Approximately 40% of non-small cell lung cancer (NSCLC) patients present with locally advanced, unresectable lesions. Treatment with thoracic radiotherapy yields survivals averaging just 9 to 10 months, and long-term survival at 5 years is poor. Recent studies indicate that chemotherapy followed by thoracic radiotherapy improves 5-year survival by three- to fourfold. Nevertheless, most patients do ultimately die of the underlying disease. New strategies designed to enhance local tumor control-use of radiation-sensitizing drugs, three-dimensional treatment planning techniques, or altered radiation fractionation schedules-may further improve survival outcome. In addition, newer cisplatin-based regimens containing either paclitaxel or vinorelbine improve survival over that achieved with older vinca alkaloid or podophyllotoxin combination regimens. Accordingly, the newer drug regimens combined with radiotherapy can be expected to further improve survival in this subset of NSCLC patients. Prospective studies are underway to test this conjecture.

Surgical resection has limited success in curing non-small cell lung cancer (NSCLC), particularly among patients with locally advanced disease (stage IIIA). Combined modality regimens, utilizing surgery, radiotherapy, and chemotherapy, have improved response rates, although they have not been shown to significantly impact survival among patients with completely resected stage I and II NSCLC. Future improvements in NSCLC therapy, currently under investigation, are likely to come from newer agents shown to be active in this disease and from alternative schedules, such as neoadjuvant or concurrent combined modality treatments. Neoadjuvant cisplatin-based chemotherapy has already been shown to increase cure rates in stage IIIA NSCLC, from 10 to 15% to 25 to 30%. Newer active agents, such as paclitaxel, vinorelbine, and gemcitabine, may be able to advance the cure rate even further. Radiotherapy, which has been shown to decrease the rate of local recurrence, may play a role as well.

Patients with clinical stage I and II non-small cell lung cancer (NSCLC) generally are considered candidates for surgical resection, with cure rates as high as 80% reported for some subsets. Locoregional and systemic adjuvant therapies have been evaluated in patients with lymph node involvement or pathologic T3 status, although considerable controversy regarding an appropriate standard of care continues to exist. Several trials have evaluated postoperative radiation therapy, the majority of which suggest that overall survival may be only minimally improved with this adjuvant therapy, but local failure is probably reduced. Trials evaluating the role of adjuvant chemotherapy have been few, often enrolling small numbers of patients. Several recent reviews summarizing the results of these trials suggest that, although some adjuvant chemotherapy regimens may have biological activity, results have not been consistent, and further study is warranted for regimens that include newer chemotherapy agents. CNS relapse is one of the most common sites of metastasis in NSCLC, and prophylactic cranial irradiation (PCI) has been evaluated in a number of trials to reduce the risk of local failure at this site. Data from these trials strongly suggest that a prospective trial of PCI in patients with NSCLC at high risk for isolated CNS relapse is warranted. Future clinical trials evaluating new radiographic, immunologic, and molecular technologies for early detection of second primary tumors also should be considered, particularly in patients with resected T1N0M0 lesions.

Approximately 45% of all lung carcinomas are limited to the chest, where surgical resection is not only an important therapeutic modality, but in many cases, the most effective method of controlling the disease. Patients with T1N0 and T2N0 tumors have early lung cancer, and most are curable by resection, with 5-year survival rates in the range of 75 to 80% for patients with T1N0 status. Patients with smaller tumors do better than patients with larger ones, while visceral pleural invasion does not seem to influence survival. Histologic type is also a significant prognostic variable, with squamous tumors having a better prognosis than tumors of nonsquamous histology. Other known prognostic factors are age and gender of the patient and completeness of resection. The "gold standard" of surgery remains lobectomy, regardless of tumor size at presentation. Stage T1N1 and T2N1 carcinomas represent a group of patients where the disease involves hilar and bronchopulmonary nodes. This group is best treated by complete resection with mediastinal lymphadenectomy. Tumor size and histology are significant prognostic variables, and 5-year survival after complete resection is in the range of 40 to 50%. Postoperative radiation therapy may improve local control, while chemotherapy results in a slightly reduced risk of death.

The necessity for a compulsive attitude toward preoperative assessment of lung cancer is to be emphasized, since rational treatment and prognosis depend largely on the stage of disease at the time of diagnosis. In the preoperative setting, the techniques used should be sequential, logical, and help to identify patients suitable for treatment with curative intent. With regard to the primary tumor (T status), the accuracy of CT or MRI to predict the need for extended resections is limited. Similarly, all noninvasive methods to determine the nodal status (N) are valuable, but mediastinoscopy has a greater sensitivity and specificity than either CT or MRI. The role of routine organ screening for the detection of distant occult metastasis in the asymptomatic patient is still controversial. Ultimately, the prognosis of the resected patient with lung cancer is based on complete intraoperative staging, which can be done by either systematic node sampling or complete lymphadenectomy. At present, neither of these techniques has been shown to improve the quality of staging or survival.

Imaging plays an integral role in diagnosing, staging, and following patients with lung cancer. Most lung tumors are detected on chest radiographs, but unfortunately, the majority of patients have advanced stage disease at presentation. There is a wide spectrum of radiologic manifestations of lung cancer, and recognition of these findings is essential for patient management. As we continue to understand more about tumor biology, new imaging techniques should emerge and have the potential to significantly improve our diagnostic capabilities.

The histopathologic appearance of lung carcinoma remains an important guide to prognosis and treatment. The newly revised World Health Organization classification retains the broadest pathologic categories of the older classification but includes several revisions, including the elimination of the small cell, intermediate cell type category; the addition of large cell neuroendocrine and spindle/giant cell categories; and an extended consideration of preneoplastic lesions. The histopathologic classification of lung cancer is expected to continue to change as clinical practice and biological understanding of these tumors change. The application of immunohistochemical testing to histologic material not only provides new assistance with conventional histologic classification, but also permits new ways to subclassify tumors, the full clinical significance of which is yet to be realized. The significance of expression of neuroendocrine markers, histologic grading of response to chemotherapy, and delineation of morphologic changes preceding the occurrence of invasive carcinoma are all areas where understanding microscopic cellular changes in the airways will be critical for clinical advance.

Lung cancer is an epidemic disease that is underrepresented in the research funding for early detection and chemoprevention arenas. Screening programs have been discouraged for both financial and political reasons. Yet, increasing evidence suggests that screening and early detection may improve outcome in lung cancer. Sputum cytology examination has been shown in several studies to lead to detection of lung cancer at an earlier stage, resulting in an improved 5-year survival rate. Monoclonal antibody detection, fluorescence bronchoscopy, and low-dose spiral CT increase diagnostic sensitivity and improve the ability to localize early-stage lesions. Utilizing these new techniques and improving the definition of high-risk groups may improve the success and cost-effectiveness of early detection based on sputum cytology. The ultimate goal of improving long-term survival in lung cancer will be achieved only when cancer can be detected in its early stages and lesions can be localized in large numbers. Advances in the last 15 years offer an encouraging vision for the value of early detection and effective treatment for lung cancer.

The anti-inflammatory cytokines are a series of immunoregulatory molecules that control the proinflammatory cytokine response. Cytokines act in concert with specific cytokine inhibitors and soluble cytokine receptors to regulate the human immune response. Their physiologic role in inflammation and pathologic role in systemic inflammatory states are increasingly recognized. Major anti-inflammatory cytokines include interleukin (IL)-1 receptor antagonist, IL-4, IL-6, IL-10, IL-11, and IL-13. Specific cytokine receptors for IL-1, tumor necrosis factor-alpha, and IL-18 also function as proinflammatory cytokine inhibitors. The nature of anti-inflammatory cytokines and soluble cytokine receptors is the focus of this review. The current and future therapeutic uses of these anti-inflammatory cytokines are also reviewed.

COPD is easily detected in its preclinical phase using spirometry, and successful smoking cessation (a cost-effective intervention) prevents further disease progression. This consensus statement recommends the widespread use of office spirometry by primary-care providers for patients >/= 45 years old who smoke cigarettes. Discussion of the spirometry results with current smokers should be accompanied by strong advice to quit smoking and referral to local smoking cessation resources. Spirometry also is recommended for patients with respiratory symptoms such as chronic cough, episodic wheezing, and exertional dyspnea in order to detect airways obstruction due to asthma or COPD. Although diagnostic-quality spirometry may be used to detect COPD, we recommend the development, validation, and implementation of a new type of spirometry-office spirometry-for this purpose in the primary-care setting. In order to encourage the widespread use of office spirometers, their specifications differ somewhat from those for diagnostic spirometers, allowing lower instrument cost, smaller size, less effort to perform the test, improved ease of calibration checks, and an improved quality-assurance program.

AIDS-related Kaposi's sarcoma (KS) occurs principally in homosexual or bisexual men infected with the newly identified human herpes virus-8, also called KS-associated herpes virus. Unlike classical forms of the disease, AIDS-associated KS is a multicentric entity that frequently involves lymph nodes and the GI tract. KS may also occur in the lung, commonly in the setting of extensive mucocutaneous disease and very rarely as an isolated event. The exact incidence of intrathoracic KS in patients with AIDS is unknown. Before the advent of highly active antiretroviral therapy (HAART), pulmonary KS had been reported in approximately 10% of patients with AIDS, 25% of patients with cutaneous KS, and in roughly 50% of postmortem examinations of patients with AIDS, KS, and respiratory infections. In the HAART era, the incidence of KS has declined precipitously in North America and Europe but not in third world countries where HAART is largely unavailable. Pulmonary KS may cause radiographic infiltrates and respiratory symptoms that mimic a variety of other infectious and neoplastic processes. An aggressive diagnostic evaluation of patients who have this condition is essential because chemotherapy and radiation therapy may provide significant palliation, particularly if used in conjunction with HAART. This review briefly explores the changing epidemiology of KS. The pathology and pathogenesis of KS is also reviewed, along with the clinical and radiographic presentation, diagnosis, and management of pulmonary KS.

Fever is a common problem in ICU patients. The presence of fever frequently results in the performance of diagnostic tests and procedures that significantly increase medical costs and expose the patient to unnecessary invasive diagnostic procedures and the inappropriate use of antibiotics. ICU patients frequently have multiple infectious and noninfectious causes of fever, necessitating a systematic and comprehensive diagnostic approach. Pneumonia, sinusitis, and blood stream infection are the most common infectious causes of fever. The urinary tract is unimportant in most ICU patients as a primary source of infection. Fever is a basic evolutionary response to infection, is an important host defense mechanism and, in the majority of patients, does not require treatment in itself. This article reviews the common infectious and noninfectious causes of fever in ICU patients and outlines a rational approach to the management of this problem.

Endothelial apoptosis can be found in a number of diseases. This review summarizes the current knowledge about the causes and consequences of endothelial apoptosis, and analyzes its possible role in the pathogenesis and treatment of several diseases. Novel forms of therapy based on the proposed pathophysiologic mechanisms are discussed.

There are large reported differences for the carboxyhemoglobin (COHb) half-life (COHb t(1/2)) in humans breathing 100% atmospheric O(2) following CO inhalation in tightly controlled experiments compared to the COHb t(1/2) observed in clinical CO poisoning (range, 36 to 131 min, respectively). Other reports have suggested that the COHb t(1/2) may be affected by gender differences, age, and lung function. We wished to test the hypothesis that the COHb t(1/2) might also be influenced by CO poisoning vs experimental CO exposure, by a history of loss of consciousness (LOC), concurrent tobacco smoking, and by PaO(2). The purpose of the present study was to measure the COHb t(1/2) in a cohort of CO-poisoned patients and to determine if those listed factors influenced the COHb t(1/2).

Malnutrition in patients with COPD is associated with an impaired pulmonary status, reduced diaphragmatic mass, lower exercise capacity, and higher mortality rate when compared to adequately nourished individuals with COPD. Nutritional support may therefore be a useful part of their comprehensive care.

Tiotropium is a long-acting anticholinergic drug. Studies with cloned human muscarinic receptors show that tiotropium binds equally well to M(1), M(2), and M(3) receptors. However, it dissociates very slowly from M(1) and M(3) receptors compared with ipratropium, and more rapidly from M(2) receptors. Binding studies with [(3)H]tiotropium in human lung show that it is approximately 10-fold more potent than ipratropium. In vitro, tiotropium has a potent inhibitory effect against cholinergic nerve-induced contraction of airways. It dissociates extremely slowly, compared with the dissociation of atropine and ipratropium. Clinical studies with single doses of inhaled tiotropium confirm that it is a potent and long-lasting bronchodilator. Furthermore, it protects against cholinergic bronchoconstriction for > 24 h. Pharmacokinetic studies show that little of the inhaled drug is absorbed, thus predicting a high margin of safety.