Three treatment options are available for management of the patient with a known thoracic mass and a solitary brain metastasis: external beam radiation, surgical resection, and stereotactic radiosurgery. Traditional external beam radiation may still represent the most appropriate choice in the management of patients with radiosensitive lesions who are in poor health or who have significant risk factors that prohibit other treatment choices. Surgery is recommended in the presence of significant edema, a large intracranial mass, significant symptoms requiring immediate attention, associated hemorrhage, and for superficial lesions. Finally, stereotactic radiosurgery, an important new technique whereby high doses of radiation are targeted directly to the mass, is recommended particularly for deep lesions that are difficult to reach surgically and for treatment of patients for whom surgery is contraindicated. Stereotactic radiosurgery has the added benefits of being noninvasive, effective, and repeatable in the presence of recurrence or other metastatic disease.

Superior pulmonary sulcus carcinoma, or Pancoast's tumor, was first identified in 1932 by H. K. Pancoast, who described a small tumor at the apex of the lung producing a characteristic pain pattern and rapid, universal mortality. Despite early indications that this type of carcinoma was amenable to neither radiation nor surgery, the current treatment approach calls for irradiation therapy (3,000 rad over 2 to 3 weeks) followed by surgical resection of the chest wall, lower brachial plexus, and en bloc resection of the lung. In selected patients with negative mediastinal nodes, this approach has been associated with a 34% 5-year and a 29% 10-year survival.

A careful preoperative assessment of patients with lung cancer is essential for identifying those at high risk for morbidity and mortality related to the surgical procedure. The clinician must assess the risk associated with such treatment, decide whether the risk is prohibitive, and institute therapy to reduce such risk. Testing modalities used in the preoperative evaluation include spirometry, full pulmonary function tests, measurement of arterial blood gases, radionuclide lung scanning, exercise testing, invasive measurement of pulmonary artery pressure, and a variety of studies involving lobar occlusion or lateral position testing. Studies evaluating the utility of these procedures are reviewed. Additionally, the impact of advanced age on postsurgical outcome is evaluated, as are the possibility of operating on high-risk patients and the use of preoperative interventions.

Thymomas are the most frequently encountered neoplasm of the anterior mediastinum. Thymic neoplasms can be divided into 3 broad categories based on histologic appearance and behavior. Thymomas are tumors with benign-appearing cellular features. If there is no gross or microscopic invasion beyond the capsule, the tumor is considered benign. Any tumor with gross or microscopic invasion through the capsule is considered malignant. In a third category, thymic tumors which have histologically malignant epithelial features, are considered thymic carcinomas and generally have an adverse prognosis. Microscopically, thymomas consist of a variable component of lymphocytic, epithelial, and fusiform (spindle) cell elements. The tumors may be classified according to the predominant cell type or are considered mixed if no cell type predominates. Prognosis is most strongly linked to clinical stage. The role of adjuvant radiotherapy or chemotherapy in the treatment of such tumors is controversial, but malignant thymomas are generally responsive to radiotherapy. Associated myasthenia gravis does not adversely affect the prognosis of thymoma, and medical attention to the myasthenia may contribute to earlier diagnosis of the thymoma. Cisplatin-based chemotherapy may be used to treat advanced disease with a modest response rate.

Improvements in cytologic techniques have made needle biopsy much more helpful in diagnosing mediastinal masses. We have added thoracoscopy to the surgical armamentarium. Tumor markers facilitate accurate diagnosis. In the field of imaging, cysts can now be identified almost certainly and aspirated. Magnetic resonance imaging has changed the workup of patients with posterior mediastinal masses. Staging investigations should be based on the type of tumor and the likelihood of spread.

The high incidence of central nervous system (CNS) failure in patients given chemotherapy for small-cell lung cancer led to the use of prophylactic cranial irradiation (PCI) to prevent the development of metastases. Seven randomized trials have investigated the use of PCI, 5 of which reported a statistically significant reduction in risk of CNS disease though none demonstrated improvement in overall survival. Recent reports have demonstrated the potential for severe toxicity with PCI, leading some investigators to recommend discontinuing its use, while others have suggested improvements in timing and dose fractionation. It appears that the subgroup of patients most likely to benefit from PCI are those with limited-stage disease in complete response after chemotherapy, in whom a reduction in the risk of CNS failure may translate into improved survival. The recommended radiation dose is 30 to 36 Gy in 2 Gy/day fractions.

Survival among patients with small-cell lung cancer (SCLC) appears to have improved over the last 15 years. However, 2- to 3-year survival is still only 10% to 25% for patients with limited disease and 1% to 2% for those with extensive disease. Moreover, relapse of SCLC and the development of other cancers are common in patients surviving beyond 2 years. Clearly, new innovative therapy is needed, and continued research with recently developed agents is warranted. Modern multimodality therapy may have a role in patients with surgically resectable stage I or II disease, but development of better chemotherapy, bone marrow transplantation, hyperfractionation radiotherapy, and radiosensitizers will be necessary for most SCLC patients. Recently discovered prognostic indicators should help target individual SCLC patients for specific intensive treatments designed to prolong survival and achieve a cure.

Hematopoietic growth factors regulate the production and differentiation of immature progenitor cells and activate mature effector cells. With recombinant DNA technology, these human proteins have been biosynthesized, and their clinical applications hold promise for beneficial therapeutic effects. The hematopoietic growth factors are generally classified in 2 groups, the colony-stimulating factors (CSFs) and the interleukins. In oncology, it has been shown that the administration of CSFs will attenuate chemotherapy-induced myelosuppression and permit administration of the planned chemotherapy doses, especially in chemosensitive tumors like small-cell lung cancer. Widespread clinical administration of the CSFs at this time without regard to the predicted risk of a given therapeutic regimen would seem to be inappropriate both therapeutically and economically. Continuing investigations should focus on important clinical end points. Until then, our ability to use the CSFs optimally, rationally, and in a cost-effective manner will remain limited.

Although systemic failure continues to plague patients receiving combined-modality treatment for limited small-cell lung cancer (SCLC), improvements in chemotherapy, including use of cisplatin/etoposide-based regimens, and radiotherapy have produced increases in median, 2-year, and 5-year survival over the last decade. Employing more conservative volumes of radiotherapy in more aggressive ways, today about 50% of SCLC patients will survive 2 years and 30%, 5 years. Moreover, integrating radiotherapy with chemotherapy early in the course of treatment can potentially eliminate resistant clones. The various factors in radiotherapy, including dose, volume, fractionation, and timing, therefore deserve scrutiny in the reporting and design of clinical trials.

Treatment of inoperable, regionally advanced non-small-cell lung cancer has been problematic, given the poor long-term results and toxicity of current treatment measures and the extensive comorbid disease commonly found in these predominantly elderly patients. The generally acknowledged standard of care has been administration of radiotherapy to the involved sites and nodal drainage sites. This may improve survival in patients with good prognostic factors. No modality, however, has demonstrated a clear benefit over the others in this setting. Of 13 randomized trials comparing radiotherapy with or without chemotherapy, 5 using non-cisplatin-containing regimens showed no benefit. However, 4 of 6 trials with cisplatin-containing regimens have shown modest benefit. Cisplatin given concurrently with radiotherapy on a daily basis was significantly better than radiotherapy alone and was associated with improved locoregional control, suggesting that the radiation sensitization properties of the drug and consequent local control may be important for enhanced survival. Determining relapse patterns of patients according to these and other treatment approaches may help guide future development of therapeutic options. Improvements in both local and systemic control will be required before a curative approach to treatment can be considered. In this regard, hyperfractionated radiotherapy or radiation sensitizers to enhance locoregional control may complement enhancement of systemic control with chemotherapy, especially if a balance can be struck between the efficacy and toxicity of these modalities.

Disappointing results of surgery and postoperative adjuvant chemotherapy or chemoradiotherapy in stage IIIA (N2) lung cancer have led to a number of phase II trials of induction (neoadjuvant) chemotherapy given prior to surgery. Preliminary results of 2 such studies indicate that mitomycin, vinca alkaloid, and platinum (MVP) given before surgical excision induces an overall response rate of 70% (9 complete responses and 71 partial responses in 112 patients). Of 80 patients who ultimately underwent surgery, complete resection was achieved in 62 (55%). Survival data reflect a median survival of 19.5 months for the entire cohort of 112 patients and 27 months for those who had complete resection. The 5-year-survival rate is expected to reach 15%. Randomized trials are now under way to establish whether this aggressive approach to therapy represents the most appropriate form of treatment for patients with stage IIIA (N2) lung cancer.

Continued development of adjuvant therapy strategies is required to improve chances of long-term survival in patients with resected non-small-cell lung cancer (NSCLC). Distant micrometastases comprise the bulk of failures in patients with resected stage I disease, although the risk of local failure increases in patients with stage II or IIIA disease, distant metastasis remains a critical problem. Optimum adjuvant treatment may require both radiotherapy and chemotherapy. Adjuvant radiotherapy has been shown to eliminate first failure in local sites in patients whose stage II or IIIA squamous cell carcinoma has been fully resected, without producing an overall improvement in survival. Adjuvant combination chemotherapy can delay time to recurrence significantly and improve failure-free survival, although once again, no statistically significant prolongation of survival has been observed. One trial combining sequential chemotherapy and radiotherapy reported a significant reduction in the incidence of distant metastases compared to treatment with radiation alone in patients with unresected stage III disease. Current and planned American trials have varied the timing, dose intensity, and scheduling of chemotherapy as well as the control arm employed. It is hoped that the results will demonstrate unequivocal benefit for adjuvant therapy in the management of patients with operable NSCLC.

Surgery has had little impact on long-term survival in patients with small-cell lung cancer (SCLC). With the evolution of modern techniques, however, surgery may play an increasingly valuable role in SCLC. Surgery may potentially cure a select minority of SCLC patients. Patients with peripheral nodules and those with regional disease achieving a complete response to chemotherapy may benefit from adjuvant surgical resection for removal of residual disease. In some cases, surgery may also be preferred over adjuvant radiotherapy, since the latter necessitates lowering the total chemotherapy dose administered to SCLC patients.

During the 1940s and 1950s, as many as 50% of thoracotomies identified nonresectable tumors. At present, better than 90% of patients undergoing thoracotomy for presumably resectable lung cancer are found to have operable tumors. This improvement is the result of major advances in the preoperative staging of this disease. Mediastinoscopy and computed tomography (CT) are the most valuable techniques for evaluating the mediastinum in patients with primary cancer of the lung. For each modality, the primary objective is to define the presence or absence of spread to mediastinal lymph nodes. In patients with non-small-cell lung cancer, surgical resection remains the treatment of choice so long as all recognizable tumor can be removed at operation. Both mediastinoscopy and CT provide critical information concerning the potential for a complete resection. Computed tomography remains the most effective noninvasive technique for the evaluation of mediastinal nodes.

Germ cell tumors are highly curable when treated appropriately. The majority of germ cell tumors arise in the testes, with a proportion having pulmonary parenchymal or mediastinal metastases. For patients who have such tumors, prompt diagnosis and treatment with chemotherapy are essential. A subset of these patients will have persistent radiographic abnormalities after chemotherapy and will benefit from post-chemotherapy resection of residual masses. These patients need to be distinguished from those who should be observed and those who require further chemotherapy. A small proportion of patients with germ cell tumors will present with tumors arising in the mediastinum. Prompt diagnosis, with adequate tissue for histopathologic and immunohistochemical staining, is essential. Primary therapy for such patients should be chemotherapy, except for some patients with mediastinal seminomas in whom radiotherapy is preferable. Mediastinal nonseminomatous germ cell tumors have a poor prognosis due, in part, to their bulk and relative chemosensitivity, but also due in part to their association with non-germ cell elements and acute leukemia. Proper coordination of the different modalities is essential in optimizing the cure rate of patients with these tumors.

In the past, physicians viewed ischemic injury as an irreversible event. Modern science has shown that this view is incorrect and that ischemic neuronal damage is an ongoing, active process that might be amenable to various therapies. Figure 2 illustrates some of the possible sites where these therapies might be active. Pending evidence of their effectiveness, cerebral protection can best be achieved by maintaining adequate CPP and CBF during periods when patients are at risk for cerebral ischemia, restoring perfusion after ischemia occurs, and optimizing the metabolic milieu of the ischemic penumbra.

Currently, only a few chemotherapeutic agents (ifosfamide, mitomycin, vinblastine, and vindesine) have consistently produced single-agent response rates greater than 15% in patients with non-small-cell lung cancer (NSCLC). While combination chemotherapy with these and other agents may prolong survival in some patients with advanced disease, complete responses and long-term disease control are achieved only infrequently. In recent years, several new drugs have produced single-agent response rates above 20% in phase I/II trials. These results have brightened the prospects for chemotherapy against NSCLC. This article reviews available data for several of these agents: navelbine, which is an analogue of vinblastine, the camptothecins CTP-11 and topotecan, and taxol, the first of a novel class of antimicrotubule drugs.

Malignant pleural effusions (MPEs) are a common complication of advanced malignancies, particularly lung and breast cancer. They are caused by a variety of mechanisms including tumor obstruction of lymphatic flow, spread of malignant cells via the systemic circulation, and tumor invasion of the pulmonary arterioles. Therapy is determined by tumor histology, stage of malignancy, and a careful assessment of a patient's performance status and comorbid diseases. A number of approaches have been used to treat patients with MPE ranging from thoracentesis to pleurectomy. Tube thoracostomy drainage followed by application of a sclerosing agent is the most common strategy. Effective sclerosing agents include quinacrine, talc, bleomycin, tetracycline and Corynebacterium parvum. Results from a recent multicenter randomized trial suggest that bleomycin may be superior in terms of control of effusion at 30 days. Further randomized studies are ongoing to determine the optimal method of draining the pleural space and the most effective sclerosing agent. Thoracoscopy using video-assisted techniques is a promising new approach to MPEs both for diagnosis and treatment. The application of biological agents such as interleukin-2, the interferons, and novel chemotherapeutic agents are experimental approaches that are under investigation.

A 62-year-old man who had aortic stenosis associated with Scheie's syndrome (mucopolysaccharidosis [MPS], type I-S) successfully underwent aortic valve replacement. The composition of acidic glycosaminoglycans (acid mucopolysaccharides) of the excised aortic valve analyzed by high-performance liquid chromatography (HPLC) supported the diagnosis of Scheie's syndrome. This article reviews the literature on aortic stenosis in MPS, a rare inherited metabolic disorder, and discusses biochemical features and surgical repair.

Advances in cytokine biology and molecular biology have led to the development of novel immunologic approaches to the treatment of septic shock, ARDS, and MOF. These advances are necessary since improvements in supportive care clearly fall short of the hoped-for reductions in mortality associated with these disorders. As noted in this review, these new therapies are directed at three distinct levels of the inflammatory cascade: (1) the inciting event or insult (eg, endotoxin); (2) the mediators (eg, TNF, IL-1); and (3) the effector cells (eg, neutrophils). The current status of these treatments has been reviewed; and while each individual therapy has shown potential, it is likely that combinations of these agents may be necessary to substantially impact on survival. That is, due to the complexity and redundancy of the inflammatory network, it is doubtful that a "magic bullet" will be found. However, it is also clear that advances in our understanding of the pathogenesis of ARDS, septic shock, and MOF at the molecular level have provided clinicians with powerful weapons with which to do battle. It remains to be seen which ones will work the best.