Infective Endocarditis

Posted by Sara Fazio • April 13th, 2013

Diagnosis of endocarditis is usually based on clinical, microbiologic, and echocardiographic findings. Treatment involves antimicrobial therapy targeted to the identified organism. Surgical indications include heart failure, uncontrolled infection, and prevention of embolic events. The latest article in our Clinical Practice series reviews diagnosis and treatment options for infective endocarditis.

Infective endocarditis has an estimated annual incidence of 3 to 9 cases per 100,000 persons in industrialized countries.

Clinical Pearls

• What are the risk factors for infective endocarditis?

The highest rates are observed in patients with prosthetic valves, intracardiac devices, unrepaired cyanotic congenital diseases, and history of infective endocarditis. Other risk factors include chronic rheumatic heart disease (CRHD) (which now accounts for less than 10% of cases in industrialized countries), age-related degenerative valve lesions, and comorbidities such as diabetes, HIV infection, IV drug use, and hemodialysis. Over a third of infective endocarditis cases in the U.S. in recent years were reported to be health care-associated (nosocomial or non-nosocomial). The clustering of several of these predisposing factors with age probably explains the higher infectious endocarditis incidence in persons older than 65 years. The male:female case ratio is more than 2:1.

• What organisms are most often responsible for causing infective endocarditis?

Streptococci and staphylococci account for 80% of infective endocarditis cases, with proportions varying according to valve (native vs. prosthetic), source of infection, patients’ age, and comorbidities. Staphylococci are now the most frequent microorganisms in several situations which results from the increased proportion of health care-associated infective endocarditis. In parallel, the incidence attributable to oral streptococcal has decreased in industrialized countries. Blood culture negative infectious endocarditis (10% of cases) may reflect two situations: infectious endocarditis in patients exposed to antibiotics before the diagnosis of infectious endocarditis and infectious endocarditis due to fastidious microorganisms. In the latter case, serology, valve or blood PCR, and highly specialized microbiological techniques lead to pathogen identification in 60% of cases, the most frequent microorganisms being Bartonella sp., Brucella sp., Coxiella burnetii (Q fever agent), HACEK bacteria, and Tropheryma whipplei.

Morning Report Questions

Q: What is the typical clinical presentation of infective endocarditis?

A: Fever is common (80% of cases). In large contemporary case series, recognition of a new murmur or worsening of a known murmur are reported in 48% and 20% of cases, respectively. Other signs are less common: hematuria 25%, splenomegaly 11%, splinter hemorrhages 8%, Janeway lesions 5%, Roth spots 5%, and conjunctival hemorrhage 5%. Sepsis, meningitis, unexplained heart failure, septic pulmonary emboli, stroke, acute peripheral arterial occlusion, and renal failure may also be presenting manifestations. Elevated inflammatory markers (ESR, C-reactive protein, or both) are observed in two thirds of cases, and leukocytosis and anemia in about half of cases.

Q: What is the appropriate treatment of noncomplicated native valve infective endocarditis?

A: For native valve infectious endocarditis due to usual microorganisms, the duration of antibiotic treatment ranges from 2 weeks (uncomplicated infectious endocarditis due to fully penicillin-susceptible streptococci treated with a beta-lactam + aminoglycoside combination) to 6 weeks (enterococcal infectious endocarditis). In streptococcal infectious endocarditis, clinical trials showed that adding gentamicin permits a shorter 14-day course of treatment in uncomplicated native valve infectious endocarditis and that aminoglycosides can be effectively given once daily instead of twice daily. In enterococcal infectious endocarditis, whenever the strain does not exhibit high-level resistance to gentamicin, gentamicin should be used in combination with a cell-wall active agent. In such cases, gentamicin is generally given for the full 6-week course of antibiotic treatment.

 

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Test Yourself! New Interactive Medical Case Now Available

Posted by Jennifer Zeis • April 11th, 2013

A 54-year-old woman presented with a headache that had started 8 days earlier. She had awoken with stabbing, squeezing pain around her entire head. She rated the pain at 10 on a scale of 0 to 10 (known as 10/10), with 10 representing the worst pain imaginable. The pain was not alleviated by nonsteroidal antiinflammatory drugs (NSAIDs). She reported having had no headache on going to sleep that night and said the headache was neither positional nor associated with blurred vision or double vision.

What diagnostic and management steps do you choose? Receive feedback on your choices and learn more about her condition and optimal treatment steps when you try this case now at NEJM.org.

Also, try your hand at previous Interactive Medical Cases.

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Measuring Pain using Functional MRI

Posted by Sushrut Jangi • April 10th, 2013

The moment we find a useful biomarker, our ability to manage a condition improves:  we treat diabetes by following the glycemic index, we treat HIV by following a viral load and a CD4 count. Conditions without biomarkers often frustrate treatment – after all, like the business adage – “you can’t manage what you don’t measure.” Although some diseases fall into this category, frustratingly, so does the symptom of pain. This week’s NEJM reports on a biomarker – specifically a neurologic signature through the use of functional MRI – with the hope that a method to objectively measure pain will allow for titration of medications to achieve effective symptomatic relief in the distressed patient.

There’s no doubt that pain is a serious problem in medicine. At the end of 2010, the IMS Institute for Healthcare Informatics reported on the top 10 most prescribed drugs in the United States, and the chart-topper was the painkiller Vicodin, with a record 131.2 million prescriptions. In hospitals, the most frequently ordered medication is Tylenol; morphine is not far behind. Yet our ability to objectively measure pain, for the past several decades, has been surprisingly basic. Most assessment tools have relied on patient descriptions of their own symptoms. For instance, the McGill Pain Questionnaire of 1975 offered more than fifty words to help a patient describe his pain, including “flickering,” “jumping,” “rasping,” “grueling,” and “drawing.” However, such detailed surveys have been largely abandoned for even more rudimentary measures (“how much pain are you in from a one to a ten?” or “can you point to the face that shows what you are feeling like?”)

Can’t we do any better than this? Maybe. Since the seat of pain perception is in the brain, one idea has been to look at activation of various centers in the central nervous system to track whether activity correlates with the experience of pain. But here’s what complicates things: feeling pain is not just about how hard you are pricked by a pin.   Lots of other neural networks modulate the way a painful stimulus feels – the emotional state of the subject, for example, or prior traumatic memories of pain. (Depressed patients are known to have lower thresholds for describing a stimulus as painful). So – the additional challenge in looking at brain activity as a biomarker means sorting out sensory pain from these layers our brain interlaces with the neural processing of pain.

Given such challenges, the investigators from this week’s report use functional MRI to look for a useful neurologic signature, or biomarker. In their study, while participants were being scanned in a functional MRI, investigators applied varying levels of thermal heat to the subject’s forearms, an example of painful heat. Subjects were also exposed to other kinds of pain – including recalling a painful incident (memory of pain) or looking at an image of an ex-lover (social pain). They found that certain areas were specifically stimulated in response to painful heat, including the anterior cingulate cortex and parts of the thalamus. They also found that given an analgesic agent reduced responses in these areas.

So were they successful in finding a biomarker? The results from this study show that the pattern they detected on functional MRI was highly sensitive and specific for painful heat, and this pattern could be used to distinguish thermal pain from the other kinds of pain (the memory of pain, pain anticipation, and pain recall). Such results are proof of a principle – a biomarker for pain probably does exist in the brain, and functional MRI may be one way to get at it.   However, questions remain – can such a signature be used to detect non-thermal pain (such as being pricked by a pin?) Might we see such a signature in chronic pain (like in fibromyalgia)?

Possibly – but perhaps it is a fool’s errand to ever expect we will be able to boil down pain, like any other meaningful human experience, to a single number. “From a 1 to a 10,” I ask a patient several times, “how much pain are you in?” He grimaces and finally responds.  “I don’t know,” he says, while I push on his stomach. “It’s really hard to explain.”

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In the same issue of NEJM, you’ll also find the editorial, “Pain, Heat, and Emotion with Functional MRI.”

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The Essential Element

Posted by Sara Fazio • April 5th, 2013

In the latest article in our Clinical Problem-Solving series, a 21-year-old woman presented with a 10-day history of progressive fatigue, weakness, light-headedness, exertional dyspnea, and dark-colored urine, followed by an episode of syncope.

Hemolytic anemia may be acquired through immune, microangiopathic, or infectious processes or may be congenital owing to an abnormality in the erythrocyte membrane, enzymes, or hemoglobin.

Clinical Pearls

•  What laboratory findings are typical in hemolytic anemia?

An indirect hyperbilirubinemia and reticulocytosis suggest hemolysis, and the fact that an elevated aspartate aminotransferase level is out of proportion to the alanine aminotransferase level corroborates that diagnosis. In addition, an elevated lactate dehydrogenase level and low haptoglobin level support a diagnosis of hemolysis, although assessment for free hemoglobin in urine or plasma is a more specific way to distinguish between intravascular and extravascular hemolysis. Spherocytes are seen in immune-mediated hemolysis and hereditary spherocytosis. Spherocytes and bite cells can be identified in cases of oxidative hemolysis related to burns or glucose-6-phosphate dehydrogenase (G6PD) deficiency.

•  What is the pathogenesis and epidemiology of Wilson’s disease?

Wilson’s disease, an autosomal recessive disorder characterized by ineffective hepatic copper metabolism, affects approximately 1 in 40,000 people. It is caused by inactivating mutations in the ATP7B gene, which encodes a copper-transporting adenosine triphosphatase. Deficiency of this protein leads to impaired excretion of copper into bile and reduced incorporation of copper into precursors of ceruloplasmin, the major copper-carrying protein in the circulation. Copper accumulates in hepatocytes; is released into the plasma; and is deposited in other organs, most notably the brain, eyes, kidneys, and skin.

Morning Report Questions

Q: What is the typical presentation and diagnosis of Wilson’s disease? 

A: More than half of patients with Wilson’s disease have hepatic abnormalities, which can include elevations of liver enzyme levels, hepatomegaly, hepatitis, cirrhosis, and acute liver failure. About one third of patients have neurologic manifestations — specifically, movement disorders (e.g., dystonia, tremor, and ataxia), dysarthria, dysphagia, and memory loss. A low serum ceruloplasmin level suggests but does not definitively establish the diagnosis of Wilson’s disease. Detection of Kayser-Fleischer rings on ophthalmologic exam, a low serum copper level, or an elevated urinary copper level would corroborate the diagnosis. If Wilson’s disease is confirmed, clinical and biochemical screening of first-degree relatives is advised, given the autosomal recessive pattern of transmission.

Q: What is the appropriate treatment for Wilson’s disease and the natural history if untreated?

A: Therapies for Wilson’s disease include chelating agents that induce urinary copper excretion (e.g., trientine, penicillamine) and copper-absorption inhibitors (e.g., zinc acetate). Penicillamine should be avoided in patients with neuropsychiatric symptoms, since up to 50% of patients have worsening of these symptoms, which are frequently irreversible. Zinc is approved for maintenance therapy and is often used alone in presymptomatic patients or those with isolated aminotransferase elevations. In patients with mild-to-moderate hepatic dysfunction, copper chelating agents with or without zinc are effective for rapid reduction of copper levels. Wilson’s disease is fatal without treatment.

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Cardiovascular Disease and a Mediterranean Diet

Posted by Sara Fazio • April 5th, 2013

In a randomized trial, participants assigned to a Mediterranean diet supplemented with either nuts or extra-virgin olive oil had a significantly lower rate of cardiovascular events at 4.8 years than participants assigned to a low-fat control diet.

A systematic review ranked the Mediterranean diet as the most likely dietary model to provide protection against coronary heart disease. Small clinical trials have uncovered plausible biologic mechanisms to explain the salutary effects of this food pattern. We designed a randomized trial to test the efficacy of two Mediterranean diets (one supplemented with extra-virgin olive oil and another with nuts), as compared with a control diet (advice on a low-fat diet), on primary cardiovascular prevention.

Clinical Pearls

•  What are the characteristics of a traditional Mediterranean diet?

The traditional Mediterranean diet is characterized by a high intake of olive oil, fruit, nuts, vegetables, and cereals; a moderate intake of fish and poultry; a low intake of dairy products, red meat, processed meats, and sweets; and wine in moderation, consumed with meals.

•  What were the primary results in this study, which evaluated the magnitude of reduction in cardiac risk due to the Mediterranean diet supplemented with either extra-virgin olive oil or nuts in a high-risk population?

In this trial, an energy-unrestricted Mediterranean diet supplemented with either extra-virgin olive oil or nuts resulted in an absolute risk reduction of approximately 3 major cardiovascular events per 1000 person-years, for a relative risk reduction of approximately 30%, among high-risk persons who were initially free of cardiovascular disease. The median follow-up period was 4.8 years. A total of 288 primary-outcome events occurred: 96 in the group assigned to a Mediterranean diet with extra-virgin olive oil (3.8%), 83 in the group assigned to a Mediterranean diet with nuts (3.4%), and 109 in the control group (4.4%).

Table 3. Outcomes According to Study Group.

Morning Report Questions

Q: Which individual components of the primary endpoint differed between study and control groups?

A: The results of multivariate analyses showed a similar protective effect of the two Mediterranean diets versus the control diet with respect to the primary end point, which was a composite of myocardial infarction, stroke, and death from cardiovascular causes. Regarding components of the primary end point, only the comparisons of stroke risk reached statistical significance. The risk of stroke was reduced significantly in the two Mediterranean-diet groups. This is consistent with epidemiologic studies that showed an inverse association between the Mediterranean diet or olive oil consumption and incident stroke.

Q: What do the authors propose as the dietary components that most likely were responsible for the observed benefits?

A: Salient components of the Mediterranean diet reportedly associated with better survival include moderate consumption of ethanol (mostly from wine), low consumption of meat and meat products, and high consumption of vegetables, fruits, nuts, legumes, fish, and olive oil. The interventions were intended to improve the overall dietary pattern, but the major between-group differences involved the supplemental items. Thus, extra-virgin olive oil and nuts were probably responsible for most of the observed benefits of the Mediterranean diets. Differences were also observed for fish and legumes but not for other food groups.

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PREDIMED: Supplemented Mediterranean Diets and the Prevention of Cardiovascular Events

Posted by John Staples • April 3rd, 2013

Mr. Smith decided to get serious about his cardiovascular health when he turned sixty. He comes to your clinic one day to tell you that he’s stopped smoking and that he’s been more attentive to the treatment of his hypertension and dyslipidemia over the last few months.

“I’m really turning things around, Doc,” he tells you, “but I need to know how to improve my diet. I know the basics – eat more vegetables and whole grains, cut back on trans- and saturated fats, avoid salt. You got any other words of wisdom on what else works?”

While composing your answer, you may want to consider the results of the PREDIMED study, an exciting multicenter primary prevention trial published in this week’s NEJM. In this trial, Dr. Ramon Estruch (Hospital Clinic, Barcelona, Spain), Dr. Miguel Angel Martínez-González (Clínica Universidad de Navarra, Pamplona, Spain) and colleagues randomized 7447 patients at high risk for cardiovascular disease to one of three arms: One group was advised to follow a Mediterranean diet supplemented with extra-virgin olive oil, a second group was advised to follow a Mediterranean diet supplemented with mixed nuts, and the controls were advised to decrease dietary fat intake. None of the patients were told to limit their total caloric intake. Patients received yearly personalized dietary advice and free olive oil, nuts, or non-food gifts (depending on their treatment assignment). They were then followed for the development of hard cardiovascular endpoints.

After a median of 4.8 years, patients following either of the supplemented Mediterranean diets were significantly less likely than the control patients to suffer from the combined endpoint of myocardial infarction, stroke or cardiovascular death. The absolute risk of developing one of these events was reduced by about 3 events per 1000 person-years, corresponding to a relative risk reduction of about 30%. Should patients and physicians be going mad for Mediterranean, nuts for nuts, and ga-ga for EVOO?

“The PREDIMED trial shows some pretty impressive numbers,” says Cardiologist and NEJM Deputy Editor Dr. John Jarcho, “But it also has its limitations.” He cites the amendment of the control arm protocol mid-trial (to allow these patients to receive the same amount of clinical support received by patients in the other arms) and the disproportionate loss to follow-up in the control arm as reasons for caution.

As for Mr. Smith? A visit to a dietician might help to convert his nutritional knowledge into practical suggestions. He might also appreciate hearing a little about the PREDIMED trial – and the broader implication that diet can make a difference.

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Hungry for more? In the same issue of NEJM, you’ll also find an editorial discussing the PREDIMED trial and a Perspective on the modern history of the relationship between the Mediterranean diet and cardiovascular health.

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Short Stature

Posted by Sara Fazio • March 29th, 2013

The latest article in our Clinical Practice series reviews evaluation of short stature in childhood and options for management of idiopathic cases (e.g., familial short stature or constitutional delay of growth and puberty), including observation and reassurance, growth hormone treatment, and low-dose oral oxandrolone in boys.

Short stature in childhood is the most common reason for referral to pediatric endocrinologists. Although evaluation for growth-inhibiting disorders is often indicated, most children with short stature are essentially healthy.

Clinical Pearls

• What diagnoses should be considered in a child with short stature and what is the most common etiology?

Clinicians who evaluate children with short stature must consider many potential causes. Although evaluation is needed to rule out disorders such as true growth hormone deficiency, Turner syndrome, hypothyroidism, and chronic diseases, the majority of children with short stature ultimately receive a diagnosis of idiopathic short stature due to normal variants such as familial short stature, constitutional delay of growth and puberty (CDGP), or both.

• When is laboratory evaluation warranted in a child with short stature?

When the height for age is less than the 1st percentile, the growth rate is less than the 10th percentile for bone age, the predicted adult height differs significantly from the midparental height, or the body proportions are abnormal, laboratory evaluation is warranted.

Figure 2. Conceptual Approach to the Evaluation and Differential Diagnosis of Slow Growth and Short Stature in Childhood.

Morning Report Questions

Q: How is the growth hormone-IGF-I axis best assessed?     

A: Assessment of the growth hormone-IGF-I axis begins with measurement of the serum IGF-I level, but since levels increase rapidly with the onset of puberty, results must be interpreted relative to bone age rather than to chronologic age. A normal IGF-I level for bone age rules out severe forms of growth hormone deficiency but not necessarily milder forms. Measurement of growth hormone levels after provocation with various agents is the classic method for assessing growth hormone deficiency, but the interpretation of the results is complicated by variation in testing procedures and the unclear sensitivity and specificity (and variation among countries) of cutoff levels used for diagnosis. The diagnostic value of low stimulated growth hormone levels (especially 5 to 10 ng per milliliter, with levels of >10 ng per milliliter conventionally thought to indicate adequate growth hormone secretion) is controversial. Moreover, relatively low growth hormone levels during late childhood may return to normal levels after puberty begins or with sex-steroid priming. A low IGF-I level and low provoked growth hormone level (e.g., <5 ng per milliliter) in a child with attenuated growth strongly suggest growth hormone deficiency.

Q: What is the role of human growth hormone in the treatment of children with idiopathic short stature?     

A: In 2003, the Food and Drug Administration (FDA) approved human growth hormone treatment for children with idiopathic short stature and height below the 1st percentile (−2.25 SD). This approval implied that at least 500,000 children in the United States (i.e., approximately 1% of children 4 to 13 years of age) have a condition for which there is available, effective, and expensive treatment (approximately $10,000 to $60,000 per patient per year). Data from randomized, controlled trials, observational dose-response studies, and systematic reviews indicate that human growth hormone therapy in children with idiopathic short stature increases the growth rate and mean adult height by 3 to 7 cm, or approximately 1 cm per year of human growth hormone treatment. The response is variable and is influenced positively by younger age at baseline, delay in skeletal maturation, and taller parents (and negatively by shorter parents).

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Arthritis and Rash

Posted by Sara Fazio • March 29th, 2013

In the latest Case Record of the Massachusetts General Hospital, a 30-year-old man with a history of IV drug use was admitted to this hospital because of fever, myalgias, polyarthritis, and rash. Results of liver-function tests were notable for mildly elevated hepatic aminotransferase levels and a normal bilirubin level.

Adulterants are compounds added to street drugs to increase profits for the seller. Levamisole, a veterinary antihelminthic agent, has become the most common adulterant of cocaine. The prevalence of levamisole in samples of cocaine sold on the street is estimated to be as high as 70%. Levamisole can lead to a dramatic vasculopathy and even vasculitis of small and medium-size blood vessels, conditions that are characterized by thrombosis, leukocytoclasis, and necrotizing lesions in blood vessels. This syndrome is accompanied by a confusing array of autoantibodies, including high titers of antineutrophil cytoplasmic antibodies (ANCA), antiphospholipid antibodies, and antibodies to double-stranded DNA. The cutaneous vasculopathy induced by levamisole has a predilection for fatty tissues, often leading to large ulcerative and necrotic lesions of the breasts, thighs, and flanks that mimic warfarin-induced necrosis.  Distinctive necrosis of the earlobe is common.

Clinical Pearls

• What musculoskeletal symptoms may accompany hepatitis C (HCV) infection?

HCV may cause arthralgias in patients with rheumatoid-factor positivity, generally caused by the high prevalence of mixed cryoglobulins among patients with HCV. Most patients with type II or type III cryoglobulinemia test positive for rheumatoid factor because the IgM component of the mixed cryoglobulin is directed against the Fc portion of IgG, which is the definition of rheumatoid-factor activity. HCV-associated cryoglobulinemic vasculitis is generally accompanied by purpura with a predilection for dependent areas, particularly the legs.

• What are the manifestations of serum sickness associated with acute hepatitis B (HBV) infection?

In a minority of patients, acute infection with HBV causes a syndrome resembling serum sickness. Polyarthritis and urticaria almost always occur as part of the prodromal stage of the syndrome, preceding the icteric phase by several days to several weeks. These symptoms are usually abrupt in onset. The polyarthritis is symmetric, with a predilection for small joints of the hands and knees, and may appear in an additive or migratory pattern associated with morning stiffness. A rash occurs at approximately the same time as the arthritis in half of all cases. The rash is most often urticarial, but erythematous macules and papules and petechiae are also reported. The syndrome usually persists for days or weeks, with a mean duration of approximately 20 days. Patients often have both fatigue and generalized weakness at some point in the course of the illness. The joint and skin manifestations typically resolve completely before or at the onset of the icteric phase of hepatitis. Approximately 40% of patients with the syndrome ultimately become jaundiced.

Morning Report Questions

Q: What is the cause of serum sickness associated with HBV? 

A: Serum sickness is a disorder caused by antigen-antibody or immune complexes formed in association with antigen excess. A spectrum of biologically active immune complexes contributes to the inflammation associated with serum sickness. In general, they are small, soluble antigen-antibody complexes that are not removed by the phagocytic macrophages that reside in the liver and spleen. The resultant circulating immune complexes contribute to the vascular and cellular phases of inflammation. The diverse antigens are composed of epitopes of HBsAg, HBc, and viral DNA. Antibodies to these antigens bind their specific antigens and form immune complexes. Complement proteins and phagocytic cells are also required for the development of serum sickness.

Q: What are the characteristic serologies associated with early HBV infection? 

A: The characteristic laboratory features of acute HBV infection include the detection of HBV DNA and HBsAg, the production of IgM antibody against hepatitis B core antigen (HBc), and less often, the presence of hepatitis B e antigen (HBeAg). The level of circulating HBV DNA is also typically elevated. Taken together, these features result in a molecular and serologic profile that is diagnostic of acute HBV infection.

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Circulating Tumor DNA

Posted by Jamie Colbert • March 27th, 2013

Fifty years ago, oncologists relied upon the clinical exam to follow breast cancer patients with metastatic disease. Patients were treated with chemotherapy, and then the physicians waited for symptoms to return before deciding on the next treatment course. Some patients could go months or even years without symptoms, but during this time they played a waiting game. Technology did not yet exist to allow physicians to detect cancer progression in the absence of overt clinical clues.

Beginning in the 1970s, the development of CT scans allowed physicians to finally look inside the human body to see cancer progression in patients who were otherwise asymptomatic. Novel imaging techniques enabled oncologists to detect relapse at much earlier stages, and decisions about further chemotherapy could now be made when the burden of metastatic disease was much lower.

During the 1990s, novel circulating tumor markers such as Cancer Antigen 15-3 were discovered. It was hoped that serum measurement of CA 15-3 could alert oncologists to the rising burden of metastatic disease before that disease even became radiographically apparent. However, studies of CA 15-3 have shown that this tumor marker has only a sensitivity of 65% for detecting the presence of metastatic disease.

What if instead of looking for circulating tumor surrogates, we actually tried to identify circulating bits of actual tumor? One method to do this is to assay for pieces of circulating tumor DNA.

This week’s NEJM presents a study from England in which 52 women with metastatic breast cancer underwent either targeted or whole genome sequencing to identify tumor specific DNA alterations. The researchers were able to identify breast cancer DNA fingerprints in 30 of these patients, and they designed special assays to detect the “fingerprint DNA” of their tumors. Using these assays the researchers were able to detect the presence of the breast cancer DNA fingerprints in the peripheral blood of 29 of the 30 patients. This novel technique proved to have a higher sensitivity for detecting presence of metastatic disease when compared with assays of CA 15-3 or circulating tumor cells. Furthermore, the researchers found that measurement of levels of circulating tumor DNA corresponds both with treatment response and survival: those who survived longer had lower levels of circulating tumor DNA compared with those who survived a shorter period of time.  This observation should fuel prospective trials to test the assay of circulating tumor DNA as a prognostic determinant.

Marc Lippman and Kent Osborne write in an accompanying editorial that this study “provides proof of the concept that circulating tumor DNA represents a sensitive biomarker of tumor burden.” However, this test is not yet ready for prime time. For one thing, the researchers were only able to identify useful DNA biomarkers in 60% of the women enrolled in the study. More importantly, the process of identifying specific DNA fingerprints for each patient’s breast cancer is a laborious process that is currently too time-intensive and costly for more widespread use.

Further research may help identify better methods of selecting a patient’s individual tumor DNA fingerprint so that this technology can become practical clinically. Looking forward, one can imagine a time in the near future when this novel approach to measuring cancer disease burden becomes a routine part of oncology treatment algorithms.

Connect with Dr. Colbert on Twitter: @jcolbertMD

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Test Yourself: New Case Challenge Now Available

Posted by Jennifer Zeis • March 23rd, 2013

“A 30-year-old man with a history of intravenous drug use was admitted to this hospital because of fever, myalgias, arthritis, and rash.”

Read the full case description. What is the diagnosis? What diagnostic test is most likely to be helpful? Cast your vote on the diagnosis and submit a comment about what diagnostic test is indicated. The correct diagnosis, along with the full description of the case and the procedures performed, will be published as the Case Records of the Massachusetts General Hospital in the March 28 issue of NEJM, live on NEJM.org at 5 PM ET Wednesday, March 27. Check NEJM.org starting at 5 PM ET Wednesday to see if you were correct.

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