Infection-Driven Lymphomas: The List Grows
Lecuit M et al. Immunoproliferative small intestinal disease associated with Campylobacter jejuni. N Engl J Med 2004; 350:239-48.
By Michael Williams, M.D.
An increasing number of bacterial and viral infections have been linked with specific subtypes of lymphoma. This paper reports a patient with a 12-month history of chronic diarrhea and wasting, whose small bowel biopsies were positive for immunoproliferative small intestinal disease (IPSID), a rare form of marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). This entity is also known as alpha chain disease, due to the production of an IgA heavy chain paraprotein. Campylobacter jejuni infection was documented serologically and by molecular and immunologic techniques in this patient. Antibiotic therapy was instituted for five months with rapid resolution of symptoms, clearance of clonal B cells from the small bowel and peripheral blood, and disappearance of the IgA paraprotein. The patient remains in clinical remission one year after diagnosis. Archival jejunal biopsy specimens from six other patients with IPSID, as well as a variety of control patient samples, were studied by FISH (fluorescent in situ hybridization) and immunohistochemistry for evidence of C. jejuni infection. Four patients, but none of the controls, were positive; all were negative for Helicobacter pylori.
The pathogenesis of C. jejuni and H. pylori-related MALT lymphomas is proposed to occur via bacterial antigen stimulation of helper T cells, which in turn drive B cell proliferation (Parsonnet and Isaacson, N Engl J Med 2004; 350:213-5). Clonal transforming events then occur within these proliferating B cells, including chromosomal translocations, which permit the emergence of neoplastic clones that nonetheless remain dependent in most cases on continued antigenic drive. Elimination of antigen via antimicrobial therapy may thus lead to tumor regression (Cavalli et al, ASH Education Program, Hematology 2001, pp. 241-58). Of interest in this report is the remission of stage IV disease, including the leukemic phase and IgA paraprotein. Localized gastric MALT regresses in about 70 perecent of cases upon eradication of H. pylori; regression of more advanced stage disease is unusual and suggests evolution to an antigen-independent phase. The fact that these enteric infections are exceedingly common, whereas MALT lymphomas are relatively rare, indicates that as yet undefined host and/or environmental factors are operative in pathogenesis.
C. jejuni thus is added to the growing list of infectious agents associated with lymphoproliferative diseases (Table). An increased incidence of lymphoma is also observed in the context of other disorders with chronic B cell stimulation and immune dysregulation, such as rheumatoid arthritis, SjÖgren's syndrome, HIV infection, and congenital or acquired immunodeficiency syndromes. It is likely that additional etiologically important infectious agents and environmental exposures will be identified. Understanding T and B cell signaling pathways activated via bacterial antigens and antigen-presenting cells, as well as the genetic factors underlying subsequent transforming events, will shed light on the pathogenesis of lymphoproliferative disease and identify potential therapeutic targets. These insights also may provide approaches for earlier detection and prevention of lymphoma. Clinicians should search for evidence of relevant infections, especially in patients with MALT-type or lymphoplasmacytic lymphomas, and provide appropriate antimicrobial eradication therapy where appropriate.
Return to Top
Cardiotoxicity and Iron. Is There a Clinical Remedy?
Oudit GY, Sun H, Trivieri MG, Koch SE, Dawood F, Ackerley C, Yazdanpanah M, Wilson GJ, Schwartz A, Liu PP, Backx PH. L-type Ca2+ channels provide a major pathway for iron entry into cardiomyocytes in iron-overload cardiomyopathy. Nat Med. 2003 Sep; 9(9): 1187-94
By Martha Mims, M.D., and Josef Prchal, M.D.
Primary and secondary iron overload are important causes of morbidity and mortality in the population of patients treated by most hematologists; iron-induced cardiac dysfunction is a primary source of this disability. Iron is thought to exert its detrimental effects on tissue via free radical induced damage, but the details of how iron enters the cell have remained elusive until recently. In this paper, Oudit et al. provide convincing evidence that L-type Ca2+ channels (LVDCC) are a major pathway for entry of iron into cardiac myocytes. They demonstrate that mice infused with iron over a period of 12 weeks have significantly decreased survival largely due to heart failure as evidenced by decreased left ventricular relaxation and contractility as well as increased diastolic pressure. Mice injected with iron, but also treated with either amlodipine or verapamil, which block the LVDCC, had improved survival and considerably less cardiac dysfunction. Pathologic examination of the mouse hearts confirmed major differences in iron deposition and fibrosis. Their results were corroborated by examination of transgenic mice which over-express the a1 subunit of the LVDCC and which accumulate significantly more cardiac iron than control mice. These transgenic mice are also largely protected from the negative consequences of iron cardiotoxicity by treatment with a calcium channel blocker.
From sickle cell and thalassemic patients, to those with myelodysplasia, refractory anemia, or an inherited iron overload syndrome, many patients treated by hematologists may benefit from these well tested calcium channel blockers. In most of these patients, phlebotomy for iron depletion is not an option and they are committed to cumbersome desferroxamine infusions with variable compliance. The data reported here provide a potential therapeutic strategy for protecting the heart (but not the liver) from the effects of iron overload which deserves testing in humans. LVDCCs are essentially absent in the liver, thus liver iron accumulation is unaffected by the calcium channel blockers, and cirrhosis will remain a major contributor to disability in patients suffering from clinically significant iron overload. The anterior pituitary and the beta cells of the pancreas do express LVDCCs and thus may also experience the beneficial effects of calcium channel blockade. However, efficacy of the calcium channel blockers for iron overload will have to be proven in clinical trials.
Return to Top
Risk of DVT and PE With Air Travel
Pérez-Rodriguez E, Jimenez D, Diaz G, et al. Incidence of air travel-related pulmonary embolism at the Madrid-Barajas airport. Arch Intern Med 2003; 163:2766-2770.
Schwartz T, Siegert G, Oettler W, et al. Venous thrombosis after long-haul flights. Arch Intern Med 2003; 163:2759-2764.
Martinelli I., Taioli E., Battaglioli T, et al. Risk of venous thromboembolism after air travel. Arch Intern Med 2003; 163:2771-2774.
Dalen JE. Economy class syndrome. Too much flying or too much sitting? (ed) Arch Intern Med 2003; 163:2674-2676.
By Andrew Schafer, M.D.
Highly publicized, recent reports of pulmonary embolism (PE) after long-haul flights have created a demand for further data with which clinicians can make rational decisions regarding prophylaxis. The December 8/22, 2003, issue of the Archives of Internal Medicine includes three original reports and an editorial by Dr. James Dalen which extend our understanding of this problem. Pérez-Rodrigues et al retrospectively reviewed cases of PE among travelers arriving in Madrid, and found that air travel is a risk, albeit a low one, for PE and that the incidence of PE increases with the duration of flight. These data confirm previous reports of similar studies of passengers arriving at airports in London and Paris. Schwartz et al performed ultrasound of leg veins of 964 passengers before and after flights of >8 hours duration, and found an incidence of deep vein thrombosis (DVT) of 2.8 percent compared with 1.0 percent in non-flying controls. All subjects had normal baseline ultrasound findings. Almost 80 percent of cases of DVT were limited to calf veins, and all but one subject was asymptomatic. Both this report and the one by Martinelli et al examined the prevalence of thrombophilia in patients with flight-associated venous thromboembolism (VTE). The latter paper reported that air travel doubles the risk of VTE; when thrombophilia or oral contraceptive use was present, the risk increased to 16-fold and 14-fold, respectively.
The consensus that is emerging from these and earlier reports is that air travel does indeed pose a very small but definite increased risk of VTE. The risk seems to be related to flight duration, and appears particularly with flights longer than about 6 hours or 2,500 miles. Further, specific factors that have been identified to compound the risk of flight-associated VTE include: advanced age, underlying venous disease or previous VTE, thrombophilia, use of oral contraceptives, and obesity. What is it about air travel that predisposes such individuals to VTE? "Cabin-related" factors that have been implicated include: dehydration (leading to hemoconcentration), low cabin humidity, reduction in oxygen pressure inside the plane, and smoking. However, the most important determinant is probably prolonged, uninterrupted sitting in cramped quarters which leads to venous stasis, along with compression of popliteal vessels on the edge of the seat which may also cause venous injury and a nidus for thrombus formation. Prolonged sitting as a risk for VTE was first suggested by Homans 50 years ago (N Engl J Med 1954; 250:148). Significant increase in fatal PE was noted after prolonged sitting in crowded air raid shelters during the London blitz of World War II. In fact, Lewis Dexter proposed that the marked increase in incidence of VTE in the 20th century can be traced to the widespread use of chairs in the general population.
Future research should attempt to sort out the various potential components of risk of VTE with air travel. More importantly, risk-stratified prophylactic regiments should be established through prospective trials. At least two studies have now demonstrated the efficacy of below-the-knee elastic stockings in this setting (1, 2). In addition to simple preventive measures, such as avoidance of prolonged sitting and leg-crossing, maintaining hydration, abstinence from alcohol and smoking, etc., randomized studies of prophylactic anticoagulation (e.g. single-dose low-molecular-weight heparin) are needed in high-risk travelers.
References
- Scurr JH, Machin SJ, Balley-King S, et al. Frequency and prevention of symptomless deep-vein thrombosis in long-haul flights: a randomized trial. Lancet 2001; 357:1485-1489.
- Belcaro G, Geroulakos G, Nicolaides AN, et al. Venous thromboembolism from air travel: the LONFLIT Study. Angiology 2001; 52:369-374.
Return to Top
Cancer Protein Surgery
Lane, A. A., Ley, T. J. Neutrophil elastase cleaves PML-RARa and is important for the development of acute promyelocytic leukemia in mice. Cell 2003; 115, 305-318.
By Robert Lowsky, M.D., FRCPC
The generation of fusion proteins by chromosome translocation contributes to leukemogenesis and is a hallmark of many cases of leukemia. For example, the t(15:17) translocation creates two fusion proteins, PML-RARa and RARa-PML, and it has been generally thought that these full length fusion products promote acute promyelocytic leukemia (APL). The paper by Lane and Ley, however, introduces an intriguing change to this model and suggests that cleavage products from the fusion protein play a contributing role in the development and progression of leukemia.
The expression of full length PML-RARa directed to the promyelocyte compartment in mice creates a long latency model of APL that has a 100 percent penetrance by one year, implying that additional genetic alterations are also important. When PML-RARa is retrovirally transduced into whole bone marrow, only an APL-like disease develops. In contrast, expression of PML-RARa in the monocytic compartment does not result in leukemia. Taken together, these data suggest that only the promyelocyte compartment provides the appropriate "soil" critical for the oncogeneic PML-RARa "seed" to flourish.
In their paper, Lane and Ley report that the PML-RARa fusion protein can be cleaved by neutrophil elastase, a serine protease, maximally produced in promyelocytes, including human APL cells. The elimination of this enzyme in mice provides protection from APL. These findings suggest that proteolytic processing of fusion proteins may be an important step in the molecular pathogenesis of leukemia and targeting these enzymes may have a therapeutic benefit.
This study poses challenges for scientists and clinicians. Scientists need to begin to define the mechanism(s) through which cleavage potentiates leukemogenesis. Clinicians need to confirm the presence of elastase generated PML-RARa products in blasts isolated from their patients with APL. Additionally, the observations of Lane and Ley warrant further experiments to determine if they can be extrapolated to other leukemogenic fusion proteins. Nonetheless, this study points to potential new avenues for developing approaches to targeted therapy for leukemia.
Return to Top
Nature vs. Nurture Revisited, Again
Kadan-Lottick NS, Ness KK, Bhatia S, Gurney JG. Survival variability by race and ethnicity in childhood acute lymphoblastic leukemia. JAMA 2003;290:2008-2014.
By J. Douglas Rizzo, M.D.
Kadan-Lottick and colleagues report provocative decrements in survival for children treated for acute lymphoblastic leukemia (ALL) over three decades (1973-1999) by racial/ethnic groups. Using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database, the authors describe survival deficits in Black, Hispanic, and Native American children compared to White and Asian children. Children diagnosed as infants had worse survival than those in older age cohorts and five year survival improved over successive decades for the combined groups. Unfortunately, after adjusting for age at diagnosis, treatment decade, and sex, substantial differences remain in the risk of death by racial/ethnic group. In the most recent treatment decade (1990-1999), the risk of death was 1.5 times higher for Blacks and 1.8 times higher for Hispanics compared to White children. This suggests that despite advances in risk assessment and "customization" of therapy over the last three decades, there remains a survival gap amongst Black and Hispanic children with ALL.
Imperfect race/ethnicity assignment, lack of socioeconomic data or information for known ALL prognostic factors are limitations of the study. However, the main findings replicate those of several other studies, including the Children's Cancer Group and Pediatric Oncology Group studies where ALL prognostic factors were known. Taken together, the overall conclusion is that Black, Hispanic, and Native American children experience diminished survival compared to Whites and Asians. These survival differences, similarly described in adults with various malignancies, should encourage clinical and basic scientists to identify modifiable explanations. Differentiation of outcome by race/ethnicity is likely attributable to biological, sociocultural and environmental factors (Figure), and all require further study. Environmental or sociodemographic factors associated with outcome disparity have typically been considered "modifiable," while biologic characteristics that vary by racial/ethnic groups have been elusive. We can anticipate that burgeoning research in proteomics and genomics may enhance our understanding of biologic differences between racial/ethnic groups that determine outcome. Perhaps a greater understanding of the biologic construct that underlies the concept of race/ethnicity can be developed, rather than simply attributing "unexplained differences" in outcome to biologic disparity. New tools should allow exploration of whether racial groups differ by important genetic polymorphisms for chemotherapy detoxification or resistance, or manifest different drug pharmacokinetics. Do gene polymorphisms exist between racial groups that correlate with tumor invasiveness or aggressiveness, or propensity for sanctuary site involvement or metastatic disease? Are there genetic factors that modulate the interaction between carcinogen exposure and DNA damage and repair mechanisms? It is likely that racial differences are attributable to a combination of biologic and sociologic/environmental factors and their interaction. Research in all of these areas should pursue the elimination of discrepant outcomes. New tools for understanding the human genome and greater experience make further exploration of biologic factors feasible and may yield discoveries that lead to targeted prevention strategies for different racial/ethnic groups and re-definition of the term "customizable" therapy.
Return to Top
Ironing Out the Causes of Genetic Hemochromatosis
Papanikolaou G, Samuels ME, Ludwig EH et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nature Genetics 2004;36:77-82.
By Nancy Andrews, M.D., Ph.D.
Iron overload, although relatively common in adults, is almost unheard of in children. But rare genetic lesions that cause early onset hemochromatosis have provided important insights into how the body deals with this precious (and toxic) metal. Normally, humans are programmed to absorb very little iron from the diet, to meet iron needs but avoid toxicity. Genetic errors tip the delicate balance, almost always in favor of iron overload, resulting in hemochromatosis. Excess iron build-up in the liver, heart, and endocrine glands causes damage to those tissues, leading in the worst cases to cirrhosis, cardiomyopathy, and endocrine failure. The sequelae of hemochromatosis typically appear in mid-life or later. But two types of genetic errors can cause accelerated, "juvenile" hemochromatosis, which is often lethal by the third decade. Classical hemochromatosis is usually associated with a cysteine to tyrosine (C282Y) mutation in HFE, a molecule that plays a modest role in regulating body iron levels. Juvenile hemochromatosis is now known to be caused by mutations in either of two genes - the gene encoding hepcidin, an iron regulatory hormone, or, as just reported by Papanikolaou et al., the gene encoding hemojuvelin (also called HFE2), a novel protein of uncertain function.
Hepcidin is a potent plasma peptide that dampens intestinal iron absorption and prevents release of excess iron stored in macrophages. Too little hepcidin leads to high plasma iron levels and iron overload. Patients with classical (HFE) hemochromatosis don't make enough hepcidin; patients with juvenile hemochromatosis due to hepcidin mutations don't make any. But what does hemojuvelin do?
Curiously, hemojuvelin resembles a molecule known to be involved in the patterning of neuronal connections in chickens. It is expressed in muscle, heart and liver, but patients with hemojuvelin mutations appear to be normal in all regards except for iron overload. They produce less hepcidin than they should, suggesting that hemojuvelin is also involved in regulating hepcidin levels. It is not yet clear how this happens, but working out the molecular details of hemojuvelin action and hepcidin regulation will undoubtedly help to elucidate the complex mechanisms that normally maintain iron balance.
In all, five genes are known to be mutated in patients with genetic iron overload (Table). At present, clinical diagnostics only test for mutations in HFE. Homozygosity for HFE C282Y mutations clearly predisposes patients to hemochromatosis; co-existence of HFE C282Y and another amino acid substitution, H63D, is sometimes associated with clinical disease. It is likely that new genetic tests for mutations in the other four genes will be developed within the next few years, allowing for better risk assessment and better genetic counseling. In addition, molecular insights into hemochromatosis could lead to new treatments to complement or replace serial phlebotomy, which is currently the most effective means of removing excess iron.
Return to Top
A 50s Moment for T Cells: Forgetful Memory to Prevent Graft-Versus-Host Disease
Chen BJ, Cui X, Sempowski GD, Liu C, Chao NJ. Transfer of allogeneic CD62L- memory T cells without graft-versus-host disease. Blood, 2004 Feb; 103:1534-41.
By Stephen Emerson, M.D., Ph.D.
Do you have trouble remembering where you saw that important paper in Blood? How about where you left your copy of Blood? Your car keys? Don't despair, It turns out that memory T cells, highly educated, trained, and motivated as they are, are not always so good at killing foreign target tissues. In this paper, Chen et al. report that mouse memory T cells show a surprising weakness in causing graft-versus-host disease (GVHD), which might be directly exploited in the clinic.
T lymphocytes are known to provide a two-edged sword in stem cell transplantation (SCT) for leukemia, lymphoma, and other cancers. They are essential for tracking down and killing the patient's last remaining malignant cells (the graft-versus-tumor or "GVT" effect), but they also will destroy normal tissues (GVHD), causing sometimes lethal hepatic, gastrointestinal, and skin disease. Separating GVT from GVHD is thus one of the Holy Grails of SCT. However, attempts to identify T cell subsets that kill allogeneic tumor cells but not normal cells have thus far not succeeded in clinical practice. Recent suggestions have been made that regulatory T cells and host dendritic cells blockade might perhaps be more effective, but these approaches are new and largely untested.
Chen et al. now find that memory T cells do not cause GVHD, but retain the ability to kill tumor cells. Using the cell surface protein CD62L (normally expressed on naïve T cells) to identify CD62L- memory cells, the authors separate donor memory from naïve T cells and show that nearly all of the ability to cause GVHD tracks to the naïve, CD62L+ cells. Even more remarkably, CD62L- memory T cells from allogeneic donor mice immunized with a host strain leukemia/lymphoma cell line also cause no GVHD, but retain significant anti-leukemia killing in vivo. Therefore, they suggest that memory T cells in humans could be separated from naïve T cells and returned to a stem cell graft for therapy. In theory this approach could be simply applied to unstimulated allogeneic T cells, or better yet to allogeneic T cells cultured in the laboratory with the patient's own tumor cells.
How this is possible is not yet clear. One possibility, suggested by another recent report in Blood (Yi Zhang et al., Blood First Edition-online, February 5, 2004; DOI 10.1182/blood-2003-09-3135) is that most memory T cells, although well-educated, have somehow aged as part of their prior exposure to antigen and do not have the same ability to accumulate in allogeneic recipients. Thus memory T cells may survive long enough to kill the small number of residual tumor cells, but not long enough to sustain widespread, clinically apparent GVHD. The best news, of course, is that the utility of memory cells could be directly tested in clinical transplantation. These studies come at a time when advances in human ex vivo dendritic cell cultures, tumor-specific immunization, and adoptive immunotherapy could be directly integrated with production, isolation, and selective infusion of memory T cells. Exciting studies such as these will undoubtedly be designed, performed, and tested in the near future. If we remember...
Return to Top
Cellular Microarrays: Profiling Intact Cells
Soen Y, Chen DS, Kraft DL, Davis MM, Brown PO.Detection and Characterization of Cellular Immune Responses Using Peptide-MHC Microarrays. PLoS Biology 2003 1(3):429-438.
By Peter Lee, M.D.
DNA microarray technology has revolutionized biology by allowing the simultaneous gene expression analysis of the entire human genome within a cell or tissue sample. In hematology, this has led to novel ways to subcategorize the acute and chronic leukemias which may have more direct correlation with clinical outcome. Microarray technology has since been extended to proteins, in which various antigens spotted onto arrays allow the rapid identification of specific antibodies within a serum sample. Now, microarray technology has been further extended to allow the analysis of intact cells. In this study, Soen et al. spotted peptide-MHC complexes (the ligands for T cell receptors) onto microarrays to capture T cells in an antigen-specific manner. When different pMHC complexes are spotted onto an array, T cells specific for each pMHC combination bind to the specific spot, which are then visualized via fluoresence microscopy after counterstaining with a fluorescent-labeled antibody. The power of this approach is in its ability to easily construct arrays which allow the simultaneous assessment of T cells specific for hundreds of different antigens. This represents a significant advance for the analysis of antigen-specific T cell responses over currently available methods, which allow analysis of T cells specific for only a single pMHC combination at a time. Furthermore, the number of cells bound to each spot is directly proportional to the size of the response, making this method quantitative. As a number of hematologic conditions are associated with defective immune responses, such as in chronic lymphocytic leukemia or post-transplant patients, a method to rapidly survey the intactness of the T cell repertoire of a patient, such as against CMV or EBV, could help guide the targeted use of prophylactic anti-microbial agents. Moreover, captured cells can be further analyzed for their biological responsiveness. By loading cells with calcium-sensitive dyes, the dynamic responses of antigen-specific T cells could be assessed by measuring transient spikes in intracellular calcium levels upon binding to the microarray. Hence, this method allows the simultaneous identification, quantitation, and functional analysis of a large number of T cell populations for each patient.
This approach is not limited to the analysis of T cells. By spotting different molecules or antibodies onto microarrays, essentially any cell, including tumor cells, can be specifically captured, quantitated, and analyzed for biological responses. This technology thus opens up a new way in which both immune responses and cancer cells could be rapidly studied directly ex vivo from patients. In hematology, one may imagine that microarrays will be created which allow the specific capture and analysis of leukemic cells directly from blood and/or bone marrow samples. Such 'leukemia arrays' may be applied to rapidly diagnose leukemia and provide subtype information within minutes while using only a small blood sample. By analyzing whole cells, the microarray approach to analysis is kept within the context of the originating cell and visualized under a microscope very much like a blood smear. Cell types can be defined by their morphologic appearance, standard pathology staining methods, and counter- staining with specific antibodies. Hence, the profiles generated are complete with originating cell type, which is essential in the analysis of clinical samples. Taken together, this could be viewed as a new generation 'blood smear' for the 21st century.
Return to Top
Folate, Neural Tube Defects, and Antibodies Against Folate Receptors
Rothenberg SP et al. Autoantibodies against folate receptors in women with a pregnancy complicated by a neural tube defect. N Engl J Med 2004; 350:134-142.
By Josef Prchal, M.D.
Neural tube defects, including spina bifida, are among the commonest congenital malformations. They are associated with great monetary costs to society and emotional turpitude for the affected families. The initial report about a decade ago that the incidence of these disorders could be greatly reduced by early prenatal folic acid supplementation provided cost-effective prevention for this devastating problem to about 75 percent of females at risk, although the scientific rationale for folate supplementation had been largely lacking. In this paper, Rothenberg and co-workers report that the majority (nine of 12) of mothers who recently had or were pregnant with at the time of testing a fetus with this disorder had antibodies against the folate receptor. However, these antibodies were also detected in ten percent of females (two of 20) who had or were carrying a fetus without a neural tube defect.
While these data provide some rationale for the efficacy of folate supplementation (the excess folate can out-compete blocking antibodies against receptors), this is hardly the full story. This study has the obvious limitation of very small numbers of patients and controls, and the presence of antibodies does not fully correlate with having a newborn with neural defects. The ability of folic acid to methylate DNA is a prototype of changing the activity of genes by epigenetic effects (Beaudet AL. Is medical genetics neglecting epigenetics? Genet Med. 2002 4:399-402). In contrast to genetic changes, i.e inherited or acquired mutations of DNA sequence, epigenetic changes modulate the activity of genes by methylation of DNA and methylation and acetylation of proteins acting as a lattice for DNA (histones). We are only starting to learn about the control of gene expression by epigenetic mechanisms; however, we are witnessing the rapid growth of technology and better understanding of epigenetic mechanisms. These changes have the potential to affect many known and unknown genes and gene clusters that remain to be identified. Only future identification of genetic or epigenetic loci responsible for neuronal defects will allow appropriate specific preventive and therapeutic strategies; however, the identification of autoantibodies against folate receptors is a useful start.
Return to Top
Effect of Awareness of a Randomized Controlled Trial on Use of Experimental Therapy
Clark, W. F., Garg, A. X., Blake, P. G., Rock, G. A., Heidenheim, A. P., Sackett, D. L. (2003). Effect of Awareness of a Randomized Controlled Trial on Use of Experimental Therapy. JAMA 290: 1351-1355.
By Samuel Silver, M.D., Ph.D.
The randomized controlled trial (RCT) has become a primary vehicle for assessing the effectiveness of a therapeutic intervention. The results of these trials have changed standards of practice. Clark et al analyze three RCTs from the Canadian Apheresis Group and demonstrate that increased usage of the experimental arm occurs during and outside of the trials, a phenomenon they term "jumping the gun." The Canadian Apheresis Group captures ~90 percent of apheresis activity in Canada. Three RCTs spanning 1982-2000 randomized patients to apheresis or non-apheresis care for multiple sclerosis (MS), thrombotic thrombocytopenic purpura (TTP) and myeloma cast nephropathy. Apheresis was found to be beneficial in TTP, but ineffective in MS. During the conduct of all three RCTs, there were large and significant increases in the mean annual number of patients undergoing apheresis. Before the MS trial, 13 patients (pts)/yr underwent apheresis compared to 49 pts/yr during the trial (p<.001); likewise for TTP (30 pts/yr versus 56 pts/yr [p=.004]) and myeloma cast nephropathy (44 pts/yr versus 72 pts/yr [p=.004]). However the majority of patients undergoing apheresis for these conditions during the period of these trials did not participate in the trials: 61 percent, 72 percent, and 57 percent of patients with MS, TTP, and myeloma cast nephropathy, respectively, treated with apheresis during the clinical trials period for those diseases were not on study. After the trials concluded, the number of aphereses for patients with MS rapidly declined and aphereses for those with TTP rapidly increased in use, concordant with the trial outcomes. In a post-trial survey, 78 percent of responding physicians agreed that the "jumping the gun" phenomenon explained the increase in non-trial apheresis activity.
Clinical trials are the currency of therapeutic advances in clinical practice. The RCT is the gold standard. Not every clinical question can or should be tested by a RCT, but the Canadian Apheresis Group has demonstrated that even uncommon diseases such as TTP can be a subject for these trials. Clark and colleagues now sound a cautionary note. The very fact that these trials exist changes the therapeutic environment - a clinical "Heisenberg Uncertainty Principle." Physicians want to do the best for their patients. When a therapy becomes an experimental arm on a RCT, physicians may have access off protocol to what may be perceived (falsely) as the "newest and best therapy." This is a specious extension of the American Federation of Clinical Oncologic Societies' consensus statement: "[that] treatment in a clinical trial is often a patient's best option." (J Clin Oncol 1998;16:1628-1630). Properly executed RCTs remain the gold standard of therapeutic efficacy, but should not be a free license to use the experimental arm off study.
Return to Table of Contents
|
