Survival of patients with locally advanced, unresectable (stage III), non-small-cell lung cancer treated with radiotherapy is poor. Trials of the addition of chemotherapy to radiotherapy have produced conflicting results.

Our current understanding of sepsis and multiple organ dysfunction needs to be revised, as the uniformly negative results of new therapies for these disorders suggest. Previous theories for the pathogenesis of these conditions are incomplete; reasons for this include the following. First, the surrogate models that have been used to study these disorders are not analogous to the clinical situation. Second, patients who have less severe manifestations of these diseases are often overlooked. And third, patients' preexisting conditions have not been taken into account. Considerable new evidence indicates that, in addition to a massive proinflammatory reaction, a compensatory anti-inflammatory response contributes to the onset of these disorders. At a local site of injury or infection and during the initial appearance of pro- and anti-inflammatory mediators in the circulation, the beneficial effects of these mediators outweigh their harmful effects. Only when the balance between these two forces is lost do these mediators become harmful. Sequelae of an unbalanced systemic proinflammatory reaction include shock, transudation into organs, and defects in coagulation. An unbalanced systemic compensatory anti-inflammatory response can result in anergy and immunosuppression. The proinflammatory and anti-inflammatory forces may ultimately reinforce each other, creating a state of increasingly destructive immunologic dissonance.

The term "race" has many definitions, ranging from a family unit to a species, but in common and medical usage, defining "race" has meant separating Homo sapiens into three to six groups. This division of Homo sapiens into race taxons started in the 18th century, when the sciences of genetics and evolutionary biology were not yet invented. These disciplines have since shown that human race taxonomy has no scientific basis. Race categories are social constructs, that is, concepts created from prevailing social perceptions without scientific evidence. Despite modern proof that race is arbitrary biological fiction, racial taxons are still used widely in medical teaching, practice, and research. Human diversity is inconsistently taught in medical schools and erratically presented in medical texts. Race taxons have been "medicalized"; that is, race groupings have been legitimized by their use in medical literature and practice as acceptable descriptive labels that are integral to the proper diagnosis and treatment of disease in humans. Assumptions about disease that are made because a race has been assigned can result in important negative consequences for individual patients and inaccurate genetic inferences for populations. In contrast, ethnicity is a concept that incorporates social, religious, linguistic, dietary, and other variables to identify individual persons and populations. Ethnicity may be able to impart clinical clues to diagnosis if the clinician taking the history is well informed and open minded. Ethnic boundaries are dynamic and imprecise, and a strict methodical approach to ethnicity that is equal to the approach required for the study of other variables is necessary if the concept of ethnicity is to be clinically useful.

Six years ago, we proposed a patient benefit-centered definition of medical futility that included both quantitative and qualitative components. We distinguished between an effect of a treatment that is limited to some part of a patient's body and a benefit that improves the patient as a whole. The quantitative portion of our definition stipulated that physicians should regard a treatment as futile if empirical data show that the treatment has less than a 1 in 100 chance of benefiting the patient. The qualitative portion of our definition stipulated that if a treatment merely preserves permanent unconsciousness or cannot end dependence on intensive medical care, physicians should consider the treatment futile. In this paper, we clarify and modify our original proposal and respond to the following major criticisms: 1) Medical futility is simply an attempt to increase the power of the physician over the patient and to repeal recent hard-gained advances in patient autonomy; 2) no professional or societal consensus has been achieved about the definition of futility; 3) futility is a value-laden determination, the usurpation of which by medicine is inappropriate unless only a so-called value-free or strict physiologic definition of futility is used; 4) the concept of futility is not practically useful because empirical treatment data cannot be applied with certainty to any given patient; 5) futility undermines our pluralistic society and threatens, among other things, the free exercise of religion; and 6) because cost considerations will ultimately dictate all such decisions, futility is an unnecessary concept.

To review the virology, epidemiology, pathogenesis, natural history, clinical manifestations, and current treatment of hepatitis C virus (HCV) infection.

The role of high-dose chemotherapy in the management of women with breast cancer remains one of the most controversial issues in oncology. During the past decade, numerous pilot studies have shown the feasibility of administering high-dose chemotherapy followed by autologous bone marrow transplantation or peripheral blood stem-cell transplantation (referred to as high-dose chemotherapy) to women with metastatic disease. However, it appears that survival improves in few treated patients. This treatment strategy is now being evaluated in the adjuvant setting in patients who are at high risk for developing recurrent disease. The National Cancer Institute has selected two randomized, adjuvant breast cancer trials for its High-Priority Clinical Trials Program. These trials are comparing conventional-dose chemotherapy with high-dose chemotherapy in patients in the early stages of breast cancer who are at high risk for disease recurrence. This paper focuses on the rationale for the randomized studies evaluating adjuvant high-dose chemotherapy in the early stages of breast cancer and reviews the efforts to overcome physician and patient biases so that the trials can be completed.

To review the diagnostic criteria for autoimmune hepatitis, to characterize the variant forms of autoimmune hepatitis, and to indicate appropriate therapies for this condition.

To review the pathologic and clinical features of and establish the frequency of cytomegalovirus encephalitis in adults and to review the methods available for diagnosis and treatment.

To compare the cost-effectiveness of interferon-alpha with that of hydroxyurea as initial therapy for patients with chronic myelogenous leukemia (CML) in the chronic phase.

Current recommendations for the treatment of hypercholesterolemia include drug therapy for persons at sufficiently elevated risk for coronary heart disease. However, no guidelines incorporate the effects of alternative interventions that decrease risk for coronary heart disease but are not used specifically to alter blood lipids. We did a simulation study to estimate the number of hypercholesterolemic adults who would continue to exceed a high-risk threshold after receiving aspirin, antihypertensive medication, and estrogen-replacement therapy. We found that of all persons who are currently candidates for hypolipidemic medication because they are at high risk for coronary heart disease, 6 to 8 million would no longer have this therapy recommended if the abilities of alternative interventions to reduce risk were considered. Pharmaceutical cost savings associated with alternative interventions range from $3 to $4 billion per year. Current guidelines should be revised to account for this effect.

Effective prophylaxis for infection with the human immunodeficiency virus (HIV) is important for health care providers at risk for exposure to infected blood. The average risk from percutaneous exposure is approximately 0.3%, but exposures involving a high titer of HIV or a large volume of infections material are apt to be much riskier. A convergence of indirect evidence strongly suggests that chemoprophylaxis with zidovudine after exposure to HIV may be efficacious. Treatment with zidovudine after percutaneous exposure appears to reduce the odds of infection by almost 80%. Zidovudine prophylaxis effectively prevents perinatal HIV transmission, and treatment during acute retroviral infection may attenuate HIV disease. Reports of "aborted" HIV infection among health care providers who have been stuck with contaminated needles suggest that antiretroviral treatment in the window of opportunity after exposure to HIV could prevent virus propagation and allow local cutaneous host defenses to clear the infection. Although efficacy has not been shown in controlled clinical trials, these data support a potential benefit from treatment after exposure. It is difficult to define the optimal regiment that should be used for prophyaxis, given the emergence of antiretroviral resistance among source patients. Current recommendations favor the use of zidovudine plus lamivudine for 4 weeks. Use of indinavir or other protease inhibitors is advised when the source patient is likely to harbor resistant virus or when exposure is especially hazardous.

To provide a comprehensive, literature-based guide to the diagnosis of and the management and referral of patients with oral diseases associated with human immunodeficiency virus (HIV) infection.

A probability model expresses the relation between the presence of clinical findings (input or independent variables) and the probability that a clinical state will occur (the dependent variable); for example, it expresses the probability that a disease is present or will develop or the probability that an outcome state will be reached. Probability models are developed by using selected study groups. Although these models are most often used to make predictions for groups of patients, they can also predict clinical states for individual patients. The following seven criteria provide a basis for the critical appraisal of probability models. In particular, physicians can use these criteria to decide when a specific probability model should be used to make a prediction in an individual patient. Five of the criteria are concerned with the applicability of a model to a particular patient: 1) the comparability of the patient and the study group used to develop the model; 2) the congruence between the clinical state of interest to patient and physician and the model's outcome; 3) the availability of all input variables where and when the prediction is to be made; 4) the usefulness of a quantitative estimate of the predicted clinical state; and 5) the degree of uncertainty in the probability estimate. The other two criteria are concerned with how well the probability model "works": 6) the fit of probabilities calculated from the model to the outcomes actually observed and 7) the model's ability to discriminate between outcome states relative to chance and to other, more traditional, prediction methods. We illustrate the use of these criteria by applying them, in the form of questions, to a convenient, tabular version of a model that estimates a patient's chances of surviving for 10 years after having definitive surgical therapy for primary cutaneous melanoma.

To better understand the health problems of veterans of the Persian Gulf War by analyzing previous war-related illnesses and identifying possible unifying factors.

To review the efficacy and safety of electrical and pharmacologic conversion of atrial fibrillation, strategies for maintenance of sinus rhythm, and the importance of antithrombotic therapy.

To review the literature on the cardiac effects of diabetes mellitus and hypertension.

Active immunization against infectious disease is important. However, much of our world faces poverty, social injustice, and warfare, all of which cause universal immunization to remain a distant dream. Agents that provide passive immunity thus remain essential biologicals. The most important of these are human or equine antisera against rabies, tetanus, diphtheria, and snake antivenins. Homologous products are either unavailable or unaffordable in places where they are needed the most. Less expensive heterologous (equine) antisera can be purified and are safe to use, but these antisera are also in short supply. Monoclonal antibodies have been developed but are even less likely to be affordable in poor countries. Several traditional sources of equine antisera are becoming depleted as a result of economic disincentives; a poor reputation based on the high adverse reaction rates of the old, unpurified products; and the activities of animal rights activists who object to the use of horses as blood donors. Purified, pepsin-digested equine antisera are preferred; but developing countries sometimes are forced to make crude products that are less safe or have no specific therapy available at all.