slowly reviews the slide, followed by a rapid scan. Information from each scan is sent to a computer, which interprets images using a series of algorithms. Image processing and pattern recognition techniques are used to classify images on each slide. The system takes 6 to 8 minutes on average to analyze a slide. Results are printed out. One computer can scan 160 slides a day, or roughly 50,000 a year, says Alan Nelson, NeoPath’s CEO and founder.

The Papnettesting system, on the other hand, involves sending smears from the laboratory to a special NSI facility, where they are reviewed by a scanning station and sent back to the laboratory for further review. With the Papnet system, once a cytotechnologist designates a patient’s Pap smear slide as negative, the laboratory sends the slide to a Papnet facility, where a scanning station selects the 128 cells on the slide most likely to be abnormal. The 128 images are recorded on a digital tape cassette, which is returned to the client laboratory within two to four working days along with the original Pap smear slides. A cytotechnologist specially trained in the use of Papnet equipment then evaluates the 128 color images from each slide on a Papnet review station. The review station’s software ensures that the cytotechnologist displays each image at 200 times magnification. If all the cells appear normal, the cytotechnologist classifies the smear as negative. If any of the 128 images appear to be abnormal, the slide is reexamined manually under a microscope and, if abnormalities still appear, it is referred to a pathologist for a final diagnosis.

The Cytyc system is based on the monolayer sample preparation. In conventional smears, the physician dabs a smear onto a microscope slide and sprays it with a fixative. But, physicians who use the Cytyc method use a swab to get a sample of cervical cells and then place the sample in a vial filled with Cytyc’s proprietary preservative solution, PreservCyt. At the laboratory, the vial is inserted into a ThinPrep 2000 Processor, which automates the process of preparing cervical specimens. A gentle dispersion step breaks up blood, mucus, non-diagnostic debris and large sheets of cells and homogenizes the cell population. The cells are then automatically collected on Cytyc’s proprietary TransCyt Filter, which incorporates an eight-micron membrane specifically designed to collect abnormal and cancerous cells. The processor monitors the rate of flow through the filter during the collection process. A thin layer of cells is then transferred to a glass slide, which is automatically deposited into a preservative solution. The slide can then be read by a cytotechnologist.

Roche’s monolayer preparation system, called CytoRich, has a similar approach to sample selection as Cytyc but differs in how the cells get onto the slides. Roche uses syringing to gently break up cell clusters and mucus in the sample and density gradient centrifugation, rather than filters, to remove debris. The cells with diagnostic clusters in place are transferred to slides containing specialized columns for discrete staining, which is done automatically (Cytyc doesn’t have automated staining).

I would like to correct a significant error conveyed by the article “The Internationalization of the Japanese” in the April edition of IN VIVO. The error pertains to TAP Pharmaceuticals, a subsidiary of TAP Holdings, the US-based joint venture of Abbott Laboratories and Takeda Chemical Industries.

On page 16 the article suggests that “TAP’s success may lead to its demise—Takeda will have the opportunity to purchase Abbott’s 50% equity during renegotiations which will come up soon.” In fact, TAP is a 50-50 partnership in perpetuity. Neither partner has a contractual right or option to acquire the other partner’s equity in this joint venture.

<Body>Catherine V. BabingtonVice President, Investor Relations and Public AffairsAbbott Laboratories