The Envelope Please: The ASH Meeting Top Ten List
By Margaret V. Ragni, MD, MPH
Dr. Ragni is Professor of Medicine in the Department of Medicine, Division Hematology/Oncology at the University of Pittsburgh and Director, Hemophilia Center of Western Pennsylvania. She was also the Editor-in-Chief of ASH News Daily 2007.
Continuing in the rich tradition of ASH meetings, the 49th annual meeting in Atlanta was notable for outstanding presentations on new genetic mechanisms of disease, inhibitors of novel molecular pathways, host response in gene transfer, new targeted therapies in clinical trials, and pressing public health issues. Among the firsts were a phenomenal Trainee Day, a one-hour "Best of ASH" meeting summary, and late-breaking abstracts. The emphasis on young physicians and scientists in workshops and sessions about writing a successful grant, finding a good mentor, and landing the ideal career was outstanding. Perhaps not coincidentally, three of the six late-breaking abstracts were authored by a fellow or medical student! And, in a new tack, a French edition of ASH News Daily was published.
On behalf of the dedicated ASH News Daily authors, Drs. Jay Coghill, Naomi Galili, Irene Ghobrial, Xavier Leleu, Alice Ma, Ruben A. Mesa, Vida Almario Passero, Azra Raza, and Robert L. Redner, the top ten hits at the ASH meeting are…The envelope please…
10. Targeting P13K/AKT for T-ALL may be a NOTCH above the rest.
New targets for T-ALL include the activating mutations in the NOTCH1 receptor. Among these, the gamma-secretase inhibitors (GSIs), which block NOTCH1 activation, have been of great interest. Their use is limited, however, by the development of resistance. In his presentation, Dr. Adolfo Ferrando described the molecular sequelae of resistance to NOTCH inhibitor therapies in T-ALL and the molecular basis for use of the alternative inhibitors of the P13K/AKT pathway, which are now in clinical trial.
9. Hepcidin regulation of dietary iron absorption is unmasked.
Investigating the role of hepcidin in the regulation of iron absorption, Dr. Bruce Beutler (standing in for his father) described elegant studies of mice with the Mask phenotype. These mice have iron deficiency and regional alopecia of truncal hair, which is corrected with iron supplementation. In contrast to typical iron deficiency in which the iron regulator hepcidin is greatly decreased, and with it, hepcidin inhibition of iron absorption and iron release from macrophages, Mask mice have elevated hepcidin and profound iron deficiency. Utilizing positional cloning, Dr. Beutler's group (along with his father's research group) identified a splicing error in the Tmprss6 gene as the cause of the Mask phenotype. TMPRSS6 is required for normal absorption of dietary iron. In mice with the Mask phenotype, the hepcidin gene transcription is inhibited, resulting in inhibition of hepcidin upregulation and the Mask phenotype.
8. RNAi identifies RPS14 as the cause of 5q- MPD.
In a tour de force, Dr. Benjamin Ebert reported at the Plenary Session on exciting research using RNA interference that led his team to identify the causal gene of the 5q- syndrome, a subset of MPD. Patients with this disorder have a block in RBC maturation. Thus, by assessing each of 41 candidate genes for capacity to induce hematopoietic differentiation in CD34+ cells, RPS14 gene, which encodes for ribosomal protein, was identified as the causal gene. Subsequent simultaneous sessions described targeted therapeutics taking advantage of these findings, such as lenalidomide, which has eliminated transfusion dependence in up to 75 percent of individuals with the 5q- MPD syndrome.
7. Imatinib for childhood ALL comes of age.
The successes of the tyrosine kinase inhibitor imatinib in CML have led to studies of the drug in childhood Ph+ ALL. In this Plenary abstract, Dr. Kirk Schultz detailed the results of his Children's Oncology Group protocol in which imatinib was given, with high-dose chemotherapy, for 42 to 280 days. What the group found was that the longer imatinib was used, the better the event-free survival: 84.7 percent among those receiving imatinib for 280 continuous days, as compared with 41.2 percent among those given imatinib for the shortest duration.
6. AMG 531 does for platelets what EPO does for RBCs.
AMG 531, the novel thrombopoietin (TPO) receptor stimulating agent, garnered great attention. In a phase III randomized, double-blind, placebo-controlled trial in splenectomized ITP patients reported by Dr. Terry Gernsheimer, AMG 531 increased platelet counts to a significantly greater degree than placebo. The primary endpoint, maintaining a platelet count greater than 50,000/ul for at least six weeks of the last eight weeks on study, was achieved by 38 percent of those treated versus none of the placebo group. The drug was considered safe, although one patient developed thrombosis. More studies are warranted for this promising agent.
5. Oral agent prevents clots at the Xa intersection.
Among the hot topics of discussion at the Plenary Session was the new oral anti-Xa inhibitor, rivaroxaban, currently in phase III clinical trials. This new oral anticoagulant requires no monitoring and has no interaction with food. When compared with enoxaparin for thromboprophylaxis following hip arthroplasty, rivaroxaban showed a four-fold lower incidence of VTE, PE, and all-cause mortality, with a similar safety profile. Review by the FDA is projected for late 2009.
4. Hematologists and consumer groups aggregate to prevent thrombosis.
Venous thromboembolism (VTE) headlined several special sessions at the annual meeting, bringing together advocacy groups, grassroots organizations, and hematologists. The presentations made from diverse perspectives underscored the heavy toll VTE disorders take and the major advances that are needed to bring new understanding and new treatment to the field. With more than 600,000 individuals developing VTE each year in the United States, this disorder is a major cause of morbidity and mortality. There are ongoing epidemiologic studies to determine VTE risk, based on age, race, and gender, which will be useful in the development of optimized prevention and treatment approaches. Mechanistic studies of age-related cellular and molecular changes that affect the vascular epithelium are also in study. Health-care delivery, outreach and education programs, development of multidisciplinary teams, and heath-services research are among the programs already underway.
3. The formidable partners, infection and inflammation, assume a malignant role.
A discussion of molecular mechanisms of infectious agents in cancer development was highlighted at the ASH/ASCO Joint Symposium. Dr. Francis Megraud discussed the role of genetic mutations and epigenetic changes in malignant transformation, using the examples of Helicobacter pylori and inflammation in the development of gastric cancer. Dr. Maura Gillison focused on the malignant transformation with human papillomavirus (HPV) and oropharyngeal squamous cell carcinoma. Dr. Eric Klein completed the session with a talk on the new gamma retrovirus XMRV in patients with prostate cancer who have a common polymorphic variant of the RNASEL gene, which is involved in antiviral activity of interferons. Understanding the pro-inflammatory pathways activated by these pathogens should lead to potential new targeted treatments and preventions of some of these common cancers.
2. Getting to know JAK opens up the world of MPD.
The Ham-Wasserman Lecture was presented by Dr. Radek Skoda in recognition of his seminal work with c-MPL and hereditary thrombocythemia. It was his initial report with Dr. Kralovics of the JAK2V617F defect that generated the explosion of myeloproliferative disorders (MPDs) research. In his talk, Dr. Skoda provided an exciting journey through mutated genes, delineating, on a molecular basis, why some MPDs affect red cells, others white cells, and still others platelets. Further, these findings at the bench have provided molecular markers for disease as well as targets for treatment, and will also be the basis for the upcoming revised WHO diagnostic criteria for MPDs.
1. Cutting the cord launched the field of stem cell transplantation.
In recognition of his research leading to the first ever cord blood stem cell transplant that launched the field of cord blood transplantation, Hal E. Broxmeyer, PhD, was awarded the E. Donnall Thomas Lecture and Prize. He was honored for his prescient work on stem cells and its profound influence on research. His research has revolutionized clinical outcomes for many hematologic diseases and has provided hope for many previously considered untreatable.
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Highlights of ASH Meetings in Texas and Washington
Mark your calendar for the third annual Highlights of ASH. Join ASH February 1-2, 2008, in Seattle, WA, or February 8-9, 2008, in Austin, TX, for the official Highlights of ASH. You'll hear renowned experts present their analyses of the most influential abstracts from the 2007 ASH annual meeting. The meeting is geared toward practitioners and is the only "Highlights" meeting produced by ASH in collaboration with the ASH program committee.
The co-chairs of Highlights of ASH, Jane N. Winter, MD, from the Robert H. Lurie Comprehensive Cancer Center at Northwestern University, and Ari M. Melnick, MD, from the Albert Einstein College of Medicine, served as co-chairs of the 2007 ASH Education Program and the 2007 ASH Scientific Program, respectively. It is from this vantage point that Highlights of ASH has been developed. Together, they identified topics and speakers based on the most important information presented at the ASH meeting, without limitation by topic or institutional affiliation. In addition to hearing analysis of groundbreaking research presented at the 2007 ASH annual meeting, attendees will discuss real cases with leaders in the field, network with colleagues, and earn CME credits.
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ASH Moves Forward with Sickle Cell Research Agenda
By George Buchanan, MD, and Marilyn Telen, MD
Dr. Buchanan is Children's Cancer Fund Distinguished Chair in Pediatric Oncology and Hematology, and Director of Pediatric Hematology-Oncology at the University of Texas Southwestern Medical Center.
Dr. Telen is Wellcome Clinical Professor in Medicine, Division of Hematology, at the Duke Comprehensive Cancer Center, and Chief of the Hematology Division.
At the end of 2007, the Society released a summary of recommendations titled Toward a New Research Paradigm: Building A New Sickle Cell Disease (SCD) Research Agenda. The document captures the discussions of the ASH Workshop on Sickle Cell Disease in May 2007. The Workshop's goal was to explore new SCD research objectives and create a real-world model to achieve them. The Workshop document presents a synopsis of the new research priorities identified and a blueprint for execution of the new sickle cell research strategy.
Five research areas were identified and prioritized by workshop participants. In rank order, they are: 1) development of improved and new treatments, 2) identification of predictors of SCD outcomes, 3) improved pain management and quality of life, 4) elucidation of the pathophysiology of organ complications (kidneys, brain, heart, and lungs), and 5) initiation of international strategies for collaborative SCD research.
The document identifies barriers to a new research agenda, acknowledging the psychosocial, economic, and clinical care delivery problems that affect people with SCD, especially adults. The document also recognizes that NIH's funding and organizational structure does not optimally support multi-disciplinary and longitudinal approaches to SCD, and notes that the lack of cohesive interaction among the many SCD stakeholders hampers new research initiatives.
In an effort to avoid fragmentation and disengagement, workshop participants recommended that NIH assemble a single national DHHS-funded, multi-center collaborative research group. Children and adults with SCD residing in areas of the United States not served by current government-funded programs or who do not have access to care for financial or other reasons must be included. The research agenda describes two models for the NHLBI and other agencies to consider.
New research should focus on multi-disciplinary approaches to characterize the genetic and environmental factors that contribute to the heterogeneity of disease phenotype and response to therapy. Continued improvement in drug therapies and pain management techniques remains a high priority. Additional study must also focus on preventing and reducing organ complications for those with SCD.
To maximize quality SCD treatment, ASH emphasizes the need to align the efforts of SCD stakeholders, including government entities, physicians, scientists, foundations, community advocates, and SCD patients and their families. ASH recommends the creation of a new Sickle Cell Research Group. This group would be composed of clinicians and scientists at academic medical centers that serve a large number of SCD patients.
ASH has responded to the NHLBI's Request for Information (RFI): Defining a Research Agenda for Sickle Cell Disease and Other Hemoglobinopathies by submitting this document and has also distributed it to other Federal Agencies and the sickle cell community.
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Wallace H. Coulter Award for Lifetime Achievement in Hematology: Inaugural Award Winner Ernest Beutler, MD
Wallace H. Coulter
By Marshall A. Lichtman, MD
Dr. Lichtman is Professor of Medicine, Biochemistry and Biophysics, at the University of Rochester Medical Center in Rochester, NY.
The establishment of The Wallace H. Coulter Award for Lifetime Achievement in Hematology by the Coulter Foundation and the American Society of Hematology's naming Ernest Beutler, MD, as its first recipient is the happy convergence of two people who are among the most important contributors to hematology in the last 50 years.
The science and practice of hematology is dependent on blood-cell enumeration. The methods for cell counting through the first half of the 20th century were manual, tedious, laborious, and subject to frequent error. In the late 1950s, a transformation in particle, including cell, counting occurred. This transformation was the result of the genius of Wallace Coulter who patented the method he developed to count and measure the volume of particles electronically.
Mr. Coulter had a strong interest in electronics in high school and attended the Georgia Institute of Technology with a major interest in electrical engineering. He worked for a series of electronics firms, including General Electric and Raytheon. After World War II, he began to consider methods of measuring industrial and biological particles electronically to improve accuracy and ease of measurement. In the mid-1950s, he and his brother Joseph produced prototype models of the Coulter Counter. The Model A was the first instrument put into practice, and in 1958 the brothers established Coulter Electronics. Over the next 40 years, the company grew to employ 5,000 people and operate in 20 countries, and the instruments it developed revolutionized particle counting, sizing, and more. I was a happy beneficiary of this landmark work when I dispensed with my diluting pipette and used a Model B Coulter Counter rigged to a computer, with an oscilloscope interpolated, permitting tallies of cell counts and Polaroid photos of their volume distribution curve. Who in clinical or research hematology throughout the world has not benefited from Mr. Coulter's innovations?
The Coulter Principle, which formed the basis for future developments and advanced instruments, is that cells are poor conductors of electricity as compared to a salt solution. If cells are diluted in a saline solution and drawn through a tiny aperture carrying a current, each cell produces slight impedance to current flow. The pulse created by the resistance to current flow of each particle flowing through the aperture can be amplified and counted. Moreover, the size of the pulse can be made proportional to cell volume. Thus, the number and size distribution of particles in a measured volume of a dilute suspension of cells can be converted electronically to the blood cell count and volume. Thousands of cells can be counted per second. Since platelets, white cells, red cells, and contaminating particles are sufficiently different in frequency and size, they can be discriminated. It is an irony of progress that the red cell count and volume is measured so precisely that the packed cell volume (hematocrit), theretofore the most simple and accurate measure of red cell concentration in the blood, has become a derived value, the product of the red cell count and the mean red cell volume.
The early device and its successors provided an unparalleled level of accuracy, efficiency, and breadth of application for enumerating and measuring the size of cells from any tissue source. Those readers who labored over red cell and white cell counts using a diluting pipette and hemacytometer chamber have some sense of the effect of Coulter's instrument and its later multi-parameter output on hematology and related disciplines.
The development of flow cytometry and sorting has had a stunning and incalculable impact on research, diagnosis, and therapy. Adaptations that permit characterizing the phenotype or DNA content of cells and sorting and isolating cells by their physical or surface properties have advanced studies of cells dramatically. This remarkable instrument evolved from Joseph and Wallace Coulter's earliest developments. A small subsidiary owned by Coulter, Los Alamos Particle, Inc., in collaboration with the Health Physics Division of the Los Alamos National Laboratories, used the ideas that had evolved to develop the prototype flow cytometer. The instrument developed used the Coulter Principle to separate fluid droplets containing cells by differences in cell volume. They could electrically charge droplets with cells of the desired volume and deflect them electrostatically into a collecting reservoir. Later, workers at Stanford advanced this technology by using cells stained with fluorescent dyes and measured cell size by light scatter and the fluorescence intensity generated by a laser. The cell-containing droplets could be charged based on size and on the conversion of the laser-generated optical signal into an electronic pulse. These two variables (dual parameters) could be used to decide whether to deflect the cell into a collecting reservoir. The addition of laser light scatter to the Coulter Principle of electronic counting and sizing resulted in VCS (volume, conductivity, scatter of laser light) technology.
Mr. Coulter's ideas and instruments were among the most important innovations in diagnostic and investigative medicine in the 20th century when one considers their impact on the disciplines of cell biology, hematology, immunology, and oncology, and also on industrial processes.
Dr. Beutler's contributions were of a different nature. He provided scientific insight into a remarkable range of hematologic diseases. He is a foremost student of blood storage, red cell metabolism, hemolytic anemias, iron metabolism and its disorders, lipid storage diseases (Gaucher disease, in particular), and a range of clinical genetic disorders, and has contributed to many other areas in insightful ways (e.g. hematopoietic stem cell transplantation, leukocyte disorders, platelet transfusion, and others). He contributed to refined methodologies of measurement (e.g. red cell enzymes) and diagnostic tests of importance for clinical genetic and hematologic disorders. His contributions have been highlighted in an article written by Drs. Josef Prchal and Karl Blume in this issue of The Hematologist (see below) and in a short biography published in Leukemia.1 A singular contribution of his was the first demonstration of the human female as a mosaic of X-chromosome gene expression. Dr. Beutler had already contributed extensively to our understanding of red cell glucose-6-phosphate dehydrogenase (G6PD) and the clinical impact of its deficiency. He used this enzyme as an X-chromosome marker to establish the mosaic state of X-chromosome gene expression in the human female. Coat color genes are on the X chromosome in mice but not in humans, making Dr. Beutler's discovery applicable to human genetics. Thus, the work was of profound importance for the understanding of gene regulation and for other biologic processes. For example, the concept was used to demonstrate that human tumors were monoclonal, providing the once elusive definition of a neoplasm as a tissue abnormality arising from the genetic alteration in a single cell.
In parallel to Mr. Coulter, who in hematology around the world has not benefited from Dr. Beutler's enormously productive career; his insights into human disease and its diagnosis and management; his gifted writings; his contributions to agencies, organizations, and institutions; and his mentoring of innumerable disciples? His warm friendship and gentle humor have also been shared by the lucky ones among us who have had the opportunity to interact with him more intimately.
"In choosing a Nobel prize winner, there is usually no unambiguous or incontestable best choice," said Arne Tiselius, himself a Nobel Laureate in Chemistry, and later President of the Nobel Foundation. "One can only hope the selection is worthy," he continued. Here, I would argue we have an unambiguous and incontestable best choice, Ernest Beutler.
- Lichtman MA. An Introduction of Ernest Beutler. Leukemia. 2001:15;656-657.
Ernest Beutler, MD
By Josef Prchal, MD, and Karl Blume, MD
Dr. Prchal is Professor of Medicine and Genetics at the University of Utah.
Dr. Blume is Professor of Medicine at Stanford University.
Ernest Beutler, MD, Chairman of the Department of Molecular & Experimental Medicine at The Scripps Research Institute, was the inaugural recipient of The Wallace H. Coulter Award for Lifetime Achievement in Hematology in December 2007. This award is bestowed on an individual who has demonstrated a lifetime of contributions to the field of hematology and who had a significant impact on research, education, and practice. One cannot think of anyone more deserving of this new award than Ernest Beutler. His accomplishments in academic hematology and the biologic sciences over the last five decades are singular.
Dr. Beutler's original discoveries in science and the art of hematology span a wide spectrum, involving many areas of biochemistry, molecular biology, genetics, cell biology, pathophysiology, diagnosis, and therapy. His contributions not only have given us new insights into the mechanisms of diseases but have also changed the way we practice medicine in general and hematology in particular.
He proposed the phenomenon of X-chromosome inactivation in human females, based on his work with glucose-6-phosphate dehydrogenase (G6PD), concurrently and independent of the studies of the mouse geneticist Dr. Mary Lyon. This insight represented the first example of the modulation of expression of genes by an epigenetic mechanism. This brilliant observation provided an explanation of the remarkable heterogeneity of the phenotype expressed by heterozygous females for G6PD deficiency, hemophilia, and other X-linked disorders. Following the studies by Drs. Gartler and Linder on the clonality of myomas, Dr. Beutler promptly demonstrated the clonality of malignant human tumors that changed the way we understand carcinogenesis.
With his typical rigorous approach, Dr. Beutler established and standardized methods for measurements of red blood cell enzymes that provided the explanation for several heretofore mysterious hemolytic anemias. He also developed a simple and accurate method for the early identification of newborns with galactosemia using small samples of erythrocytes. This method has since been used on millions of newborns for early detection and institution of dietary treatment, making possible the avoidance of the debilitating complications of galactosemia. His critical knowledge of red cell metabolism led to improvement in blood storage preservation that increased the shelf life of blood — a major contribution to transfusion medicine with immeasurable benefits to the general public.
Dr. Beutler is a true clinician-scientist who has taken care of patients most of his career. He also has made many innovative clinical observations demonstrating that the fusion of knowledge of basic science and the art of medicine often leads to pioneering discoveries. In 1959, he was the first to propose that sickle cell disease could be treated by altering the hemoglobin in patients' erythrocytes, either by increasing methemoglobin levels or inducing the formation of fetal hemoglobin. The latter approach bore fruit 40 years later with the introduction of the treatment of sickle cell disease with hydroxyurea. Dr. Beutler has also been a major contributor to the understanding of the biochemical genetics, molecular biology, and treatment of hereditary lipid storage diseases. He developed the first clinically practical biochemical method for the diagnosis of Gaucher disease and for identifying carriers. His group cloned the glucocerebrosidase gene and identified most of the mutations that cause Gaucher disease. He pioneered enzyme replacement therapy for Gaucher disease in the 1970s. When enzyme replacement became commercially available, his careful studies showed that the dose of the very costly enzyme that was being used for treatment was recommended at nearly 10 times the effective dose.
In 1975, in his role as a clinical hematologist, Dr. Beutler initiated a very successful clinical bone marrow transplantation program. Inspired by the findings of Dr. E. Donnall Thomas and his group that patients with advanced leukemia enjoy survival superior to that seen with chemotherapy, Dr. Beutler and his transplant team at the City of Hope National Medical Center became one of the first to successfully explore transplantation in acute leukemia patients in complete first remission.
Dr. Beutler repeatedly seized on lessons learned from genetic diseases to devise better treatments. When Dr. Dennis Carson, then an assistant professor in his new department at The Scripps Research Institute, designed 2-chlorodeoxyadenosine (cladribine) as a promising anti-lymphocyte compound, Dr. Beutler initiated and directed clinical studies that established this agent as the most effective treatment for hairy cell leukemia. Most recently, Dr. Beutler has revolutionized our thinking about the clinical penetrance of hereditary hemochromatosis, thought to be "the most common disease of Europeans." Dr. Beutler organized what was probably the largest DNA-based epidemiology study to date, comprising more than 41,000 participants. This study demonstrated that although the hereditary hemochromatosis genotype was common, the clinical phenotype was rare. Initially received with skepticism, since they ran counter to common belief, his findings have now been extensively confirmed.
Among his many contributions to hematology has been to serve as an editor of a leading hematology textbook of which seven editions have appeared since its inception in 1970. He was the President of ASH in 1979 and has served on the editorial board of the Society's journal, Blood. He also established the first combined online and print biomedical journal, Blood Cells, Molecules and Diseases. He was elected to the National Academy of Sciences and the Institute of Medicine, has been a consultant to many scientific and medical organizations, served on the Editorial Board of numerous scientific and medical journals, and has received many prestigious awards including an Honorary Doctor of Sciences from the Tel Aviv University.
One can only hope that all trainees in academic hematology may have the good fortune of the attentive, generous, and superior intellectual guidance that we experienced as trainees of Dr. Beutler.
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Emergency Preparedness: Looking Forward Five Years After SARS
By Michael Gardam, MD, Leah Gitterman, MHSc, and Armand Keating, MD
Dr. Gardam is Director, Infection and Prevention Control Unit, UHN.
Ms. Gitterman is the Pandemic Planning Strategist with the Infection Prevention and Control Unit, UHN.
Dr. Keating is Professor of Medicine and Director, Division of Hematology, University of Toronto. He is Secretary of ASH.
It has been almost five years since Toronto experienced its outbreak of severe acute respiratory syndrome (SARS). The outbreak, which occurred during the spring of 2003, resulted in 251 cases and 43 deaths. Unlike some other countries that identified a significant number of cases in the community setting, SARS in Toronto was spread predominantly in hospitals. Indeed, 43 percent of the SARS cases occurred in health-care workers — the highest percentage of any country that experienced an outbreak. It is important to note, however, that almost all the mortality occurred not in health-care workers, but in patients who had the misfortune of being admitted to the hospital for some other medical problem when SARS appeared.
Fortunately, the worldwide spread of SARS was a limited phenomenon and aggressive control measures were able to eventually halt its spread in all the countries that developed cases. The control measures used in Toronto were unprecedented in their scope and were imposed upon hospitals in the form of provincial government directives. Within hospitals, additional infection control precautions were used for all patients, outpatient and inpatient services were scaled back as were hospital staffing levels, and patients and staff were routinely surveyed for symptoms of febrile respiratory illness. The two main reasons for scaling back patient-care activities were to free up resources in the event that additional cases occurred and required admission, and to provide less "fuel for the fire" as SARS spread to patients in hospitals. In the Toronto region overall, medical admissions were decreased by 10 to 12 percent, while elective surgical admissions decreased by 15 to 22 percent.2 Elective cardiac procedures, on the other hand, were decreased by 66 percent and high acuity visits to emergency departments decreased by 37 percent.2 Outside the hospital, more than 20,000 contacts of SARS cases were placed in home quarantine.3
The impact of SARS on Toronto's Princess Margaret Hospital (PMH), Canada's largest facility for the treatment of hematologic and solid tumors, was mixed. Staff and patients were extremely fortunate that no known patients with SARS were admitted to PMH or made outpatient visits. This was despite many cases being admitted to adjacent and neighboring facilities, including the two other hospitals – Toronto General and Toronto Western – which, with PMH, make up the University Health Network. This being said, PMH administrators and staff, like all Toronto health-care workers, were faced with the stress of the outbreak and of complying with governmental directives that required scaling back services. Furthermore, as PMH is dependent upon other hospitals for intensive care services, there was the added concern amongst patients and staff that patients who required ICU care would be transferred to neighboring units that were caring for SARS patients. Early experience with SARS had suggested that solid organ transplant recipients had very poor outcomes when infected;4 hence, there was reason to believe that bone marrow transplant recipients, especially those who had received allogeneic transplants, would have a poor prognosis. Consequently, the admission of new allotransplant candidates was curtailed at PMH for several weeks because there was no assurance that the patients who might require critical care would be transferable to the ICU of other hospitals. Nonetheless, short-term admissions for chemotherapy administration were minimally affected, except for a week's delay for new cases. Overall, however, the caseload was maintained, despite the challenges faced by PMH staff in screening all patients and distinguishing the symptoms and signs of SARS from chemotherapy effects, especially among those with febrile neutropenia.
While morale among staff was high initially, the need for gowning and masking at all times became burdensome, and for some, debilitating. A further unexpected consequence was the cessation of formal education programs for residents and fellows, largely because there was a moratorium on meetings in hospitals and no movement of staff and trainees from hospital to hospital.
As horrible and surreal as the SARS experience was, it helped identify some very significant weaknesses in the health-care system that we now have the opportunity to strengthen. Certainly, years of underfunding and neglect had left the Ontario public health system in disarray and unable to deal with significant public health emergencies. Closer to home, it also identified that advanced hospital planning to deal with infectious diseases and other emergencies is essential; one of the reasons for the aggressive control measures was because hospitals did not have any experience or plans to deal with this type of event.
Currently PMH, like most hospitals in North America, is in the midst of planning for the next influenza pandemic. No one can accurately predict what a future pandemic will look like; however, even a mild pandemic would have a significant impact on our ability to provide care. Most current planning models assume a "moderate" pandemic like that experienced in 1957. Unlike SARS, which only affected local hospitals, a pandemic will be far more pervasive, involving a large segment of the world's population over a period of months. Toronto hospitals were able to access staff and supplies from surrounding areas during the SARS outbreak, and the health-care system outside the city was still reasonably able to care for patients; this option would not be available during a pandemic as all health-care systems would be affected at roughly the same time.
Along with the stockpiling of supplies and the development of policies and screening tools, cancer hospitals are also grappling with continuing to provide care in a setting where their clinical programs, emergency departments, and intensive care units will be inundated with influenza patients. Some of the issues that need to be addressed include the adequacy of intensive care beds for critically ill cancer patients, the desirability and ethical considerations of giving marrow-ablative chemotherapy when influenza is widespread, protecting patients from acquiring influenza while in the hospital, the use of antiviral agents and vaccines, and the necessity of freeing up inpatient and outpatient space to care for influenza patients which will require limiting cancer care to certain patient populations. This last issue is particularly contentious as we are not used to prioritizing care to this extent, and one can imagine the chaos if different hospitals develop different prioritization criteria. In order to help provide some guidance on this issue, the provincial cancer care agency, Cancer Care Ontario, has recently published the results of an extensive consultative process with its membership on prioritizing cancer care during a pandemic.6 These are the first disease-specific guidelines developed for the delivery of care during a pandemic. Central to this process was the use of an ethical framework based on patient need and the efficacy of treatment to help guide decision-making.7 These guidelines divide patient care into three priority groups:
- Priority A patients are those who are deemed critical and require services/treatment even in the event of a pandemic because their situation is immediately life-threatening.
- Priority B patients are those who require services/treatment but whose situation is deemed non-life-threatening; in the event of a pandemic, services/treatment could be discontinued for the period of the pandemic wave (6-8 weeks).
- Priority C patients are those whose condition is deemed as non-life-threatening and who can be deferred; those services would be discontinued while there is pandemic activity in the province.
Each priority group is then subdivided into multiple categories. The guidelines recognize that local or regional circumstances may influence a cancer program's ability to follow the criteria. If some regions are harder hit than others, a re-referral system is recommended for patients with potentially life-threatening or rapidly progressive cancers. This plan will help to ensure that Ontario's cancer system and PMH will be in the best position to provide critical cancer care.
It is our hope that the lessons learned from the Toronto SARS outbreak can be translated into improved health preparedness response planning for future health emergencies such as pandemic influenza. Our patients are highly vulnerable to infectious diseases, and it is a cruel irony that the very places patients go for treatment might be where they acquire a deadly infectious disease.
During the SARS outbreak, Michael Gardam, MD, was Director of Infection Prevention and Control at UHN, Leah Gitterman, MHSc, was a patient escort and helped screen PMH staff for febrile respiratory illness, and Armand Keating, MD, was Chief of Medical Services at PMH.
- World Health Organization.
- Schull MJ, Stukel TA, Vermeulen MJ, et al. CMAJ. 2007;176:1827-32.
- Lim S, Closson T, Howard G, Gardam M. Lancet Infect Dis. 2004;4:697-703.
- Kumar D, Tellier R, Draker R, et al. Am J Transplant. 2003;3:977-81.
- Walker D, Keon W, Laupacis A, et al. Ministry of Health and Long-Term Care; 2004. Cancer Care Ontario.
- Upshur R, Faith K, Gibson J, et al. University of Toronto Joint Centre for Bioethics. 2005.
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2008 ASH-AMFDP Application Deadline Approaching
The ASH-AMFDP award is a partnership between ASH and the Harold Amos Medical Faculty Development Program (AMFDP) of the Robert Wood Johnson Foundation. The ASH-AMFDP award provides four years of postdoctoral research support, including an annual stipend of up to $75,000 and an annual grant of $30,000 toward the support of research activities. The deadline for the 2008 ASH-AMFDP Award is March 19, 2008.
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ASH Minority Medical Student Award Program (MMSAP) Application Available
The MMSAP is an eight- to 12-week summer research experience for first- and second-year minority medical students. The benefits of this program include the guidance of two mentors, a research stipend, and an allowance for travel to the ASH annual meeting. The application deadline is March 14, 2008, and the deadline to request ASH's assistance to match an applicant with a host institution and research mentor is February 1, 2008.
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Call for Honorific Award Nominations
ASH members are invited to submit nominations for the William Dameshek Prize, Henry M. Stratton Medal, and E. Donnall Thomas Lecture and Prize for the year 2007. Letters of nomination must include a brief paragraph summarizing the nominee's contributions to hematology as well as a current bio-sketch or curriculum vitae. Nominations are due by February 1, 2008 and should be sent by postal mail to American Society of Hematology, Attn: Courtney Krier, 1900 M Street, NW, Suite 200, Washington, DC 20036, or via e-mail to ckrier@hematology.org.
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New Honorific Award
The Wallace H. Coulter Award for Lifetime Achievement in Hematology is bestowed on an individual who has demonstrated a lifetime commitment and outstanding contribution to hematology, and who has made a significant impact on education, research, and/or practice. The first Wallace H. Coulter Award for Lifetime Achievement was presented at the 2007 ASH annual meeting. It was presented to Ernest Beutler, MD. Wallace Henry Coulter was a prolific inventor who made important contributions to hematology and to ASH.
Nominate a colleague, mentor, or friend for this new prestigious award by submitting a nomination (including full name, institution, and reason for the nomination) by February 1, 2008. This award will be presented at the 50th ASH annual meeting in December 2008.
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ASH Members Awarded Membership in the Institute of Medicine of the National Academies
Katherine A. High, MD
Division of Hematology,
Howard Hughes Medical Institute,
The Children's Hospital of Philadelphia
Ronald Levy, MD
Professor and Chief,
Division of Oncology,
Stanford University School of Medicine
Jeffrey V. Ravetch, MD, PhD
Theresa and Eugene M. Lang Professor and Head,
Leonard Wagner Laboratory of Molecular Genetics and Immunology,
Rockefeller University
David T. Scadden, MD
Gerald and Darlene Jordan
Professor of Medicine, Co-Chair,
Department of Stem Cell and Regenerative Biology, and Co-Director,
Harvard Stem Cell Institute,
Harvard University
Director,
Center for Regenerative Medicine,
Massachusetts General Hospital
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