Despite reports of the clinical presentations and devastating consequences of paradoxical embolus (PDE) for more than a century, this diagnosis continues to be frequently missed. Because the prevalence of patent foramen ovale (PFO) is 27 to 35% in the normal population and the presence of deep vein thrombosis or pulmonary embolus may not be clinically obvious, a high suspicion for PDE is needed in the event of unexplained arterial occlusion. While contrast echocardiography and transcranial Doppler ultrasound have facilitated clinical recognition of PDE, the optimum approach to diagnosis requires clarification. Primary therapy for patients with PDE is anticoagulation, with thrombolytics considered in carefully selected individuals, but there is little published information regarding long-term treatment and outcomes. Prevention remains essential whenever possible. It is not yet defined whether prophylactic treatment of persons with recognized predispositions to PDE (eg, PFO and pulmonary hypertension) is beneficial.

The incidence of malignant pleural mesothelioma is increasing. Untreated, patients with this disease experience a rapid and horrendous clinical decline. Surgery plays a role in the diagnosis, staging, and treatment of this malignancy. Surgery, chemotherapy, and radiotherapy alone have been unable to achieve major improvements in survival for most patients. More recent phase II trials suggest that surgery, at one time a purely palliative approach, may have a potentially curative role when used in combination with chemotherapy and radiotherapy.

Malignant mesothelioma of the pleura occurs primarily in individuals who were exposed to asbestos either in the workplace or home. The incidence of malignant mesothelioma is rising and, reflective of the malignancy's long latency period, is expected to continue to increase into the next century. Current treatment measures, including surgery, radiation therapy, chemotherapy, intrapleural therapy, and combined-modality therapies, have had varying impacts on survival. This paper explores current trends in the treatment of malignant pleural mesothelioma.

Surgical resection remains an important form of treatment for pulmonary metastases from a variety of solid tumors. The most significant factors in selecting patients for operation include control of the primary tumor, ability to resect all metastatic disease, absence of extrathoracic metastases, lack of better alternative systemic therapy, and sufficient cardiopulmonary reserve for the planned resection. A solitary pulmonary nodule and long tumor doubling times and disease-free intervals usually define patients who experience better long-term survival after pulmonary resection but do not constitute absolute criteria by which to select such patients. Complete surgical resection is critical to achieving long-term survival and is best accomplished via a standard or "clamshell" thoracotomy or a median sternotomy. The decision to proceed with the surgical resection of pulmonary metastases should be a multidisciplinary one, made jointly by the thoracic surgeon and the medical oncologist.

Treatment of lung cancer remains frustrating. Most patients with lung cancer are not candidates for curative therapy, and new therapies have not made a substantial impact on survival. Consequently, some clinical investigators have focused their efforts on developing prevention strategies. Chemoprevention, the administration of agents to block or reverse carcinogenesis, is being investigated in ongoing trials. Studies of chemoprevention in lung cancer have included trials to reverse premalignant lesions such as sputum atypia or squamous metaplasia of the bronchial epithelium. Clinical trials of lung cancer prevention have often studied groups of participants with tobacco or asbestos exposure. Other clinical trials are being conducted among patients who have been treated for an early-stage lung cancer. As the result of diffuse epithelial injury, these patients are at very high risk for developing second primary tumors, predominantly in the lungs and upper aerodigestive tract. It is our hope that these studies may establish a new strategy for preventing lung cancer.

With lung resection remaining the cornerstone of curative therapy in patients with lung cancer, aggressive perioperative management continues to play a critical role. This review summarizes the most important factors in successful perioperative management. These include patient selection, with an emphasis on which patient variables and hemodynamic assessments are most useful in determining operability. Postoperative management, in particular, patient-controlled analgesia, and pulmonary toilet, are essential to facilitate early patient mobility and to minimize complications, respectively. Aggressive perioperative management can result in reduced postoperative morbidity and mortality, reduced length of hospital stay and expenditures for complications, and it expands the population that can receive potentially curative therapy.

The identification of new chemotherapeutic agents for the treatment of non-small cell lung cancer should proceed in a structured, logical fashion. Agents should be evaluated on the basis of multiple objective and subjective end points. A 15% or greater major objective response rate, demonstrated in multiple single-agent phase II trials, is considered the lower limit for an agent to be deemed clinically active in this disease. A number of drugs previously have been identified in this category, including cisplatin, ifosfamide, mitomycin, paclitaxel, and the vinca alkaloids vinblastine and vindesine. Most of these conventional agents have been explored alone, in a variety of doses and schedules, and in combination. In the last several years clinical development has produced new agents, including chloroquinoxaline sulfonamide, docetaxel, edatrexate, gemcitabine, irinotecan, topotecan, and vinorelbine, which hold promise for more successful treatment of this lethal disease.

Radiologic evaluation of the patient with non-small cell lung cancer (NSCLC) includes chest radiographs for detecting nodules, computed tomography (CT) for further characterizing them, CT and magnetic resonance imaging (MRI) to evaluate the mediastinum, and extrathoracic imaging of bones, the adrenal gland, the central nervous system, and liver. The current practice standards for each are reviewed. Asymptomatic solitary pulmonary nodules, which are usually detected on chest radiographs obtained for other indications, inevitably require a precise diagnosis. The radiologic characteristics that differentiate benign from malignant pulmonary lesions are given. Mediastinal CT is the preferred modality for examining the mediastinum in patients with NSCLC. Magnetic resonance imaging is used selectively, eg, in patients with superior sulcus tumors who are candidates for surgery. When evaluation for N2/N3 disease is requested, mediastinoscopy should replace CT using the latter as a "roadmap." The role of extrathoracic imaging in evaluating asymptomatic patients with NSCLC at initial presentation is equivocal. Computed tomographic scanning of the head is reasonable in most patients with lung cancer, given the significant incidence of occult brain metastases in this population and that solitary brain lesions may be resected in some protocol settings. Routine liver and adrenal gland scanning is similarly controversial. Bone scans do not appear to be useful in patients with NSCLC unless they have clinical signs, symptoms, or laboratory findings to indicate possible metastases. Although heavily affected by local practice, radiologic evaluation of the patient with NSCLC should attempt to provide accurate determination of local disease and a search for distant metastases.

A wide range of genetic and phenotypic abnormalities have been identified in lung cancer. However, only a few are known to have an impact on patient outcome and thus may influence choice of therapy. Biologic and molecular factors known in this regard include the epidermal growth factor family and its receptors, markers of neuroendocrine differentiation in non-small cell lung cancer, and mutations of the ras gene family. None of these factors, however, can be considered a standard for selection of patients for therapy until additional information is gleaned from ongoing prospective studies.

Better early detection strategies for lung cancer are clearly needed. About 20 years ago, cytomorphologic criteria were developed for use in staging bronchial epithelium carcinoma. Yet, when sputum cytology was added to chest radiograph in the largest early-screening-of-lung-cancer study carried out to date, the three-arm trial sponsored by the National Cancer Institute, no major outcome benefit was shown. Sputum samples of participants in one of these trials, the Johns Hopkins Lung Project, have been archived. Currently, sputum immunostaining using two monoclonal antibodies directed at a difucosylated Lewis X epitope and a 31-kilodalton protein show correlation between positive staining of these samples and eventual development of lung cancer in the sampled population. Strategies to neutralize the stimulation of growth factors like gastrin-releasing peptide, which are seen in small-cell disease, are also being explored. Development of an epithelial-directed diagnostic test is the most important goal in obtaining early detection tools for lung cancer. Several new tests await prospective trials to evaluate their utility. In developing an early detection test for lung cancer, due to the chronic nature of the risk and the vast at-risk population, cost and patient compliance are two major concerns.

It is believed that population-based screening for cancer should be advocated only when screening reduces disease-specific mortality. Four randomized controlled studies on lung cancer screening have been conducted in male cigarette smokers, and none has demonstrated reduced mortality. Accordingly, no organization that formulates screening policy advocates any specific early detection strategies for lung cancer. Yet, despite this public policy against screening, there is considerable evidence that chest x-ray screening is associated with earlier detection and improved survival. Two randomized trials, the Memorial Sloan-Kettering and Johns Hopkins Lung Projects, were specifically designed to evaluate the effectiveness of sputum cytologic study. Both evaluated the efficacy of the addition of sputum cytologic studies to annual chest radiographs, and both demonstrated that cytologic study did not favorably influence outcome. All individuals in experimental and control groups in both studies had annual chest radiographs. Because survival rates observed in both studies were about three times higher than predicted, based either on the National Cancer Institute's Surveillance Epidemiology and End Results database or based on the American Cancer Society's annual Cancer Statistics, raises the possibility that the periodic chest radiographs performed in all patients in both studies contributed to an improved outcome. In the Mayo Lung Project and in the Czechoslovak study on lung cancer screening, the experimental groups underwent a program of relatively intensive and regular rescreening with chest radiographs and sputum cytologic study, while the control groups underwent either less-frequent rescreening or no rescreening. In both studies, the screened groups achieved meaningful improvements in stage distribution, resectability, and survival. However, increases in cumulative incidence of lung cancer in the experimental group in both studies (which in the Mayo Lung Project reached statistical significance) prevented significant improvements in survival from translating into corresponding reductions in mortality. The possibility that screening may be associated with lung cancer "overdiagnosis" has been widely postulated to account for higher survival and incidence rates and equivalent mortality rates. However, analysis of autopsy information and of disease outcome in individuals with screen-detected early stage lung cancer who do not undergo surgical resection strongly supports the conclusion that screening does not lead to overdiagnosis of lung cancer. Similarly, lead-time and length bias do not adequately account for the differences in cumulative incidence observed in the Mayo and Czech studies.(ABSTRACT TRUNCATED AT 400 WORDS)

Enhancement of dose and dose intensity increases tumor response and may enhance long-term progression-free survival in patients with small cell lung cancer. Several strategies are identified to intensify therapy safely: a traditional induction/intensification mode, in which high-dose therapy with hematopoietic stem cell support is used to treat patients responding to conventional-dose therapy; and multicycle dose-intensive approaches, in which higher-dose therapy is administered over multiple cycles at initiation of therapy. This paper reviews some of the recently completed and activated trials (particularly those developed at the Dana-Farber Cancer Institute) exploring these concepts.

Chemotherapy remains the mainstay of treatment for small cell lung cancer (SCLC). For patients with limited-stage disease, the addition of thoracic radiotherapy confers a moderate improvement in local control and a modest survival benefit, but these improvements come at the cost of increased toxic reactions. The optimal method for integrating chemotherapy and thoracic radiotherapy is unresolved. Concurrent and alternating strategies are appealing because they allow uninterrupted delivery of chemotherapy, but they have not been proven to be superior to conventional sequential approaches. Based on limited data, delivery of thoracic radiation early in the treatment course may be preferable to delivery later in the course. There is evidence of a radiation dose-response effect for SCLC, and, in standard regimens, thoracic radiation doses in the range of 50 to 60 Gy are recommended. The use of limited radiation fields (to postchemotherapy tumor volumes) appears reasonable. Results for alternative thoracic radiation fractionation schedules such as accelerated hyperfractionation are promising and worthy of further investigation. The role of prophylactic cranial irradiation (PCI) is controversial and should be individualized. It should be considered for the favorable subgroup of patients with limited-stage disease who achieve a complete response to chemotherapy and thoracic radiotherapy. If given, we recommend a total dose of 30 to 36 Gy in 2-Gy fractions; PCI should not be delivered concomitantly with chemotherapy.

In the United States, small cell lung cancer (SCLC) accounts for about 20% of all cases of lung cancer. Without treatment, tumor progression in patients with SCLC is rapid, with a median survival of 2 to 4 months. Modern chemotherapy has yielded multifold increases in median survival, but only minimal improvements have occurred over the last decade. Combination chemotherapy with etoposide/cisplatin prolongs survival, especially in patients with limited disease. In patients at high risk of toxicity from standard combination chemotherapy, single-agent chemotherapy may have a viable role, but whether its efficacy is comparable to combination regimens must be established in clinical trials. Clearly, new, more effective drugs will be required for any major improvements in the treatment of SCLC. Combined-modality therapy employing chemotherapy and chest irradiation appears to produce excellent cytotoxic effects and is relatively well tolerated in patients with limited disease. A recent meta-analysis of 13 randomized trials showed a modest but significant 14% reduction in the relative mortality rate of patients receiving chemotherapy/chest irradiation vs those receiving chemotherapy alone. Surgery as sole treatment can produce cures in highly selected patients with limited disease and can reduce the rate of local recurrence. The use of surgery after definitive treatment remains experimental and should not be considered other than in controlled clinical trials.

Radiotherapy (RT) in conjunction with surgery may have a number of roles in the treatment of patients with potentially resectable esophageal carcinoma. The use of RT alone either preoperatively or postoperatively can be expected to improve resectability rates only modestly. The risk of locoregional failure, a common problem in esophageal carcinoma, has been substantially reduced with preoperative or postoperative RT in trials with a duration of follow-up of 3 or more years, although this effect has not been seen in trials with shorter follow-up. Because of the high risk of distant failure associated with these tumors and perhaps because of the inadequate doses used, most trials of RT have not shown notable improvements in overall survival rates. The risk of severe complications following preoperative or postoperative RT is small, provided that very high doses or fraction sizes are avoided. Concurrent chemotherapy and RT administration have been shown to be superior to RT alone in patients who have medically or surgically inoperable conditions; randomized trials using this combined modality in patients with resectable disease have only recently begun. In addition to evaluating the efficacy of this approach, investigators hope to establish the optimal sequencing and timing of administration of these modalities with regard to each other and to surgery.