Nonmalignant Pulmonary Disease Research Articles

Specialist Palliative Care Consultation for Patients with Nonmalignant Pulmonary Diseases: A Retrospective Study.

Few patients with chronic nonmalignant pulmonary diseases receive specialist palliative care consultation, despite their high symptom burden in end of life. To study palliative care decision making, survival, and hospital resource usage in patients with nonmalignant pulmonary diseases with or without a specialist palliative care consultation. A retrospective chart review of all patients with a chronic nonmalignant pulmonary disease and a palliative care decision (palliative goal of therapy), who were treated in Tampere University Hospital, Finland, between January 1, 2018 and December 31, 2020. A total of 107 patients were included in the study, 62 (58%) had chronic obstructive pulmonary disease (COPD), and 43 (40%) interstitial lung disease (ILD). Median survival after palliative care decision was shorter in patients with ILD than in patients with COPD (59 vs. 213 days, p = 0.004). Involvement of a palliative care specialist in the decision making was not associated with the survival. Patients with COPD who received palliative care consultation visited less often emergency room (73% vs. 100%, p = 0.019) and spent fewer days in the hospital (7 vs. 18 days, p = 0.007) during the last year of life. When a palliative care specialist attended the decision making, the presence and opinions of the patients were recorded more often, and the patients were more frequently referred to a palliative care pathway. Specialist palliative care consultation seems to enable better end-of-life care and supports shared decision making for patients with nonmalignant pulmonary diseases. Therefore, palliative care consultations should be utilized in nonmalignant pulmonary diseases preferably before the last days of life.

Causes of Death in Long-Term Nasopharyngeal Carcinoma Survivors.

PurposeTo assess the causes of death (COD) and long-term survival after nasopharyngeal carcinoma (NPC) diagnosis.MethodsUsing linked data from the Surveillance, Epidemiology, and End Results program, patients with NPC diagnosed from 1990 to 2010 and followed up >5 years were identified. Chi-squared test, the Kaplan–Meier method, and the Cox proportional hazard model were used for analyses.ResultsAmong the 3,036 long-term NPC survivors, 1,432 survived for >5–10 years and 1,604 survived for >10 years. The most common COD was primary NPC (36.9%), followed by other causes (28.7%), other cancers (15.3%), cardiac disease (12.9%), and non-malignant pulmonary disease (6.2%). With a median follow-up of 125 months, deaths from NPC decreased with increasing time from diagnosis, while death because of cardiac disease and other causes increased. In those aged <50 years, death due to NPC remained the main COD over time, while cardiopulmonary disease-related death was the leading COD in patients aged ≥50 years. In White patients, death due to NPC decreased, and death due to cardiac disease increased over time. Death from NPC remained significant in Black and Asian patients even 15 years after the diagnosis of NPC, while death due to cardiac disease significantly increased after 9 years of diagnosis in Black patients. Multivariate analyses showed that the independent factors associated with inferior NPC-specific survival were older age, Asians, American Indian/Alaska Native, regional stage, distant stage, and diagnosis in the early years.ConclusionsThe probability of death from primary NPC remains significant even 15 years after the NPC diagnosis. Our study advocates continued surveillance for NPC survivors beyond the traditional 5 years. Individualized follow-up strategies are required for patients with NPC of different ages and races.

Circulating tumor cells as a biomarker for precise management in lung cancer.

e21018 Background: Circulating tumor cells (CTCs) have potential utility in various clinical application for cancer management. In this study, we evaluated whether circulating tumor cells (CTCs) provide early diagnostic information and/or precisely indication of patient response to chemotherapy. Methods: 56 patients with newly diagnosed lung cancer, 42 patients with nonmalignant pulmonary disease and 27 healthy controls were enrolled in this study. CTCs were measured at baseline in all eligible subjects and after two cycles of chemotherapy in 25 advanced lung cancer patients, with a strategy of negative enrichment combined with immunostaining-fluorescence in situ hybridization (imFISH). The receiver operating characteristic (ROC) curve was plotted to determine the sensitivity and specificity of the CTC detection for diagnosis. Kaplan-Meier curve and two-sided log-rank test were used for univariate survival analyses. Results: The number of CTCs was significantly increased in lung cancer patients, compared with benign lung disease patients and healthy controls. And it reached 87.5% sensitivity and 95.7% specificity at a cutoff value of 2 cells/3.2ml (AUC = 0.975, 95%CI, 0.953-0.998, p＜0.001).Moreover, the sensitivity of CTCs was much higher than individual or the combination of serum tumor markers, especially in the early detection of lung cancer. Twenty-five advanced lung cancer patients were subsequently followed for an average of 18.2 months (range 6-36 months) ， during which all patients experienced disease progression, and 16 patients died. A change in CTC count after two cycles of chemotherapy was highly predictive for PFS (13.5 v 8.5 months; p = 0.025) and OS (27.6 v 16.8 months; p = 0.009) in favor of a reduction in CTC number compared with an increase. Interestingly, among the patients whose post-treatment computed tomography(CT) results indicated stable disease(SD), PFS (14.0 v 8.7months; p = 0.033) and OS(25.8 v 15.9 months; p = 0.018) in patients whose CTC number decreased after two cycles of treatment were still significantly longer than those whose post-treatment CTCs number increased or unchanged. Conclusions: CTCs may act as precise biomarker for early detection and therapy monitoring that could compensate for imaging.

Long-Term Survival Among Histological Subtypes in Advanced Epithelial Ovarian Cancer: Population-Based Study Using the Surveillance, Epidemiology, and End Results Database.

BackgroundActual long-term survival rates for advanced epithelial ovarian cancer (EOC) are rarely reported.ObjectiveThis study aimed to assess the role of histological subtypes in predicting the prognosis among long-term survivors (≥5 years) of advanced EOC.MethodsWe performed a retrospective analysis of data among patients with stage III-IV EOC diagnosed from 2000 to 2014 using the Surveillance, Epidemiology, and End Results cancer data of the United States. We used the chi-square test, Kaplan–Meier analysis, and multivariate Cox proportional hazards model for the analyses.ResultsWe included 8050 patients in this study, including 6929 (86.1%), 743 (9.2%), 237 (2.9%), and 141 (1.8%) patients with serous, endometrioid, clear cell, and mucinous tumors, respectively. With a median follow-up of 91 months, the most common cause of death was primary ovarian cancer (80.3%), followed by other cancers (8.1%), other causes of death (7.3%), cardiac-related death (3.2%), and nonmalignant pulmonary disease (3.2%). Patients with the serous subtype were more likely to die from primary ovarian cancer, and patients with the mucinous subtype were more likely to die from other cancers and cardiac-related disease. Multivariate Cox analysis showed that patients with endometrioid (hazard ratio [HR] 0.534, P<.001), mucinous (HR 0.454, P<.001), and clear cell (HR 0.563, P<.001) subtypes showed better ovarian cancer-specific survival than those with the serous subtype. Similar results were found regarding overall survival. However, ovarian cancer–specific survival and overall survival were comparable among those with endometrioid, clear cell, and mucinous tumors.ConclusionsOvarian cancer remains the primary cause of death in long-term ovarian cancer survivors. Moreover, the probability of death was significantly different among those with different histological subtypes. It is important for clinicians to individualize the surveillance program for long-term ovarian cancer survivors.

Causes of death in long-term bladder cancer survivors: A population-based study.

Long-term(>5 years) bladder cancer survivors represent a distinct subgroup of bladder cancer patients and information about the causes of death in this subgroup is limited. The aim of this study was to review the causes of death in long-term bladder cancer survivors. The Surveillance, epidemiology and end results (SEER) database was used to analyze the causes of death of long-term bladder cancer survivors. Patients' characteristics and survival outcomes were reported for the entire cohort in our study. Kaplan-Meier analysis and Cox proportional hazard model for survival analysis. A total of 147781 bladder cancer patients with>5 years survival were identified. This cohort included 81843 patients surviving 5-10 years and 65938 patients surviving>10 years. Among the patients who survived 5-10 years, 6.9% died because of primary bladder cancer, 11.0% due to cardiac disease and 7.7% due to nonmalignant pulmonary disease. Among patients surviving>10 years, 3.1% died because of primary bladder cancer, 8.6% due to cardiac disease and 5.8% due to nonmalignant pulmonary disease. On multivariate analysis, factors associated with longer cardiac disease-specific survival among long-term bladder cancer survivors include younger age at diagnosis（<40 years; vs. 40-69 years, P=0.030 or>69 years, P<0.001), married status (vs. single status, P<0.001), white race (vs. African American race, P=0.002), male (vs. female, P<0.001), grade I (vs. grade III, P=0.003 or grade IV, P<0.001). The probability of death from primary bladder cancer is still important among various causes of death even 20 years after being diagnosed with bladder cancer. Furthermore, cardiopulmonary causes contributed to a considerable proportion of deaths in long-term bladder cancer survivors.

Template-ready PCR method for detection of human telomerase reverse transcriptase mRNA in sputum

Human telomerase reverse transcriptase (hTERT) mRNA in tissue is a biomarker of lung cancer, but hTERT mRNA in sputum had not been successfully detected with conventional reverse transcription PCR methods. Here, we developed a novel PCR protocol: Template-Ready PCR (TRPCR), to detect sputum hTERT mRNA, in which probes serve as templates of amplification. While free probes and dsDNA were removed in template preparation through aspiration and restriction digestion, probes that formed into heterocomplex with target RNA remained intact for PCR amplification. By fishing out the heterocomplex and amplifying the probes, TRPCR achieved sensitivity higher than reverse transcription-quantitative PCR (RT-qPCR). ROC curve of sputum hTERT mRNA by TRPCR assay showed the discrimination in high sensitivity and specificity between patients with lung cancer and lung cancer-free donors at the PCR Ct cutoff of 33. We further validated this approach through TRPCR assay of sputum from 858 lung cancer patients and 480 non-malignant pulmonary disease patients. 722 (84.2%) cases from 858 with lung cancer patients were detected as positive, whereas 461 (96.0%) cases from 480 non-malignant pulmonary disease patients were detected as negative, suggesting that TRPCR assay of sputum hTERT mRNA can serve as a non-invasive molecular diagnosis of lung cancer.

Dose and dose rate extrapolation factors for malignant and non-malignant health endpoints after exposure to gamma and neutron radiation.

Murine experiments were conducted at the JANUS reactor in Argonne National Laboratory from 1970 to 1992 to study the effect of acute and protracted radiation dose from gamma rays and fission neutron whole body exposure. The present study reports the reanalysis of the JANUS data on 36,718 mice, of which 16,973 mice were irradiated with neutrons, 13,638 were irradiated with gamma rays, and 6107 were controls. Mice were mostly Mus musculus, but one experiment used Peromyscus leucopus. For both types of radiation exposure, a Cox proportional hazards model was used, using age as timescale, and stratifying on sex and experiment. The optimal model was one with linear and quadratic terms in cumulative lagged dose, with adjustments to both linear and quadratic dose terms for low-dose rate irradiation (<5mGy/h) and with adjustments to the dose for age at exposure and sex. After gamma ray exposure there is significant non-linearity (generally with upward curvature) for all tumours, lymphoreticular, respiratory, connective tissue and gastrointestinal tumours, also for all non-tumour, other non-tumour, non-malignant pulmonary and non-malignant renal diseases (p<0.001). Associated with this the low-dose extrapolation factor, measuring the overestimation in low-dose risk resulting from linear extrapolation is significantly elevated for lymphoreticular tumours 1.16 (95% CI 1.06, 1.31), elevated also for a number of non-malignant endpoints, specifically all non-tumour diseases, 1.63 (95% CI 1.43, 2.00), non-malignant pulmonary disease, 1.70 (95% CI 1.17, 2.76) and other non-tumour diseases, 1.47 (95% CI 1.29, 1.82). However, for a rather larger group of malignant endpoints the low-dose extrapolation factor is significantly less than 1 (implying downward curvature), with central estimates generally ranging from 0.2 to 0.8, in particular for tumours of the respiratory system, vasculature, ovary, kidney/urinary bladder and testis. For neutron exposure most endpoints, malignant and non-malignant, show downward curvature in the dose response, and for most endpoints this is statistically significant (p<0.05). Associated with this, the low-dose extrapolation factor associated with neutron exposure is generally statistically significantly less than 1 for most malignant and non-malignant endpoints, with central estimates mostly in the range 0.1-0.9. In contrast to the situation at higher dose rates, there are statistically non-significant decreases of risk per unit dose at gamma dose rates of less than or equal to 5mGy/h for most malignant endpoints, and generally non-significant increases in risk per unit dose at gamma dose rates ≤5mGy/h for most non-malignant endpoints. Associated with this, the dose-rate extrapolation factor, the ratio of high dose-rate to low dose-rate (≤5mGy/h) gamma dose response slopes, for many tumour sites is in the range 1.2-2.3, albeit not statistically significantly elevated from 1, while for most non-malignant endpoints the gamma dose-rate extrapolation factor is less than 1, with most estimates in the range 0.2-0.8. After neutron exposure there are non-significant indications of lower risk per unit dose at dose rates ≤5mGy/h compared to higher dose rates for most malignant endpoints, and for all tumours (p=0.001), and respiratory tumours (p=0.007) this reduction is conventionally statistically significant; for most non-malignant outcomes risks per unit dose non-significantly increase at lower dose rates. Associated with this, the neutron dose-rate extrapolation factor is less than 1 for most malignant and non-malignant endpoints, in many cases statistically significantly so, with central estimates mostly in the range 0.0-0.2.

Causes of death in long-term lung cancer survivors: a SEER database analysis

Background: Long-term (>5 years) lung cancer survivors represent a small but distinct subgroup of lung cancer patients and information about the causes of death of this subgroup is scarce.Methods: The Surveillance, Epidemiology and End Results (SEER) database (1988–2008) was utilized to determine the causes of death of long-term survivors of lung cancer. Survival analysis was conducted using Kaplan–Meier analysis and multivariate analysis was conducted using a Cox proportional hazard model. Clinicopathological characteristics and survival outcomes were assessed for the whole cohort.Results: A total of 78,701 lung cancer patients with >5 years survival were identified. This cohort included 54,488 patients surviving 5–10 years and 24,213 patients surviving >10 years. Among patients surviving 5–10 years, 21.8% were dead because of primary lung cancer, 10.2% were dead because of other cancers, 6.8% were dead because of cardiac disease and 5.3% were dead because of non-malignant pulmonary disease. Among patients surviving >10 years, 12% were dead because of primary lung cancer, 6% were dead because of other cancers, 6.9% were dead because of cardiac disease and 5.6% were dead because of non-malignant pulmonary disease. On multivariate analysis, factors associated with longer cardiac-disease-specific survival in multivariate analysis include younger age at diagnosis (p < .0001), white race (vs. African American race) (p = .005), female gender (p < .0001), right-sided disease (p = .003), adenocarcinoma (vs. large cell or small cell carcinoma), histology and receiving local treatment by surgery rather than radiotherapy (p < .0001).Conclusion: The probability of death from primary lung cancer is still significant among other causes of death even 20 years after diagnosis of lung cancer. Moreover, cardiac as well as non-malignant pulmonary causes contribute a considerable proportion of deaths in long-term lung cancer survivors.

High risks of lung disease associated with early-life and moderate lifetime arsenic exposure in northern Chile

BackgroundArsenic in drinking water has been associated with increases in lung disease, but information on the long-term impacts of early-life exposure or moderate exposure levels are limited. MethodsWe investigated pulmonary disease and lung function in 795 subjects from three socio-demographically similar areas in northern Chile: Antofagasta, which had a well-described period of high arsenic water concentrations (860μg/L) from 1958 to 1970; Iquique, which had long-term arsenic water concentrations near 60μg/L; and Arica, with long-term water concentrations ≤10μg/L. ResultsCompared to adults never exposed >10μg/L, adults born in Antofagasta during the high exposure period had elevated odds ratios (OR) of respiratory symptoms (e.g., OR for shortness of breath=5.56, 90% confidence interval (CI): 2.68–11.5), and decreases in pulmonary function (e.g., 224mL decrease in forced vital capacity in nonsmokers, 90% CI: 97–351mL). Subjects with long-term exposure to arsenic water concentrations near 60μg/L also had increases in some pulmonary symptoms and reduced lung function. ConclusionsOverall, these findings provide new evidence that in utero or childhood arsenic exposure is associated with non-malignant pulmonary disease in adults. They also provide preliminary new evidence that long-term exposures to moderate levels of arsenic may be associated with lung toxicity, although the magnitude of these latter findings were greater than expected and should be confirmed.

Lung cancer circulating tumor cells isolated by the EpCAM-independent enrichment strategy correlate with Cytokeratin 19-derived CYFRA21-1 and pathological staging

BackgroundCytokeratin 19-derived CYFRA21-1 is an acceptable lung cancer biomarker. However, whether CYFRA21-1 correlates with lung cancer circulating tumor cells (CTCs) remains unclear. MethodsCTCs in 42 lung cancer patients and 10 nonmalignant pulmonary disease patients were isolated by means of an EpCAM-independent enrichment strategy. Correlation of lung cancer CTCs with serum concentration of CYFRA21-1 and pathological staging was investigated. ResultsAmong lung cancer patients in this study, 39% (7/18) of those with normal CYFRA21-1 (≤3.3ng/ml) and 62% (13/21) of high CYFRA21-1 (>3.3ng/ml) patients were found to have ≥3 CTCs/7.5ml blood. The CTCs-positive rate of stage I to IV lung cancer patients was 20% (2/10), 45% (5/11), 54% (6/11) and 70% (7/10), respectively. Comparing M0 vs M1 patients, the CTCs-positive rate was 43% (13/30) and 70% (7/10), respectively. All M1 patients (10/10) had one or more CTCs detected, whereas none of the nonmalignant pulmonary disease patients had detectable CTCs. ConclusionLung cancer CTCs isolated by the EpCAM-independent enrichment approach correlate with CYFRA21-1 and TNM staging. Correlation of CTCs and CYFRA21-1 in lung cancer patients is of potential clinical utility in terms of early diagnosis and predicting prognosis.

Déclaration et reconnaissance en maladie professionnelle après dépistage tomodensitométrique de maladies pleuropulmonaires bénignes dans le programme multirégional de surveillance postprofessionnelle de personnes exposées à l’amiante

BackgroundUnderreporting of occupational diseases related to asbestos exposure remains a matter of concern in France. The aim of this study was to evaluate the number of claims for compensation for asbestos-related non-malignant pulmonary or pleural occupational disease in subjects having undergone a chest CT-scan in a multiregional screening programme. MethodsAmong the 5444 voluntary retired asbestos-exposed subjects recruited in four regions between 2003 and 2005 who had undergone a chest CT-scan, the number of claims for compensation for an asbestos-related pulmonary or pleural benign disease was analysed in 2006 and 2010. ResultsFollowing CT-scan screening, 17.2% of participants were acknowledged as presenting with an asbestos-related non-malignant occupational disease, essentially pleural plaques, by the French National Health Insurance fund. Underreporting decreased as duration of follow-up after CT-scan increased. Nevertheless, 4 years after CT-scan, underreporting was still as high as 36% for subjects identified as presenting with pleural plaques. Mean duration between the date of CT-scan and the date of recognition as occupational disease was 7.4 months, shorter in cases where screening was coordinated by specialized centres. ConclusionA plan of action for an easier claiming process for compensation of asbestos-related diseases is desired. This could probably be obtained through improved sensitization of physicians engaged in the follow-up of asbestos-exposed subjects, and by standardization of the interpretation and reporting of asbestos-related abnormalities observed on chest CT-scans.

DNA-Based Sputum Cell Image Analysis for Lung Cancer in a Clinical Setting

To measure cell nuclei characteristics, previously reported to express probability for lung cancer, in subjects with different forms ofpulmonary disease and those without disease.Sputum and buccal cell samples were obtained from 846 patients without pulmonary disease, with nonmalignant disease, chronic obstructive pulmonary disease, asbestosis and lung cancer, stained for DNA, scanned by cytometer and scored. This was related to specificity and sensitivity for lung cancer. At score 4.5 sensitivity was 53.8% and specificity 70.9%. This score and higher were defined as high scores (HS) and used to compare groups with lung cancer and other pulmonary disease.Among subjects without disease, 21.1% had HS in sputum cells. Among those with nonmalignant pulmonary disease, 31.7% had HS, and among subjects with lung cancer, 53.8% had it. Repeated evaluations showed that about one third of those with HS on the first occasion were normal on repeat sampling. Among subjects without lung cancer, 33.8% of never-smokers had sputum cell HS compared to 22.7.2% among smokers.Results demonstrate that the DNA cellular characteristics on cytometry were more frequent among subjects with lung cancer but also among subjects with other pulmonary disease compared to subjects witbout pulmonary disease.

Squamous Cell Carcinoma Antigen in Lung Cancer and Nonmalignant Respiratory Diseases

Squamous cell carcinoma antigen (SCC) has been found in elevated amounts in patients with squamous cell lung cancer (SQLC). Elevated levels have also been found among patients with nonsquamous cell lung cancer (NSQLC) and in subjects with nonmalignant pulmonary disease (NMPD). The purpose of the current study was to evaluate SCC levels among a large number of patients with SQLC, NSQLC, and NMPD. Six hundred thirty-nine lung cancer patients, including 201 SQLC patients and 299 patients with NMPD, who were diagnosed at our hospital up to 2006 were entered. Serum SCC levels were measured with a commercially available kit. Elevated levels (>1.5 ng/ml) of SCC were observed in 52.7% of SQLC patients, but in only 14.2% of NSQLC patients. There was a statistically significant difference in positive rate between SQLC and NSQLC patients. None of the NSQLC patients had serum SCC levels greater than 40.0 ng/ml. Among subjects with NMPD, 28.4% had elevated levels of SCC. However, none of the NMPD patients had serum SCC levels greater than 20.0 ng/ml. Serum levels of SCC can be elevated (<20.0 ng/ml) in some NMPD patients without coexisting SQLC. Patients with NSQLC and NMPD with elevated SCC levels greater than 40 ng/ml may have coexisting SQLC or squamous cell carcinoma in an extrapulmonary site.

Aberrant promoter methylation in pleural fluid DNA for diagnosis of malignant pleural effusion

Accumulating evidence implicates epigenetic changes such as hypermethylation in carcinogenesis. We investigated whether DNA methylation of 5 tumor suppressor genes in pleural fluid samples could aid in diagnosis of malignant effusion. In samples from 47 patients with malignant pleural effusions and 34 with nonmalignant effusions, we used a methylation-specific polymerase chain reaction to detect aberrant hypermethylation of the promoters of the DNA repair gene O(6)-methylguanine-DNA methyltransferase (MGMT), p16(INK4a), ras association domain family 1A (RASSF1A), apoptosis-related genes, death-associated protein kinase (DAPK), and retinoic acid receptor beta (RARbeta). Promoter hypermethylation was associated with malignant effusion for MGMT (Odds ratio (OR) = infinity), p16(INK4a) (OR = infinity), RASSF1A (OR = 13.8; CI, 1.71-112), and RARbeta (OR = 3.17; CI, 1.10-9.11), but not for DAPK. Instead, DAPK methylation was associated with the length of smoking (p < 0.05). Patients with hypermethylation of MGMT, p16(INK4a), RASSF1A or RARbeta were 5.68 times more likely to have malignant effusions than patients without methylation (p = 0.008). Methylations per patient were more numerous for lung cancer than nonmalignant pulmonary disease (0.915 vs. 0.206, p < 0.001). Sensitivity, specificity, and positive predictive value of methylation in one or more genes for diagnosis of malignant effusion were 59.6%, 79.4%, and 80.0% respectively. In conclusion, aberrant promoter methylation of tumor suppressor genes in pleural fluid DNA could be a valuable diagnostic marker for malignant pleural effusion.

Biomarkers to assess the utility of potential reduced exposure tobacco products.

To date, we have no valid biomarkers that serve as proxies for tobacco-related disease to test potential reduced exposure products. This paper represents the deliberations of four workgroups that focused on four tobacco-related heath outcomes: Cancer, nonmalignant pulmonary disease, cardiovascular disease, and fetal toxicity. The goal of these workgroups was to identify biomarkers that offer some promise as measures of exposure or toxicity and ultimately may serve as indicators for future disease risk. Recommendations were based on the relationship of the biomarker to what is known about mechanisms of tobacco-related pathogenesis, the extent to which the biomarker differs among smokers and nonsmokers, and the sensitivity of the biomarker to changes in smoking status. Other promising biomarkers were discussed. No existing biomarkers have been demonstrated to be predictive of tobacco-related disease, which highlights the importance and urgency of conducting research in this area.

Biomarkers to assess the utility of potential reduced exposure tobacco products

To date, we have no valid biomarkers that serve as proxies for tobacco-related disease to test potential reduced exposure products. This paper represents the deliberations of four workgroups that focused on four tobacco-related heath outcomes: Cancer, nonmalignant pulmonary disease, cardiovascular disease, and fetal toxicity. The goal of these workgroups was to identify biomarkers that offer some promise as measures of exposure or toxicity and ultimately may serve as indicators for future disease risk. Recommendations were based on the relationship of the biomarker to what is known about mechanisms of tobacco-related pathogenesis, the extent to which the biomarker differs among smokers and nonsmokers, and the sensitivity of the biomarker to changes in smoking status. Other promising biomarkers were discussed. No existing biomarkers have been demonstrated to be predictive of tobacco-related disease, which highlights the importance and urgency of conducting research in this area.

Bronchiectasis in Persons With Skin Lesions Resulting From Arsenic in Drinking Water

Arsenic is a unique human carcinogen in that it causes lung cancer by exposure through ingestion (in drinking water) as well as through inhalation. Less is known about nonmalignant pulmonary disease after exposure to arsenic in drinking water. We recruited 108 subjects with arsenic-caused skin lesions and 150 subjects without lesions from a population survey of over 7000 people in an arsenic-exposed region in West Bengal, India. Thirty-eight study participants who reported at least 2 years of chronic cough underwent high-resolution computed tomography (CT); these scans were read by investigators in India and the United States without knowledge of the presence or absence of skin lesions. The mean (+/-standard deviation) bronchiectasis severity score was 3.4 (+/-3.6) in the 27 participants with skin lesions and 0.9 (+/-1.6) in the 11 participants without these lesions. In subjects who reported chronic cough, CT evidence of bronchiectasis was found in 18 (67%) participants with skin lesions and 3 (27%) subjects without skin lesions. Overall, subjects with arsenic-caused skin lesions had a 10-fold increased prevalence of bronchiectasis compared with subjects who did not have skin lesions (adjusted odds ratio=10; 95% confidence interval=2.7-37). These results suggest that, in addition to being a cause of lung cancer, ingestion of high concentrations of arsenic in drinking water may be a cause of bronchiectasis.

Asbestos Exposure, Pleural Mesothelioma, and Serum Osteopontin Levels

We investigated the presence of osteopontin in pleural mesothelioma and determined serum osteopontin levels in three populations: subjects without cancer who were exposed to asbestos, subjects without cancer who were not exposed to asbestos, and patients with pleural mesothelioma who were exposed to asbestos. A group of 69 subjects with asbestos-related nonmalignant pulmonary disease were compared with 45 subjects without exposure to asbestos and 76 patients with surgically staged pleural mesothelioma. Tumor tissue was examined for osteopontin by immunohistochemical analysis, and serum osteopontin levels were measured by an enzyme-linked immunosorbent assay. There were no significant differences in mean (+/-SE) serum osteopontin levels between age-matched subjects with exposure to asbestos and subjects without exposure to asbestos (30+/-3 ng per milliliter and 20+/-4 ng per milliliter, respectively; P=0.06). In the group with exposure to asbestos, elevated serum osteopontin levels were associated with pulmonary plaques and fibrosis (56+/-13 ng per milliliter) but not with normal radiographic findings (21+/-5 ng per milliliter), plaques alone (23+/-3 ng per milliliter), or fibrosis alone (32+/-7 ng per milliliter) (P=0.004). Serum osteopontin levels were significantly higher in the group with pleural mesothelioma than in the group with exposure to asbestos (133+/-10 ng per milliliter vs. 30+/-3 ng per milliliter, P<0.001). Immunohistochemical analysis revealed osteopontin staining of the tumor cells in 36 of 38 samples of pleural mesothelioma. An analysis of serum osteopontin levels comparing the receiver-operating-characteristic curve in the group exposed to asbestos with that of the group with mesothelioma had a sensitivity of 77.6 percent and a specificity of 85.5 percent at a cutoff value of 48.3 ng of osteopontin per milliliter. Subgroup analysis comparing patients with stage I mesothelioma with subjects with exposure to asbestos revealed a sensitivity of 84.6 percent and a specificity of 88.4 percent at a cutoff value of 62.4 ng of osteopontin per milliliter. Serum osteopontin levels can be used to distinguish persons with exposure to asbestos who do not have cancer from those with exposure to asbestos who have pleural mesothelioma.

Pulmonary complications in patients with head and neck and lung neoplasms.

The occurrence of second primary neoplasms in patients with head and neck carcinoma assumes greater importance as our ability to control local disease improves. Both the primary lesions and the therapeutic interventions can predispose patients to pulmonary complications. To explore the incidence of pulmonary complications in patients with head and neck cancer who also undergo lung surgery. Survey; case series. A tertiary care university hospital. The clinic and hospital charts of 32 patients with multiple interventions of the head and neck and lung were retrospectively reviewed, and data were recorded on the clinical and pathologic specifics of primary and secondary neoplasms, pulmonary complications, and treatment outcomes. Twenty-eight (88%) of these patients underwent a diagnostic or therapeutic surgical procedure for a head and neck primary neoplasm. All patients (100%) underwent a pulmonary resection for malignant or nonmalignant pulmonary disease. Overall, 31 patients (97%) experienced either major or minor pulmonary complications after surgery, 51 (79%) of which occurred during the immediate postoperative course. Major complications occurred in 11 patients (34%), which were fatal in one. Our data suggest that patients with head and neck cancer who also experience a second pulmonary disease requiring lung resection are at high risk of developing serious pulmonary complications. These risks should be considered in planning optimal therapy.

Immunoassay of Neuron-Specific Enolase (Nse) and Serum Fragments of Cytokeratin 19 (Cyfra 21.1) as Tumor Markers in Small Cell Lung Cancer: Clinical Evaluation and Biological Hypothesis

NSE is a biochemical marker for small cell lung cancer (SCLC) diagnosis and management. CYFRA 21.1 is a newly developed immunoassay to detect the serum fragments of cytokeratin 19 which are also expressed in SCLC with or without neurofilaments. The aim of this study was to evaluate the diagnostic performance and prognostic role of the two markers in SCLC and their contribution to chemotherapy monitoring and patient follow-up. We studied 62 patients with pathologically proven SCLC: 28 with limited disease (LD) and 34 with extensive disease (ED), and 100 patients with non-malignant pulmonary disease. Immunoradiometric assays (IRMA) were employed to test NSE and CYFRA 21.1 in patients and control subjects. For each patient subset results were expressed as median and interquartile distribution range. NSE and CYFRA 21.1 sensitivity was 0.52 (33/62) and 0.56 (35/62), respectively. In the group of patients with LD, NSE and CYFRA 21.1 sensitivity was 0.42 (12/28) and 0.54 (15/28) and in patients with ED, NSE and CYFRA 21.1 were positive in 0.62 (21/34) and 0.59 (20/34) of cases, respectively. Combining the two markers, a sensitivity of 0.78 (22/28) in LD, 0.82 (28/34) in ED and a global sensitivity of 0.80 (50/62) was obtained. Only NSE was significantly linked to the extension of disease (Mann-Whitney U test p = 0.002) while CYFRA 21.1 did not correlate. The analysis of survival and the evaluation of the two markers at diagnosis showed CYFRA 21.1 to be strongly linked to the patients' outcome, independently of both clinical prognostic factors and NSE levels (log rank and Cox's model). The markers' performance during chemotherapy was tested in a group of 33 patients with at least one marker above cut-off. NSE can be considered a reliable marker of tumor mass modifications under chemotherapy, while CYFRA 21.1 expression seems to be relatively independent of tumor volume modifications. An applicable model of biomarkers in SCLC could be the concurrent assay of NSE and CYFRA 21.1 in pre-therapeutic assessment and therapy planning. CYFRA 21.1 does not play an important role during therapy monitoring and follow-up; in these phases NSE alone may be employed.