INTRODUÇÃO. Estudos epidemiológicos têm demonstrado que a exposição à poluição atmosférica está associada ao aumento de doenças cardiorrespiratórias. Trabalhos experimentais anteriores, utilizaram uretana para induzir a formação de nódulos pulmonares em camundongos e expor estes animais à poluição de \"mundo real\". Ou seja, os animais foram expostos a gases e partículas da mesma forma com que a população está exposta na cidade de São Paulo. Evidenciou-se então, o papel promotor e dose dependente da atmosfera poluída na progressão dos tumores de pulmão. Sabe-se que substâncias carcinogênicas como hidrocarbonetos policíclicos aromáticos (HPA), metais, ácidos graxos e aldeídos, estão presentes na fração particulada respirável da poluição (material particulado fino - MP 2,5), e a exposição prolongada a este último vem sendo considerada um risco para o desenvolvimento do câncer de pulmão. O objetivo deste estudo é verificar se a exposição crônica ao MP2,5 concentrado, a partir do ar ambiente da cidade de São Paulo, tem potencial carcinogênico. MÉTODOS. Foram utilizados 60 camundongos machos suíços (30g); e 60 AJ (20g), com quatro a seis semanas de vida. Os camundongos suíços foram pré-tratados com um carcinógeno completo, o ácido carbâmico (uretana-U), enquanto que os AJ receberam um carcinógeno iniciador 4-(methylnitrosamino)-1-(3-pyridil)-1-butanona (NNK), por serem pré-dispostos ao desenvolvimento de tumores de pulmão. Em seguida todos os animais foram expostos no Concentrador de Partículas Atmosféricas Harvard ao MP 2,5 diariamente, por 2 horas, durante quatro meses. Cada linhagem foi dividida em quatro grupos (n=15 cada): 2 controles com salina e carcinógeno (CsS e CsU ou CajS e CajNNK) e 2 expostos com salina e carcinógeno (EsS e EsU ou EajS e EajNNK). Foi realizada a análise histopatológica dos pulmões, a contagem e classificação das lesões pulmonares encontradas. Foi feito estudo imunoistoquimico para p53 e PCNA. RESULTADOS. Os animais dos grupos expostos, em ambas as linhagens, apresentaram maior número de lesões neoplásicas. As médias de lesões (nódulos e hiperplasia) obtidas foram: CsU: 1,07( DP+ 1,54), CsSl: 0( DP+ 0), EsU: 2,57 ( DP+ 2,77) e EsS: 0,40 ( DP+ 1,12), com p < 0,001; CajNNK: 4,94( DP+ 3,54), CajS: 0,15( DP+ 0,37), EajNNK: 9,14 ( DP+ 7,70) e EajS:0,80 ( DP+ 1,93), com p<0,001. Não houve alterações para o p53 em ambas as linhagens e, apenas os grupos AJ controle e exposto NNK apresentaram diferença para o PCNA. CONCLUSÃO. A exposição crônica ao MP 2,5 proveniente da poluição atmosférica da cidade de São Paulo tem potencial para promover tumores em camundongos de duas linhagens diferentes, com ou sem o pré-tratamento por carcinógenos / INTRODUCTION. Epidemiological studies have shown that exposure to air pollution is associated with increased cardiorespiratory diseases. Previous experimental studies, we used urethane to induce lung nodule formation in mice and these animals exposed to pollution from \"real world.\" In these studies, animals were exposed to gases and particles in the same way that the population is exposed in the city of São Paulo. It was evident then, the role of promoter and dose dependent polluted atmosphere in the progression of lung tumors. It is known that carcinogens such as polycyclic aromatic hydrocarbons (PAHs), metals, aldehydes and fatty acids, are present in the respirable fraction particulate pollution (fine particulate matter - PM2.5), and prolonged exposure to the latter has been considered a risk factor for the development of lung cancer. The objective of this study is to verify whether chronic exposure to PM 2.5 concentration from the air of the city of São Paulo, has carcinogenic potential. METHODS. A total of 60 male Swiss mice (30 g) and 60 AJ (20g), with four to six weeks of life. The Swiss mice were pretreated with a carcinogen completed, the carbamic acid (urethane-U), while AJ received a carcinogen primer 4 - (methylnitrosamino) -1 - (3-pyridil)-1-butanone (NNK) as being predisposed to developing lung tumors. Then all the animals were exposed to atmospheric Harvard Particle Concentrator to PM 2.5 daily for two hours for four months. Each strain was divided into four groups (n = 15 each): 2 with saline controls and carcinogen (CsS and CsU or CajS and CajNNK) and 2 exposed to saline and carcinogen (EsS and EsS or EajS and EajNNK). After the exposure time, the animals were anesthetized and euthanized. The lungs were fixed, processed histologically and imunohistochemistry was performed on slides with tumor presence of antibodies to p53 and PCNA. Later, in histopathology of pulmonary nodules made counting and classification of lesions found. RESULTS. The animals exposed groups in both strains showed a high percentage of neoplastic lesions. Mean lesions (nodules and hyperplasia) were obtained: CsU: 1.07 (SD + 1.54), CsS: 0 (DP + 0), EsU: 2.57 (SD + 2.77) and EsS: 0.40 ( + SD 1.12), p < 0.001; CajNNK: 4.94 (SD + 3.54), CajS: 0.15 (SD + 0.37), EajNNK: 9.14 (SD + 7.70) and EajS: 0 , 80 (SD + 1.93), with p < 0.001. There were no changes to the p53 in both strains, and only groups A / J control and exposed to NNK differ PCNA. CONCLUSION. The chronic exposure to PM 2.5 air pollution from the city of São Paulo has the potential to promote tumors in mice of two different strains with or without pretreatment by carcinogens

No description available.

<p>Karcinom bronha najče&scaron;ći uzrok smrti među malignim bolesti u svetu. U XX veku je registrovan značajan porast kako incidence, tako i mortaliteta karcinoma bronha u većini zemalja. Medijana preživljavanja u svim stadijumima bolesti se značajno pobolj&scaron;ala poslednjih godina XX veka, ali nedovoljno u odnosu na očekivano. U najvećem broju slučajeva, bolest se otkriva u uznapredovalom stadijumu, kada je radikalno hirur&scaron;ko lečenje kao optimalan vid lečenja nemoguće. Neodjuvantna terapija kod bolesnika sa lokalno uznapredovalim karcinomom pluća i zahvaćenim N2 limfnim čvorovima jedan je od modusa multimodalnog lečenja bolesnika sa nemikrocelularnim karcinomima pluća (NSCLC) u cilju pobolj&scaron;anja ishoda njihovog lečenja. Ovakav pristup podrazumeva prevođenje pacijenta iz vi&scaron;eg u niži stadijum bolesti - &bdquo;downstaging&rdquo;. Na taj način pacijent postaje potencijalno resektabilan u smislu daljeg hirur&scaron;kog lečenja koji bi mogao da obezebedi sveukupni onkolo&scaron;ki benefit. Osnovni ciljevi ove doktorske disertacije su bili: procena odgovora na neoadjuvantnu terapiju kod bolenika sa IIIA stadijumom nemikrocelularnog karcinoma bronha u odnosu na T faktor i N faktor, procena TNM klasifikacije pre i posle primenjene neoadjuvantne terapije kod bolesnika sa IIIA stadijumom nemikrocelularnog karcinoma bronha, određivanje stepena tumorske regresije patohistolo&scaron;kom analizom hirur&scaron;kog resekata nemikrocelularnog karcinoma bronha operisanih bolesnika nakon primenjene neoadjuvantne terapije, kao prognostički faktor za period bez bolesti i ukupnog preživljavanja i određivanje stepena regresije tumora u maligno izmenjenim limfnim čvorovima nakon primenjene neoadjuvantne terapije kod bolesnka sa IIIA stadijumom nemikrocelularnog karcinoma bronha, kao prognostički faktor za period bez bolesti i ukupnog preživljavanja.Rezultati su pokazali da neoadjuvantna terapija prema RECIST kriterijumima dovodi značajnog smanjenja veličine tumora, T faktora, kao i do znčajnog downstaging&ldquo;-a nodalnog statusa, N faktora, u terapiji bolesnika sa IIIA stadijumom nemikrocelularnog karcinoma bronha. Neoadjuvantna terapija prema RECIST kriterijumima dovodi značajnog smanjenja klinikog stadijuma bolesti, u terapiji bolesnika sa IIIA stadijumom nemikrocelularnog karcinoma bronha Nakon primenjene neoadjuvantne terapije nema značajne razlike u T faktoru koji je određen radiolo&scaron;ki prema RECIST kriterijumima (ycT) i patohistolo&scaron;ki (ypT) na hirur&scaron;kom materijalu. Nakon primenjene neoadjuvantne terapije prisutna je značajna razlika u N faktoru koji je određen radiolo&scaron;ki prema RECIST kriterijumima (ycN) i patohitolo&scaron;ki (ypN) na hirur&scaron;kom materijalu. Nakon primenjene neoadjuvantne terapije prisutna je značajna razlika u kliničkom stadijumu bolesti koji je određen radiolo&scaron;ki prema RECIST kriterijumima (yc) i patohitolo&scaron;ki (yp) na hirur&scaron;kom materijalu. Gradusi tumorske regresije su usko povezani sa procentom očuvanog tumorskog tkiva. Stepen tumorske regresije u resekatu primarnog tumora nije u korelaciji sa ukupnim preživljavanjem i procenom perioda bez bolesti kod pacijenata sa IIIA stadijumom nemikrocelularnog karcinoma bronha.</p> / <p>Lung cancer is the most common cause of death among malignant diseases in the world. In the twentieth century was a significant increase in both incidence and mortality of lung cancer in most countries. Median survival in all stages of the disease has improved significantly in recent years of the twentieth century, but not as we expected. In most cases, the disease is detected at an advanced stage, when the radical surgical treatment is considered impossible. Neoadjuvant therapy, in patients with locally advanced carcinoma of the lung, and with affected the lymph nodes N2, is one of the modes of multimodal treatment of patients with non-small cell lung cancer (NSCLC) in order to improve the outcome of their treatment. This involves translating the patient from a higher to a lower stage of the disease - &quot;downstaging&quot;. In this way the patient is considered for further surgical treatment that could provide him overall oncology benefit. Main objectives of this PhD dissertation are: evaluation of response to neoadjuvant therapy in stage IIIA NSCLC patients in relation to T factor and N factor; evaluation of TNM classification before and after use of neoadjuvant therapy in stage IIIA NSCLC patients; determination of degree of tumor regression with pathohistologic analysis of resection specimen of NSCLC obtained from patients after application of neoadjuvant therapy, as a prognostic factor for disease-free period and overall survival rate; and determination of degree of tumor regression in malignant lymph nodes after application of neoadjuvant therapy in stage IIIA NSCLC patients, as a prognostic factor for disease-free period and overall survival rate. Results have shown that neoadjuvant therapy according to RECIST criteria leads to significant reduction of tumor size, T factors, as well as significant downstaging of nodal status, N factor, in treatment of stage IIIA NSCLC patients. Furthermore, neoadjuvant therapy according to RECIST criteria leads to significant reduction of clinical stage of the disease in treatment of stage IIIA NSCLC patients. However, after neoadjuvant therapy is applied there is no significant difference in T factor determined radiologically according to RECIST criteria (ycT) and by pathohistologic analysis (ypT) of resected specimen. Neoadjuvant therapy leads to significant difference in N factor which is determined radiologically according to RECIST criteria (ycN) and by pathohistologic analysis (ypN) of resection specimen. After neoadjuvant therapy is applied there is significant difference in clinical stage of the disease determined radiologically according to RECIST criteria (yc) and by pathohistologic analysis (yp) of resection specimen. Tumor regression grading is closely linked to the percentage of preserved tumor tissue. Degree of tumor regression in surgical resection of primary tumor does not correlate to the overall survival rate and estimation of disease-free period in stage IIIA NSCLC patients.</p>

Introdução. Os glicosaminoglicanos e os proteoglicanos são moléculas abundantes na matriz extracelular. Vários estudos têm demonstrado que uma produção ou degradação aberrante dessas moléculas tem influência no comportamento do câncer de mama, cólon e pâncreas. Outras proteínas como o solCD44 e a cofilina-1 também tem demonstrado influência direta na progressão dos tumores. Desta forma, a análise da expressão destas moléculas em tecidos e fluidos corporais tem despertado grande interesse como rastreador de indivíduos de alto risco e marcador diagnóstico e/ou prognóstico da doença. Objetivos. Conhecer o impacto do ácido hialurônico e dos proteoglicanos (biglicam, glipicam, perlecam, sindecam e versicam) na carcinogênese bem como seu impacto na sobrevida dos pacientes; verificar se a concentração de solCD44 e cofilina-1 presente no escarro de pacientes com câncer de pulmão permite rastreá-los entre pacientes com doença pulmonar obstrutiva crônica e voluntários saudáveis. Resultados. Uma associação significativa direta foi encontrada entre os tumores com alto percentual de expressão de AH e de microvasos no estroma tumoral. As concentrações de heparam e condroitim sulfato nas amostras tumorais foram mais elevadas quando comparadas às amostras não tumorais. Com exceção do sindecam, todos os outros proteoglicanos apresentaram uma expressão gênica significativamente menor nos tecidos tumorais e biglicam e versicam apresentaram associações com as características clinico patológicas. A expressão proteica de biglicam, perlecam e versicam foi significativamente maior no tecido normal do que nas áreas de estroma tumoral e de células tumorais. Pela análise de regressão de COX controlada para idade, tipo histológico e expressão gênica de biglicam, sindecam e glipicam obtiveram alta taxa de sobrevida os pacientes do sexo feminino com elevada expressão gênica de perlecam e menor risco de óbito em estadio T1, ausência de metástases nodais e expressão gênica de versicam. A Maristela Peres Rangel Tese de doutorado - USP concentração de cofilina demonstrou-se mais elevada no escarro de pacientes com câncer de pulmão quando comparado ao escarro de pacientes de alto risco e de voluntários saudáveis. A concentração de solCD44 também demonstrou-se mais elevada no escarro de pacientes com câncer de pulmão quando comparado ao escarro de pacientes de alto risco e de voluntários saudáveis. Através da curva ROC, a cofilina-1 presente no escarro foi capaz de distinguir os pacientes de alto risco dos pacientes com câncer de pulmão com área abaixo da curva de 0.69 e com um ponto de corte de 802.5 pg/mL a curva apresentou 60% de sensibilidade e 54% de especificidade. O solCD44 presente no escarro também foi capaz de distinguir os pacientes de alto risco dos pacientes com câncer de pulmão através da curva ROC com área abaixo da curva de 0.67 e com um ponto de corte de 65.8 pg/mL a curva apresentou 50% de sensibilidade e 84% de especificidade. Conclusão. A expressão do ácido hialurônico demonstrou ter correlação no processo de crescimento tumoral através da angiogênese. A análise biomolecular apontou a diminuição dos proteoglicanos no tecido tumoral e, portanto, estes podem ser potenciais biomarcadores prognósticos de câncer de pulmão. As análises feitas em escarro demonstraram que a elevada expressão proteica de solCD44 e da cofilina-1 no escarro nos pacientes com câncer de pulmão mostram-se como promissores alvos de detecção do CP / Introduction. The relationship between the extracellular matrix (ECM) components and cancer cells have an important role on cancer development and progression. Between the most important molecules present on the ECM are the glycosaminoglycans and their respective proteoglycans. Studies have reported that they have different behaviours when in the presence of malignant tissues and influence the development of breast, pancreas and colon cancers. Likewise, proteins as solCD44 and cofilin-1 also have shown direct influence in tumor progression. Regarding that, there is growing interest among scientists in analyzing the expression of these molecules in body fluids as a screening tool of high risk patients and as a diagnostic and prognostic lung cancer biomarker. Objectives. The aims of this study were to recognize the impact of hyaluronan and the proteoglycans (biglycan, glypican, perlecan, syndecan e versican) on lung cancer carcinogenesis as well as its impact on patient\'s survival; verify if the solCD44 e cofilina-1 concentrations in the sputum of lung cancer patients could distinguish them from patients with COPD and healthy volunteers. Results. A direct association was found between tumors expressing high amounts of hyaluronan and CD34 in tumoral stroma. Heparan and chondroitin sulphate concentrations were higher in tumor specimens when compared to normal lung tissue. All proteoglycans, in exception of syndecan, showed a lower expression in tumoral tissue and biglycan and versican showed association with the clinical pathological features. Protein expression of biglycan, perlecan and versican was higher in the normal tissue when compared to stroma and tumoral cells. COX regression controlled by age, histological types and gene expression of biglycan, syndecan e glypican demonstrated that female patients had higher survival rates with high gene expression of perlecan and the patients with T1 stage, lack of linfonode Maristela Peres Rangel Tese de doutorado - USP metastasis and gene expression of versican had lower risk of death. Cofilin-1 concentration was higher in the sputum of lung cancer patients when compared to a high risk group and healthy volunteers. Also, the solCD44 concentration was higher in the sputum of lung cancer patients when compared to a high risk group and healthy volunteers. ROC cruve analysis demonstrated that sputum cofilin-1 was capable to distinguish high risk patients from lung cancer patients with na area under the curve of 0.69 and with a cut off at 802.5 pg/mL the curve presented 60% de sensitivity and 54% specificity. Sputum solCD44 was also capable to distinguish high risk patients from lung cancer patients with na area under the curve of 0.67 and with a cut off at 65.8 pg/mL the curve presented 50% de sensitivity and 84% specificity. Conclusions. Hyaluronan expression showed a correlation with tumoral growth through angiogenesis processes. The biomolecular analysis demonstrated that matrix proteoglycans are potencial lung cancer prognostic biomarkers. Sputum analyses showed that solCD44 and cofilin-1 are potencial molecules in lung cancer detection

Made available in DSpace on 2016-01-26T12:51:52Z (GMT). No. of bitstreams: 1 paulo saad_tese.pdf: 455472 bytes, checksum: 76fed03b80932ea6f964693d4c8d92cf (MD5) Previous issue date: 2006-06-19 / Cigarettes accounts for the death of millions of people a year worldwide, directly related to lung cancer. Some studies have shown that larger plasmatic indexes of beta-carotene or a great ingestion of foods rich in carotenoids diminish the risk of developing this neoplasia. On the other hand, studies suggest that the smokers' lung can alter the metabolism of beta-carotene, that is, producing greater risk of cell alterations and neoplasias. It is probable that the alpha-tocopherol has beneficial effect on this association. Objective: To evaluate the participation of beta-carotene and alpha-tocopherol in the development of lung cancer induced by urethane and its relationship with cigarette exposition. Material and Method: Balb C mice were divided into 10 groups: G1(cigarette), G2 (cigarette and urethane), G3 (only urethane), G4, G5 and G6 (cigarette, urethane and beta-carotene to 0.25, 0.05 and 0.005%, respectively), G8 (urethane and beta-carotene to 0.25%), G7, G10 and G11 (cigarette, urethane and beta-carotene to 0.25 and alpha-tocopherol 0.25; 0.05 and 0.005%, respectively).The exposition to the cigarette was for 10 minutes, twice a day, 5 days a week, during 16 weeks. For induction of tumors, urethane was administered intraperitonealy, in the dose of 3.0mg/Kg. Nodules and hyperplasias were quantified; morphometric analyses of the nodules were performed. Kruskal-Wallis and of Mann-Whitney tests were used for statistical analysis. Results: Group G3 presented greater number of nodules (P=0.001), smaller stromal fraction (P=0.011) and greater sum of the tumor area (P=0.047) compared to group G2. Group G8 showed smaller number of nodules (P=0.013) and hyperplasias (P=0.05) compared to group G3. Both smaller doses of beta-carotene (G5 and G6) were statistically similar, although with smaller number of nodules when compared to group G4 (P=0.04). Group G4 presented smaller number of hyperplasias than G8, however, the number of nodules did not alter (P=0.045%). Stromal fraction of groups G3 and G4 was similar, although smaller than G2 and G5 (P=0.011). According to the alpha-tocopherol, the stromal fraction of group G7 was greater than the one of the groups G2, G3, G4 and G10 (P=0.011). The 0.25%-beta-carotene diet increased the area of the nodules, demonstrated by the largest area (P=0.03), smaller area (P=0.03), sum of the areas (P=0.018) and average of the areas (P=0.006) in group G4 when compared to G2. Conclusion: According to these results, it was concluded that passive tobacco can be a protecting factor in the evolution of tumors induced by urethane in mice, however, there is no evidence that this could be dose-dependent. The supplementation of beta-carotene in 0.25%-dose can also be a protecting factor, however, associated to passive tobacco it has smaller effect than in lower doses (0.05 and 0.005%). The exposition to cigarette smoke does not alter the number of nodules induced by urethane in mice when in the presence of 0.25%-beta-carotene diet; however the hyperplasia number with the presence of the cigarette diminished. The association of the alpha-tocopherol to the 0.25%- beta-carotene and the passive tobacco produces a protecting factor, mainly in the dose of 0.25%. / O hábito de fumar cigarros é responsável pela morte de milhões de pessoas por ano em todo o mundo, estando diretamente relacionado ao câncer de pulmão. Estudos demonstraram que maiores índices plasmáticos de beta-caroteno ou a grande ingestão de alimentos ricos em carotenóides diminuem o risco de desenvolver esta neoplasia. Por outro lado, existem estudos que sugerem que o pulmão de fumantes pode alterar o metabolismo do beta-caroteno, gerando maior risco de alterações celulares e neoplasias. É provável que o alfa-tocoferol tenha efeito benéfico sobre esta associação. Objetivo: Avaliar a participação do beta caroteno e do alfa-tocoferol no desenvolvimento de câncer de pulmão induzido por uretana e sua relação com a exposição ao cigarro. Material e Método: Camundongos Balb C foram divididos em 10 grupos: G1(cigarro), G2(cigarro e uretana), G3 (uretana), G4, G5 e G6 (cigarro, uretana e beta-caroteno a 0,25; 0,05 e 0,005% respectivamente), G8 (uretana e Beta-caroteno a 0,25%), G7, G10 e G11 (cigarro, uretana e beta-caroteno a 0,25 e alfa-tocoferol a 0,25; 0,05 e 0,005% respectivamente). A exposição ao cigarro ocorreu durante 10 minutos, 2 vezes por dia, 5 dias por semana, por 16 semanas. Para a indução de tumores, foi administrada uretana por via intraperitoneal na dose de 3,0mg/Kg. Foram quantificados nódulos e hiperplasias, realizada análise morfométrica dos nódulos e submetidos aos testes de Kruskal-Wallis e de Mann-Whitney para análise estatística. Resultados: O grupo G3 apresentou maior número de nódulos (P=0,001), menor fração estromal (P=0,011) e maior soma da área de tumor (P=0,047) comparado ao grupo G2. O grupo G8, mostrou-se com menor número de nódulos (P=0,013) e hiperplasias (P=0,05) comparados ao grupo G3. As duas doses menores de beta-caroteno (G5 e G6) se mostraram estatisticamente semelhantes, porém com menor número de nódulos quando comparados ao grupo G4 (P=0,04). O grupo G4 apresentou menor número de hiperplasias que G8, porém o número de nódulos não se alterou (P=0,045). A fração estromal dos grupos G3 e G4 foram semelhantes, porém menores que G2 e G5 (P=0,011). Quanto ao alfa-tocoferol, a fração estromal do grupo G7 foi maior que a dos grupos G2, G3, G4 e G10 (P=0,011). A dieta com beta-caroteno a 0,25% aumentou a área dos nódulos, demonstrada pela maior área (P=0,03), menor área (P=0,03), soma das áreas (P=0,018) e média das áreas (P=0,006) no grupo G4 comparada com o grupo G2. Conclusão: Com estes resultados, concluiu-se que na evolução de tumores induzidos por uretana em camundongos o fumo passivo se comporta como um fator protetor, porém não há evidência de que seja dose-dependente. A suplementação de beta-caroteno na dose de 0,25% também age como protetor, porém associada ao fumo passivo tem efeito menor do que em doses mais baixas (0,05 e 0,005%). A exposição à fumaça do cigarro não altera o número de nódulos quando na presença de dieta com beta-caroteno a 0,25%, porém o número de hiperplasias com a presença do cigarro diminui. A associação do alfa-tocoferol ao beta-caroteno 0,25% e ao fumo passivo gera um fator protetor, principalmente na dose 0,25%.

INTRODUÇÃO: A avaliação do mediastino quanto à presença de metástases linfonodais é importante na escolha do tratamento dos pacientes com câncer de pulmão de não pequenas células. Apesar da tomografia computadorizada ser o exame de imagem de escolha no estadiamento do câncer de pulmão, tem limitações conhecidas quanto à avaliação dos linfonodos regionais. O objetivo deste trabalho é avaliar a acurácia do SPECT/TC utilizando o radiofármaco 99mTc-sestamibi no estadiamento linfonodal do mediastino em pacientes com diagnóstico de carcinoma de pulmão de não pequenas células e candidatos a tratamento cirúrgico. MÉTODOS: Foi realizada coleta prospectiva de dados de 41 pacientes entre dezembro de 2006 a fevereiro de 2009. Os pacientes foram submetidos à tomografia computadorizada de tórax e ao SPECT/TC com 99mTc-sestamibi no prazo máximo de 30 dias antes da cirurgia. O SPECT/TC foi considerado positivo quando havia captação no mediastino e a tomografia de tórax, quando havia linfonodos maiores do que 10 mm no menor eixo. Os resultados da interpretação do SPECT/TC com sestamibi e da TC de tórax foram comparados aos encontrados na patologia, definido como método padrão ouro. RESULTADOS: O SPECT/TC identificou de maneira correta seis dos 19 casos com envolvimento dos linfonodos hilares e um dos sete casos com metástases ganglionares no mediastino pela patologia. Os valores de sensibilidade, especificidade, valores de predição positivo e negativo para o 99mTc-sestamibi SPECT/TC na avaliação do hilo foram respectivamente de: 31,6%, 95,5%, 85,7% e 61,8% e para o mediastino de 14,3%, 97,1%, 50% e 84,6%. A tomografia de tórax encontrou sensibilidade para a análise dos linfonodos hilares e mediastinais de 47,4% e 57,1%, especificidade de 95,5%, e 91,2%, valores de predição positivo de 90% e 57,1% e negativo de 67,7% e 91,2%, respectivamente. CONCLUSÃO: Nos pacientes com câncer de pulmão de não pequenas células com doença inicial e ressecável o SPECT/TC com 99mTc-sestamibi no estadiamento linfonodal do mediastino apresentou baixa sensibilidade e acurácia, apesar da alta especificidade. O SPECT/TC não adicionou informações relevantes à TC de tórax, que poderiam justificar o seu emprego no estadiamento pré-operatório do carcinoma de pulmão de não pequenas células / INTRODUCTION: The proper nodal staging of non-small cell lung cancer is important to choose the best treatment modality. Although CT is the first-line imaging test for primary staging of lung cancer, it is well known its limitations on mediastinum nodal staging. The aim was to evaluate the accuracy of SPECT/CT using 99mTc-sestamibi in the nodal staging of patients with non-small cell lung cancer and potential candidates towards surgical treatment. METHODS: A prospective data collection of 41 patients was conducted from December 2006 to February 2009. The patients underwent chest CT and SPECT/CT with 99mTc-sestamibi within 30 days interval before surgery. SPECT/CT was considered positive when there was focal uptake of sestamibi in the mediastinum and CT scan when there was lymph nodes larger than 10 mm in short axis. The results of SPECT/CT and CT were correlated with pathology findings after surgery. RESULTS: SPECT/CT correctly identified six of 19 cases with involvement of hilar lymph nodes and one of seven cases with nodal metastases in the mediastinum. The sensitivity, specificity, positive and negative predictive value for 99mTc-sestamibi SPECT/CT in the assessment of the hilum were respectively: 31.6%, 95.5%, 85.7% and 61.8% and for the mediastinum 14.3%, 97.1%, 50% and 84.6%. Chest tomography showed a sensitivity of hilar and mediastinal lymph nodes of 47.4% and 57.1%, specificity of 95.5% and 91.2%, positive predictive value of 90% and 57.1% and negative predictive value of 67.7% and 91.2%, respectively. CONCLUSION: SPECT/CT with 99mTc-sestamibi showed very low sensitivity and accuracy for nodal staging of patients with non-small cell cancer despite its high specificity. Moreover, the performance of SPECT/CT added no relevant information compared to CT that could justify its use in the routine preoperative staging of non-small cell lung carcinoma

Introdução. Os glicosaminoglicanos e os proteoglicanos são moléculas abundantes na matriz extracelular. Vários estudos têm demonstrado que uma produção ou degradação aberrante dessas moléculas tem influência no comportamento do câncer de mama, cólon e pâncreas. Outras proteínas como o solCD44 e a cofilina-1 também tem demonstrado influência direta na progressão dos tumores. Desta forma, a análise da expressão destas moléculas em tecidos e fluidos corporais tem despertado grande interesse como rastreador de indivíduos de alto risco e marcador diagnóstico e/ou prognóstico da doença. Objetivos. Conhecer o impacto do ácido hialurônico e dos proteoglicanos (biglicam, glipicam, perlecam, sindecam e versicam) na carcinogênese bem como seu impacto na sobrevida dos pacientes; verificar se a concentração de solCD44 e cofilina-1 presente no escarro de pacientes com câncer de pulmão permite rastreá-los entre pacientes com doença pulmonar obstrutiva crônica e voluntários saudáveis. Resultados. Uma associação significativa direta foi encontrada entre os tumores com alto percentual de expressão de AH e de microvasos no estroma tumoral. As concentrações de heparam e condroitim sulfato nas amostras tumorais foram mais elevadas quando comparadas às amostras não tumorais. Com exceção do sindecam, todos os outros proteoglicanos apresentaram uma expressão gênica significativamente menor nos tecidos tumorais e biglicam e versicam apresentaram associações com as características clinico patológicas. A expressão proteica de biglicam, perlecam e versicam foi significativamente maior no tecido normal do que nas áreas de estroma tumoral e de células tumorais. Pela análise de regressão de COX controlada para idade, tipo histológico e expressão gênica de biglicam, sindecam e glipicam obtiveram alta taxa de sobrevida os pacientes do sexo feminino com elevada expressão gênica de perlecam e menor risco de óbito em estadio T1, ausência de metástases nodais e expressão gênica de versicam. A Maristela Peres Rangel Tese de doutorado - USP concentração de cofilina demonstrou-se mais elevada no escarro de pacientes com câncer de pulmão quando comparado ao escarro de pacientes de alto risco e de voluntários saudáveis. A concentração de solCD44 também demonstrou-se mais elevada no escarro de pacientes com câncer de pulmão quando comparado ao escarro de pacientes de alto risco e de voluntários saudáveis. Através da curva ROC, a cofilina-1 presente no escarro foi capaz de distinguir os pacientes de alto risco dos pacientes com câncer de pulmão com área abaixo da curva de 0.69 e com um ponto de corte de 802.5 pg/mL a curva apresentou 60% de sensibilidade e 54% de especificidade. O solCD44 presente no escarro também foi capaz de distinguir os pacientes de alto risco dos pacientes com câncer de pulmão através da curva ROC com área abaixo da curva de 0.67 e com um ponto de corte de 65.8 pg/mL a curva apresentou 50% de sensibilidade e 84% de especificidade. Conclusão. A expressão do ácido hialurônico demonstrou ter correlação no processo de crescimento tumoral através da angiogênese. A análise biomolecular apontou a diminuição dos proteoglicanos no tecido tumoral e, portanto, estes podem ser potenciais biomarcadores prognósticos de câncer de pulmão. As análises feitas em escarro demonstraram que a elevada expressão proteica de solCD44 e da cofilina-1 no escarro nos pacientes com câncer de pulmão mostram-se como promissores alvos de detecção do CP / Introduction. The relationship between the extracellular matrix (ECM) components and cancer cells have an important role on cancer development and progression. Between the most important molecules present on the ECM are the glycosaminoglycans and their respective proteoglycans. Studies have reported that they have different behaviours when in the presence of malignant tissues and influence the development of breast, pancreas and colon cancers. Likewise, proteins as solCD44 and cofilin-1 also have shown direct influence in tumor progression. Regarding that, there is growing interest among scientists in analyzing the expression of these molecules in body fluids as a screening tool of high risk patients and as a diagnostic and prognostic lung cancer biomarker. Objectives. The aims of this study were to recognize the impact of hyaluronan and the proteoglycans (biglycan, glypican, perlecan, syndecan e versican) on lung cancer carcinogenesis as well as its impact on patient\'s survival; verify if the solCD44 e cofilina-1 concentrations in the sputum of lung cancer patients could distinguish them from patients with COPD and healthy volunteers. Results. A direct association was found between tumors expressing high amounts of hyaluronan and CD34 in tumoral stroma. Heparan and chondroitin sulphate concentrations were higher in tumor specimens when compared to normal lung tissue. All proteoglycans, in exception of syndecan, showed a lower expression in tumoral tissue and biglycan and versican showed association with the clinical pathological features. Protein expression of biglycan, perlecan and versican was higher in the normal tissue when compared to stroma and tumoral cells. COX regression controlled by age, histological types and gene expression of biglycan, syndecan e glypican demonstrated that female patients had higher survival rates with high gene expression of perlecan and the patients with T1 stage, lack of linfonode Maristela Peres Rangel Tese de doutorado - USP metastasis and gene expression of versican had lower risk of death. Cofilin-1 concentration was higher in the sputum of lung cancer patients when compared to a high risk group and healthy volunteers. Also, the solCD44 concentration was higher in the sputum of lung cancer patients when compared to a high risk group and healthy volunteers. ROC cruve analysis demonstrated that sputum cofilin-1 was capable to distinguish high risk patients from lung cancer patients with na area under the curve of 0.69 and with a cut off at 802.5 pg/mL the curve presented 60% de sensitivity and 54% specificity. Sputum solCD44 was also capable to distinguish high risk patients from lung cancer patients with na area under the curve of 0.67 and with a cut off at 65.8 pg/mL the curve presented 50% de sensitivity and 84% specificity. Conclusions. Hyaluronan expression showed a correlation with tumoral growth through angiogenesis processes. The biomolecular analysis demonstrated that matrix proteoglycans are potencial lung cancer prognostic biomarkers. Sputum analyses showed that solCD44 and cofilin-1 are potencial molecules in lung cancer detection

Leung, Jackie. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 117-131). / Abstract also in Chinese. / Abstract --- p.i / 論文摘要 --- p.iii / Acknowledgement --- p.iv / List of publications --- p.vi / List of Tables --- p.vi / List of Figures --- p.vi / Table of Contents --- p.ix / Chapter Chapter 1: --- Introduction --- p.1 / Chapter 1.1. --- Liver cancer --- p.1 / Chapter 1.1.1. --- Hepatocellular Carcinoma (HCC) --- p.2 / Chapter 1.2. --- Lung Cancer --- p.5 / Chapter 1.3. --- Pteris semipinnata L --- p.8 / Chapter 1.4. --- Extract of PsL: 5F --- p.10 / Chapter 1.5. --- Animal models in chemotherapy researches --- p.13 / Chapter 1.5.1. --- Model of HCC --- p.13 / Chapter 1.5.2. --- Model of lung cancer --- p.15 / Chapter 1.6. --- Apoptosis: Significance of programmed cell death --- p.17 / Chapter 1.6.1. --- The extrinsic pathway --- p.18 / Chapter 1.6.2. --- The intrinsic pathway --- p.19 / Chapter 1.7. --- Apoptotic molecules related to this study --- p.22 / Chapter 1.7.1. --- Bcl-2 family --- p.22 / Chapter 1.7.1.1. --- Bax --- p.22 / Chapter 1.7.1.2. --- Bcl-2 --- p.23 / Chapter 1.7.2. --- Nuclear factor kappa B --- p.25 / Chapter 1.7.3. --- Inducible nitric oxide synthase --- p.27 / Chapter 1.8. --- Side-effects of chemotherapy --- p.29 / Chapter 1.8.1. --- Chemotherapy and liver dysfunction --- p.30 / Chapter 1.8.2. --- Nephrotoxicity of chemotherapeutic agents --- p.31 / Chapter 1.9. --- Aim of study --- p.33 / Chapter Chapter 2: --- Materials and Methodology --- p.34 / Chapter 2.1. --- Animals --- p.34 / Chapter 2.1.1. --- HCC model --- p.34 / Chapter 2.1.2. --- Lung cancer model --- p.35 / Chapter 2.2. --- Tumors induction --- p.36 / Chapter 2.2.1. --- HCC induction in C3H/HeJ mice --- p.36 / Chapter 2.2.2. --- Lung cancer induction in A/J mice --- p.37 / Chapter 2.3. --- 5F preparation --- p.38 / Chapter 2.4. --- 5F treatment --- p.39 / Chapter 2.5. --- Harvest of samples and tissues --- p.41 / Chapter 2.6. --- Tumor assessment --- p.43 / Chapter 2.7. --- Investigation of apoptosis and cell proliferation --- p.44 / Chapter 2.8. --- Immunohistochemistry --- p.47 / Chapter 2.9. --- Biochemical test --- p.51 / Chapter 2.9.1. --- Liver Function Tests (LFT) --- p.52 / Chapter 2.9.1.1. --- Aspartate aminotransferase (AST) & Alanine aminotransferase (ALT) --- p.52 / Chapter 2.9.2. --- Renal Function Test (RFT) --- p.53 / Chapter 2.9.2.1. --- Serum creatinine level (CRE) --- p.53 / Chapter 2.9.2.2. --- Blood Urea Nitrogen index (BUN) --- p.54 / Chapter 2.10. --- Statistical analysis --- p.55 / Chapter Chapter 3: --- Results --- p.56 / Chapter 3.1. --- Anti-tumor effect of 5F is dose- dependent --- p.56 / Chapter 3.2. --- 5F reduces cell proliferation and induces apoptosis in-vivo --- p.60 / Chapter 3.3. --- Effects of 5F on apoptotic signaling molecules --- p.68 / Chapter 3.3.1. --- 5F up-regulates pro-apoptotic Bax and Bak --- p.68 / Chapter 3.3.2. --- 5F down-regulates anti-apoptotic NF-kappa B and Bcl-2 --- p.76 / Chapter 3.3.3. --- 5F up-regulated iNOS in HCC but not in lung cancer --- p.88 / Chapter 3.3.4. --- Regulation on Erk1/2 was associated with treatment of 5F --- p.93 / Chapter 3.4. --- Side-effect studies of 5F --- p.97 / Chapter Chapter 4: --- Discussion --- p.105 / Chapter Chapter 5: --- Conclusion --- p.116 / Bibliography --- p.117

INTRODUÇÃO: A avaliação do mediastino quanto à presença de metástases linfonodais é importante na escolha do tratamento dos pacientes com câncer de pulmão de não pequenas células. Apesar da tomografia computadorizada ser o exame de imagem de escolha no estadiamento do câncer de pulmão, tem limitações conhecidas quanto à avaliação dos linfonodos regionais. O objetivo deste trabalho é avaliar a acurácia do SPECT/TC utilizando o radiofármaco 99mTc-sestamibi no estadiamento linfonodal do mediastino em pacientes com diagnóstico de carcinoma de pulmão de não pequenas células e candidatos a tratamento cirúrgico. MÉTODOS: Foi realizada coleta prospectiva de dados de 41 pacientes entre dezembro de 2006 a fevereiro de 2009. Os pacientes foram submetidos à tomografia computadorizada de tórax e ao SPECT/TC com 99mTc-sestamibi no prazo máximo de 30 dias antes da cirurgia. O SPECT/TC foi considerado positivo quando havia captação no mediastino e a tomografia de tórax, quando havia linfonodos maiores do que 10 mm no menor eixo. Os resultados da interpretação do SPECT/TC com sestamibi e da TC de tórax foram comparados aos encontrados na patologia, definido como método padrão ouro. RESULTADOS: O SPECT/TC identificou de maneira correta seis dos 19 casos com envolvimento dos linfonodos hilares e um dos sete casos com metástases ganglionares no mediastino pela patologia. Os valores de sensibilidade, especificidade, valores de predição positivo e negativo para o 99mTc-sestamibi SPECT/TC na avaliação do hilo foram respectivamente de: 31,6%, 95,5%, 85,7% e 61,8% e para o mediastino de 14,3%, 97,1%, 50% e 84,6%. A tomografia de tórax encontrou sensibilidade para a análise dos linfonodos hilares e mediastinais de 47,4% e 57,1%, especificidade de 95,5%, e 91,2%, valores de predição positivo de 90% e 57,1% e negativo de 67,7% e 91,2%, respectivamente. CONCLUSÃO: Nos pacientes com câncer de pulmão de não pequenas células com doença inicial e ressecável o SPECT/TC com 99mTc-sestamibi no estadiamento linfonodal do mediastino apresentou baixa sensibilidade e acurácia, apesar da alta especificidade. O SPECT/TC não adicionou informações relevantes à TC de tórax, que poderiam justificar o seu emprego no estadiamento pré-operatório do carcinoma de pulmão de não pequenas células / INTRODUCTION: The proper nodal staging of non-small cell lung cancer is important to choose the best treatment modality. Although CT is the first-line imaging test for primary staging of lung cancer, it is well known its limitations on mediastinum nodal staging. The aim was to evaluate the accuracy of SPECT/CT using 99mTc-sestamibi in the nodal staging of patients with non-small cell lung cancer and potential candidates towards surgical treatment. METHODS: A prospective data collection of 41 patients was conducted from December 2006 to February 2009. The patients underwent chest CT and SPECT/CT with 99mTc-sestamibi within 30 days interval before surgery. SPECT/CT was considered positive when there was focal uptake of sestamibi in the mediastinum and CT scan when there was lymph nodes larger than 10 mm in short axis. The results of SPECT/CT and CT were correlated with pathology findings after surgery. RESULTS: SPECT/CT correctly identified six of 19 cases with involvement of hilar lymph nodes and one of seven cases with nodal metastases in the mediastinum. The sensitivity, specificity, positive and negative predictive value for 99mTc-sestamibi SPECT/CT in the assessment of the hilum were respectively: 31.6%, 95.5%, 85.7% and 61.8% and for the mediastinum 14.3%, 97.1%, 50% and 84.6%. Chest tomography showed a sensitivity of hilar and mediastinal lymph nodes of 47.4% and 57.1%, specificity of 95.5% and 91.2%, positive predictive value of 90% and 57.1% and negative predictive value of 67.7% and 91.2%, respectively. CONCLUSION: SPECT/CT with 99mTc-sestamibi showed very low sensitivity and accuracy for nodal staging of patients with non-small cell cancer despite its high specificity. Moreover, the performance of SPECT/CT added no relevant information compared to CT that could justify its use in the routine preoperative staging of non-small cell lung carcinoma

Cancer du poumon associé à l’exposition au nickel, au chrome VI et au cadmium dans le milieu de travail utilisant deux études populationnelles cas-témoins à Montréal. Au début des années 1990, le nickel, le chrome VI et le cadmium ont été classés en tant qu’agents cancérigènes de classe 1 par le CIRC (Centre International de Recherche sur le Cancer). Cependant, les résultats des études ayant permis la classification de ces métaux n’ont pas toujours été reproduits, et d’importantes questions demeurent quant aux effets de ces métaux à de faibles niveaux d’exposition. Un plus grand nombre de recherches empiriques est donc nécessaire afin de réaffirmer la cancérogénicité de ces agents, et d’identifier les circonstances dans lesquelles ils peuvent être néfastes. L'objectif de cette étude était d'explorer la relation entre l’exposition à un des métaux (soit le nickel, le chrome VI, ou le cadmium) et les risques subséquents de développer un cancer du poumon chez des travailleurs provenant de différents milieux de travail qui sont exposés à ces métaux à de différents degrés. Deux études cas-témoins de base populationnelle menées à Montréal ont fourni les données nécessaires pour examiner la cancérogénicité de ces métaux. La première étude était menée entre 1979 et 1986 chez des hommes âgés de 35 à 70 ans ayant un cancer dans l’un de 19 sites anatomiques de cancer sélectionnés. La seconde étude était menée entre 1996 et 2001 chez des hommes et des femmes âgés de 35 à 75 ans, avec un diagnostic de tumeur maligne au poumon. Dans ces deux études, les cas ont été recensés dans tous les hôpitaux de l'île de Montréal, tandis que les contrôles populationnels appariés par âge et stratifiés par sexe, ont été sélectionnés des listes électorales. Une entrevue avec chaque sujet a permis d'obtenir un historique d'emploi détaillé ainsi que des informations précises sur les facteurs de risques socio-économiques et personnels. Les descriptions de poste ont été évaluées par une équipe d'experts chimistes et hygiénistes afin de déterminer si le sujet a été exposé à chaque agent, et pour mesurer à la fois la concentration et la durée de chaque exposition, ainsi que l’exposition cumulative tout au long de la vie de chaque participant. Pour déterminer si une exposition à l’un des trois métaux en cause était associée à une augmentation de l'incidence du cancer du poumon, des données ont été analysées par régression logistique : des ajustements ont été effectués pour des facteurs de confusion pertinents incluant un historique détaillé du tabagisme. Des mesures catégoriques d'exposition cumulée ont été également analysées, ainsi que la modification des effets par le tabagisme. Les deux études ont été analysées séparément, puis par la suite combinées afin d'augmenter la puissance statistique. Les niveaux d'exposition mesurés dans cette population ne semblaient pas poser un excès de risque de cancer du poumon pour les travailleurs exposés au chrome VI. Cependant, ceux qui ont été exposés au nickel ont subi une augmentation significative du risque, et ce, quel que soit leur niveau d'exposition. Le risque de développer un cancer du poumon suite à une exposition au cadmium était élevé, mais pas de manière significative. Pour chacun des trois métaux, le risque de cancer du poumon était très élevé parmi les non-fumeurs, mais pas parmi les fumeurs. L’effet combiné du tabagisme et de l’exposition aux métaux était compatible avec un excès de risque additif. Cependant, les intervalles de confiance dans cette étude tendaient à être larges, et une faiblesse de puissance statistique peut limiter l’interprétation de certains résultats. Cette étude est unique dans la mesure où elle a fourni des preuves empiriques sur les risques de développer le cancer du poumon liés aux faibles niveaux d’exposition au nickel, au chrome VI, ou au cadmium provenant de divers contextes de travail. Dans la plupart des autres études, la majorité des expositions pertinentes n’ont pas été bien contrôlées. À l'inverse, cette étude a bénéficié de la collecte et de la disponibilité d'information détaillée concernant le tabagisme et d’autres facteurs de risque. Les résultats de cette étude ont d'importantes conséquences pour la santé publique, tant au niveau de la détermination des risques pour les travailleurs actuellement exposés à ces métaux, qu'au niveau de l’évaluation des risques pour la population en général, elle-même exposée à ces métaux par le biais de la pollution et de la fumée de cigarette. Cette analyse contribuera fort probablement à une réévaluation par le CIRC de la cancérogénicité de ces métaux. L'exploration de la relation entre les risques de cancer du poumon et l'exposition au nickel, au chrome VI et au cadmium est donc opportune et pertinente. / Nickel, chromium VI and cadmium were designated as IARC class 1 lung carcinogens in the early 1990s. However, the study results informing this designation have not been consistently replicated in the past two decades, and there remain some important questions about these metals’ effects at low levels of exposure. Further empiric research is therefore required to confidently reaffirm the carcinogenicity of these agents and to understand the circumstances in which they may be harmful. The objective of this study was to investigate the relationship between exposure to either nickel, chromium VI or cadmium and subsequent risk of lung cancer among workers exposed to these substances at a variety of levels and in a wide range of occupations. Two large population-based case-control studies conducted in Montreal provided the data to investigate the carcinogenicity of these substances. Study I was conducted from 1979 to 1986, and included males aged 35 to 70 diagnosed with cancer at any of 19 selected cancer sites. Study II was conducted from 1996 to 2001 and included men and women aged 35 to 75 diagnosed with lung malignancies. In both studies, cases were ascertained in all hospitals on the island of Montreal, while age- and sexstratified population controls were selected from electoral lists. Detailed job histories, as well as lifestyle and socioeconomic measures, were elicited by interviewers with each subject. Job descriptions were then evaluated by an expert team of chemists and hygienists in order to determine whether the subject was exposed to each agent, and if so, to create measures of concentration, duration, and cumulative exposure over the course of each participant’s lifetime. In order to determine whether lifetime exposure to any of the metals of interest was associated with increased incidence of lung cancer, exposure data were analysed by logistic regression, adjusting for relevant confounders including detailed smoking history. Categorical measures of cumulative exposure were analysed, and effect modification by smoking was also explored. Study I and II were first analysed separately, and then combined when appropriate to increase statistical power. At the exposure levels experienced by this population, subjects exposed to nickel incurred a small but significantly increased risk of cancer compared to those unexposed. Meanwhile, there did not appear to be any excess risk of lung cancer among workers exposed to chromium VI. Lung cancer risk was somewhat elevated, albeit not significantly so, after cadmium exposure. For each of the three metals, lung cancer risk was significantly elevated among non smokers, but not among smokers. The joint effect of smoking and exposure to each of the metals was compatible with an additive excess risk. However, confidence limits in this study tended to be wide, and lack of statistical power may limit interpretation of some of the results. This study is unique in providing empiric evidence on lung cancer risks associated with low levels of exposure to nickel, chromium VI, or cadmium originating from a variety of occupational contexts. While many studies have failed to control for important co-exposures, this study benefited from the collection and availability of detailed histories of exposure to tobacco and other potential confounders. The results of this study have important public health implications, both in terms of determining ongoing risk experienced by exposed workers, and in terms of assessing risk to the general population exposed to these metals by means of pollution and cigarette smoke. This analysis will likely contribute to an upcoming IARC re-evaluation of the carcinogenicity of these metals. Examination of the relationship between exposure to cadmium, chromium VI and nickel and subsequent risk of lung cancer is therefore timely and pertinent.