Lung cancer is usually suspected in individuals who have abnormal chest radiograph findings or have symptoms caused by either local or systemic effects of the tumor. The method of diagnosis of suspected lung cancer depends on the type of lung cancer (ie, small cell lung cancer or non-small cell lung cancer), the size and location of the primary tumor, the presence of metastasis, and the overall clinical status of the patient. Achieving a diagnosis and staging are usually done in concert because the most efficient way to make a diagnosis often is dictated by the stage of the cancer. The best sequence of studies and interventions in a particular patient involves careful judgment of the probable reliability of a number of presumptive diagnostic issues, so as to maximize the sensitivity and to avoid performing multiple or unnecessary invasive procedures. In this article, we consider all manner of clinical presentations of lung cancer in light of currently available diagnostic procedures. Published data supporting a particular diagnostic approach is weighed based on the quality of the benefit as well as the estimated net benefit. Recommendations are graded in terms of strength to provide clinicians with guidance as to the most efficient and approach to the diagnosis of lung cancer in individual patients.

To determine the test performance characteristics of various modalities for the diagnosis of suspected lung cancer.

The preoperative physiologic assessment of a patient being considered for surgical resection of lung cancer must consider the immediate perioperative risks from comorbid cardiopulmonary disease, the long-term risks of pulmonary disability, and the threat to survival due to inadequately treated lung cancer. As with any planned major operation, especially in a population predisposed to atherosclerotic cardiovascular disease by cigarette smoking, a cardiovascular evaluation is an important component in assessing perioperative risks. Measuring the FEV(1) and the diffusing capacity of the lung for carbon monoxide (DLCO) measurements should be viewed as complementary physiologic tests for assessing risk related to pulmonary function. If there is evidence of interstitial lung disease on radiographic studies or undue dyspnea on exertion, even though the FEV(1) may be adequate, a DLCO should be obtained. In patients with abnormalities in FEV(1) or DLCO identified preoperatively, it is essential to estimate the likely postresection pulmonary reserve. The amount of lung function lost in lung cancer resection can be estimated by using either a perfusion scan or the number of segments removed. A predicted postoperative FEV(1) or DLCO < 40% indicates an increased risk for perioperative complications, including death, from lung cancer resection. Exercise testing should be performed in these patients to further define the perioperative risks prior to surgery. Formal cardiopulmonary exercise testing is a sophisticated physiologic testing technique that includes recording the exercise ECG, heart rate response to exercise, minute ventilation, and oxygen uptake per minute, and allows calculation of maximal oxygen consumption (.VO(2)max). Risk for perioperative complications can generally be stratified by .VO(2)max. Patients with preoperative .VO(2)max > 20 mL/kg/min are not at increased risk of complications or death; .VO(2)max< 15 mL/kg/min indicates an increased risk of perioperative complications; and patients with .VO(2)max < 10 mL/kg/min have a very high risk for postoperative complications. Alternative types of exercise testing include stair climbing, the shuttle walk, and the 6-min walk. Although often not performed in a standardized manner, stair climbing can predict .VO(2)max. In general terms, patients who can climb five flights of stairs have O(2)max > 20 mL/kg/min. Conversely, patients who cannot climb one flight of stairs have .VO(2)max < 10 mL/kg/min. Data on the shuttle walk and 6-min walk are limited, but patients who cannot complete 25 shuttles on two occasions will have .VO(2)max < 10 mL/kg/min. Desaturation during an exercise test has been associated with an increased risk for perioperative complications. Lung volume reduction surgery (LVRS) for patients with severe emphysema is a controversial procedure. Some reports document substantial improvements in lung function, exercise capability, and quality of life in highly selected patients with emphysema following LVRS. Case series of patients referred for LVRS indicate that perhaps 3 to 6% of these patients may have coexisting lung cancer. Anecdotal experience from these case series suggest that patients with extremely poor lung function can tolerate combined LVRS and resection of the lung cancer with an acceptable mortality rate and good postoperative outcomes. Combining LVRS and lung cancer resection should probably be limited to those patients with heterogeneous emphysema, particularly emphysema limited to the lobe containing the tumor.

This chapter describes the components of the initial evaluation for a patient either suspected or known to have lung cancer. The components of the initial evaluation are based on the recognized manifestations of localized lung cancer, ie, symptoms referable to the primary tumor, intrathoracic spread of lung cancer, and patterns of metastatic dissemination. Features of the history and physical signs may be useful indicators of the extent of disease. A standardized evaluation, relying on symptoms, signs, and routinely available laboratory tests, can serve as a useful screen for metastatic disease. Also described are the common features of the various paraneoplastic syndromes associated with lung cancer.

More than 150,00 patients a year present to their physicians with the diagnostic dilemma of a solitary pulmonary nodule (SPN) found either on chest radiography or chest CT. A thoughtful and timely workup of this finding is essential if lung cancer is to be recognized early and the chance for cure optimized. Based on the literature to date, recommendations are made for appropriate imaging modalities and diagnostic testing, as well as indications for obtaining preoperative tissue diagnosis for the patient with an SPN.

Although virtually all individuals with advanced lung cancer succumb to the disease, a substantial portion of individuals diagnosed at an earlier stage can be cured. This dichotomy has provoked interest in lung cancer screening. To date, randomized controlled trials of chest x-ray and sputum cytology have failed to demonstrate that screening with either modality decreases lung cancer mortality; neither of these technologies can be recommended. Early studies of lung cancer screening with low-dose CT (LDCT) appear promising; however, only data from observational studies are available. We recommend that individuals should only be screened with LDCT in the context of well-designed clinical trials.

To review the available data on the early detection of lung cancer, with a focus on three technologies: chest x-ray (CXR), sputum cytology, and low-dose CT (LDCT) scanning.

Lung carcinogenesis is a chronic and multi-step process resulting in malignant lung tumors. This progression from normal to neoplastic pulmonary cells or tissues could be arrested or reversed through pharmacologic treatments, which are known as cancer chemoprevention. These therapeutic interventions should reduce or avoid the clinical consequences of lung cancer by treating early neoplastic lesions before the development of clinically evident signs or symptoms of malignancy. Preclinical, clinical, and epidemiologic findings relating to different classes of candidate chemopreventive agents provide strong support for lung cancer prevention as an attractive therapeutic strategy. Smoking prevention and smoking cessation represent an essential approach to reduce the societal impact of tobacco carcinogenesis. However, even if all the goals of the national antismoking efforts were met, there still would be a large population of former smokers who would be at increased risk for lung cancers. Lung cancer also can occur in those persons who never have smoked. This article focuses on what is now known about pharmacologic strategies for lung cancer prevention. Randomized clinical trials using beta-carotene, retinol, isotretinoin or N-acetyl-cysteine did not show benefit for primary and tertiary lung cancer prevention. There is also evidence that the use of beta-carotene and isotretinoin for lung cancer chemoprevention in high-risk individuals may increase the risk for lung cancer, especially in individuals who continue to smoke. There is a need for relevant in vitro models to identify pathways that activate chemopreventive effects in the lung. An improved understanding of cancer prevention mechanisms should aid in the design of clinical trials and in the validation of candidate chemopreventive targets as well as the discovery of new targets. Until such studies are completed, no agent or combination of agents should be used for lung cancer prevention outside of a clinical trial.

To describe empiric research related to lung cancer prevention strategies, including chemoprevention aimed at reducing lung cancer incidence and various smoking avoidance and cessation interventions aimed at reducing smoking rates.

In the United States, lung cancer remains the leading cause of cancer death in both men and women even though an extensive list of risk factors has been well-characterized. Far and away the most important cause of lung cancer is exposure to tobacco smoke through active or passive smoking. The reductions in smoking prevalence in men that occurred in the late 1960s through the 1980s will continue to drive the lung cancer mortality rates downward in men during the first portion of this century. This favorable trend will not persist unless further reductions in smoking prevalence are achieved.

To provide an evidence-based background for developing the American College of Chest Physicians (ACCP) lung cancer guidelines, a systematic review of the literature was performed to identify published lung cancer guidelines and evaluate their quality.

We describe a case of a 30-year-old man who developed a recurrent pleural effusion after sustaining a gunshot wound to the left side of his chest with subsequent complete paralysis at the T2 level. Subarachnoid-pleural fistulas have rarely been reported as complications of penetrating and blunt trauma, thoracic surgery, as well as spinal surgery. Concomitant injuries may overshadow or complicate the diagnosis of subarachnoid-pleural fistulas. The diagnosis should be considered in any patient with a pleural effusion that is associated with severe neurologic injury, as the fistula rarely heals without surgical intervention and may lead to CNS infection or pneumocephalus.

Nosocomial pneumonia is the second most frequent nosocomial infection and represents the leading cause of death from infections that are acquired in the hospital. In the last decade, a large body of data has accumulated that points to the substantial impact of inadequate antibiotic treatment as a major risk factor for infection-attributed mortality in ventilator-associated pneumonia (VAP) patients. In most instances, high-risk pathogens (eg, highly resistant Gram-negative bacilli, such as Pseudomonas aeruginosa and Acinetobacter spp, as well as methicillin-resistant staphylococci) are the predominant microorganisms causing excess mortality. Among various risk factors for mortality from VAP, which include the severity of the underlying disease and the degree of functional physiologic impairment caused by the pulmonary infectious process, only inappropriate antibiotic therapy is directly amenable to modification by clinicians. Secondary modifications of an initially failing antibiotic regimen do not substantially improve the outcome for these critically ill patients. Therefore, the best approach for reducing infection-related mortality seems to be the initial institution of an adequate and broad-spectrum antibiotic regimen in severely ill patients, which should be modified in a de-escalating strategy when the results from microbiologic testing become available. To circumvent the inherent danger of the emergence of resistance in ICU patients, additional measures have to be implemented and tested in clinical trials to reduce antibiotic consumption, shorten the duration of antibiotic treatment, and reduce the selection pressure on the ICU flora. This latter goal could be met by new antibiotic strategies including scheduled changes of recommended empiric antibiotic regimens at fixed intervals on a rotating basis.

A number of hormones, including hypothalamic neuropeptides acting as neurotransmitters and neuromodulators in the CNS, are involved in the physiologic regulation of breathing and participate in adjustment of breathing in disease. In addition to central effects, some hormones also control breathing at peripheral chemoreceptors or have local effects on the lungs and airways. Estrogen and progesterone seem to protect from sleep-disordered breathing, whereas testosterone may predispose to it. Progesterone and thyroxine have long been known to stimulate respiration. More recently, several hormones such as corticotropin-releasing hormone and leptin have been suggested to act as respiratory stimulants. Somatostatin, dopamine, and neuropeptide Y have a depressing effect on breathing. Animal models and experimental human studies suggest that also many other hormones may be involved in respiratory control.

Lymphoid interstitial pneumonia (LIP) is regarded as both a disease and a nonneoplastic, inflammatory pulmonary reaction to various external stimuli or systemic diseases. It is an uncommon condition with incidence and prevalence rates that are largely unknown. Liebow and Carrington originally classified LIP as an idiopathic interstitial pneumonia in 1969. Although LIP had since been removed from that category, the most recent consensus classification sponsored by the American Thoracic Society and the European Respiratory Society recognizes that some cases remain idiopathic in origin, and its clinical, radiographic, and pathologic features warrant the return of LIP to its original classification among the idiopathic interstitial pneumonias. LIP also belongs within a spectrum of pulmonary lymphoproliferative disorders that range in severity from benign, small, airway-centered cellular aggregates to malignant lymphomas. It is characterized by diffuse hyperplasia of bronchus-associated lymphoid tissue. The dominant microscopic feature of LIP is a diffuse, polyclonal lymphoid cell infiltrate surrounding airways and expanding the lung interstitium. Classically, LIP occurs in association with autoimmune diseases, most often Sjögren syndrome. This has led to consideration of an autoimmune etiology for LIP, but its pathogenesis remains poorly understood. Persons who are seropositive for HIV, and children in particular, are at increased risk of acquiring LIP. Some studies suggest causal roles for both HIV and Epstein-Barr virus. The incidence of LIP is approximately twofold greater in women than men. The average age at diagnosis is between 52 years and 56 years. Symptoms of progressive cough and dyspnea predominate. There is great variability in the clinical course of LIP, from resolution without treatment to progressive respiratory failure and death. Although LIP is often regarded as a steroid-responsive condition, and oral corticosteroids continue to be the mainstay of therapy, response is unpredictable. Approximately 33 to 50% of patients die within 5 years of diagnosis, and approximately 5% of cases of LIP transform to lymphoma.

Experimental methods to quantify alveolar fluid clearance have been adapted for our studies in patients with acute lung injury (ALI) or ARDS. We recently completed a study of 79 patients with ALI/ARDS that was designed to examine alveolar fluid clearance in the setting of alveolar epithelial injury from ALI/ARDS. Pulmonary edema fluid and plasma were sampled serially in the first 4 h after endotracheal intubation and the initiation of positive-pressure ventilation. Net alveolar fluid clearance was calculated from sequential edema fluid protein measurements. Patients with maximal alveolar fluid clearance had a significantly lower mortality rate and a shorter duration of mechanical ventilation. Several mechanisms may account for the decrease in the rate of alveolar fluid clearance in ALI/ARDS patients, including hypoxia, reactive oxygen species, reactive nitrogen species, and the loss of an intact epithelial barrier in the distal airspaces of the lung. Despite the epithelial injury in patients with ALI/ARDS, some experimental studies have suggested that alveolar fluid clearance could be increased with therapy using cyclic adenosine monophosphate agonists or other pharmacologic agents.

Pulmonary fibrosis is a component of over 200 interstitial lung diseases. Some have known etiologies, however, for many diseases, the etiology remains unknown or obscure. This brief review examines the prevalence and classification of these diseases, the approach to be taken for the investigation of a patient suspected of having pulmonary fibrosis, the indications for the performance of lung biopsy, and current thoughts concerning the pathogenesis of the idiopathic forms of fibrotic lung disease. A brief review of established and emerging therapeutic strategies is included.

Substantial experimental evidence supports the idea that the fibroblast may play a significant role in the vascular response to injury, especially under hypoxic conditions. Fibroblasts have the ability to rapidly respond to hypoxic stress and to modulate their function to adapt rapidly to local vascular needs. Fibroblasts appear to be uniquely equipped to proliferate, transdifferentiate, and migrate under hypoxic conditions. Proliferative responses to hypoxia depend on the activation of Galpha(i) and Gq kinase family members, and on the subsequent stimulation of protein kinase C and mitogen-activated protein kinase family members. Extracellular nucleotides (eg, adenosine triphosphate [ATP]) are likely to be increased in the hypoxic adventitial compartment and can act as autocrine/paracrine modifiers of the hypoxia-induced proliferative response. The proliferative effects of ATP appear to be mediated largely through G-protein-coupled P2Y receptors in fetal and neonatal fibroblasts. Hypoxia, acting through Galpha(iota)-coupled pathways, also can directly up-regulate alpha-smooth muscle actin expression in fibroblast subpopulations, suggesting that hypoxia may play a direct role in mediating the "transdifferentiation" of fibroblasts into myofibroblasts in the vessel wall. In addition, chronic hypoxia causes stable (at least in vitro) phenotypic changes in fibroblasts that appear to be associated with changes in the signaling pathways used to elicit proliferation. However, it is also becoming clear that, similar to the heterogeneity described for vascular smooth muscle cells, numerous fibroblast subtypes exist in the vessel wall, and that each may respond in unique ways to hypoxia and other stimuli and thus serve special functions in response to injury. In fact, adventitia may be considered to be compartments in which cells with "stem-cell-like" characteristics reside. Future work is needed to determine more precisely the role of the fibroblast in the wide variety of vascular complications observed in many humans diseases, and in the genes and gene products that confer unique properties to this important vascular cell.

Goblet cell hyperplasia (GCH) has been established as a pathologic characteristic of mild, moderate, and severe asthma. Abnormalities in goblet cell number are accompanied by changes in stored and secreted mucin (MUC). The functional consequences of these changes in MUC stores and secretion can contribute to the pathophysiologic mechanisms for multiple clinical abnormalities in patients with asthma, including sputum production, airway narrowing, exacerbations, and accelerated loss in lung function. CD4(+) T cells and their T-helper type-2 cytokine products are important mediators of GCH, and MUC5AC is the dominant MUC gene that is expressed in goblet cells. The mechanism of cytokine-induced GCH, the relationships between MUC gene up-regulation and GCH, and the role of ion channels are all currently being explored. The process of working out the molecular mechanisms of GCH and goblet cell degranulation should provide new targets for novel therapeutic interventions. Such new treatments are urgently needed, because mucus hypersecretion is an important cause of morbidity and mortality in patients with asthma, and no specific treatments are available.