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- Volume 53, 2002
Annual Review of Medicine - Volume 53, 2002
Volume 53, 2002
- Review Articles
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Progress with Chronic Myelogenous Leukemia: A Personal Perspective over Four Decades
Vol. 53 (2002), pp. 1–13More Less▪ AbstractOur understanding and treatment of chronic myelogenous leukemia (CML) has progressed since 1960 in parallel with work on cancer in general. CML provided the first evidence of a specific genetic change associated with a human cancer (the Philadelphia chromosome) and the clonal nature of these disorders. With improved cytogenetic and molecular techniques over subsequent decades, the specific genetic rearrangements of CML and many other tumors were defined and the complex mechanisms of carcinogenesis gradually unraveled. During this period, improved treatments for CML (chemotherapy, interferon, bone marrow transplantation) were implemented, and therapy targeted to the specific genetic change in the leukemic cells has recently been brought to promising clinical trials. Similar efforts are under way for other human cancers, and although the problem is enormously complex, there is real hope for major improvements in controlling these disorders.
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Diagnosis and Treatment of Venous Thromboembolism
Vol. 53 (2002), pp. 15–33More Less▪ AbstractThe diagnosis of deep vein thrombosis (DVT) and pulmonary embolism (PE) has been improved and simplified over the past decade thanks to advances in noninvasive and readily accessible technology. With high degrees of sensitivity and specificity, venous ultrasonography is favored as the initial investigation for DVT. To diagnose PE, most clinicians rely on diagnostic algorithms that combine clinical assessment, noninvasive lung studies, and, if necessary, venous ultrasonography of the legs and D-dimer testing. Substantial progress has also occurred in the treatment of acute venous thromboembolism with the introduction of low-molecular-weight heparins. This class of antithrombotic agents has changed initial therapy from an inpatient, intravenous regimen that required laborious monitoring to an outpatient practice using weight-adjusted doses of once-daily subcutaneous injections. In addition, several new anticoagulants with theoretical advantages over existing agents have entered phase III studies. Aspects of thrombosis treatment that remain controversial include vena caval interruption and the indications for thrombolysis and surgical thromboembolectomy.
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Cyclooxygenase-2: A Therapeutic Target
Vol. 53 (2002), pp. 35–57More Less▪ AbstractCyclooxygenase (COX), also known as prostaglandin endoperoxide synthase, is the key enzyme required for the conversion of arachidonic acid to prostaglandins. Two COX isoforms have been identified, COX-1 and COX-2. In many situations, the COX-1 enzyme is produced constitutively (e.g., in gastric mucosa), whereas COX-2 is highly inducible (e.g., at sites of inflammation and cancer). Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both enzymes, and a new class of COX-2 selective inhibitors (COXIBs) preferentially inhibit the COX-2 enzyme. This review summarizes our current understanding of the role of COX-1 and COX-2 in normal physiology and disease.
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New Therapeutics for Chronic Heart Failure
Vol. 53 (2002), pp. 59–74More Less▪ AbstractTraditionally, clinicians have viewed heart failure either as a problem of excessive salt and water retention caused by abnormalities of renal blood flow, or as a hemodynamic problem associated with a reduced cardiac output and excessive peripheral vasoconstriction. Recently, clinicians have begun to adopt a neurohormonal model in which heart failure progresses because of the toxic effects of endogenous biological systems that become activated in heart failure. We review the rationale for existing heart failure therapies and discuss the reasoning behind the development of some emerging therapies.
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Thrombotic Thrombocytopenic Purpura: The Systemic Clumping “Plague”
Vol. 53 (2002), pp. 75–88More Less▪ AbstractIn thrombotic thrombocytopenic purpura (TTP), a multimeric form of von Willebrand factor (vWf) that is larger than ordinarily found in the plasma causes systemic platelet aggregation under the high-shear conditions of the microcirculation. A divalent cation–activated, vWf-cleaving metalloprotease that metabolizes large vWf multimers to smaller forms in normal plasma is severely reduced or absent in most patients with TTP. The vWf-cleaving metalloprotease either is not produced or is defective in children with chronic relapsing TTP. When the enzyme is provided by the infusion of normal plasma, these patients remain free of TTP symptoms for about three weeks. An IgG autoantibody to the vWf-cleaving metalloprotease is found transiently in many adult patients with acute idiopathic, recurrent, and ticlopidine/clopidogrel-associated TTP. These patients require plasma exchange, i.e., concurrent replacement of the inhibited vWf-cleaving metalloprotease by plasma infusion and plasmapheresis. The vWf-cleaving metalloprotease is present in fresh-frozen plasma, in cryoprecipitate-depleted plasma (cryosupernatant), and in plasma that has been treated with solvent and detergent. The pathophysiology of platelet aggregation in bone marrow transplantation/chemotherapy–associated thrombotic microangiopathy, and in the hemolytic-uremic syndrome, is not established. In neither condition is there a severe decrease in plasma vWf–cleaving metalloprotease activity.
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Positron Emission Tomography Scanning: Current and Future Applications
Vol. 53 (2002), pp. 89–112More Less▪ AbstractWhole-body positron emission tomography (PET) imaging with 18F deoxyglucose (FDG) is a molecular imaging modality that detects metabolic alterations in tumor cells that are common to neoplastic cells. FDG-PET has recently been approved by the Health Care Finance Administration for Medicare reimbursement for diagnosing, staging, and restaging lung cancer, colorectal cancer, lymphoma, melanoma, head and neck cancer, and esophageal cancer. This review discusses the scientific evidence that led to the emergence of PET imaging as an accepted clinical tool in patients with solitary pulmonary nodules, lung cancer, colorectal cancer, melanoma, lymphoma, breast cancer, and other cancers. When possible, we compare the performance of PET to that of anatomical imaging. We discuss future clinical applications of this imaging modality.
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Attention Deficit/Hyperactivity Disorder Across the Lifespan
Vol. 53 (2002), pp. 113–131More Less▪ AbstractAttention deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder presenting for treatment in youth. ADHD is often chronic with prominent symptoms and impairment spanning into adulthood. ADHD is often associated with co-occurring anxiety, mood, and disruptive disorders, as well as substance abuse. The diagnosis of ADHD by careful review of symptoms and impairment is both reliable and valid. Recent genetic, imaging, neurochemistry, and neuropsychological data support the biological underpinning of the disorder. All aspects of an individual's life must be considered in the diagnosis and treatment of ADHD. Pharmacotherapy, including stimulants, antidepressants, and antihypertensives, plays a fundamental role in the management of ADHD across the lifespan.
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Will the Pig Solve the Transplantation Backlog?
Vol. 53 (2002), pp. 133–147More Less▪ AbstractThe increasing shortage of human cadaveric organs for purposes of transplantation has become the critical limiting factor in the number of transplants performed each year. Some of this deficit is being met by the use of organs or partial organs from living donors, but this source is insufficient. Xenotransplantation—the transplantation of organs between species, namely from the pig to human—could provide a solution if immunologic and other associated problems could be solved. When a pig organ is transplanted into a primate, hyperacute rejection, induced by anti-pig antibody and mediated by complement and the coagulation system, develops rapidly. This immediate problem can now be overcome, but the return or persistence of anti-pig antibody leads to a delayed form of humoral rejection, acute humoral xenograft rejection, which leads to destruction of the organ within days or weeks. We review the various approaches being investigated to overcome this barrier. Whether they will also prevent subsequent acute cellular rejection remains unknown. Brief mention is made of the potential physiologic incompatibilities between pig and human organs, as well as the microbiologic safety aspects of xenotransplantation. Finally, the question of patient and societal acceptance of xenotransplantation is discussed.
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Immunologic Control of HIV-1
Vol. 53 (2002), pp. 149–172More Less▪ AbstractBy destroying CD4+ T cells, human immunodeficiency virus-1 (HIV-1) infection results in immunodeficiency and the inability of the immune system to contain the virus in most individuals. Although treatment of HIV-1 infection with potent antiretroviral medications has resulted in enormous clinical benefit, there is a growing recognition of the limitations of this therapy. As a result, novel approaches to treating HIV-1 infection are being considered. One such strategy is immunotherapy, which seeks to boost immune responses against HIV-1 and control the virus. This approach is based on studies of other viruses in which a coordinated immune response contains the chronic infection. Recent studies show that CD4+ helper responses, CD8+ T cell activity, and antibodies may contribute to control of the virus without antiretroviral therapy in some HIV-positive individuals. Based on this understanding of the immunologic correlates of control of HIV-1, exciting new immunotherapeutic strategies for HIV-1 infection are being designed and tested.
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The Expanding Pharmacopoeia for Bipolar Disorder
Vol. 53 (2002), pp. 173–188More Less▪ AbstractOver the past decade, the number of treatments available for bipolar disorder has undergone an extraordinary expansion. In that period, valproate and olanzapine have received regulatory approval in the United States for the acute treatment of mania, and carbamazepine has been indicated for this condition in many other countries. In addition to those agents, a number of other anticonvulsants (in particular lamotrigine, gabapentin, and topiramate) are in trials, as are the atypical antipsychotics clozapine and risperidone, and other novel compounds. This article critically reviews the evidence from controlled trials of these proposed “mood stabilizers,” highlighting the strengths and limitations of the data for each compound. A major challenge to the field is the capacity to prove the prophylactic properties of agents for which effectiveness in acute mania and/or bipolar depression has been demonstrated. Finally, as the mechanisms of agents such as lithium are now becoming apparent, and the possibility of understanding the molecular defects underpinning the condition is no longer highly fanciful, the prospect of targeted therapies is considered feasible by both academia and the pharmaceutical industry.
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Heart Transplantation: A Thirty-Year Perspective
Vol. 53 (2002), pp. 189–205More Less▪ AbstractHeart transplantation has evolved over the past 30 years into a mainstay of therapy for heart failure patients. As the surgical technique and basic immunology were defined, heart transplantation became a real therapeutic option. Over the next few decades, thoracic transplant teams at Stanford University and other institutions refined this mode of therapy. This review addresses the history, current surgical technique, recipient and donor selection, postoperative care, immunosuppression, short- and long-term complications, and clinical outcomes associated with this procedure.
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Clinical Trials of HIV Vaccines*
Vol. 53 (2002), pp. 207–221More Less▪ AbstractDevelopment of a preventive vaccine for HIV is the best hope of controlling the AIDS pandemic. Evidence from natural history studies and experiments in animal models indicates that immunity against HIV is possible, suggesting that vaccine development is feasible. These studies have shown that sufficient levels of neutralizing antibody against HIV can prevent infection, although the effect is type-specific. In contrast, HIV-specific cytotoxic T lymphocyte (CTL) activity has broad cross-reactivity, and although CTL activity alone cannot prevent HIV infection, it can control the level of viremia at a low level. Evaluation of candidate vaccines in human trials has focused on approaches that can safely elicit HIV-specific antibody and T cell responses. Current strategies have been unable to induce antibody with broad neutralizing activity against primary HIV isolates. However, recombinant poxvirus and DNA vaccines have elicited CTL responses that are broadly cross-reactive against primary HIV isolates from diverse clades. Future advances will require the discovery of new immunogens that can induce neutralizing antibody, as well as efficacy trial evaluation of regimens optimized for CTL induction.
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Chemoprevention of Aerodigestive Tract Cancers
Vol. 53 (2002), pp. 223–243More Less▪ AbstractEpithelial cancers are a major worldwide health problem. Since the mid-1970s, advances in multidisciplinary cancer therapeutics have only slightly improved the mortality rate from epithelial malignancies. Chemoprevention is the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent progression to invasive cancer. Chemopreventive medicine is based on translating basic biologic research into clinical chemical interventions, thus attempting to impede carcinogenesis. Its principles build on the concepts of field cancerization (diffuse epithelial injury that results from carcinogen exposure) and multistep carcinogenesis (a stepwise accumulation of cellular and genetic alterations that progress to cancer). Chemoprevention targets the carcinogenic process at earlier and potentially more reversible stages, focusing on the inhibition of one or many steps in the progression towards cancer. Strategies of chemoprevention include primary prevention in groups at high risk, reversal of premalignant lesions, and prevention of second primary tumors.
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Diabetes and Cardiovascular Disease
Vol. 53 (2002), pp. 245–267More Less▪ AbstractThis review focuses on several topics related to the epidemiology of diabetes and cardiovascular disease (CVD). These include the CVD risk factors common in the metabolic syndrome, behavioral risk factors and diabetes, gender differences in the association between diabetes and CVD risk, and how the clinical definition of diabetes influences the association of diabetes and CVD. Nontraditional risk factors potentially linking diabetes and CVD are also discussed, including chronic inflammation, advanced glycation endpoints, autonomic neuropathy, sleep-disordered breathing, and genetic susceptibility to diabetes-associated CVD risk.
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Immune Reconstitution in Patients with HIV Infection
Vol. 53 (2002), pp. 269–284More Less▪ AbstractThe peripheral T cell pool is damaged by HIV-1 infection and can be regenerated by production of new T lymphocytes either from the thymus or from proliferation of post-thymic T cells. A critical question for AIDS patients is whether treatment with antiretroviral drugs can restore the capability to produce new T lymphocytes. The development of a new assay of thymus function in adults (the measurement of T cell receptor excision circles, TRECs), and studies of thymus biopsies in untreated and treated HIV-1-infected patients, have suggested that in select patients the thymus can regenerate on antiretroviral therapy. New strategies to overcome the thymic atrophy of aging are needed to improve thymic function in the majority of AIDS patients.
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Multiple Sclerosis
Vol. 53 (2002), pp. 285–302More Less▪ AbstractMultiple sclerosis (MS) is a common inflammatory disease of the central nervous system (CNS). Diagnosis rests upon identifying typical clinical symptoms and interpreting supportive laboratory and radiological investigations. The etiology is unknown; however, strong evidence suggests that MS is an autoimmune disease directed against CNS myelin or oligodendrocytes. Genetic factors are important in the development of MS. Contributing environmental determinants (possibly including infectious agents) appear important but remain unidentified. Both cell-mediated and humorally mediated immune mechanisms contribute to pathological injury. Axonal damage occurs in addition to demyelination and may be the cause of later permanent disability. Distinct pathological subtypes may differentiate among patients with MS. Treatment is directed at acute attacks (with corticosteroids) and reduction of attack frequency (primarily with type-1 β interferons and glatiramer acetate). Research into the causes and treatments of MS has expanded our knowledge of this disease and promises improved care for MS patients in the future.
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Gene Expression Profiling of Lymphoid Malignancies*
Vol. 53 (2002), pp. 303–318More Less▪ AbstractComprehensive gene expression profiling using DNA microarrays is providing a molecular classification of cancer into disease categories that are homogeneous with respect to pathogenesis and clinical behavior. Gene expression profiling revealed that diffuse large B cell lymphoma (DLBCL) consists of at least two molecularly distinct diseases that are derived from distinct stages of B cell differentiation and have strikingly different clinical outcomes. By contrast, chronic lymphocytic leukemia (CLL) was found to be a single disease defined by a characteristic gene expression signature. Nonetheless, gene expression profiling distinguished two clinically divergent CLL subtypes and provided evidence that signaling through the B cell antigen receptor may play a role in the clinically aggressive subtype. Gene expression analysis also illuminated the mechanism of lymphomagenesis caused by BCL-6 translocations and provided evidence that the NF-κB signaling pathway is a new molecular therapeutic target in DLBCL.
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Lipotoxic Diseases
Vol. 53 (2002), pp. 319–336More Less▪ AbstractI review evidence that leptin is a liporegulatory hormone that controls lipid homeostasis in nonadipose tissues during periods of overnutrition. When adipocytes store excess calories as triacylglycerol (TG), leptin secretion rises so as to prevent accumulation of lipids in nonadipose tissues, which are not adapted for TG storage. Whenever leptin action is lacking, whether through leptin deficiency or leptin resistance, overnutrition causes disease of nonadipose tissues with generalized steatosis, lipotoxicity, and lipoapoptosis. Examples of such disorders of liporegulation include generalized lipodystrophies, mutations of leptin and leptin receptor genes, and diet-induced obesity. Lipotoxicity of pancreatic β-cells, myocardium, and skeletal muscle leads, respectively, to type 2 diabetes, cardiomyopathy, and insulin resistance. In humans this constellation of abnormalities is referred to as the metabolic syndrome, a major health problem in the United States. When lipids overaccumulate in nonadipose tissues during overnutrition, fatty acids enter deleterious pathways such as ceramide production, which, through increased nitric oxide formation, causes apoptosis of lipid-laden cells, such as β-cells and cardiomyocytes. Lipoapoptosis can be prevented by caloric restriction, by thiazolidinedione treatment, and by administration of nitric oxide blockers. There is now substantial evidence that complications of human obesity may reflect lipotoxicity similar to that described in rodents.
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Directions of Drug Discovery in Osteoporosis
Vol. 53 (2002), pp. 337–354More Less▪ AbstractOsteoporosis is a condition of increasing importance and prevalence in all parts of the world and particularly in Asia. Recent advances have led to the introduction of effective drugs that decrease bone resorption and stabilize bone mass. However, these drugs have been identified by serendipity rather than rational drug design and are not ideal because of limited bioavailability, mode of administration, or other unwanted effects. There is still a place for even more suitable and effective resorption inhibitors than those currently available. The more compelling need in this field is an acceptable drug that is anabolic for bone, that safely and acceptably increases bone mass and improves the disturbances in bone microarchitecture that characterize established and advanced osteoporosis. Possible approaches to identifying more effective resorption inhibitors and new anabolic agents are discussed.
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Early Management of Prostate Cancer: How to Respond to an Elevated PSA?
Vol. 53 (2002), pp. 355–368More Less▪ AbstractSupport for prostate cancer screening efforts is provided by observational studies reporting decreases in prostate cancer–specific mortality in areas where screening is performed with digital rectal exam (DRE) and measurement of serum prostate-specific antigen (PSA) levels. The combination of PSA and DRE is an excellent cancer-screening tool with sensitivity and positive predictive value superior to that of mammography and breast exam. Use of percent free PSA further improves the specificity of PSA testing, particularly in the range of 4–10 ng/ml, at which most false positive PSA tests occur. Men older than 50 with a >10-year life expectancy should be considered for prostate cancer screening. Those with an abnormal DRE or a PSA above 4 ng/ml should be referred to a urologist for further discussion of the risks and benefits of a prostate biopsy. Furthermore, those with a significant change in either DRE or PSA results, or those at higher risk for prostate cancer with a PSA level above 2.5 ng/ml, should also be referred for evaluation.
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Recent Advancements in the Treatment of Chronic Myelogenous Leukemia
Vol. 53 (2002), pp. 369–381More Less▪ AbstractChronic myelogenous leukemia (CML) is a clonal hematopoetic stem cell disorder characterized by the Philadelphia chromosome and resultant production of the constitutively activated Bcr-Abl tyrosine kinase. Characterized clinically by marked myeloid proliferation, it invariably terminates in an acute leukemia. Conventional therapeutic options include interferon-based regimens and stem cell transplantation, with stem cell transplantation being the only curative therapy. Through rational drug development, STI571, a Bcr-Abl tyrosine kinase inhibitor, has emerged as a paradigm for gene product targeted therapy, offering new hope for expanded treatment options for patients with CML.
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Surgical Management of Heart Failure: An Overview
Vol. 53 (2002), pp. 383–391More Less▪ AbstractCardiac transplantation remains the gold standard of surgical therapies for advanced and end-stage heart failure. However, this very limited option trades one disease for another and can benefit only a small minority of patients. Heart failure is currently considered secondary to a structural increase in ventricular chamber volume or remodeling. Surgical therapies formerly contraindicated for the failing heart, as well as new therapies, can successfully affect ventricular remodeling and improve cardiac function. Surgical revascularization for patients with ejection fractions <20% is becoming common. Mitral valve repair is being explored, with surprisingly low operative mortality and encouraging intermediate results. Direct surgical approaches to restoring normal geometry and size to failing hearts, such as left ventricular reduction (Batista procedure), endoventricular patch plasty (Dor procedure), cardiomyoplasty, and prosthetic external constraints are under clinical investigation. Developments in mechanical assist therapy and a new generation of implantable intracorporeal assist devices are also discussed.
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Nephron-Sparing Surgery for Renal Cell Carcinoma
Vol. 53 (2002), pp. 393–407More Less▪ AbstractNephron-sparing surgery (NSS) provides effective curative therapy for patients with localized renal cell carcinoma. In patients with imperative indications, it represents an alternative to renal replacement therapy. For selected patients with systemic comorbidities that threaten global renal function, NSS preserves unaffected nephrons with excellent cancer-specific survival. Elective partial nephrectomy for patients with a small (≤4 cm), unifocal tumor and a normal contralateral kidney is associated with a low risk (0%–3%) of local recurrence and cancer-specific survival rates of 90%–100%. Comparisons between radical and partial nephrectomy demonstrate equivalent cancer control over five years. Minimally invasive techniques of NSS are feasible but await improved technologies and long-term outcome data before they become fully acceptable treatment options.
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The Mechanisms of Action of PPARs
Vol. 53 (2002), pp. 409–435More Less▪ AbstractThe peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPARγ, PPARα, and PPARδ, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with cofactors such that the rate of transcription initiation is increased. The PPARs play a critical physiological role as lipid sensors and regulators of lipid metabolism. Fatty acids and eicosanoids have been identified as natural ligands for the PPARs. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, have proven effective in the treatment of dyslipidemia and diabetes. Use of such ligands has allowed researchers to unveil many potential roles for the PPARs in pathological states including atherosclerosis, inflammation, cancer, infertility, and demyelination. Here, we present the current state of knowledge regarding the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases.
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Cancer Gene Therapy: Scientific Basis
Vol. 53 (2002), pp. 437–452More Less▪ AbstractGene therapy of cancer has been one of the most exciting and elusive areas of therapeutic research in the past decade. Critical developments have occurred in gene therapy targeting cancer cells, cancer vasculature, the immune system, and the bone marrow, itself often the target for severe toxicity from therapeutic agents. We review some recent developments in the field. In each instance, clear preclinical models validated the therapeutic approach and efforts have been made to evaluate the target impact in both preclinical and early clinical trials. Although no cures can consistently be expected from today's cancer gene therapy, the rapid progress may imply that such cures are a few short years away.
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Ischemic Stroke Therapy
C. Stapf, and J. P. MohrVol. 53 (2002), pp. 453–475More Less▪ AbstractStroke is the most common life-threatening neurologic disease and the leading cause of serious long-term disability. The advent of new treatment options for selected patients suffering ischemic stroke (such as systemic administration of tissue plasminogen activator or catheter-guided intra-arterial thrombolysis), the structural reorganization of patient care facilities into stroke units, and interdisciplinary cerebrovascular centers have broadened the scope of possible therapeutic interventions in the acute and postacute phase after cerebral ischemia. This review summarizes currently available and recommended treatment modalities for acute ischemic stroke from an interdisciplinary perspective, including medical, neurointerventional, and neurosurgical therapies.
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The Pathophysiology of Asthma
Vol. 53 (2002), pp. 477–498More Less▪ AbstractAsthma is a chronic disorder of the airways that is characterized by reversible airflow obstruction and airway inflammation, persistent airway hyperreactivity, and airway remodeling. The etiology of asthma is complex and multifactorial. Recent advances have demonstrated the importance of genetics in the development of asthma, particularly atopic asthma. Environmental stimuli, particularly early childhood infections, have also been associated with the development of asthma. Most current data seem to suggest that these factors drive the development of a Th-2 lymphocyte–predominant immune response, which has been associated with atopy and IgE-mediated inflammation. The concept of reversible airflow obstruction has also recently been challenged. It is now clear that chronic airway changes occur, which may contribute to progressive airflow obstruction. We discuss the important influence of genetic and environmental factors on the emergence of the asthmatic phenotype. The significance of Th-1 and Th-2 lymphocyte–mediated immunity are discussed, and the inflammatory processes leading to chronic airway inflammation are detailed.
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Viral Persistence: HIV's Strategies of Immune System Evasion
Vol. 53 (2002), pp. 499–518More Less▪ AbstractIn contrast to most animal viruses, infection with the human and simian immunodeficiency viruses results in prolonged, continuous viral replication in the infected host. Remarkably, viral persistence is not thwarted by the presence of apparently vigorous, virus-specific immune responses. Several factors are thought to contribute to persistent viral replication, most notably the destruction of virus-specific T helper cells, the emergence of antigenic escape variants, and the expression of an envelope complex that structurally minimizes antibody access to conserved epitopes. Not as well understood, though potentially important, is the ability of at least one viral encoded protein (Nef) to prevent presentation of viral antigens in the context of major histocompatibility complex. The future success of antiviral therapies and vaccination strategies may depend largely on understanding how and to what degree each of these factors (and presumably others) contributes to immune evasion.
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Breast Cancer Risk Reduction: Strategies for Women at Increased Risk
Vol. 53 (2002), pp. 519–540More Less▪ AbstractBreast cancer risk reduction now represents an achievable medical objective. Current interventions include selective estrogen receptor modulators (SERMs), prophylactic surgery, and lifestyle change. For SERMs, current evidence supports tamoxifen use for breast cancer risk reduction whereas raloxifene requires further study. Prophylactic mastectomy and prophylactic oophorectomy, effective in retrospective clinical experiences, should be considered only for women at substantial risk willing to accept the irreversible consequences of these procedures. Although dietary fat intake is under clinical trial evaluation, lifestyle change, including weight loss, dietary change, and increased physical activity, can be recommended based on other health considerations. Use of any intervention requires careful breast cancer risk assessment, risk-benefit calculations, and informed decision making with full patient participation. Future breast cancer risk assessment may incorporate additional biologic measures of estrogen exposure and/or analyses of collected breast cells. Under active evaluation are novel SERMs, aromatase inhibitors/inactivators, gonadotrophin-releasing hormone agonists, retinoids, statins, and tyrosine kinase and cyclooxygenase-2 inhibitors.
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Potential New Therapies for the Treatment of HIV-1 Infection
Vol. 53 (2002), pp. 541–555More Less▪ AbstractThe development and clinical use of chemotherapeutic agents for the treatment of persistent HIV-1 infection over the past decade has profoundly and favorably affected the course of HIV-1 disease for many infected individuals. Unfortunately, the long-term use of these therapies is complicated by unwanted metabolic side effects, by issues of adherence, and by the selection of viral variants with reduced susceptibility. These complications have spurred the search for new anti-HIV-1 agents having improved pharmacological properties and expressing activity against viral variants resistant to the currently available agents. This brief review describes the current state of this search as well as potentially novel viral targets for chemotherapeutic intervention.
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The Challenge of Viral Reservoirs in HIV-1 Infection
Vol. 53 (2002), pp. 557–593More Less▪ AbstractA viral reservoir is a cell type or anatomical site in association with which a replication-competent form of the virus accumulates and persists with more stable kinetic properties than the main pool of actively replicating virus. This article reviews several cell types and anatomical sites proposed as potential reservoirs for HIV-1. It is now clear that HIV-1 persists in a small reservoir of latently infected resting memory CD4+ T cells, which shows minimal decay even in patients on highly active antiretroviral therapy (HAART). The persistence of virus in this reservoir is consistent with the biology of these cells and the long-term persistence of immunologic memory. The viral replication that continues in patients on suppressive HAART may also contribute to the stability of this reservoir. There may be other reservoirs, but the latent reservoir in resting CD4+ T cells appears to be sufficient to guarantee lifetime persistence of HIV-1 in the majority of patients on current HAART regimens, and unless new approaches are developed, eradication will not be possible. The clinical implications of this and other HIV-1 reservoirs are discussed.
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Rational Approach to AIDS Drug Design Through Structural Biology*
Vol. 53 (2002), pp. 595–614More Less▪ AbstractThe discovery and development of more than a dozen drugs in the past 15 years for the treatment of AIDS offer an excellent example of progress in the field of rational drug design. At this time, the principal targets are reverse transcriptase and protease, enzymes encoded by the human immunodeficiency virus. The introduction of protease inhibitors, in particular, has drastically decreased the mortality and morbidity associated with AIDS. This review presents the methods used to develop such drugs and discusses the remaining problems, such as the rapid emergence of drug resistance.
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Mechanisms of Cancer Drug Resistance
Vol. 53 (2002), pp. 615–627More Less▪ AbstractThe design of cancer chemotherapy has become increasingly sophisticated, yet there is no cancer treatment that is 100% effective against disseminated cancer. Resistance to treatment with anticancer drugs results from a variety of factors including individual variations in patients and somatic cell genetic differences in tumors, even those from the same tissue of origin. Frequently resistance is intrinsic to the cancer, but as therapy becomes more and more effective, acquired resistance has also become common. The most common reason for acquisition of resistance to a broad range of anticancer drugs is expression of one or more energy-dependent transporters that detect and eject anticancer drugs from cells, but other mechanisms of resistance including insensitivity to drug-induced apoptosis and induction of drug-detoxifying mechanisms probably play an important role in acquired anticancer drug resistance. Studies on mechanisms of cancer drug resistance have yielded important information about how to circumvent this resistance to improve cancer chemotherapy and have implications for pharmacokinetics of many commonly used drugs.
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Thalidomide: Emerging Role in Cancer Medicine
Vol. 53 (2002), pp. 629–657More Less▪ AbstractThalidomide—removed from widespread clinical use by 1962 because of severe teratogenicity—has antiangiogenic and immunomodulatory effects, including the inhibition of tumor necrosis alpha factor. It has now returned to practice as an effective oral agent in the management of various disease states including erythema nodosum leprosum, for which it was approved by the U.S. Food and Drug Administration in 1998, and more recently certain malignancies, including multiple myeloma. Although thalidomide's mechanism of action remains incompletely understood, considerable insight has been generated by extensive preclinical studies in multiple myeloma. Moreover, clinical trials have confirmed benefit in relapsed disease, and the role of thalidomide in treating newly diagnosed patients is currently under study. Its use in other tumors is under evaluation, with promise in renal cell carcinoma, prostate cancer, glioma, and Kaposi's sarcoma. Activity has also been demonstrated in chronic graft-versus-host disease and in symptom relief as part of palliative care.
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Previous Volumes
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Volume 75 (2024)
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Volume 74 (2023)
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Volume 73 (2022)
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Volume 72 (2021)
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Volume 71 (2020)
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Volume 70 (2019)
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Volume 69 (2018)
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Volume 68 (2017)
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Volume 67 (2016)
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Volume 66 (2015)
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Volume 65 (2014)
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Volume 64 (2013)
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Volume 63 (2012)
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Volume 62 (2011)
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Volume 61 (2010)
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Volume 60 (2009)
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Volume 59 (2008)
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Volume 58 (2007)
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Volume 57 (2006)
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Volume 56 (2005)
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Volume 55 (2004)
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Volume 54 (2003)
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Volume 53 (2002)
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Volume 52 (2001)
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Volume 51 (2000)
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Volume 50 (1999)
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Volume 49 (1998)
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Volume 48 (1997)
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Volume 47 (1996)
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Volume 46 (1995)
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Volume 45 (1994)
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Volume 44 (1993)
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Volume 43 (1992)
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Volume 42 (1991)
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Volume 41 (1990)
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Volume 40 (1989)
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Volume 39 (1988)
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Volume 38 (1987)
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Volume 37 (1986)
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Volume 36 (1985)
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Volume 35 (1984)
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Volume 34 (1983)
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Volume 33 (1982)
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Volume 32 (1981)
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Volume 31 (1980)
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Volume 30 (1979)
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Volume 29 (1978)
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Volume 28 (1977)
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Volume 27 (1976)
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Volume 26 (1975)
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Volume 25 (1974)
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Volume 24 (1973)
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Volume 23 (1972)
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Volume 22 (1971)
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Volume 21 (1970)
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Volume 20 (1969)
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Volume 19 (1968)
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Volume 18 (1967)
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Volume 17 (1966)
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Volume 16 (1965)
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Volume 15 (1964)
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Volume 14 (1963)
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Volume 13 (1962)
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Volume 12 (1961)
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Volume 11 (1960)
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Volume 10 (1959)
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Volume 9 (1958)
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Volume 8 (1957)
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Volume 7 (1956)
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Volume 6 (1955)
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Volume 5 (1954)
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Volume 4 (1953)
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Volume 3 (1952)
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Volume 2 (1951)
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Volume 1 (1950)
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Volume 0 (1932)