The aim of the study was to analyze the relation between tumor volume (V(path)), tumor marker index (TMI) and prognosis in 261 completely resected (R0) stages I and II non-small cell lung cancer (NSCLC) patients by univariate and multivariate analyses. V(path) was calculated as an ellipsoid body. TMI represents the geometric mean of normalized CYFRA 21-1 and CEA values. Patients with a V(path)< or =13.7cm(3) had a significantly better 5-year-survival rate than patients with a V(path)>13.7cm(3) (78.1% vs. 47.9%; p<0.001). Patients with a TMI< or=0.54 had a 5-year-survival rate of 79.1% compared to only 47.2% in patients with a TMI>0.54 (p<0.001). Besides age (>70 years), performance status and gender, both V(path) (>13.7 cm(3)) and TMI (>0.54) bore significance in the multivariate Cox model with a hazard ratio (HR) of 1.9 (95% CI: 1.1-3.3, p=0.016) and 2.3 (95% CI: 1.3-4.2, p=0.006), respectively. Based on a combination of V(path) and TMI, a low risk group (17% of the patients) with both parameters in the normal range could be identified. Patients with elevated V(path) or TMI (31%) had an intermediate HR of 3.4 (95% CI: 1.3-9.2). When both factors were elevated (52% of patients) the HR increased to 5.95 (95% CI: 2.4-14.9). The elevation of V(path) and TMI was found in 46.2% of stage I and in 59.1% of stage II. The 5-year-survival rates were found to be 89.1, 62.2 and 43.0%, respectively. In conclusion, elevated levels of TMI and V(path) have a strong negative prognostic impact on survival in operated early stage of NSCLC. These patients might be considered for adjuvant chemotherapy.

Cystatins regulate tumour-associated cysteine proteases, however, their role in tumour progression is not clear yet. To assess their relevance in the progression of non-small cell lung cancer (NSCLC) the protein level, cysteine protease activity (CPI) and localization of type I (stefins A and B) and type II (C, E/M and F) cystatins were defined in tumours and control lung counterparts from 165 patients. The medians of CPI activity, stefins A and B were significantly greater in tumour than in lung tissue (2.1-fold, 1.7-fold, 1.2-fold, respectively, all p<0.001). The median levels of cystatin C and cystatin E/M were lower in tumour tissue (0.9-fold, p=0.06; 0.6-fold, p<0.01). In all the samples the levels of cystatin F were below the detection limit. Immunohistochemical analysis revealed the presence of all cystatins in tumour cells and infiltrated inflammatory cells such as macrophages and neutrophils. In univariate survival analysis patients with high levels of stefin A, stefin B and CPI activity exhibited a better survival probability (p=0.05, p=0.05, p<0.01, respectively). In contrast, cystatins C and E/M provided no prognostic information. In multivariate analysis the most powerful predictor of survival was the pTNM stage (p<0.0001; RR 3.5), followed by stefin A, stefin B and CPI activity (all p=0.03; RR 1.5). Our results suggest that only stefins A and B, i.e. type I cystatins, are up-regulated in lung tumours and thus able to counteract harmful tumour-associated proteolytic activity. As biological markers they may add independent prognostic information for better assessment of low- and high-risk patients with NSCLC.

RESUMO: O objectivo da presente meta-análise foi determinar o valor prognóstico de níveis séricos pré-terapêuticos elevados de Cyfra 21-1, ajustados a co-variáveis clássicas no CPNPC.Baseou-se em elementos registados em bases de dados de estudos controlados (período de 1993 a 2001), publicados e não publicados, apresentados na forma de abstracts ou incluídos em palestras, conferências ou outras apresentações, que tinham como principal end point a determinação do valor prognóstico dos níveis séricos pré-terapêuticos elevados de Cyfra 21-1, cotejados com outras variáveis prognósticas no CPNPC (estádio TNM, PS, e outras) e em que se teve, também, em atenção o tipo de tratamento instituído (cirurgia versus não cirurgia).Foram seleccionadas nove instituições que seguiram 2063 doentes com CPNPC por um período compreendido entre 27 e 78 meses.A sobrevida foi definida como o tempo decorrido entre a data da determinação do valor sérico pré-terapêutico de Cyfra 21-1 até à data da morte do doente. Considerou-se como valor cut-off do mar cador os 3,6 ng/ml; os doentes foram divididos em dois grupos etários, acima e abaixo da mediana de idades, isto é, dos 63 anos.Os elementos colhidos foram analisados estatisticamente utilizando-se o método de Kaplan-Meir para a determinação da distribuição das sobrevidas, enquanto na análise univariada teve-se em conta o teste log-rank e no estudo da regressão multivariada o modelo de Cox.Na série apresentada predominou o sexo masculino (84%), estando 51% dos doentes com um PS de 0-1; 70% dos doentes estavam incluídos no estádio IIIB (27%) ou IV (43%); 50% eram carcinomas epidermóides, só 21% foram submetidos a terapêutica cirúrgica e 49% revelaram valores pré-terapêuticos de Cyfra 21-1 acima de 3,6 ng/ml.Pela análise univariada das sobrevidas, constatou-se que estas foram piores no grupo com Cyfra 21-1 aumentado, sendo outros factores de pior prognóstico o estádio avançado da doença (TNM), o PS≥2, e a idade superior a 63 anos; por esta avaliação, os grupos histológicos do tumor e o sexo dos doentes não se revelaram factores de prognóstico.A análise multivariada das sobrevidas de toda a população estudada confirmou o valor pré-terapêutico elevado de Cyfra 21-1 como factor prognóstico negativo, sendo também factores de pior prognóstico o estádio da doença e o PS; aqui, a idade não se mostrou como determinante prognóstico negativo, mas, no grupo acima dos 63 anos, houve a tendência para que tal acontecesse.Por essa mesma análise, observou-se que, nos doentes não cirúrgicos, eram factores de prognóstico negativos a idade, o aumento do valor sérico pré-terapêutico de Cyfra 21-1, o estádio da doença e o PS, enquanto nos doentes cirúrgicos tal não ocorria com a idade e o PS.Em face dos dados apresentados, os autores concluem que a determinação sérica pré-terapêutica dos valores de Cyfra 21-1 é uma variável a considerar na avaliação prognóstica dos doentes com CPNPC, independentemente da terapêutica instituída, existindo concordância entre a presente meta-análise e os dados individuais das diferentes instituições seleccionadas, o que é um forte argumento de que se trata de um verdadeiro determinante prognóstico. COMENTÁRIO: Os factores de prognóstico clássicos incluem o estádio anatómico da doença (TNM), o performance status (PS) e outras condições, como a idade, o sexo, a perda de peso (W) e o(s) local(ais) de metastisação 1.Contudo, os tumores malignos do pulmão apresentam uma grande heterogeneidade no seu comportamento evolutivo, pelo que são necessárias outras variáveis que permitam determinar os casos com pior prognóstico e que, de algum modo, possam influenciar a respectiva programação terapêutica.Das variáveis biológicas, com bem demonstrado valor prognóstico no cancro do pulmão, podem citar-se os níveis séricos elevados de fosfatase alcalina ou de desidrogenase láctica (LDH), a hiperleucocitose ou a hiponatremia 1. Mais recentemente 2, indicam-se também como factores de prognóstico a ploidia, as mutações p53, ou o aumento de expressão da proteína bcl-2, cuja aplicação, na prática clínica, ainda não é rotineira, pela complexidade (e custos) das técnicas envolvidas na sua manipulação, mas sobre os quais recai um interesse sucessivamente crescente pelas implicações que potencialmente acarretam na área dos chamados novos alvos terapêuticos.Dentro da problemática do estudo dos marcadores tumorais séricos, acessíveis na prática clínica diária, tem tomado um lugar de crescente interesse a determinação do valor sérico pré-terapêutico de alguns, como é o caso da citoqueratina Cyfra 21-1, cujo valor, como factor de prognóstico nos CPNPC, tem sido objecto de múltiplos trabalhos, de resultados nem sempre concordantes.Daí o relevo da presente meta-análise, que vem confirmar a importância desse marcador tumoral como determinante prognóstico nos CPNPC.Enquanto as recomendações da American Thoracic Society/European Respiratory Society (ATS/ERS) não indicam qualquer marcador tumoral na avaliação pré-terapêutica dos CPNPC 3, nas recomendações da Société de Pneumologie de Langue Française (SPLF) 4, o Cyfra 21-1 é apontado como tendo valor na avaliação pré-terapêutica deste grupo de tumores, onde revela valor prognóstico independente.Estas afirmações são feitas com base em estudos prospectivos de grupos de doentes, mas questionase o seu interesse clínico, caso a caso, não sendo indicado como factor de prognóstico isolado 4.Por outo lado, numa revisão de 500 trabalhos publicados 5, defende-se que os marcadores tumorais não têm lugar na avaliação prognóstica dos doentes com CPNPC, o que não está de acordo com outros que afirmam que o Cyfra 21-1 se correlaciona bem com o TNM e o PS, constituindo um factor de prognóstico independente, e recomendando-o, mesmo, como uma co-variável a incluir em futuros ensaios clínicos 6.A meta-análise que apresentámos vem reforçar a opinião de que os valores séricos pré-terapêuticos elevados de Cyfra 21-1, nos CPNPC, constituem um factor de prognóstico isolado, independentemente do estádio da doença e da terapêutica instituída, reforçando as conclusões de outro publicado recentemente 7, em que esse marcador tumoral se revelou também nesse grupo de tumores, em estádios IIIB/IV, como um factor de prognóstico, quer isoladamente, quer quando associado a dois outros, o antigénio carcinoembrionário (CEA) e a neuroenolase específica (NSE).Nos doente cirúrgicos, o valor pré-terapêutico elevado de Cyfra 21-1, eventualmente, poderá indicar a necessidade de quimioterapia adjuvante, o que poderá ser mais um argumento a reforçar as conclusões do projecto IALT 8, em que se defende que aquela abordagem terapêutica poderá ser útil, também, nos estádios mais localizados da doença.

This study was designed to evaluate the utility of the bone markers total alkaline phosphatase (TAP), bone-specific alkaline phosphatase (BAP), aminoterminal propeptide of type I collagen (PINP), carboxyterminal propeptide of type I collagen (PICP), pyridinoline crosslinks (PYD), deoxypyridinoline crosslinks (DPD), cross-linked carboxyterminal telopeptide of type I collagen (ICTP), cross-linked carboxyterminal telopeptide of type I collagen (CTx, beta-CrossLaps) and tartrate-resistant acid phosphatase 5b (TRAP 5b) in comparison with bone scintigraphy for the diagnosis of bone metastasis in lung carcinoma patients. The study population consisted of 49 patients with bone metastasis confirmed by plain radiography and/or computed tomography, 89 patients without bone metastasis, 12 patients with benign lung diseases and 18 healthy persons. All patients were of male gender. The bone markers were measured using commercially available tests. Serum and urine were collected from fasting patients at the time of bone scan between 7.00 and 8.00 a.m. The sensitivity of bone scintigraphy was 100%, its specificity 76.4%, resulting in a diagnostic efficiency of 84.8%. The positive predictive value was calculated to be 70% and the negative one to be 100%. The concentrations of the bone markers TAP, BAP, PINP, PYD, DPD and ICTP were significantly higher in patients with bone metastasis than in those without bone metastasis (p<0.01). The levels of PICP and CTx only tended to be higher in the patients with bone metastasis compared to those without bone metastasis. There was no significant difference in the TRAP 5b levels between the two groups. There was also no difference in the marker levels between osteoblastic, osteolytic and mixed osteoblastic-osteolytic lesions. Contrary to BAP, PICP, CTx and TRAP 5b, the markers TAP, PINP, PYD, DPD and ICTP were found to be higher (p<0.01-0.05) in patients with bone metastasis than in patients with benign lung diseases. In addition, PYD, DPD and ICTP differentiated patients with benign lung diseases from the healthy controls. Based on cut-off values that correspond to 95% specificity in the group of healthy persons, the sensitivity of the marker assays were as follows (specificity in brackets): TAP 33.3% (97.5%), BAP 22% (100%), PINP 18.4% (97.5%), PICP 2.1% (95.2%), PYD 91.8% (24.1%), DPD 83.7% (34.5%), ICTP 75.5% (44.6%), CTx 45.8% (77.5%) and TRAP 5b 14% (84%). The corresponding data for the diagnostic efficiency were as follows: TAP 73.6%, BAP 77.1%, PINP 67.7%, PICP 61.1%, PYD 48.5%, DPD 55.2%, ICTP 56.1%, CTx 65.6% and TRAP 5b 58.7%, respectively. The positive predictive values ranged from 20% (PICP) to 100% (BAP) and the negative values from 62.7% (PICP) to 84% (PYD). In the ROC analysis, TAP, followed by RAP, PINP and PYD, showed the best performance. The levels of TAP, BAP, PINP, PYD, DPD and ICTP were found to be higher in the patients with bone metastasis compared to those with metastastic lesions in other sites (p<0.01, except for ICTP having a p value of < 0.05). The levels of TAP, BAP, PYD, DPD and ICTP increased significantly with the number of metastases. There was also a steady increase in T scores of the markers PINP, PYD, DPD and ICTP with the extent of the metastatic bone disease. It is concluded that the currently available bone markers cannot replace bone scintigraphy, either for screening or in the diagnosis of bone metastasis, in lung carcinoma patients. However, a panel consisting of TAP, BAP, PINP, PYD, DPD and ICTP may be of some value as an adjunct tool to bone scintigraphy for this purpose.

The purpose of this study was to determine the prognostic significance of a high pretreatment serum CYFRA 21-1 level (a cytokeratin 19 fragment) adjusted for the effects of well-known co-variables in non-small-cell lung cancer (NSCLC). This meta-analysis based on individual updated data gathered comprehensive databases from published or unpublished controlled studies dealing with the prognostic effect of serum CYFRA 21-1 level at presentation in NSCLC of any stage (nine institutions, 2063 patients). Multivariate regression was carried out with the Cox model. The proportional hazard assumption for each of the selected variables retained in the final model was originally checked by log minus log plots baseline hazard ratio. The follow-up ranged from 25 to 78 months. A total of 1616 events were recorded. In the multivariate analysis performed at the 1-year end point, a high pretreatment CYFRA 21-1 level was an unfavourable prognostic determinant in all centres except one (Hazard ratio (95% confidence interval): 1.88 (1.64–2.15), P <10 −4 ). Other significant variables were stage of the disease, age and performance status. Within the first 18 months, the procedure disclosed a nearly similar hazard ratio for patients having a high pretreatment serum CYFRA 21-1 level (1.62 (1.42–1.86), P <10 −4 ). For patients who did not undergo surgery, the hazard ratio during the first year of follow-up was 1.78 (1.54–2.07), P <10 −4 . Finally, in the surgically treated population, at the 2-year end point, a high pretreatment CYFRA 21-1 and a locally advanced stage remained unfavourable prognostic determinants. In conclusion CYFRA 21-1 might be regarded as a putative co-variable in analysing NSCLC outcome inasmuch as a high serum level is a significant determinant of poor prognosis whatever the planned treatment.

O objectivo da presente meta-análise foi determinar o valor prognóstico de níveis séricos pré-terapêuticos elevados de Cyfra 21-1, ajustados a co-variáveis clássicas no CPNPC.

This international multicenter study was designed to evaluate the technical performance of the new double-monoclonal, single-step Elecsys neuron-specific enolase (NSE) enzyme immunoassay (EIA) and to assess its utility as a sensitive and specific test for the diagnosis of small-cell lung cancer (SCLC). Intra- and interassay coefficients of variation, determined in five control or serum specimens in six laboratories, ranged from 0.7 to 5.3 (inter-laboratory median: 1.3%) and from 1.3 to 8.5 (inter-laboratory median: 3.4%), respectively. Laboratory-to-laboratory comparability was excellent with respect to recovery and inter-assay coefficients of variation. The test was linear between 0.0 and 320 ng/ml (highest measured concentration). There was a significant correlation between NSE concentrations measured using the Elecsys NSE and the established Cobas Core NSE EIA II in all subjects (n = 723) and in patients with lung cancer (n = 333). However, NSE concentrations were systematically lower (approximately 9%) with the Elecsys NSE than with the comparison test. Based on a specificity of 95% in comparison with the group suffering from benign lung diseases (n = 183), the cut-off value for the discrimination between malignant and benign conditions was set at 21.6 ng/ml. NSE was raised in 73.4% of SCLC patients (n = 188) and was significantly higher (p < 0.01) in extensive (87.8%) as opposed to limited disease (56.7%). NSE was also elevated in 16.0% of the cases with non-small cell lung cancer (NSCLC, n = 374). It is concluded that the Elecsys NSE EIA is a reliable and accurate diagnostic procedure for the measurement of NSE in serum samples. The special merits of this new assay are the wide measuring range (according to manufacturer's declaration up to 370 ng/ml) and a short incubation time of 18 min.

In a series of 130 consecutive patients suffering from small cell lung cancer (SCLC), we compared response evaluations according to standard criteria of the WHO with response evaluations according to changes in the neuron-specific enolase (NSE) levels during systemic therapy. For assessment by changes in the marker levels, the difference between two consecutive levels must exceed 30%. This value is based on the formula: Dc = 2(square root 2) x CV (CV: inter-assay coefficient of variation of the NSE test, set at 10 %). Of the 130 patients who entered this study, 18 patients received best supportive care and were excluded from the therapy monitoring. In the remaining 112 patients, 502 evaluations for response to therapy by both methods were performed, ie. 4.5 observations per patient. We found a concordance between the response evaluations according to the marker criteria and the clinical assessment in 69.7 % of the observations when including cases with positive lead-time and those with a temporary drop in the NSE levels due to a short-term response to therapy. The latter cases met the criteria consistent with the clinical evaluations at the next observation. The concordance with the clinical response evaluation increased to 84.2% when considering only those changes in the NSE levels where at least one of the consecutive marker levels was in the pathological range (> 14.5 ng/ml). Most discordant results were due to insufficient changes in the NSE levels at clinical remission or progression. A further limitation to the general use of NSE for therapy monitoring was founded on the marker negativity throughout the follow-up period, despite tumor progression or relapse. Changes in the levels between pretreatment NSE and after the first cycle of chemotherapy were shown to provide prognostic information. Patients with a drop in the NSE levels proved to have a significantly better survival probability than those with unchanging or rising marker values (p = 0.004). It is concluded that in the majority of evaluations, changes in the NSE levels are consistent with clinical findings based on imaging techniques but remain of doubtful utility in an individualpatient. NSE measurement can only be recommended as an adjunct to the clinical assessment in the follow-up of SCLC patients.

Cellular orders in normal tissue and in tumors can be described on the basis of physical terms. Assuming that the peptidase cathepsin B is involved as an essential factor in tumor progression we analyzed the corresponding distribution pattern and determined the entropy of this cell fraction in tumors by syntactic structure analysis using nearest neighbor relationships. Of the 120 surveyed sections from primary lung tumors 62 (51.7 %) were identified with cathepsin B expressing cells. Cathepsin B-positive tumor cells have significantly shorter mean cell-cell distances (p<0.01) and form significantly higher number of tumor cell clusters (p<0.01) when compared with cathepsin B-negative tumor cells. The diameters of the cathepsin B positive tumor cell clusters are increased in moderately and intensively stained tumor cell areas compared to the cathepsin B negative ones (p<0.1 and p<0.05, respectively). The mean cell-cell distance between positive tumor cells was significantly shorter in squamous cell carcinomas (SCC) compared to adenocarcinomas (AC) (p<0.01). We found an increased number of tumor cell clusters in intensively stained areas of SCC compared with AC (p<0.05). Interestingly, in dedifferentiated tumors cells which strongly expressed cathepsin B, have significantly (p<0.01) shorter mean cell-cell distances compared with those well differentiated tumors. In conclusion, cathepsin B positive tumor cells have shorter mean cell-cell distances and form higher number of tumor cell clusters. Our findings indicate that cathepsin B positive tumor cells of primary lung tumors seem to detach as tumor cell clusters instead of single tumor cells. This process appears to be more pronounced in squamous cell carcinomas than in adenocarcinomas.

Das akute Empyem ist durch den eitrigen Erguß charakterisiert. Zwischen den Plaurablättern können sich fibrinöse Adhäsionen bilden. Bei unvollständiger Resorption des eitrigen Exsudates entwickelt sich in der Intermediärphase eine zunehmende Organisation und Demarkation des Exsudates. Dies führt in Spätstadien zu Pleuraschwarten und vollständig abgekapselten Empyemresten. Neben den klassischen Empyemursachen kommt es gehäuft zur traumatischen oder iatrogenen Entstehung von Pleuraempyemen. Differentialdiagnostisch sind vor allem empyemartige Ergüsse bei Tumorpatienten abzugrenzen. Der Verlauf ist in erster Linie abhängig von der Virulenz und Art des Erregers, vom immunologischen Status des Patienten und von den eingeleiteten Therapiemaßnahmen.