Celecoxib, a selective cyclo-oxygenase-2 inhibitor, enhances the response to preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer.

PURPOSE: Preclinical studies suggest that treatment with a selective cyclo-oxygenase-2 (COX-2) inhibitor may augment the antitumor effects of chemotherapy. In this study, patients with non-small-cell lung cancer (NSCLC) were preoperatively treated with celecoxib in combination with chemotherapy. End points were toxicity, response rates, and measurement of intratumoral levels of prostaglandin E2 (PGE2). METHODS: In this phase II trial, 29 patients with stages IB to IIIA NSCLC were treated with two preoperative cycles of paclitaxel and carboplatin, as well as daily celecoxib, followed by surgical resection. Levels of PGE2 in the primary tumors and adjacent normal lung tissue were compared in 17 study patients versus 13 controls, who received preoperative paclitaxel/carboplatin without celecoxib. RESULTS: All patients completed preoperative chemotherapy, and 26 completed preoperative celecoxib. The overall clinical response rate was 65% (48% with partial response; 17% with complete response). Grade 3 or 4 neutropenia was observed in 18 patients (62%). Twenty-eight patients were explored and underwent complete resection of their tumors. There were no complete pathologic responses, but seven patients (24%) had minimal residual microscopic disease. The addition of celecoxib to a regimen of paclitaxel and carboplatin abrogated the marked increase in levels of PGE2 detected in primary tumors after treatment with paclitaxel and carboplatin alone. CONCLUSION: In comparison with historically reported response rates, these data suggest that the addition of a selective COX-2 inhibitor may enhance the response to preoperative paclitaxel and carboplatin in patients with NSCLC. Moreover, treatment with celecoxib 400 mg twice daily was sufficient to normalize the increase in PGE2 levels found in NSCLC patients after treatment with paclitaxel and carboplatin. Confirmatory trials are planned.

Guidelines for the use of spiral computed tomography in screening for lung cancer.

Screening should be considered in lung cancer, more than any other cancer. Not only is the disease highly fatal, essentially incurable, when diagnosed on the prompting of symptoms and/or clinical signs, but its occurrence is also highly concentrated in identifiably high-risk persons. The degree of usefulness of computed tomography (CT)-based screening for lung cancer must be thought of in reference to a particular, presumably optimal, regimen of pursuing early stage diagnosis. This is an algorithm that begins with the initial test ("screening CT") and ends in either discontinuation of the diagnostic pursuit or in diagnosis of lung cancer. A carefully developed, extensively pilot tested and critically reviewed, updated protocol for CT-based screening for lung cancer is presented here. Its implementation is addressed, together with quality assurance. Finally, the associated curability rate for lung cancer is addressed in the light of what is known or can be surmised from evidence already available. However, recommendation for or against screening requires further information. Principally, the patients risk for lung cancer (in the near future) and the patients life expectancy (when spared of death from lung cancer). These two factors influence when, if ever, to begin screening, and if it is initiated, when to discontinue it. Finally, cost-effectiveness of the screening program should also be considered.

Early lung cancer action project: annual screening using single-slice helical CT.

The advent of helical CT imaging held promise for the early diagnosis, and thereby, for enhanced curability of lung cancer--a highly fatal disease. In 1993, the Early Lung Cancer Action Project (ELCAP) was initiated and experimentally screened a cohort of 1,000 high-risk persons. Here we summarize the results of the baseline and annual repeat CT screening of these 1,000 subjects. CT-based screening (compared to traditional radiology) was clearly shown to enhance the detection of lung cancer at earlier and more curable stages. A discussion follows of the meaning of the results and possible future screening protocols.

Early Lung Cancer Action Project: overall design and findings from baseline screening.

BACKGROUND: The Early Lung Cancer Action Project (ELCAP) is designed to evaluate baseline and annual repeat screening by low-radiation-dose computed tomography (low-dose CT) in people at high risk of lung cancer. We report the baseline experience. METHODS: ELCAP has enrolled 1000 symptom-free volunteers, aged 60 years or older, with at least 10 pack-years of cigarette smoking and no previous cancer, who were medically fit to undergo thoracic surgery. After a structured interview and informed consent, chest radiographs and low-dose CT were done for each participant. The diagnostic investigation of screen-detected non-calcified pulmonary nodules was guided by ELCAP recommendations, which included short-term high-resolution CT follow-up for the smallest non-calcified nodules. FINDINGS: Non-calcified nodules were detected in 233 (23% [95% CI 21-26]) participants by low-dose CT at baseline, compared with 68 (7% [5-9]) by chest radiography. Malignant disease was detected in 27 (2.7% [1.8-3.8]) by CT and seven (0.7% [0.3-1.3]) by chest radiography, and stage I malignant disease in 23 (2.3% [1.5-3.3]) and four (0.4% [0.1-0.9]), respectively. Of the 27 CT-detected cancers, 26 were resectable. Biopsies were done on 28 of the 233 participants with non-calcified nodules; 27 had malignant non-calcified nodules and one had a benign nodule. Another three individuals underwent biopsy against the ELCAP recommendations; all had benign non-calcified nodules. No participant had thoracotomy for a benign nodule. INTERPRETATION: Low-dose CT can greatly improve the likelihood of detection of small non-calcified nodules, and thus of lung cancer at an earlier and potentially more curable stage. Although false-positive CT results are common, they can be managed with little use of invasive diagnostic procedures.

CT-guided transthoracic needle biopsy following indeterminate fiberoptic bronchoscopy in solitary pulmonary nodules.

We evaluated the role of computed tomography (CT)-guided transthoracic needle biopsy (TNB) in patients with solitary pulmonary nodule and indeterminate flexible fiberoptic bronchoscopy (FOB). A review of 112 patients with solitary nodules under 3 cm in size who underwent TNB was carried out. A total of 48 patients had prior FOB with negative or indeterminate results. We reviewed the results of CT-guided TNB of these 48 patients with respect to the cytology results, nodule size and location, and complications of the procedure. Among the 48 patients who had FOB with indeterminate cytology, 32 were found to have malignant cytology on subsequent TNB. Among the remaining 16 patients, eight had diagnostic thoracotomy, which showed that six of the nodules were benign and two were malignant. The remaining eight patients who did not undergo surgery have been followed for more than 2 years, without evidence of growth. Results were not influenced by size or location. TNB offers a high yield for diagnosis in this patient population.

Clinical utility of computed tomography in the diagnosis of pulmonary embolism.

This prospective clinical pilot study describes the clinical utility and cost effectiveness of computed tomography (CT) with contrast in the diagnosis and management of pulmonary embolism. The setting is a university teaching hospital, and the 20 patients, 26 to 81 years old, were found to have CT findings consistent with pulmonary embolism. Intraluminal pulmonary artery clots were observed on CT and contributed to clinical management, often obviating pulmonary arteriography. CT, particularly spiral CT, may demonstrate pulmonary embolism and offers advantages over ventilation-perfusion lung scanning and pulmonary arteriography in making the diagnosis of pulmonary embolism in high-risk patients or patients with preexisting parenchymal lung disease.

The solitary pulmonary nodule: update 1995.

PURPOSE: This study analyzed the clinical characteristics, diagnostic evaluation, prevalence of malignancy, and outcome of patients with a solitary pulmonary nodule (SPN) encountered in the outpatient practice of a pulmonologist in an urban university hospital from 1990 to 1993. PATIENTS AND METHODS: SPN was defined as a round or ovoid density < or = 3 cm in diameter within the lung parenchyma. Patients with and without lung cancer in SPNs were compared. RESULTS: Forty patients had a mean age of 65 years, an almost equal sex distribution, high prevalences of cardiovascular disease (53%) and chronic obstructive pulmonary disease (COPD) (33%), but a low incidence of tuberculosis. The mean size of SPNs was 1.8 cm. The prevalence of malignancy was 53%. In SPNs < or = 2 cm in diameter, the prevalence of malignancy was 43%. Nonsurgical biopsy techniques made a diagnosis in 78% of patients. In 94% of patients with lung cancer in SPNs, the tumor was resectable (stage 1, 2, or 3A), emphasizing the need for early detection. Despite the small size of the SPNs, the prevalence of malignancy was high. CONCLUSION: Despite the advanced age and high prevalence of cardiovascular disease and COPD in patients with SPNs, lung cancer that occurs in these lesions appears to have a favorable prognosis if detected promptly.

Elevated carcinoembryonic antigen levels correlating with disease recurrence in a patient with adenoid cystic carcinoma.

BACKGROUND: Carcinoembryonic antigen (CEA) is an oncofetal glycoprotein involved in cell recognition and adhesion. Serum CEA has been extensively studied as a potential chemical marker for malignancy, most notably in patients with colon carcinoma. Serum CEA measurements have not been reported for patients with salivary gland carcinomas. METHODS: Serum CEA was measured in a case study using enzyme immunoassay with monoclonal antibody specific for CEA. Tissue was examined with standard histologic and immunohistologic methods. RESULTS: A patient was initially seen with adenoid cystic carcinoma (ACC) of the trachea and had a markedly elevated serum CEA level which declined after surgical resection. The serum CEA level became elevated again when the patient developed abdominal metastases and then declined after debulking of the tumor. Immunohistochemical study of the tumor was positive for CEA. CONCLUSIONS: The measurement of serum CEA levels may play a role in the management of patients with ACC. Clinical investigation utilizing monoclonal antibodies against CEA, for imaging and for the delivery of chemotherapy and radiotherapy may be worthwhile.

Coexisting lymphangioleiomyomatosis and bilateral angiomyolipomas in a patient with tuberous sclerosis.

A patient with tuberous sclerosis and known bilateral angiomyolipomas presented with a complete pneumothorax prior to scheduled renal surgery. Evaluation revealed the presence of pulmonary lymphangioleiomyoma, an unusual entity known to coexist with tuberous sclerosis. Pulmonary decortication and conservative renal surgery resulted in a satisfactory long-term result.

Radiographic screening for cancer. Proposed paradigm for requisite research.

Computed tomography (CT) imaging as an excellent approach to the detection and characterization of small solitary pulmonary nodules (SSPN) raises three questions: (1) How often does CT imaging lead to detection of SSPN? (2) How often is such an SSPN malignant? (3) If malignant, how curable is it? The first question pertains to decisions about screening use of CT (clinical or mass screening), the second to decisions about screening for SSPN and diagnosis of malignancy given SSPN, and the third--in the context of known curability at ordinary clinical diagnosis--to decisions about screening for SSPN, diagnosis given SSPN and intervention given malignant SSPN. We present a three component study design that addresses these questions. The first is directed primarily to the first question. Some 1000 persons at high risk for lung cancer will be screened for SSPN using screening-type CT. The primary aim is to determine the prevalence of CT-detectable SSPN as a joint function of risk-relevant aspects of the person. The second component addresses the prevalence of malignancy among the detected cases of SSPN. To develop the prevalence function, a larger series of CT-detected SSPN will be obtained by developing a multi-center SSPN "registry." A subsequent, third component will focus on the registered cases of malignant SSPN screening incidentally detected and address their curability on the basis of long-term follow-up. This design, in lieu of a randomized trial, may represent a new paradigm for applied research on radiologic technologies in cancer screening, given its advantages in terms of research efficiency and implications to decisions about diagnostic workup and therapeutic intervention.

Simultaneous pulmonary and renal malignancy.

Simultaneous primary malignancy of the lung and kidney has been rarely recognized during life. Three patients with synchronous primary pulmonary and renal cancer are described. The pulmonary tumors were asymptomatic and were discovered on plain chest roentgenography. The renal tumors, also asymptomatic, were incidentally discovered on CT, performed for staging. Although one patient was treated with interleukin-2 for a presumed solitary pulmonary metastasis from renal carcinoma, in all three patients, both the kidney and lung tumors were eventually removed either concurrently or sequentially. Prior autopsy case series are reviewed. In the elderly, synchronous asymptomatic pulmonary and renal malignancy is not surprising, and it should be approached as a distinct clinical problem. With the use of chest roentgenography for screening high risk populations and CT for staging, simultaneous primary pulmonary and renal malignancy will probably be recognized increasingly.

Role of tryptophan degradation in respiratory burst-independent antimicrobial activity of gamma interferon-stimulated human macrophages.

To determine whether extracellular tryptophan degradation represents an oxygen-independent antimicrobial mechanism, we examined the effect of exogenous tryptophan on the intracellular antimicrobial activity of gamma interferon (IFN-gamma)-stimulated human macrophages. IFN-gamma readily induced normal monocyte-derived macrophages (MDM) to express indoleamine 2,3-dioxygenase (IDO) activity and stimulated MDM, alveolar macrophages, and oxidatively deficient chronic granulomatous disease MDM to degrade tryptophan. All IFN-gamma-activated, tryptophan-degrading macrophages killed or inhibited Toxoplasma gondii, Chlamydia psittaci, and Leishmania donovani. Although exogenous tryptophan partially reversed this activity, the increases in intracellular replication were variable for normal MDM (T. gondii [5-fold], C. psittaci [3-fold], L. donovani [2-fold]), chronic granulomatous disease MDM (T. gondii [2.5-fold], C. psittaci [5-fold]), and alveolar macrophages (T. gondii [1.5-fold], C. psittaci [1.5-fold]). In addition, IFN-alpha and IFN-beta also stimulated normal MDM to express IDO and degrade tryptophan but failed to induce antimicrobial activity, and IFN-gamma-treated mouse macrophages showed neither IDO activity nor tryptophan degradation but killed T. gondii and L. donovani. These results suggest that while tryptophan depletion contributes to the oxygen-independent antimicrobial effects of the activated human macrophage, in certain cytokine-stimulated cells, tryptophan degradation may be neither sufficient nor required for antimicrobial activity.

IFN-gamma-activated human alveolar macrophages inhibit the intracellular multiplication of Legionella pneumophila.

Human alveolar macrophages activated by human rIFN-gamma inhibit the intracellular multiplication of Legionella pneumophila, an intracellular bacterial pathogen and the agent of Legionnaires' disease. Activation of alveolar macrophages with IFN-gamma is dose dependent; significant inhibition of L. pneumophila multiplication (mean 1.60 +/- 0.20 logs) is achieved consistently with concentrations of IFN-gamma of greater than or equal to 2 x 10(-2) micrograms/ml (220 U/ml). Activation of alveolar macrophages is also time dependent. In macrophages treated continuously after explantation, macrophages infected at 48 to 96 h after explantation are more inhibitory than macrophages infected at 24 h after explantation. In macrophages not treated continuously after explantation but treated for various lengths of time before infection, the longer their exposure to IFN-gamma before infection, the greater the inhibition of L. pneumophila multiplication (96 greater than 72 greater than 48 greater than 24 h). IFN-gamma-activated alveolar macrophages exhibit morphologic signs of activation, including increased size, spreading, and aggregation. This paper demonstrates that a human resident macrophage can be activated with IFN-gamma such that it exhibits enhanced antimicrobial activity against a relevant pathogen.

In vitro and in vivo activation of human mononuclear phagocytes by interferon-gamma. Studies with normal and AIDS monocytes.

To determine the potential immunotherapeutic role of interferon-gamma (IFN-gamma) as a mononuclear phagocyte-activating agent, we examined the effector cell function of peripheral blood monocytes from healthy donors and acquired immunodeficiency syndrome (AIDS) patients after either in vitro and/or in vivo treatment with recombinant (r) IFN-gamma. When assayed immediately after a 24-hr in vitro pulse with 300 U/ml, normal and AIDS monocytes behaved similarly with little augmentation of their intrinsically high levels of H2O2 release and activity against Toxoplasma gondii; in contrast, activity toward the more resistant intracellular pathogen, Leishmania donovani, was appreciably enhanced by rIFN-gamma. In addition, upon testing 4 to 6 days after in vitro pulsing, both normal and AIDS monocytes showed clear evidence of persistent activation in all three assays. The capacity of IFN-gamma to similarly activate monocytes in vivo was confirmed in all ten treated AIDS patients by examining cells before and after 24-hr infusions of 0.03 and 0.5 mg of rIFN-gamma/square meter (M2) of body surface area. For postinfusion monocytes tested after 1 day in culture, H2O2 release and antitoxoplasma activity were essentially unchanged, but antileishmanial effects were augmented. After 5 to 7 days in culture, monocytes from treated patients showed 3.2- to 5.9-fold increases in H2O2-releasing capacity and increases of 49 to 68% and 35 to 61% in intracellular activity against T. gondii and L. donovani, respectively. These results indicate that the human monocyte can be induced by rIFN-gamma to express signs of both immediate and persistent activation and suggest that, as a direct activator of mononuclear phagocytes, rIFN-gamma may also have potential as an immunotherapeutic agent for patients with intracellular infections.

Activation of tissue macrophages from AIDS patients: in vitro response of AIDS alveolar macrophages to lymphokines and interferon-gamma.

To test the hypothesis that tissue macrophages from AIDS patients have no intrinsic defects in either antimicrobial activity or in the capacity to respond to T cell-derived activating stimuli, alveolar macrophages from 11 patients were treated with crude lymphokines produced by healthy donors. After 72 hr of pretreatment with 10% mitogen- or antigen-induced crude lymphokines (which contained 300 U/ml of interferon-gamma [IFN-gamma]), AIDS alveolar macrophages generated twofold to threefold more H2O2 and readily inhibited the replication of the intracellular pathogens Toxoplasma gondii and Chlamydia psittaci. These responses were indistinguishable from those displayed by activated alveolar cells from 12 non-AIDS patients and three healthy volunteers. As judged by the abrogating effects of a neutralizing anti-human IFN-gamma monoclonal antibody, lymphokine-induced alveolar macrophage activation appeared to be largely IFN-gamma-dependent; thus, macrophages were also stimulated with recombinant (r)IFN-gamma alone. Seventy-two hours of treatment with 300 U/ml of rIFN-gamma resulted in both enhanced oxidative and antimicrobial activity comparable to that achieved by crude lymphokines, and the responsiveness of AIDS alveolar macrophages to rIFN-gamma was identical to control cells. These in vitro results suggest that tissue mononuclear phagocytes from AIDS patients a) are free of apparent defects in intracellular antimicrobial activity, b) are fully responsive to activating T cell products, and c) support the use of IFN-gamma as a potential macrophage-activating immunotherapeutic agent in AIDS-related opportunistic infections.

Sarcoidosis, pulmonary hypertension, and acquired peripheral pulmonary artery stenosis.

An unusual case of a young woman with sarcoidosis and pulmonary hypertension who developed new bilateral continuous murmurs and was found to have peripheral pulmonary artery stenoses is reported. The patient has improved symptomatically, radiographically, and hemodynamically on steroid therapy.

Interaction between the legionnaires' disease bacterium (Legionella pneumophila) and human alveolar macrophages. Influence of antibody, lymphokines, and hydrocortisone.

We have studied the interaction between virulent Legionella pneumophila and human alveolar macrophages, the resident phagocytes at the site of infection in Legionnaires' disease. L. pneumophila multiplied 2.5-5 logs within 3 d, as measured by colony forming units, when incubated with freshly explanted alveolar macrophages in monolayer culture. At the peak of bacterial multiplication, the alveolar macrophage monolayers were destroyed. L. pneumophila multiplied more rapidly in 4-d-old than in freshly explanted alveolar macrophages. Inside alveolar macrophages, L. pneumophila were located within membrane-bound vacuoles whose cytoplasmic sides were studded with ribosomes. Alveolar macrophages that were incubated with concanavalin A (Con A) stimulated human mononuclear cell supernatants (cytokines), inhibited L. pneumophila multiplication, and the degree of inhibition was proportional to the concentration of Con A supernatant added. Anti-L. pneumophila antibody in conjunction with complement promoted phagocytosis of L. pneumophila by alveolar macrophages. By electron microscopy, most (75%) of the phagocytized L. pneumophila were intracellular. However, freshly explanted alveolar macrophages were able to kill only 0-10% of an innoculum of L. pneumophila even in the presence of antibody and complement. At the same time, alveolar macrophages also killed opsonized Escherichia coli poorly. Increasing the ratio of macrophages to bacteria, adhering the macrophages to microcarrier beads, or preincubating the macrophages for 24 or 48 h with Con A supernatants failed to augment alveolar macrophage killing of opsonized E. coli. Corticosteroids appear to increase patient susceptibility to Legionnaires' disease. However, pretreatment of alveolar macrophages and monocytes with hydrocortisone had no influence on intracellular multiplication of L. pneumophila or on the inhibition of that multiplication by activated alveolar macrophages or monocytes. Hydrocortisone did impair cytokine-induced aggregation of alveolar macrophages. These findings demonstrate that L. pneumophila multiplies in human alveolar macrophages and that they do so within a ribosome-lined phagosome; that freshly explanted alveolar macrophages kill few L. pneumophila even in the presence of antibody and complement; that activated alveolar macrophages inhibit L. pneumophila multiplication; and that steroids do not exert a direct suppressive effect on the anti-L. pneumophila activity of activated or nonactivated alveolar macrophages. Our findings indicate that alveolar macrophages may play a central role in both the pathogenesis of Legionnaires' disease and in host defense against it. This paper shows that human resident macrophage can be activated to a higher state of antimicrobial capacity and that the human alveolar macrophage can serve as an effector call in call-mediated immunity.