Predicting lung cancer by detecting aberrant promoter methylation in sputum.

Despite the promise of using DNA markers for the early detection of cancer, none has proven universally applicable to the most common and lethal forms of human malignancy. Lung carcinoma, the leading cause of tumor-related death, is a key example of a cancer for which mortality could be greatly reduced through the development of sensitive molecular markers detectable at the earliest stages of disease. By increasing the sensitivity of a PCR approach to detect methylated DNA sequences, we now demonstrate that aberrant methylation of the p16 and/or O6-methyl-guanine-DNA methyltransferase promoters can be detected in DNA from sputum in 100% of patients with squamous cell lung carcinoma up to 3 years before clinical diagnosis. Moreover, the prevalence of these markers in sputum from cancer-free, high-risk subjects approximates lifetime risk for lung cancer. The use of aberrant gene methylation as a molecular marker system seems to offer a potentially powerful approach to population-based screening for the detection of lung cancer, and possibly the other common forms of human cancer.

Five year survival and later outcome of patients with X-ray occult lung cancer detected by sputum cytology.

BACKGROUND: A cohort of 51 consecutive patients with roentgenographically occult lung cancer, identified by sputum cytology and confirmed by bronchoscopy was reported previously. METHODS: All patients have now been followed beyond 5 years and the causes of death ascertained. RESULTS: The actual 5-year survival of 27 patients who were resected for cure was 74% including death for all causes. The 5-year survival of all patients who received either surgery or radiation in an attempt to cure was 54.3%. Twelve secondary cancers were found by sputum cytology; eight of these patients have died. CONCLUSIONS: Sputum cytology can be useful in the identification of early stage lung cancer in patients at high-risk where the chances of cure are favorable.

Radon progeny exposure and lung cancer risk among non-smoking uranium miners.

Studies of miners provide the basis for public health efforts to reduce residential radon progeny exposure. Because the preponderance of households do not have members who smoke indoors, studies of non-smoking miners contribute essential data for risk assessments for residential radon progeny exposure. We studied a cohort of 2,209 never-smokers who were underground uranium miners employed in the western U.S. from 1956 to the early 1990's and who participated in a screening program for lung cancer conducted by Saccomanno and colleagues. After determining the vital status and cause of death in the cohort, we conducted a nested case-control study of 55 lung cancer deaths in males and 3 age-matched controls for each case. The relative risk of lung cancer was 29.2 (95% CI 5.1, 167.2) for miners with greater than 1,450 WLM compared with those exposed to less than 80 WLM. Temporal factors affected risk, including average dose rate, which was inversely associated with lung cancer risk, and the length of time since last exposure, which was directly associated with decreased risk. As in studies of non-smokers and smokers combined, the exposure response relationship in never-smokers was consistent with a decreased slope at higher WLM, which resulted, in part, from an inverse dose rate effect.

Clinical feasibility of low energy internal atrial cardioversion with a three-electrode configuration in patients with unsuccessful conventional configurations.

Low energy internal cardioversion is a safe and highly effective method for atrial fibrillation termination. We will describe 6 patients in whom the conventional 2-electrode systems with the defibrillation leads positioned in the right atrium and in the coronary sinus or left pulmonary artery failed to terminate the arrhythmia despite the use of maximal available energies. A 3-electrode configuration including right atrium, coronary sinus and left pulmonary artery was used in order to encompass as much atrial mass as possible between the cathode and the anode. The atrial fibrillation was successfully interrupted in 4 out of 6 patients. The creation of a 3-electrode configuration may be a further technical expedient in order to increase the success rate of internal cardioversion when usual manoeuvres like lead repositioning, reversion of polarity, or addition of antiarrhythmic drugs are ineffective.

Paroxysmal supraventricular tachycardia caused by 1:2 atrioventricular conduction in the presence of dual atrioventricular nodal pathways.

One-to-two atrioventricular conduction, ie, the double response to a single sinus or atrial impulse, resulting in two QRS complexes for one P wave, is a rare manifestation of dual atrioventricular (AV) nodal pathways. This report describes the case of a 61-year-old woman with continuous episodes of supraventricular tachycardia caused by independent conduction to the ventricles of sinus impulses over both the fast and the slow AV nodal pathway, giving rise to a ventricular rate that was twice the sinus rate. A wide spectrum of electrocardiographic manifestations of 1:2 AV conduction was observed on the surface electrocardiogram. The diagnosis was suggested by several elements including evidence of dual AV nodal pathways during sinus rhythm and cycle length alternans during tachycardia. The patient underwent successful slow pathway ablation with complete disappearance of symptoms and electrocardiographic manifestations of 1:2 AV conduction.

Efficacy of two sputum collection techniques in patients with air flow obstruction.

OBJECTIVE: To compare the efficacy of two sputum collection techniques in patients with chronic obstructive pulmonary disease (COPD) in order to diagnose dysplasia or neoplasia. STUDY DESIGN: This was a crossover study design comparing induced sputum with sputum collected at home. One hundred seven patients with COPD were enrolled. Fifty-six were randomized to collect induced sputum first followed by sputum collection at home. Fifty-one randomly assigned patients collected the sputum in reverse order. RESULTS: The second sputum collection technique for both random assignments gave the greatest yield of adequate sputum. There was no significant difference in efficacy between the collection of the two sputum collection techniques in the presence of the learning (period) effect. CONCLUSION: Sputum collection is equally efficacious by the induced method and the home collection method. A learning effect was responsible for the increased yield of sputum abnormalities in the second collection session. Sputum collection at home may facilitate the amount of dysplasic and neoplastic bronchial epithelial changes in heavy smokers with COPD.

Permanent ventricular and dual chamber cardiac stimulation: role of pacing mode in relation to chronic atrial fibrillation risk and stroke development.

Ventricular single chamber permanent cardiac pacing undoubtedly eliminates symptoms related to extremely low cardiac rate, but also contributes to increased morbidity due to onset of permanent atrial fibrillation (PAF). Many studies have shown the superiority of atrial and dual chamber cardiac pacing in reducing atrial fibrillation risk and in preventing correlated embolic complications. It is not known, however, if this advantage is maintained in the elderly and in particular in the oldest old people. From 1986 onwards, we analyzed 690 chronically paced patients, 472 received a single chamber ventricular pacemaker (VP), while 218 received a dual chamber pacemaker (DP). All patients underwent regular controls every 6 months. End points of the study were the onset of atrial fibrillation, embolic events and death. Life table analysis of the incidence of all the events during a follow-up of 120 months was carried out, distinguishing two groups (VP and DP) homogeneous in mean age and type of cardiopathy. The total incidence of PAF was 51.4% in the VP and 11.4% in the DP group (P<0.05). After 7 years from implant, PAF was present in 90% of VP and 20% of DP patients (P<0.001). We found a significantly higher occurrence of cerebral ischemic events (stroke or transient ischemic attacks) in the VP group (P<0.05). Even if no great difference in mortality was found between the two groups, a significant reduction of cardiovascular mortality associated with DP has been observed in the subgroup of patients with sick sinus syndrome.

Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis.

The p16(INK4a) (p16) tumor suppressor gene can be inactivated by promoter region hypermethylation in many tumor types including lung cancer, the leading cause of cancer-related deaths in the U.S. We have determined the timing of this event in an animal model of lung carcinogenesis and in human squamous cell carcinomas (SCCs). In the rat, 94% of adenocarcinomas induced by the tobacco specific carcinogen 4-methylnitrosamino-1-(3-pyridyl)-1-butanone were hypermethylated at the p16 gene promoter; most important, this methylation change was frequently detected in precursor lesions to the tumors: adenomas, and hyperplastic lesions. The timing for p16 methylation was recapitulated in human SCCs where the p16 gene was coordinately methylated in 75% of carcinoma in situ lesions adjacent to SCCs harboring this change. Moreover, the frequency of this event increased during disease progression from basal cell hyperplasia (17%) to squamous metaplasia (24%) to carcinoma in situ (50%) lesions. Methylation of p16 was associated with loss of expression in both tumors and precursor lesions indicating that both alleles were functionally inactivated. The potential of using assays for aberrant p16 methylation to identify disease and/or risk was validated by detection of this change in sputum from three of seven patients with cancer and 5 of 26 cancer-free individuals at high risk. These studies show for the first time that an epigenetic alteration, aberrant methylation of the p16 gene, can be an early event in lung cancer and may constitute a new biomarker for early detection and monitoring of prevention trials.

Concurrent fluorescence in situ hybridization and immunocytochemistry for the detection of chromosome aberrations in exfoliated bronchial epithelial cells.

OBJECTIVE: A procedure was developed to allow concurrent detection of chromosome aberrations and identification of bronchial epithelial cells. STUDY DESIGN: Fluorescence in situ hybridization for chromosome 7 and immunocytochemistry for cytokeratin were performed on exfoliated bronchial epithelial cells in a sputum sample from a cancer patient. RESULTS: The Spectrum Orange-labeled alpha satellite probe for chromosome 7 produced red fluorescence, nuclei were counterstained with 4,6-diamidino-2-phenylindole (blue), and cytokeratin was visualized using a fluorescein isothiocyanate (FITC)-conjugated secondary antibody (green). CONCLUSION: This procedure allowed the rapid identification of airway epithelial cells with numerical chromosome aberrations in this sample. Ultimately, this procedure could increase the sensitivity and specificity of sputum cytology as a laboratory diagnostic tool for the early detection of lung cancer.

Saccomanno smear slides and Megafunnel slides for sputum specimens. A comparison.

OBJECTIVE: To compare Megafunnel slides to standard Saccomanno smear slides of sputum specimens and evaluate the use of Megafunnel slides for retrospective studies. STUDY DESIGN: Papanicolaou-stained Saccomanno smear and Megafunnel slides (Shandon Lipshaw, Inc., Shandon Inc., Pittsburgh, Pennsylvania, U.S.A.) of 65 clinical sputum specimens from 51 patients were compared for cellular morphology, staining, background and cytologic diagnosis. Recovery of diagnostic cells was quantitated using 10 of these specimens. Megafunnel slides prepared from the clinical sputum samples were immunocytochemically stained. Diagnostic cells were quantitated both before removal from 64 archived Saccomanno smear slides and after placement of these cells onto 238 Megafunnel slides. RESULTS: Saccomanno smear slides and Megafunnel slides of clinical specimens were similar in morphology, background, staining, diagnosis and cell recovery. Megafunnel slides were superior for multiple immunocytochemical stains. The production of multiple Megafunnel slides from archival smear slides provided a method of performing numerous retrospective studies. CONCLUSION: Megafunnel slides compared favorably to Saccomanno smear slides in the quality of specimens but are more expensive and labor intensive to prepare. However, the reduction in screening time by cytotechnologists may be advantageous. Additionally, their potential use for immunocytochemistry, fluorescence in situ hybridization, or other special clinical and research analyses is very promising.

Identification of a novel region of homozygous deletion on chromosome 9p in squamous cell carcinoma of the lung: the location of a putative tumor suppressor gene.

Cytogenetic and molecular studies have implied the presence of tumor suppressor genes (TSGs) on chromosome 9p that are critical in the development of lung and other cancers. The p16/CDKN2 gene, a cyclin dependent kinase inhibitor, is a well-defined TSG on 9p21. Although the frequency of mutations in the p16/CDKN2 gene has been detected in approximately 30% of non-small cell lung cancer, loss of heterozygosity on 9p has been observed in greater than 70% of non-small cell lung cancers. These and other deletion mapping studies have suggested the existence of additional TSGs on 9p. This study examined chromosome 9p for TSG loci by analyzing 23 squamous cell carcinomas of the lung with 21 microsatellite markers. Loss of heterozygosity was detected in all of the tumors, and homozygous deletions of the p16/ CDKN2 locus were observed in 6 of the 23 tumors (26%). In addition, a novel region of homozygous deletion was detected in six tumors (26%) at D9S126, approximately 2.5 cM proximal to p16/CDKN2. A single tumor contained a homozygous deletion at both the p16/CDKN2 locus and the D9S126 locus. The possibility of homozygous loss was confirmed by multiplex PCR using both the D9S126 marker and a chromosome 9p control marker. Fluorescence in situ hybridization analysis with P1 and cosmid probes containing D9S126 also confirmed these data. The minimum region of homozygous deletion was determined by testing markers immediately proximal and distal to the D9S126 region. The data identify a homozygous loss on the short arm of chromosome 9 suggesting the presence of a novel TSG locus, proximal to p16/CDKN2 and located between D9S265 and D9S259.

Dual chamber pacing in the treatment of congestive heart failure.

The present work reviews current literature and the authors' experience of dual chamber pacing in the treatment of patients with congestive heart failure (CHF). In these patients, the atrial contribution to ventricular filling may be less than optimal, especially in the presence of first degree atrioventricular block or mitral insufficiency, both of which are common in the elderly subject with CHF. Dual chamber pacing with short atrioventricular delays has proved effective in enhancing ventricular filling and, in selected cases, cardiac output, with improvement in clinical and instrumental parameters of heart failure. However, for an appropriate atrioventricular synchronization of the left chambers during pacing, the interatrial conduction time must be considered, to avoid atrial contraction against a closed mitral valve. Thus, dual chamber pacing may be a treatment option for CHF that fails to respond to medical therapy.

Cytopathological analysis of sputum in patients with airflow obstruction and significant smoking histories.

Advances in the understanding of lung cancer biology have led to observations that specific genetic changes occur in premalignant dysplasia. These observations have occurred predominantly in molecular studies of resected lung tumors and consequently, they may not be fully representative of those biological abnormalities characterizing premalignant lesions in individuals without overt lung cancer. Studies of premalignant epithelial cell biology and chemoprevention are needed in this patient subgroup. Such an initiative is now underway through the lung cancer Specialized Program of Research Excellence (SPORE) grant awarded to the University of Colorado Cancer Center (and affiliated institutions) by the National Cancer Institute. To identify participants for the early detection and chemoprevention trials of the Colorado SPORE, we initiated a sputum cytology screening program targeting persons with chronic obstructive pulmonary disease and smoking histories of 40 or more pack-years. During the first 26 months after activation of the screening program, sputum samples from 632 participants were evaluated. Of these, 533 (84%) of the subjects submitted specimens deemed adequate for cytopathological interpretation; 99 (16%) provided sputum samples unsuitable for cytodiagnosis. Of those participants who submitted adequate samples, 48% had cytodiagnoses of mild dysplasia, 26 % had moderate to severe dysplasia, and 2% presented with carcinoma in situ or invasive carcinoma. Logistic regression modeling was pursued to determine whether selected demographic and/or clinical status variables could be identified as statistically significant predictors of the specific cytological outcome to be expected (mild dysplasia, moderate dysplasia, and so forth). The only apparent associations found from both univariate and multivariate analyses were that the total number of pack-years of smoking history decreased with severity of cytodiagnosis and that those individuals with mild or moderate dysplasia were more likely to be ex-smokers than those with grades of regular metaplasia or lower. Based on the initial results of the Colorado SPORE sputum cytology screening program, we conclude that persons with chronic obstructive pulmonary disease and 40 or more pack-years of smoking history have a high prevalence of premalignant dysplasia detectable through sputum cytology and should be targeted for research programs focusing on lung cancer prevention, early detection, and exploratory biomarker studies.

Automated sputum screening with PAPNET system: a study of 122 cases.

The use of interactive, computerized PAPNET system (Neuromedical Systems, Inc, Suffern, NY) for screening of cervicovaginal smears has been favorably evaluated in several studies. In this article, the authors report on the performance of this apparatus on smears of sputum. One hundred twenty-two randomly selected, single slides of sputum specimens from an equal number of patients were subjected to PAPNET scanning. These Papanicolaou-stained slides were previously classified as inadequate, six; negative, 81; atypical, three; suspicious, one; and positive for malignant cells, 31. Images selected by PAPNET were reviewed by two observers, who were blinded to earlier interpretation and triaged into two categories: negative and review. Of the 31 smears with cancer cells, 30 were appropriately identified by PAPNET (sensitivity: 97.1%). The only case missed by PAPNET was that of small cell carcinoma that contained a single cluster of neoplastic cells. PAPNET also triggered the review of 20 of the "negative" cases, which on re-evaluation were identified as bronchial cells with squamous metaplasia and altered benign squamous cells of inflammatory type. A prospective study of PAPNET for screening of sputum samples is needed to establish the clinical value of this methodology.

A comparison between the localization of lung tumors in uranium miners and in nonminers from 1947 to 1991.

BACKGROUND: Lung cancer was noted to be increased in cigarette smoking miners and nonminers. Carcinogen particulates deposit differentially in the central, middle, and peripheral zones of the bronchial tree depending on the size of the particle. The object of this study was to evaluate the incidence of tumors; their cell types; and the relationship of particulate size to their position in the bronchial tree. METHODS: Tumor position in the bronchial tree was studied for a cohort of 467 uranium miners and 311 nonminers with lung cancer. RESULTS: An examination of all histologic subtypes showed that the proportion of lung cancers in the central zone was significantly greater in miners than in nonminers presumably due to the deposition of radon decay products attached to the silica dust particles. The higher percentage of central tumors in the miners was primarily due to the distribution of a greater proportion of squamous cell and small-cell tumors. The ratio of 0.75 for the central to middle and peripheral location for adenocarcinomas was much lower than for squamous cell and small-cell carcinomas with ratios of 1.4 and 7.3, respectively. In the mining cohort, there were ten times as many small-cell tumors in the central area as in the middle and peripheral regions, whereas, for the nonminers there were only five times as as many centrally located small-cell tumors as middle and peripheral (chi square is 7.0 degrees, P < 0.01). These data suggest that radon may be deposited preferentially to the central region of the lungs in uranium miners. CONCLUSIONS: Based on our observations of the differential positions of lung tumors in the bronchial tree for miners and nonminers and previous studies by others regarding size-dependent deposition of particulates in the bronchial tree, it is concluded that inhaled dust, radon, and cigarette smoke combine to form large particulates that deposit in the central bronchial tree. Filtered cigarette smoke or other small carcinogens from smaller particulates that deposit more peripherally.

Examination of p53 alterations and cytokeratin expression in sputa collected from patients prior to histological diagnosis of squamous cell carcinoma.

Mutations in the p53 gene are detected in greater than 50% of squamous cell carcinomas of the lung and to a lesser extent in adenocarcinomas. The p53 protein is also overexpressed in a relatively high percentage of preinvasive lesions of the bronchial epithelium. However, unlike tumor tissue, immunoreactivity does not necessarily imply that cells in preinvasive lesions carry a mutant p53 allele. In some cases, overexpression may result from a cellular checkpoint reaction to a toxic or mutagenic substance such as exposure to tobacco smoke. In any case, p53 overexpression in preinvasive lesions may serve as a biomarker for high risk assessment of lung cancer and other tumors in the aerodigestive tract. A study was designed to retrospectively analyze p53 overexpression in cells from sputum samples collected prior to histological tumor diagnosis. The rationale was based on the observation that both preinvasive and tumor cells from the bronchial epithelium are exfoliated into the airways and can be detected based on morphology in sputa. Two sets of cases were chosen: 1) patients whose first primary tumor was a squamous cell carcinoma containing a mutant p53 allele with overexpression observed in most of the tumor cells; and 2) patients whose squamous cell tumor did not contain a mutant p53 allele. Cells which stained positive for p53 expression were observed in sputum samples collected from all six patients whose tumors were positive for a mutant p53 allele. Also p53 positive cells were detected on sputum slides for two of the five cases where the tumor DNA did not contain a mutation and/or tumor cells which overexpress p53 were not detected in tissue sections. Although cells which stained positive for p53 were present in sputum from patients whose tumors contained a missense mutation, the presence of p53 overexpression was not specific for tumors which contain an altered p53 allele since overexpression was detected in sputum cells from patients whose tumor DNA did not contain a p53 mutation and/or tumor cells which stained positive for p53 were not observed in tissue sections. However, the p53 positive cells in sputa collected from the latter group of patients could have been exfoliated from other lesions which contained a mutant p53 allele. The accumulation of p53 in some sputum cells was concomitant with expression of simple epithelial type cytokeratins (CK) 8 and 18 or at least one of the other cytokeratins detected by a broad spectrum (PAN) CK antibody mixture. These data imply that most of the sputum cells which overexpress p53 are epithelial cells. Moreover, our results are consistent, at least in part, with other observations that cells which overexpress p53 in dyplasias and hyperplasias express CK 8, 18. We will continue to explore the possibility that expression of cytokeratins 8, 18 and/or other cytokeratins in conjunction with p53 overexpression and/or morphological criteria could define a new class of atypical cells which are predisposed to cancer development.

p53 and K-ras in radon-associated lung adenocarcinoma.

Mutations in the p53 tumor suppressor gene and the K-ras proto-oncogene are common genetic defects in lung cancer. Analysis of the patterns of damage in these genes may provide important insights into the mechanisms by which environmental mutagens initiate cancer. Previously, our laboratory found that a rare p53 codon 249 mutation (AGG(ARG) to ATG(MET) transversion) was present in 31% of a series of 52 large and squamous cell lung cancers from uranium miners, suggesting that this mutation might be a marker for radon exposure. In the current study, we analyzed 23 lung adenocarcinomas from the same cohort of highly exposed uranium miners. These tumors failed to show the codon 249 transversion, but 9 (39%) of 23 contained 1 or more mutations within hotspots in the K-ras gene. The results suggest that there is a histological tissue-type specificity for the codon 249 mutation; although this mutation was common in squamous and large cell tumors from very highly exposed uranium miners, it is rare in adenocarcinomas from the same cohort of miners.

[Femoro-popliteal bypass with reversed saphenous vein. Experience in a General Surgery Department]. / Bypass femoro-poplitei in safena invertita. Esperienza di una divisione di chirugia generale.

Femoro popliteal bypass with reversed saphenous vein are "the gold standard" for revascularization of lower extremities with femoro popliteal occlusion. This form of therapy is usually performed in a Vascular Surgery Department. We report the experience of a General Surgery Department, with patency of 90% at two years.

[Prognostic value of ECG changes detected by Holter monitoring in silent ischemic heart disease in the aged]. / Significato prognostico delle alterazioni ECG-grafiche rilevate all'Holter nella cardiopatia ischemica silente dell'anziano.

Ischemic Cardiomiopathy (IC) is the main cause of morbidity and mortality in the elderly and its incidence increases progressively with age. Holter monitoring (HM) is used to study IC which reveals asymptomatic ischemic episodes identifiable with the depression of the ST tract. It has been demonstrated that these electric manifestations have the same unfavourable diagnostic value as those accompanied by pain. In order to evaluate the prevalence and prognostic significance of episodes of silent myocardial ischemia in the elderly patient, we examined 99 consecutive patients with stable clinical symptoms of myocardial ischemia and a positive ergometric test (ET). The patients were randomly divided according to age (< or = 65 years, >65 years) into two groups with homogeneous clinical feature, except for a higher prevalence of women in the second group. The HM analysis, carried out for 24 hours during common every day activities and after suspending anti-ischemic therapy, showed that 62 patients (63%) had 289 episodes of electric ischemia; 216 (75%) of these were asymptomatic, and, in the group of elderly there was a higher incidence of ST depression unaccompanied by pain (A vs B = 86 vs 132 episodes, p < 0.001). Comparing the patients with and without anamnestic evidence of myocardial infarction it was found that the first group presented a higher prevalence of ST depression both asymptomatic and symptomatic (147 vs 71 silent episodes, p < 0.001, and 49 vs 24 symptomatic episodes, p = 0.015 respectively), while no statistically significant differences were found between the two age groups. Electric alterations of the asymptomatic ischemic kind were more often found in subjects with stable angina, above all if elderly; this is important from a prognostic point of view as few elderly patients are capable of performing a maximal TE and it is thus significant of reduced coronary reserve. From our data we observed that in patients with stable angina, especially if elderly, Holter revealed asymptomatic ST depression analyzed considering both its length and magnitude, is able to give prognostic evidence of subsequent coronary events.

Permanent cardiac pacing and thromboembolic risk in elderly patients.

In patients undergoing permanent cardiac pacing, the maintenance of atrial contractility is important to ensure adequate ventricular filling and to guarantee an optimal ventricular ejection capacity. The appropriate pacing mode, assuring a suitable mechanical atrioventricular coupling, prevents the onset of atrial fibrillation and contributes to reduction of the risk of subsequent systemic and pulmonary thromboembolic episodes. We examined 461 patients (266 males and 195 females, aged between 52 and 97 years, average age 76.5 +/- 18) paced for conduction disturbances of various degrees and etiology. Of them, 323 patients received ventricular demand pacemaker (VVI group, average age 77.9 years); 138 underwent dual chamber pacing (DCP group, average age 75.2 years), 117 of the latter received universal demand pacing (DDD) and 21 atrial synchronous ventricular demand pacing (VDD). The patients were subsequently divided into two age-groups: Group A (/= 75 years, 287 patients). According to pacing mode and successive development of stable atrial fibrillation (AF), we analysed the occurrence of systemic and/or pulmonary thromboembolic episodes and the incidence of fatal events. During our study, performed from January 1986 to August 1993, 70 embolic episodes were observed in the VVI group and six in the DCP group. Eighty-four patients with VVI units developed AF during follow-up, compared with only five patients in the DCP group. Our data indicate that VVI patients have a higher incidence of AF, embolic complications and cerebrovascular mortality, in comparison with the DCP group. VVI pacing should be avoided, especially in older patients, when atrial rhythmical activity is present.