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Objectives: The fragmentation of the response to the COVID-19 pandemic at national, regional and local levels is a possible source of variability in the impact of the pandemic on society. This study aims to assess how much of this variability affected the burden of COVID-19, measured in terms of all-cause 2020 excess mortality., Design: Ecological retrospective study., Setting: Lombardy region of Italy, 2015-2020., Outcome Measures: We evaluated the relationship between the intensity of the epidemics and excess mortality, assessing the heterogeneity of this relationship across the 91 districts after adjusting for relevant confounders., Results: The epidemic intensity was quantified as the COVID-19 hospitalisations per 1000 inhabitants. Five confounders were identified through a directed acyclic graph: age distribution, population density, pro-capita gross domestic product, restriction policy and population mobility.Analyses were based on a negative binomial regression model with district-specific random effects. We found a strong, positive association between COVID-19 hospitalisations and 2020 excess mortality (p<0.001), estimating that an increase of one hospitalised COVID-19 patient per 1000 inhabitants resulted in a 15.5% increase in excess mortality. After adjusting for confounders, no district differed in terms of COVID-19-unrelated excess mortality from the average district. Minimal heterogeneity emerged in the district-specific relationships between COVID-19 hospitalisations and excess mortality (6 confidence intervals out of 91 did not cover the null value)., Conclusions: The homogeneous effect of the COVID-19 spread on the excess mortality in the Lombardy districts suggests that, despite the unprecedented conditions, the pandemic reactions did not result in health disparities in the region., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

While several studies have evaluated the prognostic weight of respiratory parameters in patients with COVID-19, few have focused on patients' clinical conditions at the first emergency department (ED) assessment. We analyzed a large cohort of ED patients recruited within the EC-COVID study over the year 2020, and assessed the association between key bedside respiratory parameters measured in room air (pO 2 , pCO 2 , pH, and respiratory rate [RR]) and hospital mortality, after adjusting for key confounding factors. Analyses were based on a multivariable logistic Generalized Additive Model (GAM). After excluding patients who did not perform a blood gas analysis (BGA) test in room air or with incomplete BGA results, a total of 2458 patients were considered in the analyses. Most patients were hospitalized on ED discharge (72.0%); hospital mortality was 14.3%. Strong, negative associations with hospital mortality emerged for pO 2 , pCO 2 and pH (p-values: < 0.001, < 0.001 and 0.014), while a significant, positive association was observed for RR (p-value < 0.001). Associations were quantified with nonlinear functions, learned from the data. No cross-parameter interaction was significant (all p-values were larger than 0.10), suggesting a progressive, independent effect on the outcome as the value of each parameter departed from normality. Our results collide with the hypothesized existence of patterns of breathing parameters with specific prognostic weight in the early stages of the disease., (© 2023. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Background: During the COVID-19 pandemic, the number of individuals needing hospital admission has sometimes exceeded the availability of hospital beds. Since hospitalization can have detrimental effects on older individuals, preference has been given to younger patients. The aim of this study was to assess the utility of hospitalization for elderly affected by COVID-19. We hypothesized that their mortality decreases when there is greater access to hospitals., Methods: This study examined 1902 COVID-19 patients consecutively admitted to three large hospitals in Milan, Italy. Overall mortality data for Milan from the same period was retrieved. Based on emergency department (ED) data, both peak and off-peak phases were identified. The percentage of elderly patients admitted to EDs during these two phases were compared by calculating the standardized mortality ratio (SMR) of the individuals younger than, versus older than, 80 years., Results: The median age of the patients hospitalized during the peak phase was lower than the median age during the off-peak phase (64 vs. 75 years, respectively; p <0.001). However, while the SMR for the younger patients was lower during the off-peak phase (1.98, 95% CI: 1.72-2.29 versus 1.40, 95% CI: 1.25-1.58, respectively), the SMR was similar between both phases for the elderly patients (2.28, 95% CI: 2.07-2.52 versus 2.48, 95% CI: 2.32-2.65, respectively)., Conclusions: Greater access to hospitals during an off-peak phase did not affect the mortality rate of COVID-19-positive elderly patients in Milan. This finding, if confirmed in other settings, should influence future decisions regarding resource management of health care organizations., Competing Interests: The authors have declared that no competing interests exist.

This study aims at comparing scientific production in malignant mesothelioma (MM) among countries and evaluating publication trends and impact factor (IF). The PubMed database was searched with a strategy combining keywords listed in the Medical Subject Headings and free-text search. Publications numbers and IF were evaluated both as absolute values and after standardization by population and gross domestic product (GDP). 5240 citations were retrieved from the biennium 1951-1952 (n = 22) to 2005-2006 (n = 535). The 177% increase of MM publications from 1987 to 2006 exceeded by large the corresponding value of total cancer literature (123.5%). In these two decades, 2559 articles with IF were published: 46.4% came from the European Union (EU) (the UK, Italy and France ranking at the top), and 36.2% from the US. The highest mean IF was reported for the US (3.346), followed by Australia (3.318), and EU (2.415, with the UK, Belgium and the Netherlands first). Finland, Sweden and Australia had the best ratio between IF (sum) and resident population or GDP. The number of publications correlated with GDP (p = 0.001) and national MM mortality rates (p = 0.002). An association was found between a country commitment to MM research and the burden of disease (p = 0.04). Asbestos, survival, prognosis, occupational exposure, differential diagnosis, and immunohistochemistry were the most commonly used keywords. This report represents the first effort to explore the geographical and temporal distribution of MM research and its determinants. This is an essential step in understanding science priorities and developing disease control policies., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background and Aims: Osteopontin (OPN) is an integrin-binding protein recently shown to be related to tumorigenesis, progression and metastasis in different experimental models of malignancy. Malignant pleural mesothelioma (MPM) is a fatal disease in which the prognosis remains very poor and the knowledge of predictive factors for outcome is insufficient. The identification of new molecules involved in cancer initiation and development is a fundamental step for improving the curability of this kind of tumor. The purpose of this study is to define the role of OPN in the diagnosis of MPM by determining its prognostic and diagnostic value., Methods: A group of 24 surgically staged MPM subjects was compared with a group of 31 subjects with nonmalignant pulmonary diseases, and with 37 healthy controls. Tumor tissue was analyzed for OPN by immunohistochemical tests, and plasma OPN levels were measured by an enzyme-linked immunosorbent assay., Results: Plasma OPN levels were not significantly higher in either of the patient groups compared with the control group. Immunohistochemical analysis revealed OPN staining of tumor cells in 21 of 24 MPMs. Receiver operating characteristic curve/area under the curve (ROC/AUC) analysis comparing the plasma OPN levels in the healthy group with those of MPM patients showed 40% sensitivity and 100% specificity at a cutoff value of 60.8 ng of OPN per milliliter (AUC 0.6)., Conclusion: Plasma OPN levels do not discriminate between chronic inflammatory and malignant lung diseases and staining intensity in MPM specimens does not correlate with OPN plasma levels.

Objectives: The Cancer of RESpiratory Tract (CREST) biorepository was established to investigate biological mechanisms and to develop tools and strategies for primary and secondary prevention of respiratory tract cancer. The CREST biorepository is focused on pleural malignant mesothelioma, a rare and severe cancer linked to asbestos exposure whose incidence is particularly high in the Ligurian region., Methods: The CREST biorepository includes biological specimens from (a) patients with pleural malignant mesothelioma and lung cancer, (b) patients with nonneoplastic respiratory conditions, and (c) control subjects. Whole blood, plasma, serum, lymphocytes, pleural fluid, saliva, and biopsies are collected, and a questionnaire is administered. Collection, transportation, and storage are done according to international standards., Results: As of January 31, 2008, the overall number of subjects recruited was 1,590 (446 lung cancer, 209 pleural malignant mesothelioma, and 935 controls). The biorepository includes a total of 10,055 aliquots (4,741 serum; 3,082 plasma; 1,599 whole blood; 633 pleural fluid; and 561 lymphocytes) and 107 biopsies. Demographic, clinical, and epidemiologic information is collected for each subject and processed in a dedicated database., Conclusions: The CREST biorepository is a valuable tool for molecular epidemiology and translational studies. This structure relies on a network of contacts with local health districts that allows for an active search for patients. This is a particularly efficient approach, especially when the object of the study is a rare cancer type. The CREST experience suggests that the presence of limited resources can be overcome by the biorepository specialization, the high quality of the epidemiologic information, and the variety of samples.

Nicotinic acetylcholine receptors (nAChR) are expressed on normal bronchial epithelial and nonsmall cell lung cancer (NSCLC) cells and are involved in cell growth regulation. Nicotine induced cell proliferation. The purpose of this study was to determine if interruption of autocrine nicotinic cholinergic signaling might inhibit A549 NSCLC cell growth. For this purpose alpha-Cobratoxin (alpha-CbT), a high affinity alpha7-nAChR antagonist was studied. Cell growth decrease was evaluated by Clonogenic and MTT assays. Evidence of apoptosis was identified staining cell with Annexin-V/PI. Characterization of the basal NF-kappaB activity was done using the Trans-AM NF-kappaB assay colorimetric kit. "In vivo" antitumour activity was evaluated in orthotopically transplanted nude mice monitored by In vivo Imaging System technology. alpha-CbT caused concentration-dependent cell growth decrease, mitochondrial apoptosis caspases-9 and 3-dependent, but caspase-2 and p53-independent and down-regulation of basal high levels of activated NF-kappaB. alpha-CbT treatment determines a significant reduction of tumor growth in nude mice orthotopically engrafted with A549-luciferase cells (4.6% of living cells vs. 31% in untreated mice). No sign of toxicity was reported related to treatment. These findings suggest that alpha7-nAChR antagonists namely alpha-CbT may be useful adjuvant for treatment of NSCLC and potentially other cancers.

Background: The predictive and prognostic role of neuron-specific enolase (NSE) in non-small cell lung cancer (NSCLC) is still under debate., Patients and Methods: To study these aspects, serum NSE was prospectively measured at baseline of first-line chemotherapy treatment and tested for correlation with clinical outcome in 129 advanced NSCLC patients., Results: An objective response was achieved in 27 out of 65 (41.5%) patients with NSE < 8.6 ng/ml and in 38 out of 64 (59.4%) patients with NSE > or = 8.6 ng/ml (p = 0.05). Logistic analysis confirmed the positive association between objective response and NSE values > or = 8.6 ng/ml (odds ratio = 1.69; 95% confidence interval: 1.09-2.63; p = 0.02). Overall median survival was 10.8 months. A statistically significant prognostic effect on survival was found for performance status, stage and response to treatment, but not for baseline NSE value., Conclusion: Based on these data, baseline circulating tumor NSE levels appear to have a weak predictive role, but not a prognostic significance in patients with advanced NSCLC submitted to standard chemotherapy.

Purpose: High levels of serum-soluble mesothelin family proteins (SMRP) have been found to be associated with malignant mesothelioma (MM), but not lung cancer (LC). To verify the clinical role of this marker for both these tumors, we tested serum SMRP in the largest population of thoracic cancers ever assembled., Experimental Design: SMRP blood concentrations were measured in 107 patients with MM, 215 patients with LC, 130 patients with benign respiratory diseases (BRD), and 262 controls. Statistical comparison between mean serum SMRP levels in all groups was done and receiver operating characteristic curves were constructed to evaluate the performance of this marker., Results: SMRP levels were significantly higher in patients with MM and LC than in patients with benign respiratory diseases and controls (P < 0.001). The area under the receiver operating characteristic curve for serum SMRP discriminating MM and controls was 0.77 (95% confidence interval, 0.71-0.83), with a best cutoff of 1.00 nmol/L (sensitivity, 68.2%; specificity, 80.5%). In both MM and LC, serum SMRP levels did not differ significantly between early and late stages. High SMRP levels proved to be an independent negative prognostic factor in patients with MM., Conclusions: Our data confirm that serum SMRP is a promising marker for the diagnosis, prognosis, and clinical monitoring of MM. We found that serum SMRP dosage may prove helpful in LC diagnosis as well. These data may also have positive repercussions on secondary preventive medical strategies for workers previously exposed to asbestos.

Background: The authors assessed the predictive and prognostic role of decline in the serum levels of carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA 21-1) during chemotherapy in patients with advanced nonsmall cell lung cancer (NSCLC)., Methods: Changes in serum levels of CEA and CYFRA 21-1 during first-line, conventional chemotherapy were studied prospectively with an immunometric assay at baseline and every 2 courses in 117 patients with advanced NSCLC. Data were correlated with radiologic objective response (OR) and survival., Results: One hundred seven patients were evaluable for radiologic and serologic response assessment after 2 chemotherapy courses. The radiologic OR rate was 44% overall. The CEA and CYFRA 21-1 responses (> or =20% reduction over baseline level; assessed after the second course of chemotherapy) were 38% and 61%, respectively. Statistically significant correlations were observed between CEA and CYFRA 21-1 responses and OR (P = .01 and P = .004, respectively). The median survival from response assessment (landmark analysis) was 9 months. In a univariate analysis, disease stage, performance status, baseline lactate dehydrogenase level (LDH), OR, CEA response, and CYFRA 21-1 response were correlated significantly with survival. In particular, the median survival was 13 months for patients who had a CEA response and 11 months for patients who had a CYFRA 21-1 response compared with 8 months and 6 months for patients who did not respond, respectively. In a multivariate analysis, performance status (P = .005), baseline LDH level (P = .02), CEA response (P = .03) and CYFRA 21-1 response (P = .01) were confirmed as independent prognostic factors for survival., Conclusions: CEA and CYFRA 21-1 responses appeared to be reliable surrogate markers of chemotherapy efficacy in patients with advanced NSCLC., (Copyright 2006 American Cancer Society.)

c-Met receptor tyrosine kinase (RTK) has not been extensively studied in malignant pleural mesothelioma (MPM). In this study, c-Met was overexpressed and activated in most of the mesothelioma cell lines tested. Expression in MPM tissues by immunohistochemistry was increased (82%) in MPM in general compared with normal. c-Met was internalized with its ligand hepatocyte growth factor (HGF) in H28 MPM cells, with robust expression of c-Met. Serum circulating HGF was twice as high in mesothelioma patients as in healthy controls. There was a differential growth response and activation of AKT and extracellular signal-regulated kinase 1/2 in response to HGF for the various cell lines. Dose-dependent inhibition (IC50 < 2.5 micromol/L) of cell growth in mesothelioma cell lines, but not in H2052, H2452, and nonmalignant MeT-5A (IC50 > 10 micromol/L), was observed with the small-molecule c-Met inhibitor SU11274. Furthermore, migration of H28 cells was blocked with both SU11274 and c-Met small interfering RNA. Abrogation of HGF-induced c-Met and downstream signaling was seen in mesothelioma cells. Of the 43 MPM tissues and 7 cell lines, we have identified mutations within the semaphorin domain (N375S, M431V, and N454I), the juxtamembrane domain (T1010I and G1085X), and an alternative spliced product with deletion of the exon 10 of c-Met in some of the samples. Interestingly, we observed that the cell lines H513 and H2596 harboring the T1010I mutation exhibited the most dramatic reduction of cell growth with SU11274 when compared with wild-type H28 and nonmalignant MeT-5A cells. Ultimately, c-Met would be an important target for therapy against MPM.

Overexpression of platelet-derived growth factor (PDGF) has been observed in lung and pleural tumors. The aim of this study was to evaluate the diagnostic and prognostic role of serum PDGF in pleural mesothelioma (PM). Four groups of subjects were studied: 93 malignant PM patients, 33 primary non small cell lung cancer patients, 51 subjects exposed to asbestos, defined as high-risk controls, and 24 healthy controls. PDGF-AB mean concentration was higher in PM patients (45.8 ng/ml) than in high-risk controls (33.1 ng/ml) and healthy controls (26.8 ng/ml). Using the cut-off level of 49.8 ng/ml, corresponding to the mean+2SD of PDGF-AB in healthy controls, 43% of PM patients showed positive PDGF-AB levels. Survival was evaluated in 82 PM patients. At the end of the follow-up (median 9.8 months) 80.5% of patients had died. Median survival was 13.1 and 7.9 months for patients with PDGF-AB lower and higher than the cut-off, respectively. Adjusting for age, sex, histology and platelet count, positive PDGF-AB levels were associated with lower survival (OR=1.2, 95%CI: 0.9-1.6), even if not significantly so. In conclusion, serum PDGF may represent a useful additional parameter to prognostic factors already available for PM., (Copyright (c) 2005 S. Karger AG, Basel.)

Purpose: Fenretinide (4-HPR) is a synthetic retinoid that has shown a preventive activity in prostate cancer animal models., Experimental Design: We measured the changes in total and free prostate-specific antigen (PSA) and its association with insulin-like growth factor I (IGF-I) and IGFBP-3 levels after 1 year of treatment in 24 subjects given 4-HPR and 24 control subjects enrolled in a randomized bladder cancer prevention trial., Results: No significant effect of 4-HPR was observed on total and free fraction of PSA levels. The median percentage [95 confidence interval (95% CI)] change for % free PSA and total PSA in the 4-HPR and the control group were, respectively, 7.6 (95% CI, -4.0 to 69.3) versus 5.1 (95% CI, -21.4 to 59.8) and -7.8 (95% CI, -18.2 to 52.5) versus -12.3 (95% CI, -44.6 to 9.6). However, in patients ages <60 years, there was a trend to an increase of total free PSA and % free PSA after treatment with 4-HPR that was different from a trend to a decrease in the control group (P = 0.002 and 0.052, respectively). The interaction between age and treatment was statistically significant on free PSA (P = 0.001). A similar pattern was noted with smoking status (P = 0.011 for the interaction on free PSA). No association was observed between PSA levels and IGF-I or IGFBP-3 levels., Conclusions: We conclude that 4-HPR has no significant effect on circulating PSA, but it increases significantly free PSA levels in subjects younger than 60 years and in nonsmokers. These effects might support an activity in prostate cancer prevention but further studies are required.

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., (Copyright 2002 Elsevier Science Ireland Ltd.)

Objective: Sialyl Lewis(x) (sLe(x)) is one ligand for E selectin (CD62E), a glycoprotein that is expressed on activated endothelial cells. Adhesion mediated by endothelial E selectin and sLe(x) expressed on human tumor cells could be relevant for the development of metastases. The aim of this study was to investigate whether or not a correlation exists between pre-operative levels of ganglioside serum sLe(x) and disease-free interval and survival in colorectal cancer patients., Patients and Methods: Thirty Duke's B and 52 Duke's C patients undergoing resection for colorectal cancer were studied. The median follow-up time was 34.8 months. A pool of 57 sera from normal subjects was used as an Internal Normal Standard (INS). sLe(x) analyses were performed by a thin layer chromatography (TLC) immunostaining technique. Results were expressed as the ratio (R) between bands of INS and bands from each neoplastic serum., Results: The median R value was 0.80 in normal subjects, 0.70 in Duke's B patients and 1.0 in Duke's C patients. No significant differences were detected between sLe(x) concentrations in sera from normal and neoplastic subjects (p = 0.1). Using an arbitrary cutoff of R = 0.9, the mean disease-free interval in the whole series was 47.4 months for R <0.9 and 126.0 months for R > or = 0.9 (p = 0.04). The survival time was 76.8 months for patients with R values <0.9 and 156.3 months for patients with R values > or =0.9 (p = 0.1)., Conclusions: High serum levels of ganglioside sLe(x) significantly correlate with a favorable prognosis and with a lower occurrence of metastases. It is conceivable that soluble sLe(x) may compete with membrane-bound sLe(x) in the course of interactions between activated endothelium and tumor cells that have reached the circulation., (Copyright 2003 S. Karger AG, Basel)

We determined c-erbB-2 protein level in serum of 86 primary lung cancer patients (78 non-small cell lung carcinomas (NSCLC), 3 small cell carcinomas, 5 not histologically defined) and in 61 controls. Aim of this study was to evaluate the clinical usefulness of c-erbB-2 as marker for lung cancer diagnosis. The protein was measured with a commercially available sandwich enzyme immunoassay. Mean levels of c-erbB-2 were 72.8 +/- 122.3 fmol/ml in lung cancers and 64.6 +/- 17.5 fmol/ml in controls (P = 0.2). No association was found between c-erbB-2 levels and histotype, tumor stage, sex and smoking habits. Among NSCLC, only four patients showed a c-erbB-2 concentration higher than the selected cut-off value of 99.6 fmol/ml. Subjects with levels higher than the 75th percentile in tumors (73 fmol/ml) had a shorter median survival than those with lower levels (6.3 months versus 10.0 months, P = 0.003). Our results indicated that serum c-erbB-2 protein is not a reliable diagnostic marker. There is, however, a suggestion of a possible clinical usefulness in terms of survival prediction.

Background: HER-2/neu tissue overexpression is found in nearly 15% of patients with nonsmall cell lung carcinoma and is reported to affect prognosis adversely in surgical series. However, the prognostic role of serum HER-2/neu oncoprotein, particularly in patients with advanced lung carcinoma, remains unknown. This study was designed to assess the potential value of measuring serum levels of HER-2/neu oncoprotein in predicting response to treatment and survival in patients with locally advanced and metastatic nonsmall cell lung carcinoma., Methods: Baseline serum HER-2/neu levels (fm/mL) were studied using an enzyme-linked immunosorbent assay method in 84 patients with newly diagnosed, advanced nonsmall cell lung carcinoma who underwent chemotherapy., Results: The patients enrolled in the study included 76 males and 8 females, with a median age of 62 years (range, 36-73 years) and a median performance status of 1. Fifty patients (59.5%) had nonsquamous histology, and 34 patients (40.5%) had squamous cell carcinoma. Thirty-four patients (40.5%) had Stage III disease, and 50 patients (59.5%) had Stage IV disease. The mean baseline value of HER-2/neu in the whole series was 56.1 fm/mL (range, 13.0-103.8 fm/mL). HER2 immunohistochemistry on paraffin embedded tissue was performed in 18 patients. HER-2/neu tissue overexpression was found in only one patient, who also showed high serum levels (102 fm/mL). No correlation was observed between protein serum quantitation and gender, age, histology, stage, performance status, leukocyte count, or smoking. Nonresponding and responding patients exhibited similar oncoprotein levels (median, 57.6 fm/mL vs. 51.9 fm/mL, respectively). The overall survival rate was 42.5% at 1 year and 12% at 2 years, with a median survival duration of 10 months. At univariate analysis, high HER-2/neu serum levels were associated with an unfavorable survival outcome. Using a cut-off point for HER-2/neu of 73.0 fm/mL (corresponding to the 80th percentile of protein concentration), the survival of patients who had higher serum levels of HER-2/neu was significantly worse compared with patients who had lower serum levels (median, 7.1 months vs. 10.9 months; P = 0.004). Multivariate analysis confirmed the independent predictive value of serum HER-2/neu concentration as a negative prognostic factor (P = 0.02)., Conclusions: High pretreatment levels of HER-2/neu oncoprotein are associated with an adverse prognostic impact on survival in patients with locally advanced or metastatic nonsmall cell lung carcinoma., (Copyright 2001 American Cancer Society.)

Study Objective: The aim of our study was to assess the clinical value of CYFRA 21-1 tumor marker and carcinoembryonic antigen (CEA) as diagnostic tools that are complementary to cytology in the diagnosis of malignant mesotheliomas., Patients: We measured CEA and CYFRA 21-1 in the pleural effusions (PEs) and serum of 106 patients (benign lung disease, 34 patients; bronchogenic and metastatic carcinoma, 40 patients; mesothelioma, 32 patients)., Methods: CEA and CYFRA 21--1 levels were determined by means of two commercial enzyme immunoassays., Results: The cutoff levels of CYFRA 21--1 and CEA in malignant PEs, selected on the basis of the best diagnostic efficacy, were 41.9 ng/mL and 5.0 ng/mL, respectively. In all neoplastic PEs, CYFRA 21--1 and CEA sensitivity was 78% and 30.6%, respectively, with a specificity of 80% and 91%, respectively. The sensitivity of CYFRA 21--1 and CEA in patients with mesothelioma was 87.5% and 3.1%, respectively. The results of the CYFRA 21--1 assay were positive in 17 of 19 cases of mesothelioma (89.5%) with a negative or uncertain cytology. The association of the tumor marker assay and the cytology allowed a correct diagnosis in 30 of 32 cases of mesothelioma (93.7%)., Conclusion: This study suggests that CYFRA 21--1 would provide a useful parameter for the differential diagnosis between benign and malignant PE from mesothelioma when the result of cytology is negative or uncertain and the clinical context does not allow a more aggressive approach. Moreover, the association of CYFRA 21--1 with CEA could provide details for a differential diagnosis between mesotheliomas and carcinomas. In fact, an elevated CYFRA 21--1 level with a low CEA level is highly suggestive of mesothelioma, whereas high levels of CEA alone or high levels of both the markers suggest a diagnosis of malignant PE, excluding mesothelioma.

Purpose: To evaluate the endocrinological and clinical activity of a new slow-release formulation of leuprolide acetate in breast cancer patients., Methods: A total of 50 pre- or perimenopausal patients with early- or late-stage breast cancer who were candidates for endocrine treatment were included in the study and randomly allocated to receive either 3.75 mg of leuprolide acetate every month or 11.25 mg of leuprolide acetate every 3 months. Patients were treated until disease recurrence or progression or for a maximum of 24 months. Treatment outcome, side effects, and serum levels of gonadotrophins, estradiol, progesterone, and delta4-androstenedione were analyzed at different time points., Results: In all, 23 patients were allocated to the monthly formulation and 27, to the 3-monthly formulation. The median time on treatment was comparable. There was no evidence of any difference in clinical outcome or drug-induced side effects, hot flushes being recorded in about 50% of patients in both groups. Altogether, 35 patients were actively menstruating at the beginning of treatment; all of them became amenorrhoic after 3 months and remained so until treatment with leuprolide was continued, irrespective of the allocated treatment. All endocrine parameters, particularly estradiol levels, were suppressed to a similar extent., Conclusions: The present results indicate that the two formulations exert a comparable estrogen-suppressive effect and warrant further study of the 3-monthly formulation of leuprolide acetate in breast cancer patients.

The CD44 cell surface proteoglycan participates in a variety of functions including lymphohematopoiesis, lymphocyte homing and tumor metastasis. In addition to the standard form (CD44st), a large family of variant isoforms (CD44v) is generated by alternative splicing of a single gene. Certain CD44v (v5 and V6) are upregulated in the course of neoplastic progression and reflect the metastatic potential of tumor cells. CD44 v6 is expressed in high-grade non-Hodgkin's lymphoma cells and is released in the serum, thus providing a soluble marker that reflects tumor burden, disease progression and treatment response. Here we show that serum CD44st is elevated in approximately half of B-CLL patients. In contrast, CD44v5 and v6 are detected at normal levels in the large majority of the cases. CD44st serum levels correlate significantly with the number of circulating leukemic B cells and with the levels of another soluble B-CLL marker, beta2-microglobulin. Immunoprecipitation analyses of B-CLL sera allow detection of several high molecular weight bands and of a 78 kDa band that represents a soluble form of CD44st and is 4 kDa lower than a similar band (82 kDa) detected in B-CLL cell lysates. Elevated serum CD44st associates with a number of unfavorable prognostic factors such as high peripheral blood lymphocytosis, splenomegaly, advanced disease stage and therapy requirement. A follow-up study indicates that serum levels of CD44st are related to disease status, thus reinforcing our veiw that this molecule may represent a reliable tumor marker in B-CLL.

Cathepsin D is an acidic lysosomal protease expressed in all cells. Some studies have shown correlations between high levels of tissue cathepsin D and poor prognosis. This paper deals with 158 cases of breast cancer in which tissue concentrations in cathepsin D, age, estrogen and progesterone receptor content, and pathological characteristics of the tumor were investigated. Tumors were considered to be cathepsin D+ when a concentration > 40 pmol/mg protein (median value in our samples) was determined. The expression of cathepsin D appears to be related to grading (p = 0.04) and lymph node status (p = 0.05). We found no significant associations among cathepsin D levels, patient age, steroid receptors and histological type. Moreover, the levels of cathepsin D have been evaluated in 9 samples of recurring or metastatic neoplasia and 11 cases of benign breast lesions. We conclude that cathepsin D may be a useful prognostic predictor in breast cancer. Further investigations are required to improve and extend the applications of this assay.

A cell line termed LC 89 was established from a peritracheal lymph node metastasis removed from a 54-year-old patient who underwent surgery for pulmonary adenocarcinoma. Chromosomal analyses demonstrated structural and numerical aberrations, with a mode of 54 chromosomes per cell and several nonrandom abnormalities. The localization of intermediate filament antigens, low-molecular-weight (LMW) cytokeratins and vimentin, demonstrated a switch from LMW cytokeratins, predominantly expressed in primary tumor cells, to vimentin detected in LC 89 cells that were grown in vitro or transplanted into nude mice. In view of the phenotypic and chromosomal features, LC 89 should provide a useful addition to the cell lines currently available for in vitro and in vivo studies of lung cancer.

It has been suggested that bile CEA levels could represent a sensitive index for the detection of occult liver metastases in colorectal cancer (CRC) patients. We measured serum and gallbladder bile CEA concentrations in a control group, in a group of patients with benign disease of the biliary tree, and in patients with CRC at different stages. Neoplastic patients without evidence of liver metastases at the time of laparotomy, but with elevated biliary CEA levels, were selected for a follow-up study. Our results indicate that (a) bile CEA levels are falsely increased in several benign biliary diseases; (b) CRC patients with detectable liver metastases have elevated biliary CEA levels; (c) high biliary CEA levels do not represent a predictive parameter for the presence of occult liver metastases in CRC patients.

In this phase II study, we treated 7 patients, all males, with stage III or IV pancreatic cancer with goserelin (an LH-RH analogue). Goserelin was administered at a dose of 3.6 mg every 4 weeks. The tumour response was assessed by measuring lesions with US- or CT-scan studies, according to WHO criteria. No response was observed. The median survival was 8 months in locally unresectable tumours and 4 months in advanced disease. The accrual was actually stopped at 7 cases because there were no responses in either of our series or in those published during our study. The authors conclude that the treatment with LH-RH analogue alone cannot be recommended for further studies.

With the aim of investigating the clinical usefulness of CEA, CA 15-3, and MCA serum levels, we studied 143 women whose breast cancer was submitted to serial tumor marker determinations: 79 women had stage I-II tumors and were undergoing follow-up after local and adjuvant treatment; 64 women presented metastatic lesions. Among the stage I-II patients, 63 women remained disease-free during the observation period and 16 developed metastases. In 13 out of 16 patients, tumor markers were elevated and in 11 out of 16 patients the increased tumor markers were the first sign of disease progression. Among metastatic patients, 49 presented increased tumor markers and 15 normal value. Moreover, we observed a decrease or normalization of tumor markers in patients responding to treatment and increased values in progressive disease. No correlation was noted between site of disease and tumor markers. We concluded that tumor markers are of clinical value in the detection of metastasis and may be useful in monitoring response to treatment in metastatic patients.

The relationship between preoperative CEA, Dukes staging and disease recurrence, was analyzed in 92 patients with colon-rectal cancer, all who underwent curative surgery. Sixty-five of the 92 patients were followed for 36 months. A significant increase in disease recurrence risk is observable starting from a preoperative CEA value of greater than 7.5 ng/ml; corresponding values as such are verified by a significant fall in the actuarial survival curve in comparison to the progress of the curves of the other two groups with lower CEA values. A statistically significant correlation between preoperative CEA and staging was not observed, while both parameters result statistically very reliable (p less than 0.001) for prognosis; preoperative CEA values, less or greater than 7.5 ng/ml can help to stratify the Dukes tumours with respect to the probability of recurrence.

The presence of the Ca-125 antigen was tested in the serum of 46 patients with ovarian cancer in order to determine the prognostic value of preoperative levels and its usefulness for monitoring the clinical response in longitudinal studies; survival (S) and progression-free survival (PFS) were also evaluated. In our series, the specificity of the assay in normal subjects and in patients with benign gynecological diseases is 99.3 and 73.2% respectively, and the sensitivity is 91.9%. Preoperative Ca-125 levels are not correlated with S and PFS, whereas an advantage in S and PFS is clearly shown for patients in whom the marker level decreases after treatment. Serial determinations of Ca-125 serum levels provide a reliable test to assess response to therapy and to predict disease progression.

Unlabelled: During the cooking process of meat, mutagenic and/or carcinogenic substances can be formed that can induce tumours of the gastro-intestinal tract or of other organs in the rat. The formation of these substances is proportionate to the cooking time, the cooking surface and the quantity of fats contained in meat. A comparison is made between beef cooked on a grid where the temperature reaches 200 degrees C, and cooked in a microwave oven (Cuocorapido Candy 500 CL, frequency 2450 Mhz) where the temperature does not exceed 100 degrees C. Mutagenic substances were extracted by the Commoner technique and mutagenic activity was assayed with the Ames test., Results: no mutagenic activity was demonstrated in the extracts of meat cooked in microwave ovens, while mutagenic activity was clearly demonstrated in the extracts of meat cooked on a grid.

Serum concentrations of the CA 19-9 and CA 50 antigens were determined in 129 patients with malignant and benign biliary and pancreatic diseases. Values for the two markers were highly correlated (P less than 0.001). The concentrations of CA 19-9 and CA 50 were positive in 84.6% and 80.7% of patients with pancreatic cancer, respectively. The overall specificity of CA 19-9 (92.4%) was slightly higher than that of CA 50 (88.5%). The sensitivity of CA 50 (91.3%) was greater than that of CA 19-9 (73.9%) in patients with diseases of the biliary tract. Elevated concentrations of CA 19-9 (12.9%) and CA 50 (35.2%) were also found in a number of cases with benign disease, especially in patients with obstructive jaundice. These data suggest that both CA 19-9 and CA 50 can be useful markers of pancreatic cancer in nonjaundiced patients. The joint use of the two markers does not yield a better diagnostic resolution than the use of either one alone.

The potential synergism of sequential combinations of tamoxifen (TMX) or estradiol benzoate (E2B) with medroxyprogesterone acetate (MPA) in inhibiting the growth of 7.12-dimethylbenz(a)anthracene(DMBA) - induced rat mammary tumors has been investigated. In addition, the effect of TMX and E2B on estrogen and progesterone receptors' (ERs and PgRs) synthesis has been evaluated in the attempt to elucidate possible mechanisms involved. Previous treatment both with TMX and E2B has been shown to strongly enhance the antitumor activity of MPA. A priming on PgR synthesis has been observed only after E2B administration, TMX producing a sharp decrease in PgR levels. It is concluded that, while the priming action exerted by E2B on PgRs might explain the potentiating effect shown by E2B on MPA activity, the synergism observed between TMX and MPA should be explained on an extrareceptorial basis, an induction on PgR synthesis by TMX not being evident at the dosage and priming time employed in this study.

Knowledge of the tumor content of estrogen (ER) and progesterone (PgR) receptors has proved to be of significant value in human breast cancer. Relative determinations were performed in 589 specimens in our laboratory. The positivity of ER and PgR is correlated with the patients' age at diagnosis, tumor size and relative grade. In particular, the significance of PgR versus ER status and the possible prognostic role of these receptors are investigated.

Serum concentrations of the CA 19-9 tumour marker were determined in 35 patients with histologically proven bilio-pancreatic malignancies associated with obstructive jaundice and in 35 patients with benign extrahepatic jaundice due to choledocholithiasis. At a cut-off level of 37 U/ml the sensitivity of this assay was 82.8%, but the specificity was very low (45.7%). Thus CA 19-9 can not be employed to differentiate between malignant and benign extrahepatic jaundice. Serial samples of CA 19-9 were achieved in 7 patients with benign and in 6 patients with malignant biliary obstruction, before and after the disappearance of jaundice. Serum concentrations of this tumour-antigen returned to normal concurrently with the bilirubin values only in patients with benign obstruction, remaining unchanged in all cases of malignancies. The data suggest that patients with extrahepatic jaundice should be evaluated by other examinations or by collecting serial samples for this assay.

Testicular responsiveness to 5,000 IU of human chorionic gonadotropin was evaluated in 14 patients with prostate cancer who were being treated with a slow-release luteinizing hormone-releasing hormone agonist for a median of 21 months. Serum testosterone response to human chorionic gonadotropin was markedly reduced in most patients, with the median level increasing from 0.25 to 1.65 nmol. per l. A second human chorionic gonadotropin test was repeated later in 5 patients who had been off treatment for a median of 6 months. Median serum testosterone levels increased to a maximum of 2.6 nmol. per l. compared to 28.2 nmol. per l. in an age-matched control group (p equals 0.008). Therefore, we conclude that long-term treatment with luteinizing hormone-releasing hormone agonists in elderly men leads to gonadal impairment that may not be as reversible as generally suggested.

Estrogen (ER) and progesterone (PgR) receptors were evaluated in the tumor tissue (T) and in the mammary gland far from malignancy (D) in 36 breast cancers. Results were correlated with the pathological grading of the tumor and the axillary nodal status. It is suggested that a lower cancer malignancy with negative nodes and lower values of pathological grading (G1-G2) may be associated with a high level of ER in the mammary parenchyma far from the tumor (D).