Lablogatory

Tumor Boards and Multidisciplinary Conferences (MDC)

Even if we are not as visible to the patients that we care for as other physicians, pathologists are amazing! Of course, I admit that I’m biased since I am a pathology resident but, this does not make this fact any less true. Others may not always realize that pathologists often have to make life altering diagnoses on the most miniscule of tissue samples. Or that we need to incorporate clinical histories, imaging, and previous clinical test and pathology results just as much as the primary clinician, I’ll dare say, sometimes, even more so, since we often do not have the opportunity to talk with the patient face-to-face. And that in the future, especially as precision medicine develops an increasing foothold in the treatment decision making process, we should, and will be, taking more active leadership roles within multidisciplinary teams.

One of the places where I feel that pathologists can show their value to the patient care team is in the multidisciplinary conference (MDC) setting. These can include tumor boards where we discuss specific patient cancer cases or other interdepartmental conferences where we explore an area of common interest that doesn’t necessarily have to be neoplastic. “Doctor” is derived from the Latin word, docere, which means “to teach” and it is within MDC’s that we can shine as teachers. It is impossible to learn about you need to know in medical school in terms of patient care. Not only is the fount of knowledge ever increasing but also our training directs us toward subspecialization since the volume knowledge is so vast, we have to choose which areas we will spend more time mastering.

Way back in the day, surgery residents had to spend significant time (often at least six months) rotating on the surgical pathology service. I find that these more experienced attendings are often the ones who scrub out and sit with our pathologists at the multi-headed scope during frozen sections. And they are also the ones who can make the surgical pathology diagnosis and know the staging summaries even better than junior, and even some senior, pathology residents. But training requirements change. Most of the other clinical physicians we will interact with as colleagues were not trained in this manner.

One of the reasons I chose hematopathology was because I enjoy the daily increased face-to-face interaction I experienced while on this rotation. At most of the hospital sites I’ve trained (four at my previous program and two at my current program), hem/onc physicians and fellows often make the trek to the pathology department to discuss patient cases with the hematopathologist, especially over the microscope. They had some idea of what they were looking at, too. In fact, at a couple of the programs I interviewed (Hopkins and UW), hem/onc physicians are, or were in past in the case of UW, responsible for reading the liquid specimens (peripheral blood smears and aspirates). They also often had multiple interdisciplinary conferences – leukemia, lymphoma, coagulation/benign heme.

But, since I’m on a surgical pathology rotation right now, I was thinking about when we interact most with our surgeons – and I think that is during tumor board. A few of the “old school” surgeons will scrub out and come to the department to look over a frozen with us but most often than not, this is not the case. But during tumor boards, there is always active discussion which includes the pathology in order to come to a treatment decision on not-so-straightforward cases. And these are opportunities to demonstrate just how important the pathologist is to the process. At least in the difficult cases, we do not merely write out diagnoses for other doctors to read and move on without us to treat the patient. It is in these moments when we not only educate but can also actively participate in helping to direct care. But in order to do so, we need to be able to integrate the clinical, epidemiologic, morphologic, radiologic, ancillary diagnostic, and prognostic (lots of “-ogics” there) factors along with know the potential treatment alternatives. We don’t just deal with the morphologic and leave everything else to the referring physicians…at least, if you want to be the best pathologist that you can be. This is also the time when we can leave a lasting impression on other trainees (medical students, residents, and fellows) about how a pathologist can contribute when added to the team mix so that they will be more apt to seek out and work together with pathologists when they become attending physicians.

We are the physicians who understand the intricacies and implications of many of the ancillary tests if we understand well how they are performed and why and also what can cause erroneous or false positive/negative results. I think that I learned a lot of those types of things through serving as an accredited lab inspector (or you can help with your department’s lab self-inspections) and also by being more pro-active during my CP rotations to work with the lab staff and not just sit at my desk and read a book (or study for boards). And we can help guide other physicians regarding which tests are useful for specific situations and which tests really won’t impact prognosis or treatment management. So, be deliberate during your rotations! Try to understand the “big picture” and how important we can be (and really are) in the patient safety and care process! I think that tumor boards and interdepartment MDC’s are a great venue for us to showcase the “true” contributory potential of what pathologists to the patient care team.

-Betty Chung, DO, MPH, MA is a third year resident physician at Rutgers – Robert Wood Johnson University Hospital in New Brunswick, NJ.

Illinois Summit on Antibiotic Stewardship

Last week, I attended the Illinois Summit on Antimicrobial Stewardship at Northwestern Memorial Hospital. While the target audience was physicians, nurses, pharmacists, and administrators, as a clinical laboratory scientist I found the presentations (with a few caveats, which I’ll get to in a moment) quite informative.

The morning sessions covered the relationship between antibiotic use and resistance patterns; interpretations and implementation of the national guideless for stewardship; and using behavioral science to increase compliance with stewardship programs. Participants spent part of the afternoon in small groups to discuss designing and implementing a stewardship program.

A few notes:

-50% of antibiotics for upper respiratory infections aren’t needed; 50% of antibiotics for inpatients aren’t needed, either

-antibiotics are the only drug where use in one person impacts it effectiveness in another

-based on the literature, antibiotic stewardship programs have at least a transient effect on antibiotic effectiveness—eventually, resistance numbers begin to climb again

-hospital antibiograms are the most widely available measure of resistant organisms, but we aren’t using them as effectively as we could. For example, we typically report that, say, “62.5% of E. coli isolates are resistant to ciprofloxacin,” but we don’t say where those isolates come from. Are they urinary tract infections or upper respiratory infections? What’s the rate of resistance for infected wounds?

-a weighted antibiogram might make empirical treatments for effective. For example, “what % of urinary tract infections are resistant to ciprofloxacin?”

-it’s important to note that the IT department, hospital information systems, and laboratory information systems play a huge role in stewardship programs

-stewardship programs depend on the “5 D’s” Diagnosis, drug selection, dose, duration, and de-escalation of use

-diagnostic uncertainty—driven by lack of early organism identification—drives a significant amount of antibiotic use

-when combined with stewardship, rapid bacterial identification methods such as MALDI-ToF platforms decrease parameters such as length of patient say, time to treatment, etc.

-we can use peer pressure to drive improvements. No one wants to perform worse than the doctor next door

-our efforts might be moot, anyway; other countries take a much laxer stance on antibiotic use

While the laboratory in general and clinical microbiology departments specifically were mentioned during the presentations, I must say they were only mentioned in the context of how little perceived impact we have on stewardship. (“Well, we know the laboratory isn’t going to give us any useful information for another three days…”) It wasn’t until I participated in the small group sessions in the afternoon that attendees at my table admitted that the laboratory is an important piece of the stewardship puzzle. We have mountains of data we can assimilate (antibiogram creation, anyone?). We can bring in new technologies to make identifications faster. We can work closely with the infectious disease doctors to help guide treatment. That brings up a good point—if microbiology labs aren’t in-house, then creating an antibiotic stewardship program becomes that much harder because results can be delayed.

If you’d like to see the powerpoints from the presentations, you can do so by clicking the “downloadable content” tab at Northwestern Memorial Hospital’s antibiotic stewardship page.

–Kelly Swails, MT(ASCP), is a laboratory professional, recovering microbiologist, and web editor for Lab Medicine.

Can You Identify This Structure?

What is this dark structure in the center of this biopsy of a thyroid nodule?

A. Foreign body
B. Artifact
C. Psammoma body
D. Area of necrosis
E. Collection of fungal organisms

The structure at the center of this image is a psammoma body. Psammoma bodies are lamellated, calcific structures commonly seen in papillary carcinomas, such as this papillary carcinoma of the thyroid. The exact underlying cause or mechanism of psammoma bodies is not well understood. However, some studies have shown that in papillary thyroid carcinoma, psammoma bodies are associated with a lower disease-free survival and an overall worse prognosis.

-Kristine Krafts, MD, is an Assistant Professor of Pathology at the University of Minnesota School of Medicine and School of Dentistry and the founder of the educational website Pathology Student.

Issues for Blood Management in Hematology/Oncology

Hematology/Oncology patients comprise a unique subpopulation for whom transfusion therapy is often necessary in both the acute care setting as well as for long-term support. Red blood cells (RBCs) and platelets are the most common components transfused particularly in patients undergoing high-dose chemotherapy, intensive radiation therapy and human hematopoietic stem cell transplantation (HSCT).

Restrictive transfusion practice has become the “new world order” particularly for general medical and surgical patients. Those with hematologic malignancies or solid tumors have not frequently been a large part of many of the randomized controlled trials that speak to this approach. Literature is available, however, that provides evidence that judicious use of blood components via restrictive transfusion and single unit transfusions for inpatients and outpatients can be clinically effective, safe, and will decrease the potential for transfusion-associated adverse events.

Feasibility studies of restrictive RBC transfusion in the Hematology/Oncology population have been reported. These studies provide compelling evidence that lower transfusion triggers, targets and single unit use are not associated with increased bleeding episodes and will reduce overall transfusion exposure.¹ ² ³ The American Society of Hematology (ASH), as part of their Choosing Wisely Campaign, advises against liberal transfusion of RBCs with hemoglobin (Hgb) targets of 7- 8 g/dL, along with implementation of single-unit transfusions when possible.⁴

Recent RCTs and consensus from the AABB point to similar restrictive practice for platelet transfusion with a trigger of 10,000/µL for prophylactic transfusion in most patients.⁵ Subgroups of patients, such as those with autologous HSCTs, may not require prophylactic transfusion at this level, but can be effectively transfused using a therapeutic-only strategy.⁶ The use of lower doses of platelets has been shown to be safe and effective.⁷ Similar strategies may also be applicable for outpatients.⁸

Pursuant to those patients receiving radiation therapy, historically, there have been reports in the literature that found loco-regional control to be improved in patients whose Hgb is maintained at a higher level, typically > 10 g/dL. Many, if not most of these studies had significant confounding and have not adjusted for comorbidities. A publication in 2012, however, concluded “…that hypoxia is a well-established cause of radio-resistance, but modification of this cannot be achieved by correcting low Hgb levels by…transfusion and/or [ESAs[.”⁹ Similarly, a recent study covering over 30 years of experience with cervical cancer patients undergoing radiation therapy (the original target population from a historical perspective) adjusted for confounders and found no evidence that anemia represented an independent predictor of outcomes associated with diagnosis or treatment. ¹° Transfusion, in and of itself, has significant negative immunomodulatory effects via cell-to-cell interactions and cytokines. Thus, maintenance of Hgb levels for these patients should not be considered an absolute necessity.

Other interventions may prove successful for Hematology/Oncology patients as part of a Blood Management Program. Identification and treatment of concomitant iron deficiency anemia or other nutritional deficiencies can potentially decrease or eliminate the need for transfusion. Drugs that might increase the risk for bleeding or hemolysis should be eliminated if possible as these cause or potentiate anemia. Use of new targeted drugs such as lenalidomide in patients with 5q deletion-associated MDS may prevent the need for long-term transfusion dependence. The use of antifibrinolytics in patients who have become refractory to platelet transfusions can enable platelet function even at low levels and prevent the unnecessary use of limited platelet resources.

Outpatient transfusion in the Hematology/Oncology arena comes with some unique circumstances. Many outpatients remain stable and will be capable of lower transfusion thresholds and longer intervals for both RBCs and platelets. Evidence-based restrictive transfusion can and should be a part of outpatient treatment strategy, just as with inpatients if the accessibility to post-transfusion care is adequate. No national guidelines are available for outpatient transfusion and each patient scenario must be considered on an individual basis, but certainly the absolute need for “standing” transfusions and obligatory 2-unit transfusions should be discouraged. Consider, as well, that patients often have their own view of the “need” for transfusion when symptoms and signs do not necessarily make it requisite. Discussion with our patients is essential to allow them to understand transfusion decisions.

The risks of transfusion are both immediate and delayed, particularly for those with chronic transfusion needs. Febrile non-hemolytic, allergic, hemolytic reactions, TRALI and TACO may occur as in other patient populations and should be recognized and treated as appropriate. Alloimmunization and transfusion-related iron overload are more common in the Hem/Onc arena given the potential for increased component exposure during the acute care setting and the high percentage of those that necessitate chronic transfusion support. The potential for transfusion-associated graft vs. host disease is also more worrisome given the degree of immunosuppression in these patients. Specialized products are often necessary including leukoreduced, antigen negative, irradiated or HLA-matched components. These specialized products may not be available on a STAT basis and add significantly to the overall transfusion cost. Careful consideration is warranted and inclusion of the Transfusion Service is key.

In the end, transfusion practice for Hematology/Oncology patients should include restrictive transfusion practices with assessment of the risks and benefits at the time of each potential transfusion episode. Each patient, whether inpatient or outpatient, should be evaluated based on their current state of stability, clinical course and availability and access to care. Nutritional assessments and subsequent interventions along with pharmaceutical agents may provide additional ways by which transfusion exposure can be decreased. Special products are often necessary and needs should be discussed with the Transfusion Service. Limiting transfusion ultimately avoids unpleasant, potentially severe acute and delayed adverse events as well as preserving resources within our communities.

References:

Jansen et al. Transfus Med 2004; 14: 33
Berger et al. Haematologica 2012; 97: 116
Webert et al. Transfus 2008; 48: 81
choosingwisely.com
Kaufman et al. Ann Intern Med 2014; doi: 10.7326/M14-1589
Stanworth et al. Transfus 2014; 54: 2385
Slichter et al. N Engl J Med 2010; 362: 600
Sagmeister et al. Blood 1999; 93: 3124
Hoff Acta Oncologica 2012; doi: 10.3109/0284186X.2011.653438
Bishop et al. Int J Radiat Oncol Biol Phys 2014; doi: 10.1016/j.ijrobp.2014.09.023

-Dr. Burns was a private practice pathologist, and Medical Director for the Jewish Hospital Healthcare System in Louisville, KY. for 20 years. She has practiced both surgical and clinical pathology and has been an Assistant Clinical Professor at the University of Louisville. She is currently available for consulting in Patient Blood Management and Transfusion Medicine. You can reach her at cburnspbm@gmail.com.

Bilirubin

Occasionally I get a question about exactly what forms of bilirubin our assays are measuring, or what a direct bilirubin (DBili) measures versus a total bilirubin (TBili). This post is a short discussion on bilirubin.

Bilirubin is the degradation product of heme, which is the oxygen carrying group found in hemoglobin. Every hemoglobin molecule has four heme groups. Each of those heme groups will degrade into a bilirubin, so anything causing red blood cell destruction or increased turnover will generally result in increased bilirubin levels. This bilirubin is called unconjugated bilirubin because nothing is bound to it. Unconjugated bilirubin is extremely water insoluble and it is carried to the liver, mostly by albumin. In the liver, an enzyme called UDP-glucuronyltransferase (UDP-GT) adds glucuronic acid molecules to the bilirubin. This bilirubin is now called conjugated bilirubin, and it is water soluble.

There are four basic forms of bilirubin found in blood, unconjugated, mono-conjugated (one glucuronic acid added), di-conjugated (2 glucuronic acids added) and protein bound. They are also referred to as alpha, beta, gamma and delta bilirubins, respectively. How much of each form is measured depends on the assay used to measure it.

Most of the currently available wet chemistry assays for bilirubin use diazotized salts of sulfanilic acid to react with bilirubin and form a colored compound. The initial reaction occurs with the conjugated, water soluble forms, and is referred to as the “direct-reacting” or “direct” bilirubin. Then an accelerant is added to the assay, and the rest of the bilirubin reacts, giving you a total bilirubin. Therefore DBili is a measure of most of the conjugated forms but usually also includes any protein-bound forms that may be present. Unconjugated bilirubin is part of the total, but is not measured directly by diazo reactions.

A few assays give a direct spectrophotometric measurement of the conjugated and unconjugated forms themselves, specifically the dry slide technology available on Ortho Diagnostics instruments. Other than these few assays, to directly measure the unconjugated bilirubin requires an HPLC method which measures all the various forms separately. Transcutaneous bilirubin instruments give a measure of total bilirubin.

In disease states, monitoring the TBili concentration is important, however knowing whether the bilirubin present is conjugated or unconjugated will give you an idea of what the underlying problem may be. Elevated unconjugated bilirubin (high total with low direct) suggests increased hemolysis, or inability of the liver to conjugate bilirubin. Neonatal jaundice is usually caused by unconjugated bilirubin due mainly to immature liver enzymes, ie not enough UDP-GT to conjugate all the bilirubin present. Additionally, high unconjugated bilirubin will move into the tissues because of its water insolubility, and can cause brain damage if the concentration is high enough for long enough, a condition known as kernicterus. Elevated conjugated bilirubin (high total and high direct) suggests conditions causing inability of the liver to properly drain bilirubin into the bile (cholestasis). Prolonged high unconjugated bilirubin is a more serious condition than prolonged high conjugated bilirubin, because conjugated bilirubin can be excreted in urine and tends not to accumulate in the tissues.

-Patti Jones PhD, DABCC, FACB, is the Clinical Director of the Chemistry and Metabolic Disease Laboratories at Children’s Medical Center in Dallas, TX and a Professor of Pathology at University of Texas Southwestern Medical Center in Dallas.

Microbiology Case Study–Diabetic Foot Ulcer

A 68 year old woman with a past medical history of type 2 diabetes mellitus presented with a foot wound clinically consistent with a diabetic foot ulcer. Imaging of the patient’s foot demonstrated a large abscess of the plantar aspect of her foot with extension to the surrounding soft tissues. The patient was taken to the operating room and incision and drainage was performed. Fluid from the wound was submitted to the microbiology laboratory and was planted aerobically and anaerobically. Growth was observed on the anaerobic blood plate with the below gram stain and colony morphology:

Gram stain showing Gram positive bacilli with minimal branching.

actino2 — Anaerobic blood plate with small white bacterial colonies.

Laboratory Identification:

The fluid received from the patient’s wound was cultured on aerobic and anaerobic grow plates. The bacteria only grew on anaerobic plates. Additionally, the gram stain revealed pleomorphic gram positive bacilli. These findings were suggestive of Actinomyces. Actinomyces species was confirmed by mass spectrometry.

Discussion:

Actinomyces are anaerobic gram positive bacteria that are normal flora of the oral cavity and throat. Actinomyces have variable gram stain and colony morphology. Our case, as shown above, demonstrates the pleomorphic nature of Actinomyces and does not exhibit the classic textbook morphology. The typical gram stain morphology of Actinomyces is branching, filamentous, beaded bacilli. This morphology overlaps with Nocardia. Actinomyces can be distinguished from Norcardia based on its anaerobic growth pattern and lack of partial acid fast staining (Nocardia are strict aerobes that stain partially acid fast). The bacterial colonies of Actinomyces are non-hemolytic, non-pigmented and are classically described as white and nodular (molar tooth shaped). Actinomyces forms “sulfur granules” in patient specimens which are hard yellow granules composed of bacterial filaments solidified with exudative material.

Actinomyces has the potential to cause opportunistic infections when transferred from an endogenous site to a sterile site of the body. Actinomyces is involved in a spectrum of human disease including actinomycosis, wound infections, abscesses, oral infections, genital tract infections, and urinary tract infections. Of these diseases, actinomycosis is the most infamous and is characterized by abscess formation, draining sinus tracts with sulfur granules, and tissue fibrosis. Actinomycosis is most commonly cervicofacial, but may also be thoracic, abdominal, pelvic or involve the central nervous system.

Treatment of Actinomyces includes surgical debridement if indicated and prolonged antibiotics for 3-6 months depending on antibiotic sensitivity. Antibiotic sensitivity ranges from penicillin, amoxicillin, tetracycline, erythromycin, and clindamycin.

Jill Miller, MD is a 2^nd year anatomic and clinical pathology resident at the University of Vermont Medical Center.

-Christi Wojewoda, MD, is the Director of Clinical Microbiology at the University of Vermont Medical Center and an Assistant Professor at the University of Vermont.

What is the Patient’s Right With Respect to Laboratory Testing Orders?

I was recently in Arizona for a meeting and being there made me think of an email that I had received the day before I flew out. Apparently, the Arizona House of Representatives recently passed legislation (HB 2645) allowing direct lab test ordering by patients without a physician’s request or written authorization. This bill would still need to be signed into law to go into effect but I was still surprised to read about this bill.

Interested parties worked together to have the original bill amended with the stipulation that the laboratory would have the authority to decide which tests (or none) that patients may order. In some states, such a law I believe already exists (but don’t quote me on that…I tried finding confirming this but was not successful). But this begs the question, who takes responsibility for the test results? Currently, the Arizona bill states that test results would go to the person who provided the sample if a physician did not order the test. It would be their responsibility to consult with a physician for test result interpretation and required care and no physician would be liable for not acting on the test results if s/he did not order them.

So what is your opinion on patients self-ordering lab tests for themselves? Would this lead to patients second guessing their physicians if they want a lab test based on information that they personally gathered but that their physician disagrees with? Or would this make it easier for both the patient and physician in cases of routine testing? Are there implications that we have not thought of?

As an AP/CP resident, I’m not quite sure where I fall on this issue. Sure, having been “raised” in a training environment where vestiges of a previously patriarchal ethos and bias remain, it is difficult to imagine patients, and not physicians, choosing what tests to order. After all, hopefully, four years of medical school and multiple years of residency and eventual fellowship, should help inform these decisions more than internet searches and anecdotal stories can. But I have always been a patient advocate first. And I am always willing to take a step back to think about questions from the patient’s point of view and try to set aside my own biases, if doing so will improve patient care and safety.

But as with every human being, I’m cognizant that I do have biases. And as a resident who has had to navigate what we know as CP call, I understand that physicians, too, often have difficulty knowing what tests to order and what they should be looking for in a “good test” to provide them with the appropriate answers that they and their patients seek. I’m sure we’ve all dealt getting pages where we had to shut down what I like to refer to as “shotgun” ordering – multiple tests that are ordered hoping to find an answer in those cases where there is no differential or a very exhaustive one. Especially since without a targeted differential, test results may be difficult to interpret. Additionally, I’ve often seen other issues such as duplicate orders when a panel along with specific additional tests that are (unknowingly) included in the panel are ordered or the wrong test(s) ordered altogether. So it does pay to have another set of informed eyes look over test orders.

As a pathology resident, and even one with extensive lab and research experience prior to medical school, I can admit that I learn more and more each time I’m on a CP rotation about how to gauge the analytic and clinical validity of specific lab tests. Just because a test exists, doesn’t always mean that we should use it or always order it for every patient. This is the role I feel that we fill for referring physicians and patients. We develop and make sure tests are conducted properly, safely, and efficaciously. We also serve as a resource with knowledge on which tests, specimen sources and other analytic parameters, and patient populations are appropriate. We can also identify and troubleshoot when false positives or negatives are suspected as well as provide an interpretation of the test results within the context of clinical patient history that we can access through the EMR. But that is within the confines of the walls of the medical culture and environment, which I admit is not perfect and has areas that we can still work on to improve.

But when it comes to patients ordering tests outside the purview of direct medical care, I’m not sure what my stance is. In this country, patient autonomy is king. As physicians, we don’t always have to agree with our patient’s decisions, but we do need to respect them. We cannot arbitrarily subjugate patients to the dictatorship of a patriarchal perspective (at least not in this modern day), even within a patient care setting. So, at least in my mind, a grey zone exists in the context of a patient who is willing to pay or who can get his/her insurance to pay (although that is entirely another issue) for a specific test not ordered by their physician. But I do worry that this could set up complications for evidence-based patient care. There are multiple levels of implications that I’m sure we have not even thought of – not only for the physician who has to decide what to do when their patient brings in results from a test that they personally ordered without physician authorization but also for the patient to not feel as if they are falling through the cracks of our healthcare system if physicians decide to not act on these test results. I can imagine that there are medicolegal issues that are significant as well but I humbly admit that these are definitely beyond my expertise to comment on at this time. However, I do know that I believe that patients have a right to access their test results directly and not have to go through their provider if they choose not to.

I wrote this post not to necessarily push readers to one viewpoint or another but more so to provoke thought. So, how do you think this bill will affect healthcare in Arizona or set a precedent for other states to follow and what is your stance? I can honestly say, I’m still thinking it over…

This post is an edited version of one that appeared on 2/27/15.

-Betty Chung, DO, MPH, MA is a third year resident physician at Rutgers – Robert Wood Johnson University Hospital in New Brunswick, NJ.

Next Steps in Cytotechnology

ASCP and ASC have put together a program to enable cytotechnologists to grow their skills and advance their careers. During this workshop, attendees will learn how to engage as a part of the clinical team and broaden their skill set to include fluorescent in-situ hybridization and interpretation of applied molecular tests.

If you’d like to attend this program, you can register before April 30 to get a discount.

A Potential Paradigm Shift for Strep Cultures?

In a study published a few days ago in the Annals of Internal Medicine, researchers discuss the prevalence of Fusobacterium necrophorum in students with pharyngitis. Typically, severe sore throats are attributed to Streptococcus Group A, C, or G; however, sometimes patients can be symptomatic but negative for these three pathogens. The study authors found F. necrophorum in 20.5% of their symptomatic population (312 students aged 15 to 30 years).

This study does raise an interesting question: should micro labs inoculate a CDC plate as well as a blood plate for strep cultures? This organism is susceptible to penicillin, so the treatment course is the same as for typical strep throat, which would indicate the CDC isn’t really needed. However, as this Healthday article indicates, F. necrophorum infections can lead to Lemierre’s syndrome, a rare but serious complication. Knowing the causative agent of a sore throat would be beneficial.

–Kelly Swails, MT(ASCP), is a laboratory professional, recovering microbiologist, and web editor for Lab Medicine.

Why We Should Care and Act on the Proposed FDA Regulation of LDTs

So, I wrote briefly to bring awareness about this topic when the U.S. Food and Drug Administration (FDA) first formally proposed in July of 2014 that they intend to begin regulating laboratory developed tests (LDTs). Now that draft regulations have been released, I want to encourage you to not only learn more about this issue but also to decide where you stand and most importantly, to act — to add your individual voice to strengthen a collective voice, whichever side of the argument you choose to stand by. You can read the FDA’s proposed Framework for Regulatory Oversight of LDTs (which are currently non-binding recommendations) to help decide your opinion on this issue.

Congress declared that most diagnostic tests are considered “medical devices” in the Medical Device Amendments (MDA) of 1976. The FDA oversees medical device regulation, but until recently, had only exercised “enforcement discretion” with respect to LDTs. There are 3 classifications for a medical device based on the presumed risk and regulation thought necessary to ensure validity and safety: class 1–general controls for devices considered low risk for human use, class 2–performance standards for devices considered moderate risk for human use, and class 3–premarket approval for devices considered high risk for human use.

So, what is a LDT? Lab developed tests are neither FDA-cleared or approved and are validated and performed in the same lab in which they are developed. While the majority of molecular genetic pathology tests that are currently offered in clinical labs are LDTs (often referred to as “home brew” or “in-house developed” tests), labs can—and do—develop tests for all areas of the laboratory. They would most likely fall under class 2, or for the more highly complex tests, class 3. And the time is now for the pathology workforce to show their value as the diagnostic experts in the development, validation, and interpretation of such tests.

The completion of the Human Genome Project and the basic and translational research that followed has ushered in a new clinical practice landscape. Personalized or precision medicine is a buzz word often touted in the media these days. I was a graduate student researching transcriptional regulation and signal transduction pathways during the Human Genome Project. It was an exciting time where those of us in research could imagine a future where our discoveries would form the foundation for clinical decisions to treat disease. It was a dream that we knew would take at least a decade to begin to achieve its first nascent steps. But personalized/precision medicine, albeit still immature, has arrived and is progressively demanding our care and attention.

It is a term that can be employed to incorrectly exaggerate the implications of diagnostic tests. It can be especially dangerous when misused to support testing that lacks a transparently or rigorously vetted validation process. And inflated clinical claims by a handful of test providers have focused the FDA’s attention in the direction of LDTs. No one disagrees that these highly complex diagnostic tests should require both analytic and clinical validation and continuous monitoring. The questions are who is the best to ensure that these parameters are met? And how can we best encourage the flexibility necessary to incorporate innovation and new discoveries into timely clinical care?

Currently, the Centers for Medicare and Medicaid (CMS) are charged with overseeing all clinical laboratory testing and enforcing adherence to Clinical Laboratory Improvement Amendments (CLIA) that regulate testing on patient specimens. So, all LDTs are under the purview of CLIA regulation and their analytic validation is reviewed biannually. However, CLIA does not address clinical test validity which falls under the FDA’s purview over medical devices during the PMA process. These two regulatory schemes are meant to be complementary and the FDA also includes a more rigorous analytic validation process.

Many clinical labs also participate in the College of American Pathologists (CAP) peer-reviewed biannual inspection process which has requirements more comprehensive than those currently required by CLIA. And having just co-inspected a new molecular genetic lab for the CAP last week, I can state that I believe in the peer-review inspection process. Inspectors must have specific and extensive training in the inspection topic area(s) in order to be certified to inspect those types of labs after successful completion of a certification process. We also have access to resources available through a large network of volunteer inspectors and CAP support so that we are not overburdened and can perform a thorough inspection. Those of us who are certified inspectors also hold the conviction that fastidiously enforcing compliance to accreditation standards is the best for patient care. This is because we know that we are the frontline–we not only know how to develop and validate these tests but need to make sure that other labs follow the same standards.

The average time and cost to complete the FDA approval process from concept to market can be prohibitive to patient care, on the order of 3-7 years and an average $24 million for a successful PMA. Even the time for 510(k) fast track FDA premarketing notification for class 2 devices that are “substantially equivalent” to a pre-existing marketed device (predicate) in terms of safety and effectiveness averages at least 6 months and this process has been criticized as flawed by the Institute of Medicine (IOM). Additionally, both the time and cost for approval have progressively increased over the years, making it more difficult to obtain with the exception of highly financially solvent commercial labs.

At this point, I want to be very clear that these are my personal opinions and not those of any of the organizations that I am affiliated with who may hold more moderate or opposing opinions to mine. Since we all have personal bias, I’ll fully disclose mine: 10 years of basic science research utilizing molecular and cell biology and transgenics, completion of a basic science graduate degree with molecular based research, a future molecular genetic pathology (MGP) fellowship, and hopefully, a future career as a public health (molecular epidemiology/biomarker discovery) focused physician-scientist practicing diagnostics and molecular hematopathology research. So I may have a more vested interest toward a particular view. But what is most important to me and one of the reasons I blog, is that others become aware and inspired to become more informed and engaged in the public health policy process, not that they necessarily agree with me.

Let me give an example of where I stand on this issue which I feel would be a more cogent argument than merely stating my opinion. Advanced non-small cell lung cancer (NSCLC) patients without an EGFR mutation prior to the discovery of the EML4-ALK fusion protein had very few effective therapeutic options. The FDA gave accelerated approval in August of 2011 and regular approval in November of 2013 for the use of crizotinib, a tyrosine kinase inhibitor, for ALK-positive lung cancers diagnosed with a break-apart probe ALK rearrangement fluorescent in-situ hybridization testing kit (Abbott Vysis) on genomic material derived from formalin-fixed paraffin embedded tissue.

Subsequently, ROS1, another tyrosine kinase like ALK, regardless of fusion partner, has also been shown in NSCLC to show 72% tumor shrinkage in response to crizotinib. Since there is no FDA-approved companion test for ROS1, under the current definition of an LDT and proposed regulation (of which this would fall under “LDT for Unmet Needs”), patient specimens would either need to be sent to a lab with an FDA-approved LDT to detect ROS1 rearrangement (of which, none currently exist) or receive diagnosis and treatment at the same facility that has a developed LDT. Currently, these types of specimens can be sent to one of the CLIA-approved labs for this test and the patient treated at their home institution.

Additionally, since the aforementioned FDA approval, genomic material derived in cases of tissue limitation from cytology specimens (eg – pleural effusions) and tested through alternative methods (IHC, qRT-PCR) has been shown to yield at minimum, similarly sensitive, and concordant results. Access to these options would be unavailable if the labs that developed these LDTs could not afford the cost to undergo the FDA PMA or 510(k) process. And even if labs could afford these costs, these tests would not be available to patients in a rapid enough timeframe from the initial discovery of a biomarker and its responsiveness in clinical trials to a targeted therapeutic. If FDA regulation of LDTs does become a reality, what I would like to see is an interdisciplinary conversation that results in an expedited approval process that would still ensure test validity and patient safety.

In response to healthcare reform, many academic based labs are increasingly implementing multidisciplinary clinical care and research teams and utilizing highly complex testing platforms such as next-generation sequencing and microarrays to guide diagnosis, prognosis, and/or treatment. More so now than ever before, healthcare professionals and trainees need to learn to continuously evaluate and practice evidence-based medical care – to really scrutinize whether these tests are valid, safe, and efficacious before recommending them to their patients. The highly dynamic and fast-paced momentum of “-omics” based research demands timely recognition, clinical validation, and test incorporation in order to provide the most up-to-date personalized/precision medical care. Government regulation has proven in the past to be unable to adequately meet this challenge, but I do admit that it is possible. So the time has come for stakeholders (and I hope you realize that you are one) to become informed and stand united behind their principles on this topic. Advocacy is a potentially powerful way that we can shape the current and future healthcare landscape that we will navigate as practitioners and patients. Many of our pathology and other subspecialty advocacy organizations have come out with position statements and signed on to currently available petitions. So FIND YOUR VOICE, STAND UP, and BE COUNTED!

A recent and well-written blog post by a current patient with metastatic lung cancer on this topic can be found at http://www.curetoday.com/community/janet-freeman-daily/2015/02/call-to-action-proposed-fda-regulations-could-limit-cancer-patient-access-to-life-saving-therapies.

References:

Centers for Medicare and Medicaid (CMS). CLIA Overview: Frequently Asked Questions. Published online on 10/22/13. Accessed on 2/15/2015 at https://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/Downloads/LDT-and-CLIA_FAQs.pdf
A Gutierrez, RB Williams, GF Kwass. FDA’s Plan to Regulate Laboratory Developed Tests (webinar powerpoint). Published online on 9/3/14. Accessed on 2/15/15 at http://www.cap.org/apps/docs/membership/fda-ldt-plan-webinar.pdf
Institute of Medicine (IOM). Medical Devices and the Public’s Health: 510(k) Clearance Process. Released 7/29/11. Accessed on 2/15/15 at https://www.iom.edu/Reports/2011/Medical-Devices-and-the-Publics-Health-The-FDA-510k-Clearance-Process-at-35-Years.aspx
National Cancer Institute (NCI) at the National Institutes of Health (NIH): Clinical Trials at cancer.gov. Crizotinib Improves Progression-Free Survival in Some Patients with Advanced Lung Cancer (updated). Last updated on 12/4/14. Accessed on 2/15/15 at http://www.cancer.gov/clinicaltrials/results/summary/2013/crizotinib-NSCLC0613
Schorre. How long to clear 510(k) submission? Published online on 2/2014. Accessed on 2/15/15 at http://www.emergogroup.com/resources/research/fda-510k-review-times-research
H Thompson. How much Does a 510(k) Device Cost? About 24 Million. Published online on 11/22/10. Accessed on 2/15/15 at http://www.mddionline.com/blog/devicetalk/how-much-does-510k-device-cost-about-24-million
KM Fargen, D Frei, D Fiorella, CG McDougall, PM Myers, JA Hirsch, J Mocco. The FDA Approval Process for Medical Devices. J Neurointervent Surg, 2013; 5(4): 269-275. Accessed on 2/15/15at http://www.medscape.com/viewarticle/807243_2

-Betty Chung, DO, MPH, MA is a third year resident physician at Rutgers – Robert Wood Johnson University Hospital in New Brunswick, NJ.