Following the cloning of the cystic fibrosis (CF) gene, in vitro studies rapidly established the feasibility of gene therapy for this disease. Unlike ex vivo approaches that have been utilized for other genetic diseases such as adenosine deaminase deficiency, gene therapy for CF will likely require direct in vivo delivery of gene transfer vectors to the airways of patients with CF. Hence, major research efforts have been directed at the development of efficient gene transfer vectors that are safe for use in human subjects. Several vectors have now emerged from the laboratory for evaluation in clinical safety and efficacy trials in the United States and in the United Kingdom. Adenovirus-mediated gene transfer has been utilized for initial clinical safety and efficacy trials in the United States, while liposome-mediated gene transfer has been chosen for initial clinical safety and efficacy trials in the United Kingdom. The rationale and laboratory studies are reviewed leading to initial clinical safety and efficacy trials. Also reviewed are the currently available vectors for potential use in clinical studies, their advantages and disadvantages, and the promises and pitfalls of current gene therapy efforts for CF in the United States focusing on adenovirus vectors in current clinical trials.

Cystic fibrosis (CF) is a recessive genetic disease reflecting mutations in the gene coding for the CF transmembrane regulator (CFTR) protein, which normally functions as a cyclic adenosine monophosphate (cAMP)-regulated chloride (Cl-) channel. Functional abnormalities include thick airway secretions resulting from defective cAMP-mediated Cl- (liquid) secretion and a related defect, excessive sodium (Na+) (liquid) absorption. Novel pharmacologic agents are being tested as therapy for these ion transport defects. Aerosolized amiloride inhibits excessive Na+ absorption, and pilot studies in adult patients with CF show slowing of the disease-associated decline in lung function. Clinical trials of amiloride are currently underway in adults and adolescents, and short-term safety studies have been initiated in children. Aerosolized uridine triphosphate (UTP) induces Cl- (and liquid) secretion in CF airway epithelia via non-CFTR Cl- channels. Short-term aerosolized UTP is well tolerated by normal subjects and patients with CF, and pilot studies in normal subjects show that aerosolized UTP is an effective stimulator of mucociliary clearance. Pharmacotherapy that modifies airway epithelial ion transport may provide new opportunities for treatment of CF lung disease.

Respiratory symptoms, recurrent infectious exacerbations, and progressive lung destruction in cystic fibrosis can be attributed to bacterial persistence and the accumulation of viscous purulent secretions in the airways. Purulent secretions contain high concentrations of extracellular DNA, a viscous material released by leukocytes. To evaluate the potential clinical utility of recombinant human DNase I (rhDNase or Pulmozyme), the human enzyme was cloned, sequenced, and expressed. In in vitro studies, rhDNase has been shown to reduce the viscoelasticity, reduce the adhesiveness, and improve the mucociliary transportability of cystic fibrosis sputum. In short-term phase 1 and phase 2 clinical trials, rhDNase has been shown to be safely tolerated and to improve the FEV1, FVC, and symptoms of dyspnea. A long-term placebo-controlled phase 3 study was performed in 968 adults and children (> or = 5 years) with cystic fibrosis to determine the effect of rhDNase on the risk of respiratory exacerbations requiring parenteral antibiotics and on the FEV1. Compared with placebo-treated patients, patients treated with rhDNase once daily or twice daily experienced a reduced risk of respiratory exacerbations by 28% (p = 0.04) and 37% (p = 0.01), respectively, and had a mean improvement in FEV1 of 5.8% (p < 0.01) and 5.6% (p < 0.01), respectively. Compared with placebo-treated patients, patients treated with rhDNase spent 2.7 fewer days receiving parenteral antibiotics (p = 0.04) and spent 1.3 fewer days in the hospital (p = 0.06) over the 6-month treatment period. Inhalation of rhDNase did not cause anaphylaxis but was associated with upper airway symptoms (ie, voice alteration, hoarseness, pharyngitis) that were generally mild and transient. In conclusion, aerosol administration of rhDNase was safely tolerated, reduced the risk of infectious exacerbations requiring parenteral antibiotics, and improved pulmonary function and patient well-being.

Aerosolized tobramycin is well tolerated in children and adults with cystic fibrosis (CF). It represents a potential alternative to intravenous administration of antibiotics to control respiratory infection with Pseudomonas aeruginosa. Although its exact role in acute therapy for a CF exacerbation is not known, it has been shown to improve lung function and reduce the frequency of exacerbations in the chronic stable outpatient.

Exercise-associated cardiac asystole (EACA) in patients without structural heart disease is uncommonly encountered. Two patients who developed prolonged asystolic arrest associated with exercise are described; both demonstrated a positive head-up tilt table response, absence of underlying heart disease, and a history of vagotonia. A review of this condition in the literature suggests the occurrence of this syndrome of EACA in young men with atheletic inclination who developed syncope usually after a strenuous exercise at a high heart rate. Although the described patients usually responded by avoiding maximal exercise and the use of beta-blockade, vagolytic agent, and permanent pacing, EACA may be the link for some cases of exercise-related asystolic deaths.

Lack of familiarity with pulmonary embolism (PE) thrombolysis is understandable because most hospitals treat just a few patients each year with recognized massive PE. Therefore, most physicians are inexperienced in administering PE thrombolysis, even though they utilize these agents routinely for acute myocardial infarction. Current estimates are that no more than 10% of patients with PE receive thrombolysis in the United States. This situation may be changing now, because PE thrombolysis appears to have expanded indications. Contemporary PE thrombolysis can now be given with simpler, less expensive protocols than were previously available. In the past, this treatment strategy had been rightly regarded as a heroic measure that consumed hospital resources and physicians' time. Today, PE thrombolysis can be applied with a 2 week "time window," no mandatory angiography in many cases, a brief infusion through a peripheral vein, and no special laboratory tests.

The diagnosis of pulmonary embolism (PE) can be accurately made by perfusion lung scan and pulmonary angiography; however, when these diagnostic techniques are not promptly available, simple clinical procedures may be useful to identify patients with high probability PE. To this end, collection of clinical data through a standardized questionnaire and the use of findings from chest radiograph, ECG, and blood gas analysis may raise clinical suspicion and decide on therapeutic management. By reviewing published literature and our own experience, we found that unexplained dyspnea and chest pain are the most frequent symptoms, and sudden onset dyspnea and pleuritic chest pain are the most typical. Chest radiograph is abnormal in more than 80% of patients with PE, showing typical signs such as "sausage-like" descending pulmonary artery, Westermark sign, etc. The ECG may show findings characteristic of PE, such as tachycardia, T wave inversion in V1-V2, and PR displacement. Arterial blood gas data frequently demonstrate hypoxia and hypocapnia, being helpful in suspecting or excluding PE. Recent statistical techniques, such as discriminant or logistic analysis, may be applied to the above clinical assessment to refine and improve the noninvasive diagnosis of PE.

Pulmonary embolism (PE) is largely undiagnosed because clinical suspicion is not raised in most instances, and thus, patients with PE go undetected. In this paper, we try to define the role of clinical assessment (including chest radiography, electrocardiogram, arterial blood gas analysis) in making the diagnosis early, accurate, and at low cost, and propose a flow chart to be used in clinical practice. All patients with otherwise unexplained dyspnea or chest pain should be sent for perfusion lung scintigraphy; accordingly, underdetection of PE and mortality of PE should be reduced. If, within 1 h after the clinical suspicion has been raised, the above-mentioned simple and noninvasive examinations are available, they may be employed to reduce the number of unnecessary procedures, without losing patients actually affected by PE. Finally, when diagnostic tools are not promptly available, noninvasive techniques may be employed to identify patients with the highest probability of PE where to start with heparin coverage while waiting for definitive diagnosis.

Pulmonary embolism (PE) is still underdiagnosed even in hospitalized patients. In our recent experience, out of 92 postmortem cases of massive or submassive PE, only 28% were diagnosed before death, whereas the false-positives accounted only for 3% of cases. Similar conclusions have been drawn from large-scale autopsy studies performed in Norway and in the United States. The most important causes of an incorrect diagnosis are failure to suspect PE, and the protean nature of the disease. Remarkable differences actually exist concerning the point of origin and the final localization, as well as the size and age of thromboemboli, the presence or absence of pulmonary infarction, and the underlying pathology. Often a fatal embolus is relatively small but hardly tolerated because of the underlying cardiopulmonary situation. Attention should be called to the frequent autopsy finding of multiple PEs and pulmonary infarctions of apparently different age. This finding is important since it indicates that these patients suffered successive embolizations and the eventual death might have been prevented if an early diagnosis had been made.

The incidence of pulmonary thromboembolism is hard to assess by the pathologist as a result of seasonal variation of embolism and disappearance of emboli by thrombolysis. However, the great differences in estimates of the incidence in routine hospital autopsies is mainly related to variation in scrutiny of the investigation and in size of area searched microscopically. Obstruction of major pulmonary arteries almost always results from thromboembolism which is most often found in its acute stage. In chronic major vessel embolism, arterial obstruction by an organized mass may produce pulmonary hypertension. Recanalization of such a mass results in so-called bands and webs. There are no reliable criteria to differentiate between emboli and primary thrombi or their sequelae. In peripheral, particularly muscular pulmonary arteries, thrombi are most likely primary, especially when associated with advanced age and with pulmonary hypertension. However, small arteries may be subject to extensive microembolism following fragmentation of large thromboemboli. Thrombotic arteriopathy is the pulmonary arterial disease based upon either primary thrombosis or embolism. It is often associated with pulmonary hypertension, and characterized by irregular, nonlaminar, often obliterative, intimal fibrosis. Recanalization channels, sometimes widening to separate intravascular fibrous septa, are characteristic features. Reversibility of post-thrombotic lesions is very limited.

Even since the Surgeon General's 1964 report, the mortality rate from lung cancer has continued to rise. Although there is evidence that this continued increase in mortality will slow or level in the next decade, lung cancer mortality is a major health problem destined to remain with us for at least the next generation. There have been no established advances in the early detection or prevention of lung cancer in the last 30 years and our therapies have increased the cure rate only from 5 to 13% in this 30-year interval. Biologic advances have outpaced clinical advances in recent times and many of the advances are now ripe for clinical exploitation. There are currently more exciting clinical trials for all phases of lung cancer than at any time and it will be stimulating to witness the results of the clinical trials discussed herein. Hopefully, the results of these studies will lead to a decrease in lung cancer mortality in the next century, much as it increased in the past century.

Non-small lung cancer (NSCLC) is a disease that exhibits multiple genetic lesions. Lung Cancer Study Group (LCSG) 871 was designed to analyze this group of malignancies for alterations in growth factors and/or their receptors, oncogenes, tumor suppressor genes, and immediate early transcription factor genes. Immunohistochemical analysis showed that 32% of evaluable cases studied contained absent or abnormal Rb expression. Sequence analysis of the p53 gene revealed that 58% of these cancers contained structural alterations of this gene, whereas only 45% of these cases overexpressed p53 by immunohistochemical analysis. Finally, both Northern blot and immunohistochemical analysis showed that these tumors exhibited changes in the mRNA and protein expression levels respectively of the immediate early transcription factor genes c-fos, c-jun, and EGR, in that less expression of these genes was evident in the tumors compared with adjacent normal tissue. Understanding both the biologic and molecular significance of these findings may allow us to explore novel modalities for treatment of this disease.