Prognostic Values of VEGF and Endostatin with Malignant Pleural Effusions in Patients with Lung Cancer

Aims: Angiogenesis is important in malignant pleural effusion (MPE) formation and it is regulated by anumber of pro- and anti-angiogenic cytokines. The purpose of this study was to evaluate the prognostic valueof angiogenic factor vascular endothelial growth factor (VEGF) and angiogenesis inhibitor endostatin in lungcancer patients with MPE, and investigate the relationship between these two kinds of agent. Methods: Usingenzyme-linked immunoadsorbent assay, the concentrations of VEGF and endostatin were measured in pleuraleffusions (PE) and serum from a total of 70 lung cancer patients with MPE and 20 patients with tuberculosis.Results: Compared to patients with tuberculosis, the levels of VEGF and endostatin in both PE and serum weresignificantly higher in patients with lung cancer. There were statistically significant correlations between VEGFlevels in PE and serum (r=0.696, p<0.001), endostatin levels in PE and serum (r=0.310, p=0.022), and VEGF andendostatin levels in PE (r=0.287, p=0.019). Cox multivariate analysis revealed that elevated pleural VEGF andendostatin levels and serum endostatin level were independent predictors of shorter overall survival. Conclusion:Both pro- and anti-angiogenic factors are likely contributors to PE formation. Our results suggest that the levelsof VEGF and endostatin in PE, together with endostatin in serum, may be potential prognostic parameters forlung cancer patients with MPE.     

Role of platelet-derived growth factor-AB in tumour growth and angiogenesis in relation with other angiogenic cytokines in multiple myeloma

Angiogenesis is a complex process essential for the growth, invasion, and metastasis of various malignant tumours, including multiple myeloma (MM). Various angiogenic cytokines have been implicated in the angiogenic process. Among them, platelet-derived growth factor-AB (PDGF-AB) has been reported to be a potent stimulator of angiogenesis in many solid tumours and haematological malignancies, including MM. The aim of the study was to investigate the relationship between PDGF-AB, microvascular density (MVD), and various angiogenic cytokines, such as basic fibroblast growth factor (b-FGF), angiogenin (ANG), and interleukin-6 (IL-6), in MM patients. Forty-seven MM patients before treatment, 22 of whom were in plateau phase, were studied. We determined the serum levels of the aforementioned cytokines and MVD in bone marrow biopsies before and after treatment. Mean serum values of PDGF-AB, b-FGF, ANG, and MVD were significantly higher in patients compared with controls and with increasing disease stage. Significant positive correlations were observed between serum PDGF-AB, ANG, and IL-6 levels and MVD. Furthermore, we found significant positive correlations between PDGF-AB and b-FGF, IL-6, ANG, and β2 microglobulin. We also found that patients with high MVD had statistically significantly higher serum levels of PDGF-AB when a median MVD value of 7.7 was used as the cutoff point. Furthermore, a significant difference was found in serum levels of PDGF-AB between pre- and post-treatment patients. Finally, survival time was significantly higher in the low MVD group versus the high MVD group (76 vs 51 months). Our results showed that there is a strong positive correlation between PDGF-AB and the studied angiogenic cytokines and MVD. It seems that PDGF-AB plays a role in the complex network of cytokines inducing bone marrow neovascularization in patients with MM.     

Clinical utility of vascular endothelial growth factor in diagnosing malignant pleural effusions

While the early diagnosis of cancer has been fully respected, it is still however often difficult for clinicians to confirm malignant pleural effusions (PE), which essentially indicate the end-stage cancer. It has now been demonstrated that vascular endothelial growth factor (VEGF) is a pivotal angiogenesis factor and associated with tumor growth and metastasis. The aim of this study was then to assess the diagnostic performance of VEGF in malignant PE. In this controlled and blinded prospective study, 113 consecutive patients with PE were recruited. For each eligible case, the VEGF levels of pleural fluid (PF) and serum were examined simultaneously using enzyme immunoassay. The reference standard for malignant PE was clinical evaluation and PF cytology with pleural biopsy, other examination and follow-up added as needed. According to the final diagnoses, 81 qualified cases were grouped as malignant (n=32) and benign (n=49) PE. For PF VEGF level, the mean in malignant group was higher than that in benign group (1358+/-1493 pg/mL vs. 422+/-317 pg/mL, p=0.001). As did for serum VEGF level (650+/-533 pg/mL vs. 137+/-189 pg/mL, p<0.001). Using receiver operating characteristic analysis, the determined diagnostic cut-off points of VEGF levels of PF and serum for malignant PE were 959.25 pg/mL and 212.36 pg/mL, with sensitivities of 47%, 69% and specificities of 96%, 88%, respectively. For cascade connection and parallel operation of PF VEGF and serum VEGF, the sensitivities were 34%, 81% at specificities of 98%, 86%, respectively. These findings suggest that VEGF could be used in diagnosing malignant PE as a useful adjunct of conventional algorithm. Different VEGF test strategies, including test on PF, serum and both, may be selected according to practical needs.     

Utility of hyaluronic acid in pleural fluid for differential diagnosis of pleural effusions: likelihood ratios for malignant mesothelioma

The level of hyaluronic acid (HA) was determined in the pleural fluid of 99 patients, including 19 with malignant mesothelioma, 27 with lung cancer, 1 with breast cancer, 1 with mediastinal tumor and 51 with non-malignant diseases. With a cut-off level at 100 micrograms/ml, the pleural fluid concentration of HA was high in 36.8% of patients (7 of 19) with malignant mesothelioma and 1.3% of patients (1 of 80) with lung cancer and other malignant and non-malignant diseases. The mean concentration of pleural fluid HA was significantly higher in patients with mesothelioma than in those with lung cancer and other malignant and non-malignant diseases. The pre-test probability of MM was 5.9% in this series. The LRs for > or = 100, 50-99 and < or = 49 micrograms/ml are 28.3, 3.3 and 0.5, respectively; these put the post-test probabilities at 64, 17 and 3%, respectively. Indeed, in cases of uncommon disease such as MM, the post-test probability is low even if the cut-off level of HA is > or = 100 micrograms/ml. The discrimination between malignant mesothelioma and lung cancer needs special attention. In these two diseases, the LRs of MM for pleural fluid CEA > 30, 10-30 and < 10 ng/ml were 0.2, 1.9 and 2.4, respectively. The pre-test probability of MM for HA > or = or 100 micrograms/ml is 64%. Furthermore, because the LR for CEA is < 10 ng/ml, the post-test probability is 81%. When the combination of two markers is considered, the high level of HA and the low level of CEA may be useful for the differential diagnosis of MM from pleuritis carcinomatosa.      

Serum anti-p53 autoantibodies in pleural malignant mesothelioma,lung cancer and non-neoplastic lung diseases

Alterations of the p53 gene may lead to the production of detectable autoantibodies (p53-Abs) in cancer patients. In order to evaluate the association of p53-Abs with pleuropulmonary diseases, four groups of subjects were analyzed by ELISA for serum p53-Abs, in the framework of a molecular epidemiologic study. Two of 30 pleural malignant mesothelioma patients (MM; 6.7%) and 8/48 lung cancer patients (LC; 16.7%) were seropositive, while all 51 healthy controls (HC) were negative. Two of 55 (3.6%) at-risk controls (RC) with non-malignant respiratory diseases were positive and were not subsequently diagnosed any cancer. The difference was statistically significant between LC and RC or HC (P = 0.01), but not between MM and any other group. No correlation was found with age, sex, cancer stage or histology, cigarette smoking or occupational exposure. A longer survival (not significant) was shown in seropositive LC but not in MM. p53 expression in tumor tissue was also evaluated in a subgroup of MM. In conclusion, the presence of detectable p53-Abs in serum was associated in a statistically significant proportion of cases with LC but only occasionally with MM. The longer survival among positive LC patients and the presence of two seropositive among patients with non-neoplastic respiratory diseases should be further investigated.     

Clinical significance of the expression of tumor-associated antigen, RCAS1, and its soluble protein in pleural fluid in malignant mesothelioma

RCAS1 is a type II membrane protein which is also secreted as a soluble protein. RCAS1 may play a role in evading immune surveillance by tumor cells and be responsible for the aggressive behavior of tumors. We examined the usefulness of RCAS1 in the follow-up of malignant mesothelioma. In addition, we examined the usefulness of its soluble protein (sRCAS1) in pleural effusion for the diagnosis of malignant mesothelioma. We studied 38 patients with pleural malignant mesothelioma and examined the correlation between RCAS1 expression, clinicopathologic variables and overall survival. We also determined the pleural fluid sRCAS1 concentration with an enzyme-linked immunosorbent assay (ELISA). We found that 34 out of 38 (89.5%) malignant mesothelioma cells stained for RCAS1. The positive rate was 90.9% in biphasic type, 78.6% in epithelioid type, and 100% in sarcomatoid type. No statistically significant correlation was observed between RCAS1 expression and gender, age, histology or clinical stage. Interestingly, survival of the malignant mesothelioma patients with RCAS1 expression was significantly increased compared with those without (median survival time: 13.0 vs. 4.3 months, p=0.011). Multivariate analysis of prognostic factors, using the Cox proportional hazards model, revealed that RCAS1 expression had a significantly positive effect on survival. sRCAS1 concentrations in pleural fluid in malignant mesothelioma were lower than those in lung cancer (2.18+/-2.20 vs. 46.3+/-129 U/ml; p=0.019). RCAS1 expression is informative for the follow-up of malignant mesothelioma patients. In addition, sRCAS1 in pleural fluid may be useful for the diagnosis of malignant mesothelioma.     

Malignant pleural effusions: meaning of pleural-fluid pH determination

In 36 patients with malignant pleural effusions, we determined the pH and the glucose concentration of the pleural fluid. Twenty-one of 36 patients (58.3%) had a low pH (less than 7.30) and 15 had a normal pH (greater than or equal to 7.30; 7.13 +/- 0.12 vs. 7.37 +/- 0.05; p less than 0.0005). The patients with low pH had significantly lower glucose concentrations than those with normal pH (2.7 +/- 1.4 vs. 6.3 +/- 2.9 mmol/l; p less than 0.0005). Twenty-one of 34 patients (61.7%) had a glucose concentration lower than a cut-off value of 4.4 mmol/l; of these, 17 (81%) had a low pH. The mean survival in the low-pH group was 4.8 +/- 4.4 months, whereas the mean survival in the normal-pH group was 5 +/- 8 months (p greater than 0.4). Twelve of 36 patients (33.3%) were treated with intrapleural Corynebacterium parvum (CBP) injections. Fourteen of 21 low-pH patients (66.6%) survived more than 2 months, and 4 of them are still alive. Six of 15 normal-pH patients (40%) survived more than 2 months, and 1 of them is still alive. Three of the 5 living patients were treated with CBP (2 in the low-pH group and 1 in the normal-pH groups). Our results confirm that pH and glucose concentrations in the pleural fluid of patients with malignant effusions are frequently low. However, the survival and the response to CBP pleurodesis in patients with low-pH malignant effusions are the same as those in patients with normal-pH malignant effusions.     

Elevated insulin-like growth factor-1 and insulin-like growth factor binding protein-2 in malignant pleural effusion

Insulin-like growth factor-1 (IGF-1) and its binding proteins (IGFBPs) are produced by many tissues and are present in serum and other biological fluids. Alterations in sera of IGF-1 and 2 and IGFBPs were demonstrated in patients with malignancy, infection and other diseases causing pleural effusion. In this study the IGF-1 and IGFBP-2 content and the specific electrophoretic patterns of IGFBPs in samples of sera and pleural effusions of 25 patients with malignancy, infection and congestive heart failure were investigated. IGF-1 levels in exudative effusions of malignant solid tumors were significantly higher [(mean +/- SD), 20.9+/-7.5 nmol/L, n = 9] than in lymphoma (11.0+/-5.2 nmol/L, n = 5; p < 0.05), infection (11.4+/-6.5 nmol/L, n = 6; p < 0.05) and transudative effusion of congestive heart failure (4.3+/-3.3 nmol/L, n = 5; p < 0.02). IGFBP-2 was markedly increased in effusions of malignant solid tumors (2.14+/-0.82 mg/L, n = 9) compared with exudates of lymphoma, infection and transudates (1.10+/-0.70, 1.22+/-0.32 and 0.93+/-0.52 nmol/L, respectively, p < 0.05). Moreover, in effusion of solid tumors, IGFBP-2 levels were higher than those in corresponding sera, which suggests local production of this binding protein. The demonstration of IGFBP-2 in solid tumor cells by immunohistochemistry further supports this possibility. This work demonstrates the existence of the IGF-1/IGFBP system in pleural fluids from different etiologies and implies possible use of IGF-1 and IGFBP-2 as a potential marker of malignant effusions.     

Elevation of sialyl stage-specific mouse embryonic antigen levels in pleural effusion in patients with adenocarcinoma of the lung

Sialyl stage-specific mouse embryonic antigen (SSEA-1) levels were measured in pleural effusions obtained from patients with lung cancer and benign pulmonary disease, using a solid-phase immunoradiometric sandwich assay. The mean (+/- SEM) levels (unit/ml) of pleural fluid sialyl SSEA-1 were 3620 +/- 1419 in adenocarcinoma (n = 25), 123 +/- 30 in nonadenocarcinoma (n = 13) and 95 +/- 19 in benign pulmonary disease (n = 13), respectively. The positive rate was 64% in adenocarcinoma, 7.7% in nonadenocarcinoma, and 0% in benign pulmonary disease, respectively, when a cutoff level was defined as the mean + 3 SD value (300 unit/ml) based on pleural fluid sialyl SSEA-1 levels in benign pulmonary disease. There was a significant positive correlation between pleural fluid levels of sialyl SSEA-1 and those of carcinoembryonic antigen in adenocarcinoma patients (r = 0.8246, P less than 0.01). Pleural fluid sialyl SSEA-1 levels correlated with cytologic findings in adenocarcinoma patients. These observations suggest that sialyl SSEA-1 in pleural effusion is a useful marker to discriminate malignant from nonmalignant and adenocarcinoma from nonadenocarcinoma of the lung.     

Evaluation of pleural fluid human epididymis 4 (HE4) as a marker of malignant pleural effusion

Pleural effusion is a commonly encountered problem in clinical practice, and pleural fluid analysis is usually the first step towards identifying the underlying etiology. Numerous studies have been published analyzing the potential utility of measuring biomarkers in pleural fluid as possible indicators of a malignant effusion; however, there are no studies that have examined the presence of human epididymis 4 (HE4) in pleural effusions. The aims of this study were to assess pleural effusion and serum concentrations of HE4 in patients with different types of pleural effusions and to evaluate the diagnostic performance of HE4 in detecting malignant pleural effusion. A prospective cohort study was carried out of 88 consecutive patients presenting with pleural effusions. The patients were divided into three groups: 22 patients with transudative effusions, 32 patients with non-malignant exudative effusions, and 34 patients with malignant pleural effusions. Blood and pleural fluid HE4 levels were measured using immunoassay. Both serum HE4 levels and pleural effusion HE4 levels were significantly higher in patients with malignant effusions than in patients with transudative or non-malignant exudative effusions. A pleural fluid HE4 cutoff value of 1,675?pmol/L was found to predict malignant pleural effusions with a diagnostic sensitivity of 85.3?% and specificity of 90.7?%. The current study reports a novel finding of increased serum and pleural fluid HE4 levels in patients with malignant effusions compared to non-malignant effusions. This finding has the potential to strengthen the diagnostic performance of tumor markers in detecting malignant pleural effusions.     

Expression of basic fibroblast growth factor is associated with a good outcome in patients with squamous cell carcinoma of the esophagus

Angiogenesis is an essential step in tumor growth and metastasis, but rather than being controlled by means of a simple mechanism, the control of tumor angiogenesis may be mediated by several angiogenic factors. We investigated the expression of basic fibroblast growth factor (b-FGF) and platelet-derived endothelial cell growth factor (PD-ECGF) in squamous cell carcinoma of the esophagus in order to clarify the mechanism of angiogenesis. Expression of b-FGF and PD-ECGF was immunohistochemically investigated in tissue specimens from the tumors of 79 patients with squamous cell carcinoma of the esophagus who underwent curative esophagectomy without preoperative chemotherapy or radiation therapy, and the relationship between expression of b-FGF/PD-ECGF, microvessel density (MVD), and clinicopathological background factors was assessed. Tumor cells that expressed b-FGF were found in 41 patients (51.9%), and tumor cells that expressed PD-ECGF were found in 57 patients (72.2%). Although the mean vascular density (47.9/mm(2)) of b-FGF-positive tumors was significantly lower than that (67.2/mm(2)) of b-FGF-negative tumors (p=0.014), the difference between the 56.0/mm2 in PD-ECGF-positive tumors and 60.3/mm2 in PD-ECGF-negative tumors was not significant. Although the survival rate of patients with b-FGF-positive tumors was significantly higher than those with b-FGF-negative tumors (p=0.033), there was no significant difference between the survival rates of patients with PD-ECGF-positive and -negative tumors (p=0.580). Expression of b-FGF may be associated with promotion of angiogenesis and a good prognostic factor in squamous cell carcinoma of the esophagus.     

The prognostic significance of malignant pleural effusion at the time of thoracotomy in patients with non-small cell lung cancer

Surgery is usually not indicated for malignant pleural effusion (PE) due to its poor prognosis. However, PE is first detected at thoracotomy, and it is difficult to judge an appropriate mode of resection. Forty-nine patients with lung cancer were first diagnosed as PE and/or pleural dissemination (PD) at thoracotomy. The histological types were 36 adenocarcinoma, ten squamous cell carcinoma and three large cell carcinoma. Sixteen patients had only PE, 17 had only PD, and 16 had both PE and PD. Ten patients underwent only exploratory thoracotomy, seven partial resection, 27 lobectomy and five panpleuropneumonectomy. The overall survival rate was 26.7% at 3 years. The patients with PE and/or PD seemed to have a poorer survival compared to our previous study. The patients with only PE showed a significantly better prognosis than the patients with only PD (P=0.0001) or with PD+PE (P=0.019). The patients who underwent exploratory thoracotomy showed poor survival. There were significant differences in the survival in relation to the extent of the primary tumor. In conclusion, the patients with T1-2 of primary tumor and only a small amount of PE without PD can be expected to show long-term survival after tumor resection.     

High level of vascular endothelial growth factor in hemorrhagic pleural effusion of cancer

Angiogenic cytokines, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and angiogenin, are candidates for the induction of pleural effusions because they have been implicated in the induction of neovascularization, vascular permeability, and hemorrhage both in the inflammatory process and in tumor progression. Thus, we hypothesized that these angiogenic factors in effusion might be involved in the clinical manifestation of malignant pleural disease. We measured the levels of VEGF, bFGF, and angiogenin in pleural effusions and sera from 40 patients. Pleural effusions due to malignancy (1,350 pg/ml) contained significantly higher levels of VEGF than effusions due to inflammatory diseases (102 pg/ml; p = 0.034). Furthermore, hemorrhagic effusions showed significantly higher VEGF levels (1,942 pg/ml) than non-hemorrhagic effusions (202 pg/ml; p = 0.016) in malignant patients. In contrast, neither bFGF nor angiogenin were correlated with any clinical manifestation of pleural effusion. Immunohistochemical study revealed that malignant cells in the pleura were stained with anti-VEGF antibody. Our data suggest that VEGF secreted from tumor cells may be involved in the accumulation of pleural effusion in malignancy, and that increased levels of VEGF may induce hemorrhagic effusion.     

Clinical evaluation of four tumor markers in malignant and benign pleural effusions.

Total sialic acid (TSA), lipid-bound sialic acid (LSA), ferritin and carcinoembryonic antigen (CEA) were evaluated in 55 patients with malignant pleural effusions and in 32 patients with benign (exudative) pleural effusions. No significant differences were found in the pleural fluid TSA, LSA and ferritin levels between malignant and benign conditions. CEA levels in malignant effusions were significantly higher than those in benign effusions (43.13 +/- 72.8 ng/ml versus 2.6 +/- 5.56 ng/ml, p less than 0.01). At a cut-off level of 5 ng/ml, 60% of the patients with cancer showed elevated pleural fluid CEA levels. The specificity and diagnostic accuracy of CEA in distinguishing malignant from benign pleural exudates were both very high (91% and 71% respectively). Therefore, of the four markers investigated, only CEA could be a valuable tool in the detection of pleural malignancy.     

Circulating interleukin-6 predicts survival in patients with metastatic breast cancer

Interleukin-6 (IL-6) is a multifunctional cytokine produced by macrophages, T cells, B cells, endothelial cells and tumour cells. Interleukin-6 is able to promote tumour growth by upregulating anti-apoptotic and angiogenic proteins in tumour cells. In murine models it has been demonstrated that antibodies against IL-6 diminish tumour growth. Several reports have highlighted the prognostic importance of IL-6 in e.g., prostate and colon cancer. We addressed prospectively the prognostic significance of serum IL-6 (sIL-6), measured at diagnosis of metastasis, in 96 unselected and consecutive patients with progressive metastatic breast cancer before the initiation of systemic therapy. The median sIL-6 value for the breast cancer population was 6.6 +/- 2.1 pg/ml. Patients with 2 or more metastatic sites had higher sIL-6 values compared to those with only 1 metastatic site (respectively 8.15 +/- 1.7 pg/ml and 3.06 +/- 6.6 pg/ml; p < 0.001). Patients with liver metastasis (8.3 +/- 2.4 pg/ml), with pleural effusions (10.65 +/- 9.9 pg/ml) and with dominant visceral disease (8.15 +/- 3.3 pg/ml) had significantly higher values compared to those without liver metastases (4.5 +/- 3.4 pg/ml; p = 0.001), without pleural effusions (5.45 +/- 1.5 pg/ml; p = 0.0077) and with dominant bone disease (4.5 +/- 1.4 pg/ml; p = 0.007) respectively. No correlation between sIL-6 and age, menopausal status, performance status, tumour grade, body-mass index, histology and hormone receptor status was found. Multivariate analysis showed that high levels of serum IL-6 have independent prognostic value. We conclude that circulating IL-6 is associated with worse survival in patients with metastatic breast cancer and is correlated with the extent of disease.     

Quantitative evaluation of the apoptosis regulating genes Survivin, Bcl-2 and Bax in inflammatory and malignant pleural lesions

AIM: We aimed to identify defects in the programmed cell death pathway that can be related to pleural malignant mesothelioma (MM) unresponsiveness to chemotherapy. MATERIALS AND METHODS: We quantified mRNA levels of the apoptosis regulating genes Survivin, member of the IAP family, Bcl-2 and Bax, members of the Bcl-2 family. We studied 22 non-neoplastic pleural samples, comprising normal and inflammatory tissue specimens, and 42 pleural MMs using real-time RT-PCR. RESULTS: Very low mRNA levels of each apoptotic gene were detected in all normal pleural samples. All three genes displayed increased mRNA levels in inflammatory and tumor specimens. Survivin levels in pleuritis and MMs were significantly increased (333% and 908%, respectively) compared to normal counterparts (p=0.0147 and 0.00349, respectively). Bcl-2 and Bax levels were increased in inflammatory pleural samples (394%, p=0.001 and 188%, p=ns, respectively) and in MMs (94%, p=ns and 88%, p=0.0163, respectively). The Bcl-2/Bax ratio was higher in pleuritis than in MMs, compared to normal pleurae (441%, p=ns and 22%, p=ns, respectively); the difference between Bcl-2/Bax ratio in inflammatory and neoplastic pleural samples was significant (p=0.00375). CONCLUSIONS: These results suggest that apoptotic defects in pleural MMs are linked to increased levels of Survivin, whereas variations in Bcl-2 and Bax expression appear less significant, although further studies are needed to highlight Bcl-2 family members interactions in apoptosis control. Survivin progressive accumulation from normal pleura to MM suggests this gene may be important in mesothelial cancerogenesis. Survivin overexpression may also be involved in pleural MM resistance to oncological therapies. Therefore, Survivin may represent a promising novel target for selective therapies.     

Elevated pleural fluid RCAS1 is a diagnostic marker and outcome predictor in lung cancer patients

RCAS1, a type II membrane protein also secreted in soluble form, may be important in tumor cell evasion of immune surveillance and contribute to the aggressiveness of human tumors. We examined the implications of elevated pleural fluid RCAS1 at the onset of effusion in lung cancer patients. Of 102 patients presenting with pleural effusion, 59 proved to have a malignant effusion and 43, nonmalignant. Malignant effusions exhibited higher RCAS1 concentrations than nonmalignant effusions (mean +/- SD; 36.3 +/- 114 vs. 2.7 +/- 1.8 U/ml; p=0.014). Lung cancer patients with pleural fluid RCAS1 concentrations below 15 U/ml had a longer mean survival than those with higher concentrations (4.7 vs. 1.7 months; p<0.05). By multivariate analysis, pleural fluid RCAS1 was an independent prognostic factor in lung cancer patients with effusion. In conclusion, RCAS1 determination at onset of pleural effusion is informative for both diagnosis and outcome prediction in lung cancer patients.     

Human ovarian carcinomas: correlation of malignancy and survival with the expression of epidermal growth factor receptors (EGF-R) and EGF-like factors (EGF-F)

We have studied the concentration of epidermal growth factor receptors (EGF-R) in 115 different malignant ovarian tumors (101 ovarian carcinomas) and EGF-like factors (EGF-F) in tissue extracts of 63 different ovarian carcinomas and 20 non-malignant tissues. 36% of ovarian carcinomas are EGF-R positive. The calculated mean EGF-F level of 4.2 +/- 1.5 ng mg-1 (range: 0-15 ng mg-1) in ovarian carcinomas is significantly enhanced compared to 1.5 +/- 0.7 ng mg-1 (range: 0-4 ng mg-1) of non-malignant tissue extracts. The correlation between EGF-R positive as well as negative ovarian carcinomas and the results of a primary chemotherapy of advanced ovarian carcinomas (n = 92) revealed a significantly higher remission rate of EGF-R positive tumors (66%) compared to EGF-R negative cases (23%). 84% of tumors with progressive disease were EGF-R negative. The mean EGF-F levels were calculated for prognostic subgroups of ovarian carcinomas. Increased EGF-F levels are significantly associated with progressive disease compared to all patients or the remission group. 15/16 cases with EGF-F levels greater than 5 ng mg-1 showed progressive disease. The overall survival time of patients with tumor tissue EGF-F levels greater than 3.5 ng mg-1 was worse than that of patients with low EGF-F levels. Multivariate analysis showed that the EGF-F level was, after grading, the second most important factor for predicting overall survival.