Dr Ioannis A Dimitroulis MD, PhD (Athens), FCCP

Abstract: Liposomal cisplatin was developed to reduce the systemic toxicity of cisplatin, particularly the nephrotoxicity, and it has been used in combination with other agents in pancreatic and head and neck cancers and non-small-cell lung cancer (NSCLC). Our objective was to compare the effectiveness of lipoplatin combined with paclitaxel versus cisplatin with paclitaxel in advanced non-squamous NSCLC.

Abstract: Erlotinib is an oral, small-molecule targeting therapy that inhibits epidermal growth factor tyrosine kinase receptors. Erlotinib has been administered for the treatment of advanced pancreatic cancer and non-small cell lung cancer. In the present trial, erlotinib has been administered as second-line monotherapy in pretreated patients with advanced non-small cell lung cancer. Our objectives were to determine response, survival and toxicity. Fifty-four patients pretreated with cisplatin or its analogue-based combinations were evaluated. The disease stage of the patients was IIIB and IV. Thirty-eight patients were male, 16 were female, the median age was 65 years, and the WHO performance status was 0-2. Twenty-five cases were adenocarcinomas, 19 squamous cell carcinomas and 10 were undifferentiated. Erlotinib was administered at a dose of 150mg daily. In case of intolerable adverse reactions, the dose was reduced to 100mg daily or treatment was interrupted for a maximum of two weeks. A partial response was observed in 10 (18.52%) and stable disease in 40 (74.07%) patients. The median time to disease progression was 3 months (95% CI 1.7-10.3), and the median survival was 6 months. Concerning toxicity, 53 patients (98.15%) developed a grade 1-2 skin rash, and 1 (1.85%) grade 3. Diarrhea occurred in 9 (16.67%) patients, nausea and vomiting in 4 (7.41%) and gastritis in 2 (3.70%). The majority of patients tolerated the erlotinib treatment. Of note were the 18.52% response rate and 74.07% stable disease.

Abstract: Liposomal cisplatin is a new formulation developed to reduce the systemic toxicity of cisplatin while simultaneously improving the targeting of the drug to the primary tumor and to metastases by increasing circulation time in the body fluids and tissues. The primary objectives were to determine nephrotoxicity, gastrointestinal side-effects, peripheral neuropathy and hematological toxicity and secondary objectives were to determine the response rate, time to tumor progression (TTP) and survival.

Abstract: Cisplatin-paclitaxel and cisplatin-etoposide combination therapies were compared in limited and extensive disease in patients with small-cell lung cancer. The primary objectives were to determine median and overall survival, time to tumor progression and tolerance and the secondary objective, the response rate. From January 2003 till July 2007, 108 patients were enrolled in the study. All patients had histologically- or cytologically-confirmed small-cell lung cancer. All patients were chemotherapy and radiotherapy naive. The patients were designated to receive six cycles: in the investigational Arm A, cisplatin, 80 mg/m(2) and paclitaxel 175 mg/m(2) were infused on day 1 (1 cycle) and repeated every 3 weeks. In the control Arm B, cisplatin, 80 mg/m(2) was administered on day 1 and etoposide, 120 mg/m(2) per day was given on days 1-3 (1 cycle), every 3 weeks. In Arm A, 6 (11.3%) patients achieved a complete response and 32 (58.1%), a partial response; in Arm B, 7 (12.7%) patients achieved a complete response and 32 (58.2%) a partial response. The median survival time in Arm A patients was 12 months and in Arm B, 13 months, p=0.354. The time to tumor progression (TTP) was 8 and 6 months for Arms A and B, respectively (p=0.060). Toxicity, although common in both Arms, was acceptable. Neutropenia, anemia and diarrhea were higher in the control Arm. The cisplatin-paclitaxel combination is not superior to cisplatin-etoposide with respect to survival, TTP, toxicity and response rate. The former combination could be applied as an alternative chemotherapy regimen for patients with limited or advanced small-cell lung cancer.

Abstract: Cisplatin-paclitaxel and cisplatin-etoposide combination therapies were compared in limited and extensive disease in patients with small-cell lung cancer. The primary objectives were to determine median and overall survival, time to tumor progression and tolerance and the secondary objective, the response rate. From January 2003 till July 2007, 108 patients were enrolled in the study. All patients had histologically- or cytologically-confirmed small-cell lung cancer. All patients were chemotherapy and radiotherapy naive. The patients were designated to receive six cycles: in the investigational Arm A, cisplatin, 80 mg/m(2) and paclitaxel 175 mg/m(2) were infused on day 1 (1 cycle) and repeated every 3 weeks. In the control Arm B, cisplatin, 80 mg/m(2) was administered on day 1 and etoposide, 120 mg/m(2) per day was given on days 1-3 (1 cycle), every 3 weeks. In Arm A, 6 (11.3%) patients achieved a complete response and 32 (58.1%), a partial response; in Arm B, 7 (12.7%) patients achieved a complete response and 32 (58.2%) a partial response. The median survival time in Arm A patients was 12 months and in Arm B, 13 months, p=0.354. The time to tumor progression (TTP) was 8 and 6 months for Arms A and B, respectively (p=0.060). Toxicity, although common in both Arms, was acceptable. Neutropenia, anemia and diarrhea were higher in the control Arm. The cisplatin-paclitaxel combination is not superior to cisplatin-etoposide with respect to survival, TTP, toxicity and response rate. The former combination could be applied as an alternative chemotherapy regimen for patients with limited or advanced small-cell lung cancer.

Abstract: Pemetrexed, a novel multi-targeted agent established for the treatment of mesothelioma, has been under investigation for other malignancies, and in recent years particularly for non-small-cell lung cancer (NSCLC). In the present trial we investigated pemetrexed in combination with paclitaxel as front-line treatment in advanced or metastatic NSCLC. Our objectives were to determine the response rate, median and overall survival and toxicity. From April 2005 until May 2006, 51 patients with advanced or metastatic NSCLC were enrolled and 48 were considered evaluable. There were 39 males and nine females, median age 62 years (range 37-81 years), one patient stage IIIA N(2), 23 patients, IIIB and 24, stage IV. All patients had a cytologically- or histologically-confirmed diagnosis. Pemetrexed was administered at a standard dose of 500mg/m(2) and paclitaxel at an escalating dose starting at 135mg/m(2), then 150mg/m(2) and ending at a dose of 175mg/m(2); the level was increased every three patients. Both agents were administered on day 1, repeated every 3 weeks for six courses. A 39.6% partial response rate was observed with a median survival of 14 months. Toxicity was mild with 8.3% grade 3 and 4 neutropenia and other very mild hematologic and non-hematologic adverse reactions. The combination of pemetrexed and paclitaxel at doses of 500mg/m(2) and 175mg/m(2), respectively, has been shown to be an effective combination with very limited toxicity.

Abstract: Pemetrexed, a novel multi-targeted agent established for the treatment of mesothelioma, has been under investigation for other malignancies, and in recent years particularly for non-small-cell lung cancer (NSCLC). In the present trial we investigated pemetrexed in combination with paclitaxel as front-line treatment in advanced or metastatic NSCLC. Our objectives were to determine the response rate, median and overall survival and toxicity. From April 2005 until May 2006, 51 patients with advanced or metastatic NSCLC were enrolled and 48 were considered evaluable. There were 39 males and nine females, median age 62 years (range 37-81 years), one patient stage IIIA N(2), 23 patients, IIIB and 24, stage IV. All patients had a cytologically- or histologically-confirmed diagnosis. Pemetrexed was administered at a standard dose of 500mg/m(2) and paclitaxel at an escalating dose starting at 135mg/m(2), then 150mg/m(2) and ending at a dose of 175mg/m(2); the level was increased every three patients. Both agents were administered on day 1, repeated every 3 weeks for six courses. A 39.6% partial response rate was observed with a median survival of 14 months. Toxicity was mild with 8.3% grade 3 and 4 neutropenia and other very mild hematologic and non-hematologic adverse reactions. The combination of pemetrexed and paclitaxel at doses of 500mg/m(2) and 175mg/m(2), respectively, has been shown to be an effective combination with very limited toxicity.

Abstract: PURPOSE: Based on previous experience, we combined topotecan with paclitaxel (weekly administration) in patients with non-small-cell lung cancer (NSCLC). Our primary objective was to determine the response rate and survival and our secondary objective, the safety of the regimen. METHODS: From October 2003, until March 2005, 45 patients all with histologically or cytologically confirmed NSCLC were enrolled. All patients were chemotherapy and radiotherapy naive. Both agents were infused on day 1 of every week once for three consecutive weeks, every 28 days. Three infusions were considered as one course. The treatment plan was to give three courses (nine infusions) and then to evaluate the response. Topotecan (1.75 mg/m2) was infused for 30 min and paclitaxel (70 mg/m2) for 90 min; these doses had been established as the maximum tolerated dose in a previous phase I-II trial. RESULTS: Eighteen/45 (40%) patients responded, 2 (4.4%) complete responses and 16 (35.6%) partial responses. Twenty-one (46.7%) patients had stable disease, and 6 (13.3%) disease progression. The median duration of response was 8 months and median time to tumor progression 9 months. Grade 3 and 4 neutropenia was observed in two patients (in these two patients, the dose of both drugs was reduced by 25% and G-CSF was given), grade 4 thrombocytopenia in one patient and grade 4 anemia in one patient. CONCLUSION: This novel combination of topotecan-paclitaxel in a weekly administration rendered a 40% response rate, with very low toxicity in stages IIIA, IIIB and IV NSCLC patients.

Abstract: Our main objective was to investigate the response rate in pretreated patients with small cell lung cancer (SCLC) who received a weekly administration of topotecan and paclitaxel; our secondary objectives were to assess toxicity and survival.

Abstract: In the present study, 3 cytotoxic agents were combined as front-line chemotherapy in advanced non-small cell lung cancer (NSCLC) patients. All 3 drugs have been used in other 2-agent combinations and have been shown to be effective as first-line therapy.

Abstract: Based on previous experience, we combined topotecan with paclitaxel (weekly administration) in patients with non-small-cell lung cancer (NSCLC). Our primary objective was to determine the response rate and survival and our secondary objective, the safety of the regimen.

Abstract: BACKGROUND: In the present study, 3 cytotoxic agents were combined as front-line chemotherapy in advanced non-small cell lung cancer (NSCLC) patients. All 3 drugs have been used in other 2-agent combinations and have been shown to be effective as first-line therapy. PATIENTS AND METHODS: Sixty-one (53 male, 8 female, median age 65 years old) out of 67 patients were evaluable for response and toxicity. Eighty percent of the patients were stage IIIB and IV and 20% were inoperable stage IIIA. In order to obviate toxicity as much as possible, paclitaxel 135 mg/m2 was combined with gemcitabine 1000 mg/m2 for the first cycle, and 2 weeks later with vinorelbine 25 mg/m2, for the second cycle; this alternate schedule was repeated every 2 weeks for 9 cycles. RESULTS: No complete responses were observed; there was a 37.7% partial response rate and stable disease in 31.1% of the patients. The median survival was 13 months and 1-year survival, 53%. Myelotoxicity involved grade 3 neutropenia in 3.3% of the patients and grade 4 in 1.6%. CONCLUSION: Adverse reactions were few in this alternate administration of paclitaxel-gemcitabine and paclitaxel-vinorelbine in NSCLC patients; in more than half of the patients there was long median and 1-year survival.

Abstract: A farm childhood is apparently protective in allergic disease, but studies of this issue in Europe have been confined to particular types of farming practice. This study addressed whether or not this effect was generalisable. A cross-sectional survey of 800 schoolchildren living in rural Crete was undertaken. Standard questions relating to allergic disease were included and atopy was measured through skin-prick tests involving 10 local aeroallergens. The prevalence of atopy was 24%, but associated symptoms were far less common. At all ages, children from farming families had more frequent contact with farm animals (mainly goats), but were no less likely to be atopic. Atopy and seasonal rhinitis were significantly and independently more common among first-born children. This community has an intermediate prevalence of atopy but a very low frequency of allergic disease; farming does not seem to be an important determinant, possibly because it is of the wrong sort. Thus farming effects may be specific to local practices. First-born children in this community also appear to be at increased risk of allergic disease.

Abstract: PURPOSE: Our main objective was to investigate the response rate in pretreated patients with small cell lung cancer (SCLC) who received a weekly administration of topotecan and paclitaxel; our secondary objectives were to assess toxicity and survival. METHODS: Topotecan 1.75 mg/m2 was combined with paclitaxel 70 mg/m2; these cytotoxic agents were administered once every week (day 1) for 3 consecutive weeks (one cycle), and repeated every 28 days (three infusions per cycle) for a minimum of three cycles. RESULTS: Forty-five patients were enrolled, 41 of whom were evaluable for response and toxicity. The median number of cycles was two (range 1-6). Eleven/forty-one (26.83%) patients responded: one complete response and ten partial responses; the median duration of response was 4 months (range 2-8 months); the median overall survival was 7 months (95% CI: 4.2-9.8). Myelotoxicity was the most common adverse reaction (grade 3 neutropenia in 19.5% of the patients and grade 4 in 7.32%). Non-hematologic toxicities varied from 2.44% to 9.76%. No patient had to stop treatment due to toxicity. CONCLUSION: Topotecan combined with paclitaxel, given on day 1 on a weekly basis, produced a response rate of 26.83% in pretreated patients with SCLC. Myelotoxicity, particularly neutropenia, was the main adverse reaction, but in a minority of patients.

Abstract: Whether adjuvant chemotherapy improves survival of patients with non-small-cell lung cancer (NSCLC) is not known. We aimed to compare the effect of adjuvant vinorelbine plus cisplatin versus observation on survival in patients with completely resected NSCLC.

Abstract: A farm childhood is apparently protective in allergic disease, but studies of this issue in Europe have been confined to particular types of farming practice. This study addressed whether or not this effect was generalisable. A cross-sectional survey of 800 schoolchildren living in rural Crete was undertaken. Standard questions relating to allergic disease were included and atopy was measured through skin-prick tests involving 10 local aeroallergens. The prevalence of atopy was 24%, but associated symptoms were far less common. At all ages, children from farming families had more frequent contact with farm animals (mainly goats), but were no less likely to be atopic. Atopy and seasonal rhinitis were significantly and independently more common among first-born children. This community has an intermediate prevalence of atopy but a very low frequency of allergic disease; farming does not seem to be an important determinant, possibly because it is of the wrong sort. Thus farming effects may be specific to local practices. First-born children in this community also appear to be at increased risk of allergic disease.

Abstract: Our purpose was to evaluate the survival of patients with pleural and intraperitoneal malignant mesothelioma and, particularly, to estimate the efficacy of chemotherapy as well as radiotherapy and surgery. A review of the literature with respect to these parameters is included.

Abstract: BACKGROUND: The aim of this study was to evaluate the effectiveness of cisplatin- (CDDP) combined chemotherapy in non-cisplatin pretreated patients with non-small-cell lung cancer (NSCLC). The second cytotoxic drug administered was either etoposide or gemcitabine. First-line treatment was based on paclitaxel combined with either carboplatin or vinorelbine. PATIENTS AND METHODS: Seventy-eight patients with histologically- or cytologically- confirmed NSCLC, having failed front-line treatment, were enrolled. All patients received 80 mg/m2 of cisplatin as second-line treatment, on day 1, repeated every 3 weeks; in 48 patients the second agent was etoposide (120 mg/m2) on days 1, 2 and 3, repeated every 3 weeks and in 30 patients 1 g/m2 of gemcitabine on day 1, repeated every 3 weeks. RESULTS: All patients were evaluable for response and toxicity. No complete responses were observed. Thirteen (16.67%) patients achieved partial response, 42 (53.85%) stable disease and 23 (29.49%) had disease progression. The median duration of response was 4 months (range 2-8+ months), median time to tumor progression (TTP) 5 months (range 2-9 months) and median survival time after starting second-line chemotherapy, 6 months (range 2-9+ months). Toxicity was acceptable: 9 patients presented with nephrotoxicity (11.54%) and 13 (16.67%) with grade 3-4 neutropenia. CONCLUSION: The cisplatin combination as second-line treatment in patients with NSCLC exhibited a notable degree of activity and tumor growth control was evidenced by the 16.67% partial response and 53.85% disease stability.

Abstract: BACKGROUND: Our purpose was to evaluate the survival of patients with pleural and intraperitoneal malignant mesothelioma and, particularly, to estimate the efficacy of chemotherapy as well as radiotherapy and surgery. A review of the literature with respect to these parameters is included. PATIENTS AND METHODS: Thirty-five patients with malignant mesothelioma (28 with pleural and 7 with intraperitoneal) were enrolled. Twenty-eight patients underwent chemotherapy, 7/35 radiation and 9/35 surgery (2 with pleural and 7 with abdominal disease). Combination chemotherapy included cisplatin-gemcitabine, cisplatin (or carboplatin) with premetrexed and doxorubicin-cyclophosphamide. RESULTS: In 2/28 patients with pleural mesothelioma the tumor was excised and in 7 with intraperitoneal disease, surgical therapy was palliative and there was survival prolongation. Radiotherapy was only palliative. Chemotherapy produced a very low response: 2/28 (7.14%) patients achieved a partial response. The median survival was 17 months, 4-year survival, 24.4% and 5-year survival, 12.12%. No serious toxicity was observed. CONCLUSION: Malignant mesothelioma of the pleura and intraperitoneum is a slow-growing disease which is indicated by the long survival, despite the failure of chemotherapy, radiation therapy and surgery.

Abstract: Our purpose was to determine the efficacy of irinotecan plus paclitaxel administered on day 1, repeated every 2 weeks, in untreated patients with advanced or metastatic non-small-cell lung cancer (NSCLC). In total, 56 patients with inoperable or metastatic stage III and IV NSCLC with a histologically or cytologically confirmed diagnosis were enrolled. None of the patients had undergone prior chemotherapy or radiation therapy. Treatment involved irinotecan 125 mg m(-2) and paclitaxel 135 mg m(-2) administered on day 1 and repeated every 2 weeks for a planned number of nine cycles. With a standard dose of paclitaxel at 135 mg m(-2), the dosage of irinotecan was escalated at four levels: 75, 100, 125 and 150 mg m(-2); 125 mg m(-2) was established as the maximum tolerated dose; this dosage was administered to 46 patients. A total of 52 patients (median age 65 years, range 38-77 years) were assessable for toxicity and survival and 46 for response rate. Out of 46 evaluable patients, 19 achieved partial response (41.3%), 17 had stable disease (37%) and 10 (21.7%) experienced disease progression. The median duration of response was 6 months (range 2-9+ months). The main adverse reactions were myelotoxicity (grades 3 and 4) in 10 (19.2%) patients and diarrhoea (grade 3) in four (7.7%) patients. Irinotecan combined with paclitaxel, administered every 2 weeks, appears to be an effective treatment for advanced-stage NSCLC.

Abstract: The present study involves non-small cell lung (NSCLC) cancer patients with brain metastases, who were treated with radiation therapy, and our aim was to determine response rate and survival. A total of 167 patients were recruited, 155 (125 male, 30 female) of whom were evaluable. Performance status was 0-2 and histology or cytology included 66 (42.58%) adenocarcinomas, 62 (40.00%) undifferentiated and 27 (17.42%) squamous cell carcinomas. The stage of disease at diagnosis was IIIA-B in 92 (59.35%) patients and IV in 63 (40.65%). All patients had whole brain irradiation (3 Gy x 5 days/week for 2 weeks to a total dose of 30 Gy), which was performed by a linear accelerator and a 6-MV photon beam. Objective response was observed in 59/155 (38.06%) patients with 17 (10.97%) complete and 42 (27.09%) partial responses, and median survival of 5 months for all patients [95% confidence interval (CI) 3.9-6.1]. Responders had statistically significant longer survival than non-responders. Although responders represented less than half of our patients with NSCLC and brain metastases, they had significantly longer survival.

Abstract: Non-small cell lung cancer (NSCLC) is a common malignancy which has been increasing in incidence over the last decades. In the past, these tumors were considered quite resistant to chemotherapy and until the development of cisplatin 30 years ago, the use of cytotoxic drugs was considered palliative. Cisplatin (CDDP) proved to be an active agent and when combined with other cytotoxic drugs, effectiveness in NSCLC increased. Many trials have taken place during the last 30 years with cisplatin combinations. Despite the effectiveness of cisplatin, the renal toxicity and neurotoxicity that are produced obliged researchers and clinicians to create other combinations without CDDP. Carboplatin, an analogue of CDDP and then taxanes, gemcitabine and vinorelbine, a Vinca alkaloid, that proved to be effective in NSCLC, led to substitute combinations for CDDP. In the present article we review the literature on NSCLC chemotherapy in order to visualize the effectiveness of older drug combinations vs. the newer ones. It seems that combinations with or without cisplatin are of similar effectiveness with respect to response rate and median and overall survival but the toxicity is different with a prevalence of myelotoxicity.

Abstract: Background: Through its powerful immunoregulatory effects, infection with atypical mycobacteria may exert a protective effect on the development of childhood allergic disease. Objective: To examine the relationship between childhood atopy or allergic disease and previous infection with four species of atypical mycobacteria. Methods: Eight hundred and six children aged 8-18 years and living in rural Crete - most of whom had had previous BCG immunization - underwent skin prick testing with 10 aeroallergens; their parents completed a standardized questionnaire relating to allergic disease. No less than 8 weeks later each child underwent intradermal skin tests with 0.1 mL solutions of four selected mycobacterial reagents (Aviumin C, Gordonin, Chelonin and Ranin I). Results: Twenty-three percent of children were atopic on skin prick testing; far fewer had symptoms of asthma (5%) or hayfever in conjunction with a positive prick test to pollens (2%). Eighty percent of children had positive skin responses to one or more mycobacterial species. Among all children - and those with a BCG scar - there was no association between atopy or allergic symptoms and mycobacterial skin responses; among the few children without a BCG scar however those with positive mycobacterial responses were less likely to be atopic or to report allergic symptoms; these differences were not statistically significant. Conclusions: Our findings, in a population of BCG-immunized children, do not lend support to the suggestion that infection with atypical mycobacteria is protective against childhood allergic disease. © 2005 Blackwell Publishing Ltd.

Abstract: Our purpose was to determine the efficacy of irinotecan plus paclitaxel administered on day 1, repeated every 2 weeks, in untreated patients with advanced or metastatic non-small-cell lung cancer (NSCLC). In total, 56 patients with inoperable or metastatic stage III and IV NSCLC with a histologically or cytologically confirmed diagnosis were enrolled. None of the patients had undergone prior chemotherapy or radiation therapy. Treatment involved irinotecan 125 mg m(-2) and paclitaxel 135 mg m(-2) administered on day 1 and repeated every 2 weeks for a planned number of nine cycles. With a standard dose of paclitaxel at 135 mg m(-2), the dosage of irinotecan was escalated at four levels: 75, 100, 125 and 150 mg m(-2); 125 mg m(-2) was established as the maximum tolerated dose; this dosage was administered to 46 patients. A total of 52 patients (median age 65 years, range 38-77 years) were assessable for toxicity and survival and 46 for response rate. Out of 46 evaluable patients, 19 achieved partial response (41.3%), 17 had stable disease (37%) and 10 (21.7%) experienced disease progression. The median duration of response was 6 months (range 2-9+ months). The main adverse reactions were myelotoxicity (grades 3 and 4) in 10 (19.2%) patients and diarrhoea (grade 3) in four (7.7%) patients. Irinotecan combined with paclitaxel, administered every 2 weeks, appears to be an effective treatment for advanced-stage NSCLC.

Abstract: PURPOSE: This randomized phase III trial of advanced or metastatic non-small-cell lung cancer (NSCLC) was designed to compare a standard treatment such as carboplatin (CRP)-paclitaxel (PCT) with a new combination, vinorelbine (VRL)-PCT-two agents acting in microtubules. PATIENTS AND METHODS: Three hundred and sixty patients (stage IIIa, IIIb and IV) were included and evaluated for response rate, survival and toxicity. Arm A patients were treated with the control combination of CRP 6 AUC and PCT 175 mg/m(2) repeated every 3 weeks for six cycles, and arm B with the investigational combination of VRL 25 mg/m(2) and PCT 135 mg/m(2) repeated every 2 weeks for nine cycles. The patients were well balanced with respect to gender, disease stage and performance status. Arm A received 849 cycles (mean 4.59 per patient) and arm B 951 cycles (mean 5.39 per patient). RESULTS: Complete and partial response rates were 45.95% and 42.86% for arms A and B, respectively. Median survival was 11 and 10 months, 1-year survival 42.7% and 37.85% and 2-year survival 10.12% and 19% for arms A and B, respectively. Toxicity was similar in all patients, except for neutropenia, which was significantly greater in arm B. CONCLUSIONS: PCT combined with VRL produces similar (non-significant) response rates, survival and toxicity (except for neutropenia, as noted above) to standard CRP-PCT treatment in untreated advanced-stage NSCLC.

Abstract: It is known that, in stable asthmatics at rest, tidal expiratory flow limitation (EFL) and dynamic hyperinflation (DH) are seldom present. This study investigated whether stable asthmatics develop tidal EFL and DH during exercise with concurrent limitation of maximal exercise work rate (WRmax). A total of 20 asthmatics in a stable condition and aged 32+/-13 yrs (mean+/-SD) with a forced expiratory volume in one second (FEV1) of 101+/-21% of the predicted value were studied. Only three patients exhibited an FEV1 below the normal limits. On a first visit, patients performed a symptom-limited incremental (20 W.min(-1)) bicycle exercise test. On the second visit, the occurrence of EFL (using the negative expiratory pressure technique) and DH (via reduction in inspiratory capacity) were assessed at rest and when cycling at 33, 66 and 90% of their predetermined WRmax. FEV1 was measured to detect exercise-induced asthma, 5 and 15 min after stopping exercise at 90% WRmax. Only one patient showed EFL at rest, whereas 13 showed EFL and DH during exercise. In these 13 asthmatics, exercise capacity was significantly reduced (WRmax 75+/-9% pred) compared to the seven non-EFL patients (WRmax 95+/-13% pred). Moreover, a significant correlation of WRmax (% pred) to the change in inspiratory capacity (percentage of resting value) from rest to 90% WRmax was found. Tidal EFL during exercise was not associated with exercise-induced asthma, which was detected in only three patients. In conclusion, tidal expiratory flow limitation and dynamic hyperinflation during exercise are common in stable asthmatics with normal spirometric results and without exercise-induced asthma, and may contribute to reduction in exercise capacity.

Abstract: OBJECTIVES: The prevalence of COPD in Greece is unknown. The aim of this study was to determine the prevalence and trends of COPD among adults in Greece. METHODS: This study involved 888 randomly identified adults (475 men and 413 women) aged > 35 years, and smokers of at least 100 cigarettes, in a population-based, multiregional, cross-sectional descriptive design. The selected individuals reflected the urban/rural population distribution in Greece and, within each study region, the age group and gender of the community setting. The diagnosis of COPD was based on clinical and spirometric data including reversibility test (DeltaFEV(1) < 15%). RESULTS: The overall prevalence of COPD in the population aged > 35 years with a smoking history of > 100 cigarettes per lifetime was 8.4%. The gender-standardized COPD prevalence was 11.6% for men and 4.8% for women. The COPD prevalence by community setting was as follows: Athens, 6%; other urban areas, 10.1%; semiurban areas, 8.5%; and rural areas, 9.1%. Smoking intensity and age were significantly associated with higher COPD prevalence in both men and women. CONCLUSIONS: COPD is a substantial health problem in Greece, although prevalence rates are lower than expected when the high smoking rates are taken into account. The high proportion of the patients with mild COPD who were unaware of their illness highlights the need to increase public awareness of COPD.

Abstract: Chronic pulmonary diseases are a major cause of morbidity and mortality worldwide. The present study is a case-control study nested in a defined cohort, undertaken in Athens, Greece, in order to investigate the association between long-term exposure to ambient air pollution and the development of chronic bronchitis, emphysema or chronic obstructive pulmonary disease (COPD). Individualized personal exposure assessment has been applied based on long-term residential and occupational subject history linked with geographical air pollution distribution. The first consecutive 3904 participants from the European Prospective Study into Cancer and Nutrition (EPIC), all residents of Athens, were asked to complete a questionnaire. One hundred and sixty-eight participants reporting a history of COPD symptomatology and 168 healthy controls recruited from the same study base individually matched for age and gender, were visited by a physician at their homes for conducting spirometry and a medical interview. Eighty-four of the 168 self-identified as cases were diagnosed as having chronic bronchitis, emphysema or COPD. Logistic regression models were used for statistical evaluation. Cases were more exposed to air pollution compared to controls. The estimated odds ratio (OR) indicates an increase of 37% in the risk of medically confirmed cases per exposure quartile (p = 0.02). When most of the subjects exposed are considered vs. all others, there is a twofold increase in disease risk (p = 0.03). Our findings provide evidence that long-term exposure to air pollution is an important factor in the development of chronic respiratory diseases.

Abstract: Background: In normal subjects, and patients with obstructive and restrictive lung defects, flows during an FVC manoeuver are higher after a fast inspiration without an end-inspiratory pause as compared to a slow inspiration with an end-inspiratory pause of approximately 5 s (time dependence of FVC). Objective: In the present study, we investigated the influence of these two manoeuvres on PEF and FEV1 in asthmatic patients during methacholine challenge testing. Methods: Thirteen patients who were positive according to routine (non-standardized) methacholine challenge tests (PD20<=1.57 mg) were studied. Their average(SD) lung function data were: FVC%pred=94(15), FEV1 %pred=76(17) and FEV1/FVC%=68(12). The patients performed the two types of FVC manoeuvres in random order before and at the last methacholine dose. Results: Using the standardized FVC manoeuvres (fast before/fast after and slow before/slow after), only 10 patients (77%) had a positive test, while all 13 patients were positive with the routine test. Conclusion: These data indicate that different results can be obtained, if instead of the standardized, the non-standardized manoeuvres during methacholine challenge tests are used. The use of non-standardized FVC manoeuvres may lead to over-, or at least theoretically, to underestimation of patients with bronchial hyperresponsiveness. Therefore, standardization of FVC manoeuvres during airway challenge testing is required. Pneumon 2002, 15(2):168-175.

Abstract: Adenosine deaminase (ADA) is a widely used marker in the differential diagnosis of tuberculous effusion and there is evidence that its production is linked to � cells and monocytes. Both cell types are present in tuberculous effusions but are also present in malignant effusions where ADA activity is low. Furthermore, data on the correlation between ADA and � cells in tuberculous effusions are conflicting and based on small numbers of patients. We undertook this study to examine cell subsets in tuberculous effusion and their correlation to ADA. Pleural fluid from 73 patients was examined (thirty-seven patients with tuberculous and thirty-six patients with malignant effusion). The ����� immunocytochemical method was used to examine � cells (CD3, CD4, CDB, CD25) and macrophages (CD68) while ADA activity was measured by the Guisti colometric method. Our results showed that CD3+, CD4+ and CD25+ cells and ADA were significantly higher in tuberculous effusion (p<0.001 for all measurements) while CD68+ were significantly lower (p<0.001). �ï differences were noted in CD68+ counts. �ï correlation was found between ADA and CD3 (r=0.18), CD4 (r=0.05), CD8 (r=0.09), CD25 (r=0.06), CD68 (r=0.04). Tuberculous effusion is characterized by high ADA activity and increased numbers of CD4+ � cells, but no correlation exists between ADA activity and cell numbers.

Abstract: The lack of methodology for measuring the alveolar carbon dioxide tension (PA,CO2) has forced investigators to make several assumptions, such as that PA,CO2 is equal to end-tidal (PET,CO2) and arterial CO2 tension (Pa,CO2). The present study measured the mean PA,CO2 and Bohr's dead space ratio (Bohr's dead space/tidal volume (VD,Bohr/VT)) during tidal breathing. The method used is a new, simple and noninvasive technique, based on the analysis of the expired CO2 volume per breath (VCO2) versus the exhaled VT. This curve was analysed in 21 normal, healthy subjects and 35 chronic obstructive pulmonary disease (COPD) patients breathing tidally through a mouthpiece apparatus in the sitting position. It is shown that: 1) PA,CO2 is similar to Pa,CO2 in normal subjects, whilst it is significantly lower than Pa,CO2 in COPD patients; 2) PA,CO2 is significantly higher than PET,CO2 in all subjects, especially in COPD patients; 3) VD,Bohr/VT is increased in COPD patients as compared to normal subjects; and 4) VD,Bohr/VT is lower than the "physiological" dead space ratio (VD,phys/VT) in COPD patients. It is concluded that the expired carbon dioxide versus tidal volume curve is a useful tool for research and clinical work, because it permits the noninvasive and accurate measurement of Bohr's dead space and mean alveolar carbon dioxide tension accurately during spontaneous breathing.

Abstract: The respiratory system consists essentially of two parts, a gas-exchanging organ, the lung, and a pump to pump gas in and out the gas exchanging part, consisting of the respiratory muscles and the chest wall. The lung and its diseases have traditionally been the focal point of interest, whereas pump disorders have received comparatively little attention. Research on respiratory muscles has accelerated during the last two decades. Respiratory muscles are all skeletal muscles having similar fibre composition to the limb muscles. Fibre composition of respiratory muscles is an important factor for their endurance and contractile properties. There are two fibre types, the fast (FT) and slow (ST) twitch fibres. Of the FT fibres two subgroups named FOG and FG have been identified. Human intercostals muscles appear to have mostly ST fibres. The diaphragm has a high percentage of fatigue-resistant fibres. The main respiratory muscles are the diaphragm, intercostal muscles and muscles of the abdominal wall. The accessory muscles of respiration include the sternomastoid and other muscles of the neck, back and shoulder girdle. The intercostals muscles are subdivided into two groups: the external and internal intercostals. The contraction of the diaphragm which is the most important respiratory muscle, decreases the intrathoracic pressure and increases the abdominal pressure in normal man by lowering the diaphragmatic dome. Intercostal muscles move the rib cage and can be inspiratory or expiratory. The scaleni is now believed to be true muscles of inspiration and not "accessory". The most important accessory muscles of inspiration are probably the sternocleidomastoid muscles. The respiratory muscles are the motive power for breathing and are subject to weakness from a variety of processes that affect the motor nerves, neuromuscular junction and muscle cell. Chronic neuromuscular disorders result in altered lung volumes. The effectiveness of cough is reduced in expiratory muscle weakness. Patients with respiratory muscle weakness breath faster and with a smaller tidal volume compared to healthy subjects. The main change in blood gases in patients with respiratory muscle weakness is usually a fall in PaO2. Hypercapnia may be a late event. Muscle fatigue, which is a reversible event, can be defined as the inability to sustain the required or expected force with continued contractions. The respiratory muscles, particularly those of inspiration, can fatigue and precipitate or intensify ventilatory failure.

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Abstract: With the purpose of investigating whether the 6-course standard dose treatment of etoposide-platinum (EP) in small cell lung cancer could be reduced to 4 courses without compromising patient's survival, 70 patients were randomized to receive either 4 or 6 cycles of etoposide 120 mg/m2 i.v. days 1-3 and cisplatin 80 mg/m2 day 1. With the intention of comparing these two durations as primary treatment policies, patients were randomized on admission and not after the fourth course. From the 69 evaluable patients 34 received EPx4 cycles and 35 EPx6 cycles. Objective response for EPx4 was achieved by 21 patients (62%, 95% CI 44%-78%) compared to 24 patients (69%, 95% CI 51%-83%) of the EPx6 group. Median times to progression were 6 mo (4-19) and 7 mo (4-40) respectively (P=0.06) in the two groups. Median survivals were 8.5 mo (4-28.5) and 9.5 mo (4-51) (p=0.04) respectively. No differences in the survival of limited-disease patients were shown with 10.5 mo (6-28.5) and 12 mo (8-51) respectively, in the two groups. Patients with extensive disease had a trend favoring prolonged chemotherapy with a median survival of 9 mo (5-16) versus 6.5 mo (4-16.5) for those in the EPx4 group (p=0.09). Toxicity was not significantly more severe in the EPx6 group. In conclusion, patients achieving complete response within 4 cycles may not need continued chemotherapy, but patients with extensive disease may benefit from 2 more cycles.

Abstract: The volume of the expired CO₂ (VCO₂) plotted versus tidal volume (V_T) forms a curvilinear shaped (VCO₂-V_T) curve which was studied during spontaneous breathing at rest (Fig). The tidal volume was functionally divided into three compartments: 1) the anatomical dead-space volume (V_Danat), 2) the transitional volume (V_tr), and 3) the alveolar volume (V_A). The sum (V_Danat+V_tr) represents the total dead-space volume (V_D). The alveolar CO₂ tension (P_ACO₂) is calculated from VCO₂ and V_A. (Graph Presented) The method was applied in 26 seated normal subjects (12 male), aged 43±18 yr breathing tidally through a mouthpiece apparatus. Their lung function data were (mean±SD): FVC%pred=109±15, FEV₁%pred=109±14, FEV₁/FVC%=84±5. The results showed that: 1) The method for measuring the dead-space volume is accurate as assessed by breathing through added tubes of known capacity (error less than 2.3%), 2) P_ACO₂ is significantly higher than the end-tidal CO₂ tension, 3) P_ACO₂ is closely similar to the arterial CO₂ tension. In conclusion, the study of the VCO₂-VT curve permits during spontaneous breathing the non-invasive measurement of the dead-space ventilation and the alveolar CO₂ tension with appreciable accuracy and precision without assumptions.

Abstract: In normal subjects and patients with airway obstruction, flows during a forced vital capacity (FVC) manoeuvre are higher after a fast inspiration without an end-inspiratory pause (manoeuvre 1) as compared to a slow inspiration with an end-expiratory pause of approximately 5 s (manoeuvre 2). In this study, we investigated the influence of these manoeuvres on maximal expiratory volume-time and flow-volume curves in patients with restrictive lung disease. Eleven patients with restrictive lung disease were studied. Their average (+/-SD) lung function test results were: FVC=55+/-12% predicted value, forced expiratory volume in one second (FEV1) 52+/-20% pred, FEV1/FVC 85+/-6%, total lung capacity 55+/-8% pred, and carbon monoxide transfer factor 47+/-18% pred. The patients performed the two FVC manoeuvres in random order. We compared the ensuing spirograms and maximal expiratory flow-volume curves from which peak expiratory flow, FEV1, FEV1/FVC, maximal mid-expiratory flow, and maximal flows were computed. All spirometric indices were significantly higher with manoeuvre 1 than 2. Maximal expiratory flows at the same lung volume were also significantly higher with manoeuvre 1 than 2, in all patients. Routine spirometric indices, obtained during a forced vital capacity manoeuvre depend on the time course of the preceding inspiration in patients with restrictive lung disease. Therefore, the forced vital capacity manoeuvre should be standardized if used in clinical, epidemiological and research studies.

Abstract: Thymidine kinase (TK), carbohydrate antigen 19-9 (CA 19-9),carbohydrate antigen 125 (CA 125), squamous cell carcinoma antigen(SCC) and tissue polypeptide antigen (TPA), were evaluated in 104untreated patients with primary lung cancer acid 55 patients withbenign lung disease. The mean concentrations of TPA and CA 125 weresignificantly higher in lung cancer patients than in benign controls(p<0.001). The concentrations of all the tumor markers were wellcorrelated with the stage of lung cancer. In respect to sensitivity,specificity and accuracy, TPA was superior to the other tumor markerstested (70.2%, 88.8% and 75.8% respectively). When TPA was combinedwith the other markers, sensitivity increased from 70.2% to 98%, but asthe number of combined markers became larger, specificity decreased(from 88.8% to 40%). Nevertheless, the combination of TPA and CA 19-9showed significantly higher sensitivity in patients with resectable nonsmall eel lung cancer (NSCLC) and limited small cell lung cancer (SCLC)than TPA alone (87% vs 49% and 88.8% vs 44.4% respectively) withoutsignificant differences in specificity. The relative possibility of lung cancer was 15% when one tumor marker was positive. Thispossibility increased to 82%-100% when more than three markers werepositive.

Abstract: The authors evaluated the role of whole brain radiotherapy (WBRT) on the outcome of brain metastasis and survival in 41 patients with small cell lung cancer (SCLC) treated in their department. In addition to chemotherapy, radiotherapy was given to the primary site in all responder patients. Six patients presented brain metastasis initially and 10 patients after the fourth course of chemotherapy. Brain metastases were symptomatic in 12 of 16 patients with a median time of 5 months (1-14) until symptoms developed, All patients but 2 with brain metastasis received WBRT (30 Gy in 10 fractions) in addition to chemotherapy. The median survival time of patients with brain metastasis was 8.3 months (3.5 to 16) compared to 12 months (4 to 34+) for patients without brain metastasis. In addition, the median survival time for patients with brain metastasis who responded to systemic chemotherapy was better than that of nonresponders. The authors found no improvement in survival in patients who received concomitant WBRT after chemotherapy compared to patients who received WBRT after completion of chemotherapy. In conclusion, the role of consolidating cranial irradiation in addition to chemotherapy in SCLC patients is unclear and warrants prospective randomized studies.

Abstract: Thymidine kinase (TK), carbohydrate antigen 19-9 (CA 19-9), carbohydrate antigen 125 (CA 125), squamous cell carcinoma antigen (SCC) and tissue polypeptide antigen (TPA), were evaluated in 104 untreated patients with primary lung cancer and 55 patients with benign lung disease. The mean concentrations of TPA and CA 125 were significantly higher in lung cancer patients than in benign controls (p<0.001). The concentrations of all the tumor markers were well correlated with the stage of lung cancer. In respect to sensitivity, specificity and accuracy, TPA was superior to the other tumor markers tested (70.2%, 88.8% and 75.8% respectively). When TPA was combined with the other markers, sensitivity increased from 70.2% to 98%, but as the number of combined markers became larger, specificity decreased (from 88.8% to 40%). Nevertheless, the combination of TPA and CA 19-9 showed significantly higher sensitivity in patients with resectable non small cell lung cancer (NSCLC) and limited small cell lung cancer (SCLC) than TPA alone (87% vs 49% and 88.8% vs 44.4% respectively) without significant differences in specificity. The relative possibility of lung cancer was 15% when one tumor marker was positive. This possibility increased to 82%-100% when more than three markers were positive.

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Abstract: The authors evaluated the role of whole brain radiotherapy (WBRT) onthe outcome of brain metastasis and survival in 41 patients with smallcell lung cancer (SCLC) treated in their department. In addition tochemotherapy, radiotherapy was given to the primary site in allresponder patients. Six patients presented brain metastasis initiallyand 10 patients after the fourth course of chemotherapy. Brainmetastases were symptomatic in 12 of 16 patients with a median time of5 months (1-14) until symptoms developed. All patients but 2 with brainmetastasis received WBRT (30 Gy in 10 fractions) in addition tochemotherapy. The median survival time of patients with brainmetastasis was 8.3 months (3.5 to 16) compared to 12 months (4 to 34+)for patients without brain metastasis. In addition, the median survivaltime for patients with brain metastasis who responded to systemicchemotherapy was better than that of nonresponders, The authors foundno improvement in survival in patients who received concomitant WBRTafter chemotherapy compared to patients who received WBRT aftercompletion of chemotherapy. In conclusion, the role of consolidatingcranial irradiation in addition to chemotherapy in SCLC patients isunclear and warrants prospective randomized studies.

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Abstract: THE AIM OF THE STUDY WAS TO INVESTIGATE IF SUBCLINICAL PSYCHOMOTOR PERFORMANCE IMPAIRMENT OCCURS IN COPD PATIENTS AND TO CORRELATE IT WITH THE SEVERITY OF DISEASE.WE STUDIED 25 NORMAL SUBJECTS (GROUP I),12 PATIENTS WITH COPD AND NORMAL BLOOD GASES (GROUP II) AND 23 AMBULATORY,STABLE COPD PATIENTS WITH MILD NORMOCAPNIC HYPOXAEMIA (PaO2 53-+4mmHg),(GROUP III).GROUPS WERE MATCHED FOR AGE (<70 YEARS OLD) AND EDUCATION AND HAD NO HISTORY OF NEUROLOGIC,PSYCHIATRIC OR OTHER DISEASE.ALL GROUPS UMDERWENT A REACTION TIME TO OPTICAL AND AUDITORY STIMULI TEST USING THE "VIENNA REACTION TIMER" APPARATUS AND A LINE TRACKING TEST USING A "LINE TRACKING" APPARATUS.BOTH APPARATI WERE MANUFACTURED BY.DR.G.SCHUHFRIED GESMBH (HYRTLASTRASSE 45,A2340 MOEDLING/AUSTRIA).THE STUDY WAS SUPERVISED BY A CLINICAL PSYCHOLOGIST. THE RESULTS SHOWED THAT 1)REACTION TIME TO OPTICAL AND AUDITORY STIMULI IS INCREASED IN COPD PATIENTS COMPARED TO NORMALS AND 2) THE NUMBER AND DURATION OF MISTAKES SHOWS A STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN GROUPS (NORMALS PERFORM BETTER)WHILST THE TOTAL DURATION OF TEST DOES NOT.THIS FINDINGS ARE IMPORTANT,THEY CORRELATE TO PSYCHOMOTOR PERFORMANCE OF COPD PATIENTS AND THEREFORE TO THE QUALITY OF LIFE. ======================================================================================================================================================================================================================== Σ��Π�Σ Τ�Σ ����Τ�Σ �Τ�� �� ���Χ��Υ��Υ� ΥΠ��������Σ ΨΥΧ�����Τ���Σ ���Τ�Ρ�Χ�Σ Σ� �Σ�����Σ �� ΧΡ���� �Π�ΦΡ��Τ��� Π��Υ����Π����� (Χ�Π) ��� �� ΣΥΣΧ�Τ�Σ��Υ� �� Τ���ΡΥΤ�Τ� Τ�Σ.����Τ�Σ��� 25 ΦΥΣ�������� �Τ��� (����� �),12 �Τ��� �� Χ�Π ��� ΡaO2 60-80mmHg (OMA�� ��) ��� 23 Π�Ρ�Π�Τ�Τ���ΥΣ �Σ�����Σ �� Χ�Π ��� �Π�� ��Ρ����Π���� ΥΠ��Υ�������� (ΡaO2 53+-4mmHg),�� �Π���� �Ρ�Σ���Τ�� Σ� ΣΤ���Ρ� ��Τ�ΣΤ�Σ� (����� ���).�� ΤΡ��Σ �����Σ ��� ���Φ�Ρ�� ΩΣ ΠΡ�Σ Τ� ���ΡΩΠ���ΤΡ��� Χ�Ρ��Τ�Ρ�ΣΤ��� Τ�ΥΣ ��� ��� ��Χ�� �ΣΤ�Ρ��� ��ΥΡ�������Σ, ΨΥΧ��ΤΡ���Σ � ����Σ ��Σ�Υ,��� Τ� �Τ��� ΥΠ������Σ�� 1) ΣΤ� ������Σ�� ΧΡ���Υ ��Τ��Ρ�Σ�Σ (����Τ��� ��Τ��Ρ�Σ�) Σ� �ΠΤ��� ��� ���ΥΣΤ��� �Ρ���Σ��Τ� � �Π��� ����� �� Τ� ������� Τ�Σ ΣΥΣ��Υ�Σ "VIENNA REACTION TIMER",KAI 2)ΣΤ� �������Σ�� ����Ρ���Σ ���ΥΡ����Υ (� �Π��� ����Χ�� Τ�ΣΤ���Ρ�Τ�Τ� Τ�Σ ��Ρ�Σ Χ��Ρ�Σ)�� Τ� ������� Τ�Σ ΣΥΣ��Υ�Σ "LINE TRACKING APPARATUS".ΧΡ�Σ���Π�������� ΣΥΣ��Υ�Σ Τ�Υ ����Υ G.SCHUHFRIED GESMBH.ΣΤ� ������Σ�� ����Ρ���Σ ���ΥΡ����Υ,��Τ��Ρ�Φ���� � �Ρ����Σ ΤΩ� ���Ω� Π�Υ �Π�Τ���Σ�� �� ���Τ��������, � ���Ρ���� ΤΩ� ���Ω� ��� � ΣΥ������Σ ΧΡ���Σ �Π�Τ���Σ�Σ Τ�Σ ������Σ��Σ.� ����Τ� ����� ΥΠ� Τ�� �Π�ΠΤ��� �������Υ ΨΥΧ�����Υ.Τ� �Π�Τ���Σ��Τ� �������:1)� ΧΡ���Σ ��Τ��Ρ�Σ�Σ Σ� �ΠΤ��� ��� ���ΥΣΤ��� �Ρ���Σ��Τ� ����� �Υ������Σ ΣΤ�ΥΣ �Σ�����Σ ΣΤ�ΥΣ �Σ�����Σ �� Χ�Π.2)�Τ� � �Ρ����Σ ΤΩ� ���Ω� ��� � ���Ρ���� ΤΩ� ���Ω� ���Φ�Ρ�� ΣΤ�Τ�ΣΤ��ΩΣ Σ����Τ��� ��Τ��Υ ΤΩ� ����Ω� (�� Τ�� ����� ΤΩ� ΦΥΣ�������Ω� �� ΥΠ�ΡΤ�Ρ�� ΣΤ� �Π���Σ� ΣΤ�Σ ������Σ��Σ),��Ω � ΧΡ���Σ �Π�Τ���Σ�Σ Τ�Σ ������Σ��Σ �Χ�.Τ� �ΥΡ���Τ� �ΥΤ� ����� Σ����Τ���, �Φ�Ρ�Υ� Τ� ����Τ��� �Ρ�ΣΤ�Ρ��Τ�Τ� ��� ΩΣ �� Τ�ΥΤ�Υ Τ� Π���Τ�Τ� �Ω�Σ ΤΩ� �Σ���Ω� �� Χ�Π.

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