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Ymittos Athens, Greece

Duenas M.,CIEMAT | Santos M.,CIEMAT | Aranda J.F.,CIEMAT | Bielza C.,Technical University of Madrid | And 12 more authors.
PLoS ONE | Year: 2012

Mutations in the TP53 gene are very common in human cancers, and are associated with poor clinical outcome. Transgenic mouse models lacking the Trp53 gene or that express mutant Trp53 transgenes produce tumours with malignant features in many organs. We previously showed the transcriptome of a p53-deficient mouse skin carcinoma model to be similar to those of human cancers with TP53 mutations and associated with poor clinical outcomes. This report shows that much of the 682-gene signature of this murine skin carcinoma transcriptome is also present in breast and lung cancer mouse models in which p53 is inhibited. Further, we report validated gene-expression-based tests for predicting the clinical outcome of human breast and lung adenocarcinoma. It was found that human patients with cancer could be stratified based on the similarity of their transcriptome with the mouse skin carcinoma 682-gene signature. The results also provide new targets for the treatment of p53-defective tumours. © 2012 Dueñas et al.

Stathopoulos G.P.,Errikos Dunant Hospital
Anti-Cancer Drugs | Year: 2010

Over the last three decades, cisplatin has been one of the most effective cytotoxic agents, but its administration has been hindered by its nephrotoxicity, neurotoxicity and myelo toxicity. Recently, liposomal cisplatin, lipoplatin, has been formulated and tested thoroughly in preclinical (in vitro) and phase I, II and III trials, as documented in the literature. Experiments in animals showed that lipoplatin is less toxic than cisplatin and that it produces tumour reduction. The histological examination of treated tumours from mouse xenografts was consistent with apoptosis in the tumour cells in a mechanism similar to that of cisplatin. Lipoplatin infusion in patients and measurements of platinum levels in tumour specimens showed 10-50 times higher levels in tumours and metastases than in the adjacent normal specimens. A phase I-II study using a combination of lipoplatin and gemcitabine in pretreated patients (with disease progression or stable disease) with advanced pancreatic cancer was conducted. No nephrotoxicity was observed. With lipoplatin monotherapy the dose-limiting toxicity was determined to be 350mg/m and the maximum tolerated dose 300mg/m; when used in combination with paclitaxel the dose-limiting toxicity for lipoplatin was 250mg/m and for paclitaxel 175mg/m, and the maximum tolerated dose was 200 and 175mg/m, respectively. In two phase II randomized studies comparing the lipoplatin combination versus the cisplatin combination, it was found that the former was statistically significantly less toxic than the latter, whereas the response rate and survival were similar. Up to now, the data on lipoplatin treatment in malignant tumours are quite impressive, because of the negligible toxicity and because it is equal if not superior to cisplatin with regard to response rate. This review aims to chronologically document publications relevant to liposomal cisplatin to date. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Stathopoulos G.P.,Errikos Dunant Hospital | Ardavanis A.,Saint Savas Hospital | Papakotoulas P.,Theagenion Hospital | Pectasides D.,Attikon Hospital | And 7 more authors.
Anti-Cancer Drugs | Year: 2010

Oral topotecan has been recently brought into clinical practice at a dose of 2.3mg/m for 5 days, every 3 weeks. Published data show quite high myelotoxicity. The aim of this trial was to define the daily dose and treatment duration, which permits safe toxicity. The study was designed to begin at a low daily dosage of 1.5mg/m and was escalated by increasing the topotecan dose and the day-treatment duration. The plan was to end up with 2.3mg/m daily for 5 days. In cases of tolerability with the last dosage given, we would then continue testing a higher daily dosage. Treatment repetition was planned to be every 21 days. Dosage levels were 1.5, 2.0 and 2.3mg/m for 3 days, 2.0 and 2.3mg/m for 4 days, and 2.3mg/m for 5 days. Toxicity was scored according to the Common Toxicity Criteria. Thirty-two patients (27 male, five female, median age 60 years, range 46-77 years) with small-cell lung cancer were included. The patients on 1.5 and 2mg/m for 3 days showed no myelotoxicity. Four (25%) patients on 2.3mg/m 3-day treatment developed grade 3-4 neutropenia. Three of five patients (60%) treated for 4 days at a dose of 2.3mg/m developed grade 3-4 neutropenia and less than half (two of five, 40%) of these patients had thrombocytopenia. Eight patients (66.7%) on the 5-day treatment presented with serious grade 3-4 myelotoxicity. Two treatment-related deaths were observed in the 5-day group and one in the 4-day group. Granulocyte growth factor was applied in over 60% of the patients. In conclusion, a dose of 2.3mg/m for 5 days was intolerable. Dose-limiting toxicity was 2.3mg/m for 4 days without prophylactic granulocyte colony-stimulating factor administration. The safe duration of oral topotecan treatment and the maximum tolerated dose seem to be not longer than 3 days at a dose of 2.3mg/m. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Trafalis D.T.,National and Kapodistrian University of Athens | Alifieris C.,National and Kapodistrian University of Athens | Krikelis D.,National and Kapodistrian University of Athens | Tzogkas N.,Errikos Dunant Hospital | And 3 more authors.
International Journal of Clinical Pharmacology and Therapeutics | Year: 2012

Background: Malignant pleural mesothelioma (MPM) is an aggressive disease with poor or modest responses to chemotherapy and dismal prognosis. In most of the cases the scope of the treatment is only palliative. In the current study, the combination of i.v. topotecan and pegylated liposomal doxorubicin (PLD) in advanced multi-treated MPM was tested. Primary objective was palliation of the symptoms, with the secondary ones being the establishment of the regimen's safety and efficacy. Patients and methods: Nine patients were enrolled (7 males/2 females, median age 57.5 years, ECOG performance status ≤ 2), having progressed after 2 or 3 lines of chemotherapy including pemetrexed and cisplatin. Main symptoms were dyspnea, cough, chest pain, fatigue, and anorexia. The treatment included topotecan 1.2 mg/m2 i.v. on Days 1-3 and PLD 40 mg/m2 on Day 4, every 28 days. The patients received 4-8 chemotherapy cycles (median 5.8). Results: In all cases, symptoms were significantly improved after the 2nd treatment cycle. Respiratory function tests showed considerable enhancement, while cough and pain were drastically reduced. All patients had objective clinical benefit, 1 patient achieving partial response and 8 stable disease. Median time to progression and overall survival was 7 and 9 months, respectively. The chosen dose of the topotecan/ PLD combination was well-tolerated with no Grade 3/4 toxicities. Quality of life, as it was evaluated by the QLQ-C30 and QLQ-LC13 questionnaires, had improved scores especially the ones referring symptomatology. Conclusion: The current study shows a significant palliative effect of the topotecan/ PLD combination in pretreated patients with advanced MPM. ©2012 Dustri-Verlag Dr. K. Feistle.

Stathopoulos G.P.,Errikos Dunant Hospital | Malamos N.A.,Elenas Hospital | Markopoulos C.,Iatriko Kentro | Polychronis A.,Errikos Dunant Hospital | And 5 more authors.
Anti-Cancer Drugs | Year: 2014

The Ki-67 antigen was identified in the early steps of polymerase I-dependent ribosomal RNA synthesis. Although it seems that this protein has an important function in cell division, its exact role is still unclear and there is little published work on its overall function. The aim of the present study was to evaluate the contribution of the level of Ki-67 with respect to tumor recurrence in molecularly classified groups of breast cancer patients. Ki-67 was divided into the percentage levels up to and including 20% and over 20%. Immunohistochemistry and fluorescence in-situ hybridization are described for the results of estrogen receptor, progesterone receptor, c-erb-B2, and Ki-67 biomarkers. Formaldehyde-fixed breast samples were paraffin wax embedded and processed for paraffin sections. The protocol of the present study started in 1995 and finished in 2010. Nine hundred and sixteen patients with breast cancer were examined: 291 were grouped as luminal A, 228 as luminal B, 221 as the Her-2 subtype, and 107 as basal cell (triple negative). Follow-up ranged from 3 to 15 years following diagnosis. It was found that in luminal A patients, only one had a Ki-67 level higher than 20%. In luminal B, the Ki-67 was higher than 20% in 51.16% of the patients and recurrence occurred in 23.68%. In the Her-2 subtype, the Ki-67 level was more than 20% in 48.63%. In basal cell triple-negative patients, Ki-67 was more than 20% in 63.86%. The data presented here indicate that the level of Ki-67 may be considered one of the valuable biomarkers in breast cancer patients with respect to process and recurrence. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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