Annual Review of Medicine - Volume 53, 2002

Cardiac 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.

Nephron-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.

The 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.

Gene 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.

Stroke 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.

Asthma 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.

In 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.

Breast 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.

The 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.

A 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.

The 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.

The 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.

Thalidomide—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.