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.

We evaluated two patients with systemic cholesterol embolization (SCE) associated with the development of pleural effusions. These two patients had evidence of atherosclerosis and presented with livedo reticularis, renal insufficiency, and gangrenous cutaneous changes as manifestations of their SCE. In both cases, closed pleural biopsies demonstrated acute inflammation of the parietal pleura. Our experience with these individuals and a review of the medical literature suggest that pleural injury from atheromatous embolization may occur. Physicians caring for patients with SCE should be aware of the possible association of pleural reactions with this process.

Congenital cystic adenomatoid malformation is an uncommon congenital anomaly. We present four additional children with CCAM and review the literature. Two of these children had unusual manifestations of CCAM--one presented with a "cavitary lesion" while the other is suspected of having bilateral disease.

Thiazides were responsible for severe diuretic-induced hyponatremia (serum sodium level < 115 mEq/L) in 94 percent of 129 cases reported in the literature between 1962 and 1990. The hyponatremia developed within 14 days in most of the patients receiving thiazides but in none of the patients who were treated with furosemide. Diuretic-induced hyponatremia was four times more common in women than in men. Advanced age was not associated with a higher tendency for hyponatremia. In the majority of the patients who received thiazides, excess antidiuretic hormone activity, hypokalemia, and excess water intake were accompanying findings which, singly or together, appeared to contribute to the development of hyponatremia. In 12 patients, mortality was directly related to hyponatremia. Rapid average correction of hyponatremia and a relatively high total correction (over 20 mEq/L) in the first 24 h were significantly associated with higher mortality or demyelinating syndrome. The presence of neurologic signs is an indication for active sodium replacement. The onset of thiazide-induced hyponatremia may in some cases occur within 1 day and therefore needs to be corrected rapidly, but within a total elevation of 20 mEq/L in the first 24 h. Where the onset is judged to have been slow (over several days), the level should be corrected at a slow rate, up to a total of 12 to 15 mEq/L in 24 h.

Considering the literature, a symptomatic right-to-left (R-L) shunt through a persistent foramen ovale (PFO), developing after a pulmonary resection, can occur without elevated right-sided heart pressures, but its frequency seems to be very low. However, considering the high frequency of a PFO in the normal population (20 percent) and the high frequency of pulmonary resections carried out today, it might be possible that this kind of complication is occurring more frequently, possibly in a more "benign" form, in which it is more difficult to recognize, especially if one is unaware of the possibility of this kind of complication. This R-L shunt seems to occur more frequently after a right-sided pneumonectomy. Important clinical clues suggestive for this complication are as follows: first, a relatively symptomless interval of a few months between the operation and the onset of symptoms; second, the posture dependency of the dyspnea, ie, the dyspnea becoming worse in the upright position (platypnea); and third, the volume dependency of the R-L shunt, ie, the shunt becoming worse in a dehydrated state.

A previous study identified spirometric testing as a useful adjunct for estimating PaO2 during altitude exposure in patients with chronic obstructive pulmonary disease (COPD). We sought to examine the validity of this finding by quantitative analysis of recent published reports. We analyzed acute hypoxic exposures from five prior studies involving 71 patients. Across all studies, the change in arterial oxygen tension per unit change in inspired oxygen partial pressure (linear slope, dPaO2/dP1O2) correlated with the preexposure forced expiratory volume in 1 s (FEV1, p < 0.01). The correlation with FEV1 held for values weighted or unweighted by sample size, with rotating deletion of each study from analysis one at a time, and with semilog slope as the dependent variable. A formula derived from the semilog slope relationship with FEV1 gave accurate description of the mean hypoxic response in each prior study and individual responses from one study (n = 18): ln (PaO2alt/PaO2g) = Kn.(PIO2alt-PIO2g). We found that FEV1 modulated the values of kn in this study. We conclude, based on analysis of prior studies, that preexposure arterial oxygen tension and FEV1 both influence the prediction of PaO2 during hypoxic exposures in patients with COPD.