Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study.

BACKGROUND: Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial. PATIENTS AND METHODS: A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion. RESULTS: All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy. CONCLUSIONS: Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen.

RNA is favourable for analysing EGFR mutations in malignant pleural effusion of lung cancer.

Malignant pleural effusion (MPE) is a useful specimen allowing for the evaluation of EGFR status in nonsmall cell lung cancer (NSCLC). However, direct sequencing of genomic DNA from MPE samples was found not to be sensitive for EGFR mutation detection. To test whether EGFR analysis from RNA is less prone to interference from nontumour cells that have no or lower EGFR expression, we compared three methods (sequencing from cell-derived RNA versus sequencing and mass-spectrometric analysis from genomic DNA), in parallel, for EGFR mutation detection from MPE samples in 150 lung adenocarcinoma patients receiving first-line tyrosine kinase inhibitors (TKIs). Among these MPE samples, EGFR mutations were much more frequently identified by sequencing using RNA than by sequencing and mass-spectrometric analysis from genomic DNA (for all mutations, 67.3 versus 44.7 and 46.7%; for L858R or exon 19 deletions, 61.3 versus 41.3 and 46.7%, respectively). The better mutation detection yield of sequencing from RNA was coupled with the superior prediction of clinical efficacy of first-line TKIs. In patients with acquired resistance, EGFR sequencing from RNA provided satisfactory detection of T790M (54.2%). These results demonstrated that EGFR sequencing using RNA as template greatly improves sensitivity for EGFR mutation detection from samples of MPE, highlighting RNA as the favourable source for analysing EGFR mutations from heterogeneous MPE specimens in NSCLC.

Risk of thromboembolism in non-small-cell lung cancers patients with different oncogenic drivers, including ROS1, ALK, and EGFR mutations.

BACKGROUND: Anaplastic lymphoma kinase-positive (ALK+) and ROS proto-oncogene 1 (ROS1)-positive (ROS1+) lung cancers have been reported to be associated with an elevated risk of thromboembolic events. This study aimed to assess the long-term risk of developing thromboembolism (TE) in ROS1+ lung cancer and to compare it with other oncogenic drivers in the Asian population. MATERIALS AND METHODS: We retrospectively enrolled a cohort of ROS1+ lung adenocarcinoma in a medical center in Taiwan and a comparison cohort of ALK+ and epidermal growth factor receptor-positive (EGFR+) lung cancers. Venous and arterial TEs were identified throughout the cancer course, and the incidence rate was calculated. RESULTS: We enrolled 44 ROS1+, 98 ALK+, and 168 EGFR+ non-small-cell lung cancer (NSCLC) patients. A total of 11 (25%), 36 (36.7%), and 38 (22.6%) patients in the ROS1, ALK, and EGFR cohorts, respectively, were diagnosed with thromboembolic events throughout the follow-up course of the disease (P = 0.042). The incidence rates were 99.0, 91.9, and 82.5 events per 1000 person-years for the ROS1, ALK, and EGFR cohorts, respectively. The majority of thrombosis events in the ROS1 (91.6%) and ALK (85.4%) cohorts were venous. On the contrary, 43.2% of thromboembolic events were arterial in the EGFR cohort. A higher proportion of thromboembolic events were noted during cancer diagnosis in the ROS1 cohort (36.3%) than in the ALK (16.7%) and EGFR (10.5%) cohorts. The stage was the only clinical variable associated with thromboembolic risk. There was a significant difference in survival between patients with and without TE in the EGFR cohort, but not in the ALK and ROS1 cohorts. CONCLUSIONS: Although ROS1+ and ALK+ NSCLCs had a higher cumulative incidence of TE than EGFR+ NSCLC, the person-year incidence rates were similar among the three groups. EGFR-mutated NSCLC had more arterial events. Nevertheless, ALK+ lung cancer had higher venous events than EGFR-mutated lung cancer.

Recurrence of pericardial effusion after different procedure modalities in patients with non-small-cell lung cancer.

BACKGROUND: Lung cancer with related pericardial effusion is not rare. Intervention is a crucial step for symptomatic effusion. It is unknown, however, whether the different invasive interventions for pericardial effusion result in different survival outcomes. This study analyzed the clinical characteristics and prognostic factors for patients with non-small-cell lung cancer (NSCLC) who have undergone different procedures. METHODS: From January 2006 to June 2018, we collected data from patients with NSCLC who have received invasive intervention for pericardial effusions. The patients were divided into three categories: simple pericardiocentesis, balloon pericardiotomy, and surgical pericardiectomy. Kaplan-Meier curve and log-rank test were used to analyze the pericardial effusion recurrence-free survival (RFS) and overall survival (OS). RESULTS: A total of 244 patients were enrolled. Adenocarcinoma (83.6%) was the major NSCLC subtype. Invasive intervention, including simple pericardiocentesis, balloon pericardiotomy, and surgical pericardiectomy, had been carried out on 52, 170, and 22 patients, respectively. The 1-year RFS rates in simple pericardiocentesis, balloon pericardiotomy, and surgical pericardiectomy were 19.2%, 31.2%, and 31.8%, respectively (P = 0.128), and the median RFS was 1.67, 5.03, and 8.32 months, respectively (P = 0.008). There was no significant difference in OS, however, with the median OS at 1.67, 6.43, and 8.32 months, respectively (P = 0.064). According to the multivariable analysis, the gravity in pericardial fluid analysis, receiving systemic therapy after pericardial effusion, and the time period from stage IV lung cancer to the presence of pericardial effusion were independent prognostic factors for pericardial effusion RFS and OS. CONCLUSIONS: Patients who have undergone simple pericardiocentesis alone for the management of NSCLC-related pericardial effusion have lower 1-year RFS rates than those who have undergone balloon pericardiotomy and surgical pericardiectomy. Therefore, balloon pericardiotomy and surgical pericardiectomy should be carried out for patients with NSCLC-related pericardial effusion if tolerable.

Comparison of epidermal growth factor receptor mutations between primary and corresponding metastatic tumors in tyrosine kinase inhibitor-naive non-small-cell lung cancer.

BACKGROUND: Mutations of the epidermal growth factor receptor (EGFR) gene in non-small-cell lung cancer (NSCLC) patients predict the patients who will respond to EGFR tyrosine kinase inhibitor (TKI) treatment. A recent study has suggested that 33% of NSCLC showed primary tumor/metastasis discordance of EGFR expression by immunohistochemistry analysis. We intended to find out whether the EGFR mutations of primary lung cancers are concordant to that of corresponding metastatic tumors. MATERIALS AND METHODS: We analyzed EGFR exons 18-21 from paired primary and metastatic tumors in 67 lung cancer patients who had not received TKI before tissues were sampled. RESULTS: Using the direct sequencing method, 9 of 18 (50%) patients with EGFR mutation-positive primary lung tumors had lost the mutations in metastases. For 26 patients who were EGFR mutation positive in the metastatic tumors, 17 (65%) were negative in the primary tumors. We analyzed these paired tissues with discrepant EGFR mutations by the Scorpion Amplified Refractory Mutation System assay. Finally, the discordant rate reached 27% (18 of 67 cases). CONCLUSION: EGFR mutations in primary lung tumors do not always reflect the same situation in metastases. Analysis of EGFR mutations in the primary lung tumor would be inadequate for planning the use of TKI for advanced NSCLC.

Frequent epidermal growth factor receptor gene mutations in malignant pleural effusion of lung adenocarcinoma.

Malignant pleural effusions (MPEs) are often observed in lung cancer, especially adenocarcinoma. Epidermal growth factor receptor (EGFR) gene mutations are usually detected in lung adenocarcinoma. The purpose of the present study was to investigate the EGFR mutation rate in MPEs of lung adenocarcinoma. Between June 2005 and December 2006, 136 MPEs from lung adenocarcinoma were collected for EGFR mutation detection. In addition, between April 2001 and November 2004, 91 surgically resected specimens of lung adenocarcinoma from patients without MPEs were assessed for EGFR mutation. The EGFR mutation rate was significantly higher in the patients with MPEs than in the patients without (68.4% versus 50.5%). The EGFR mutation rate in patients with MPEs was not associated with sex, smoking history, age or cancer stage. By multivariate analysis, an age of <65 yrs, never smoking, Eastern Cooperative Oncology Group performance status 0-1, and EGFR mutation were significantly associated with a longer overall survival for lung adenocarcinoma patients with MPEs. The patients with malignant pleural effusions related to lung adenocarcinoma had a higher epidermal growth factor receptor gene mutation rate than the patients from whom surgically resected specimens were taken. Epidermal growth factor receptor tyrosine kinase inhibitors may be the treatment of choice for lung adenocarcinoma with malignant pleural effusions in east Asia.

Primary mediastinal large B-cell lymphoma mimicking liposarcoma.

A 78-year-old man consulted for acute exacerbation of chronic obstructive pulmonary disease (COPD) and an incidental finding of an anterior mediastinal tumor on chest radiograph was noted on admission. Chest computed tomography (CT) revealed a fat-containing mediastinal mass with solid component. Mediastinal liposarcoma was the initial diagnosis based on image characteristics but histopathologic examination of the excised tumor revealed lymphoma infiltration of the mediastinal adipose tissue. To our knowledge, this is the first case report of lymphomatous growth in mediastinal lipomatosis.

Collapsin response mediator protein-1 and the invasion and metastasis of cancer cells.

BACKGROUND: Numerous genetic changes are associated with metastasis and invasion of cancer cells. To identify differentially expressed invasion-associated genes, we screened a panel of lung cancer cell lines (CL(1-0), CL(1-1), CL(1-5), and CL(1-5)-F(4) in order of increasing invasive activity) for such genes and selected one gene, collapsin response mediator protein-1 (CRMP-1), to characterize. METHODS: We used a microarray containing 9600 gene sequences to assess gene expression in the cell panel and selected the differentially expressed CRMP-1 gene for further study. We confirmed the differential expression of CRMP-1 with northern and western blot analyses. After transfecting and overexpressing CRMP-1 in highly invasive CL(1-5) cells, the cells were assessed morphologically and with an in vitro invasion assay. We used enhanced green fluorescent protein-tagged CRMP-1 and fluorescence microscopy to localize CRMP-1 intracellularly. CRMP-1 expression in 80 lung cancer specimens was determined by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). All statistical tests were two-sided. RESULTS: Expression of CRMP-1 was inversely associated with invasive activity in the cell panel, an observation confirmed by northern and western blot analyses. CRMP-1-transfected CL(1-5) cells became rounded and had fewer filopodia and statistically significantly lower in vitro invasive activity than untransfected cells (all P< .001). During interphase, CRMP-1 protein was present uniformly throughout the cytoplasm and sometimes in the nucleus; during mitosis, CRMP-1 was associated with mitotic spindles, centrosomes, and the midbody (in late telophase). Real-time RT-PCR of lung cancer specimens showed that reduced expression of CRMP-1 was statistically significantly associated with advanced disease (stage III or IV; P = .010), lymph node metastasis (N1, N2, and N3; P =.043), early postoperative relapse (P = .030), and shorter survival (P = .016). CONCLUSIONS: CRMP-1 appears to be involved in cancer invasion and metastasis and may be an invasion-suppressor gene.

Detection and quantitation of circulating cancer cells in the peripheral blood of lung cancer patients.

Detection and quantitation of circulating cancer cells in peripheral blood may improve cancer staging and monitoring. This study explored the feasibility of using circulating cancer cell detection in peripheral blood for the rapid assessment of chemotherapeutic response. Cytokeratin 19 mRNA was amplified by nested reverse transcriptase-PCR in the peripheral blood of 29 healthy volunteers, 33 pneumonia patients, and 86 lung cancer patients. Circulating cancer cells in the peripheral blood were semiquantitatively determined by taking the ratio of cytokeratin 19 band intensity from the second round of nested PCR to the glyceraldehyde-3-phosphate dehydrogenase band intensity from the first round of PCR amplification. The detection limit of the method was 1 cancer cell in 107 peripheral blood mononuclear cells. The positive detection rate was 40% for lung adenocarcinoma patients of all stages, 41% for squamous carcinoma patients of all stages, and 27% for small cell lung cancer patients. Only one control sample from a pneumonia patient showed a positive result (1.6%). The quantitative method reliably and sensitively estimated cancer cell numbers in the peripheral blood of lung cancer patients. Serial measurement of the relative number of circulating cancer cells correlated with the tumor burden and treatment response of patients. This method may help rapidly assess the efficacy of anticancer treatment, redefine cancer staging, and facilitate the design of better therapeutic strategies for the treatment of cancer patients.

Global analysis of gene expression in invasion by a lung cancer model.

Metastasis is a complicated multistep process that involves interactions between cancer cells and their surrounding microenvironments. Previously, we have established a series of lung adenocarcinoma cell lines with varying degrees of invasiveness. Tracheal graft assay confirmed that cell lines with higher in vitro invasiveness had greater in vivo invasive potential. In this study, we used these model cell lines to identify invasion-associated genes using cDNA microarray with colorimetric detection. A more invasive subline, CL 1-5-F 4, derived from metastatic lung tumor of severe combined immunodeficient mice inoculated with CL 1-5 cells, was combined with CL 1-0, CL 1-1, and CL 1-5 in cDNA microarray screening. cDNA microarray membranes, each containing 9600 nonredundant expressed sequence tag clones, were used to identify differentially expressed genes in these cell lines. For statistical analysis, self-organizing map algorithm was performed to identify the expression patterns. Positive correlation between gene expression levels and cell line invasiveness was found in 2.9% of the 9600 putative genes. On the other hand, negative correlation was found in 3.3% of the genes. The trends of expression of some of the genes were also confirmed by Northern hybridization and flow cytometry. Our data demonstrated that genes related to cell adhesion, motility, angiogenesis, signal transduction, and some other expressed sequence tag genes may play significant roles in the metastasis process. These results substantiate the model system with which one can identify invasion-associated genes by using cDNA microarray and cancer cell lines of different invasiveness. This technique may allow us to explore complex interactions between multiple genes that orchestrate the process of cancer metastasis.

Successful triple coronary artery bypass in a child with multiple coronary aneurysms due to Kawasaki's disease.

A 9-year-old girl developed ischemic cardiac symptoms 3 years after she first presented with characteristic manifestations of Kawasaki's disease, namely, high fever, conjunctivitis, lymphadenopathy, macular truncal skin rash, and erythema of both hands followed by desequamation of the skin of the fingertips. This acute illness resolved spontaneously within 2 weeks. Because of progressive and severe anginal symptoms and electrocardiographic signs of myocardial ischemia, she underwent cardiac catheterization and coronary angiography, which demonstrated multiple aneurysms of both right and left coronary artery systems. The two larger aneurysms of the right main and left main coronary arteries were clotted, causing complete occlusion of these vessels. Only collateral branches from the proximal right coronary artery which were supporting the entire coronary circulation, prevented her from having a myocardial infarction. A triple saphenous vein bypass was performed with excellent immediate results. One year later the patient was completely free of symptoms; she was living a normal life and a stress electrocardiogram was entirely normal.

Pulmonary pleomorphic (spindle) cell carcinoma: peculiar clinicopathologic manifestations different from ordinary non-small cell carcinoma.

Pleomorphic (spindle) cell carcinoma, also known as monophasic sarcomatoid carcinoma, is a rare primary pulmonary malignancy. This type of tumor shows concurrent presence of malignant epithelial and homologous sarcomatoid spindle cell components by co-expressing cytokeratin and vimentin in various degrees. Sixteen cases (four central endobronchial lesions and 12 peripheral parenchymal masses) were studied clinicopathologically. Men were affected far more frequently than women (13:3). The patients were between 56 and 80 years of age. The disease is strongly associated with smoking. Among seven of the patients who underwent surgical resection, four of them had mediastinum, pleura and chest wall invasions, and three of them had regional lymph node metastases. All of the patients succumbed to early distant metastases (range 2 weeks-5 months) in organs including brain, bone, adrenal gland, and unusual sites such as esophagus, jejunum, rectum and kidney. The remaining nine inoperable cases were late stage disease and treated with chemoradiotherapy with little effect. The median duration of survival was 3 months. All parenchymal masses appeared as cavities with marked central necrosis, and only peripheral rim of tumor cells was left. More definite diagnostic results will depend on further tissue sections and can be confirmed by immunohistochemical studies. Significantly fewer Ki-67, p53 and c-erb B-2 oncoprotein expressions were also noted.

Primary pulmonary plasmacytoma with lobar consolidation: an unusual presentation.

Extramedullary plasmacytoma is a rare form of plasma cell tumor that frequently involves the upper respiratory tract. Primary pulmonary plasmacytoma is even more rare. The usual presentation of primary pulmonary plasmacytoma is a solitary pulmonary nodule. We describe the case of a 58-year-old woman who presented with the chief complaints of progressive dyspnea on exertion, cough, and subsequently, hemoptysis. The main finding on chest imaging studies, including plain radiography, sonography, computed tomography, and magnetic resonance imaging, was consolidation of the right middle lobe. Percutaneous transthoracic lung biopsy of the right middle lobe demonstrated sheets of atypical plasma cells. Immunohistochemical study showed IgA lambda monoclonality. A bone marrow study and whole body bone scan showed normal findings. To the best of our knowledge, this is the first reported case of primary pulmonary plasmacytoma presenting with lobar consolidation of the lung but without a well-defined tumor mass.

Lung cancer in pregnancy: report of two cases.

Lung cancer during pregnancy is rare, although the number of case reports has been increasing in recent years. Herein, we describe two cases of lung carcinoma complicating pregnancy with different presentations and outcomes, and review the relevant literature. The first case involved a 31-year-old patient with squamous cell carcinoma with multiple bone metastases. The initial symptoms were productive cough and dyspnea on exertion during the second trimester of pregnancy, to which the patient paid little attention. Chemoradiation was started 1 month postpartum, soon after the diagnosis was made, but with little response. She died at home several days after palliative radiotherapy. The second case involved a 34-year-old patient with poorly differentiated lung carcinoma with brain metastasis. Left hemiparesis had developed initially during the third trimester. She underwent excision of the metastatic brain tumor and received radiotherapy to the left lung tumor and brain. The patient is still alive after a follow-up period of more than 1 year. Delayed diagnosis may be the main problem in the management of lung cancer during pregnancy, because of misinterpretation of common respiratory symptoms and physicians' reluctance to use radiologic imaging studies owing to concerns over the safety of the fetus. Thus, we suggest chest radiographs with abdominal lead shielding for pregnant patients with protracted cough and hemoptysis. Treatment of unresectable lung cancer during pregnancy generally consisted of radiation therapy with or without chemotherapy in previous reports, but the optimal therapy is still unknown, owing to inadequate case numbers and insufficient follow-up data.

Osteomyelitis and tenosynovitis due to Mycobacterium marinum in a fish dealer.

Osteomyelitis caused by nontuberculous mycobacteria is rarely reported. We describe a case of tenosynovitis and osteomyelitis of the right middle finger and metacarpal bone caused by Mycobacterium marinum in a fish dealer. This 52-year-old woman suffered progressive pain, numbness, tenderness, and erythematous swelling of the right middle finger over a 2-month period. A radiograph of the right hand disclosed osteolytic lesions at the third metacarpal bone and the third proximal phalanx. She was treated successfully with repeated surgical debridement and antimicrobial agents, including clarithromycin, ethambutol, rifampin, and doxycycline for 1 month, followed by ethambutol and clarithromycin. Pathologic examination of the debrided tissue disclosed epithelioid granuloma, caseous necrosis, and numerous acid-fast bacilli, which were later identified as M. marinum using conventional biochemical tests and by the characteristic gas-liquid chromatogram of esterified cellular fatty acid. The wound healed completely after 7 months of treatment. The patient is still under treatment, and clarithromycin and ethambutol will be given for a total of 18 months.

Nontuberculous mycobacteria isolates: clinical significance and disease spectrum.

The incidence of diseases caused by nontuberculous mycobacteria (NTM) is increasing worldwide. There has been no previous report regarding the clinical significance and disease spectrum of these bacteria in Taiwan. From January 1992 to June 1996, 201 isolates of NTM were recovered from clinical specimens from 143 patients at National Taiwan University Hospital. We retrospectively studied the clinical records and radiographs of these patients. A total of 86 isolates of NTM were considered clinically significant; they were cultured from 39 patients with soft-tissue infections and/or osteomyelitis (16 patients), isolated pulmonary infections (10), keratitis (6), disseminated infections (4), peritonitis, enteritis, and conjunctivitis. The most common organisms involved in these patients were Mycobacterium fortuitum complex, followed by Mycobacterium avium-intracellulare. Positive cultures of NTM were derived from respiratory sources (sputum, bronchial washing, and pleural effusion) from 111 patients; in 11 the isolates were associated with clinically significant disease, in two they were persistent colonizers, in 79 the isolates were considered to be contaminants, and for the remainder there were insufficient cultures to classify. The organisms involved in pulmonary diseases were M. avium-intracellular (4 patients), Mycobacterium chelonae (1), Mycobacterium abscessus (1), M. fortuitum (2), Mycobacterium gordonae (1), and unidentified scotochromogens (2), M. fortuitum complex (55%) was the most common pathogen of keratitis and soft-tissue infection. Three of the four cases of disseminated disease were caused by M. avium-intracellulare. The only isolate of Mycobacterium kansasii found in this study was a contaminant. The strains of clinically significant NTM isolates found in our hospital and their disease spectrum differ from those reported in other regions of the world.

Roles of Fhit and p53 in Taiwanese surgically treated non-small-cell lung cancers.

Abnormalities of fragile histidine triad (FHIT) and TP53 have been found frequently in nonsmall cell lung cancers. In the current study, 263 primary nonsmall cell lung cancers were investigated for the expressions of Fhit and p53 by immunohistochemistry. Marked reduction of Fhit immunoreactivity (<10% positivity) in 156 (59%) tumours and overexpression of p53 protein (>10% positivity) in 89 (34%) tumours were found. Reduced Fhit expression was also noted in most squamous cell carcinomas (80 out of 99, 81%), and in a smaller fraction of adenocarcinomas (76 out of 164, 46%; P<0.001). p53 nuclear staining was demonstrated in 54 out of 99 (55%) squamous cell carcinomas and in 35 out of 164 (21%) adenocarcinomas (P<0.001). The loss of Fhit expression and p53 overexpression was significantly more common in tumours occurring in smokers (93 out of 113, 82% and 56 out of 113, 50%) than in those of nonsmokers (63 out of 150, 42%; P<0.001 and 33 out of 150, 22%; P<0.001). Notably, p53 overexpression was associated with distant metastasis of patients in the whole series (P=0.027) and in adenocarcinoma (P=0.001). It was also associated with a poorer survival of patients with adenocarcinoma (P=0.032).

Endobronchial lesions in a non-AIDS patient with disseminated Mycobacterium avium-intracellulare infection.

A 34 year old female developed Mycobacterium avium-intracellulare infection with generalized lymphadenopathy, hepatosplenomegaly, pulmonary infiltration, pleural effusion and endobronchial polypoid lesions. M. avium-intracellulare was identified by means of sputum cultures, pleural effusion culture and lymph node culture. The anti-human immunodeficiency virus (HIV) antibody was negative. The CD4+ cell count was normal. Bronchoscopic examination revealed multiple polypoid lesions, which had nearly occluded the right main bronchus, right middle lobe and left lower lobe bronchi. Neodymium yttrium aluminium garnet (Nd-YAG) laser and antimycobacterial therapy were used effectively to relieve the airway obstruction. The clinical symptoms and signs responded favourably to antimycobacterial therapy.

Comparative electrophysiologic effects of digoxin in the nonsedated chronically instrumented puppy.

The electrophysiologic effects of acute but not chronic administration of cardiac glycosides have been studied. Nineteen chronically instrumented beagle puppies underwent 2-week courses of parenteral digoxin in three dosage regimens: six received digoxin, 0.04 mg/kg/day; seven received 0.03 mg/kg/day; and 11 received 0.02 mg/kg/day. Mean serum concentrations were 3.2 ng/ml, 1.3 ng/ml, and 1.0 ng/ml, respectively. Significant electrophysiologic effects on sinus node function were produced only by the highest dose. Atrioventricular node conduction was significantly delayed among animals receiving both high and middle dosages. All three regimens significantly effected atrioventricular specialized conduction system functional refractory periods. Atropine decreased digoxin-induced effects on all measured parameters but totally eliminated the digoxin effect on the corrected sinus node recovery time.

The electrophysiologic effects of procainamide in the immature heart.

The electrophysiologic effects of procainamide in young animals have not been established. To test the effects of this drug on the immature heart, we studied eight nonsedated, chronically instrumented puppies (age range 12-28 days, median 16 days; weight range 0.7-1.1 kg, median 0.8 kg). The electrophysiologic study was performed before and 30 minutes after procainamide was given intravenously (20 mg/kg infusion). At the time of the study, the serum concentrations of procainamide (8.2 +/- 1.7 micrograms/ml to 6.2 +/- 1.6 micrograms/ml; mean +/- SEM) were in the usual adult human therapeutic range (4-10 microgram/ml). Procainamide in puppies caused a significant lengthening of the atrial and ventricular refractory periods, a significant decrease of the sinus node recovery time and the sinus of atrial echo zone, a significant decrease in the heart rate, and a significant increase in the sinoatrial conduction time.