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 QLQLC13 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.

Nowadays, the introduction of combinational therapies with biological agents against advanced or resistant to chemotherapy tumors or for the treatment of cancer patients with organ failures becomes more and more attractive. The authors describe the case of a 60-year-old female patient with a multi-refractory to conventional cytotoxic therapy laryngeal cancer that was treated with cetuximab and bevacizumab combination therapy. Bevacizumab administration was associated with appearance of multiple cutaneous ecchymoses. This is a first-time reported adverse effect. Due to the recent launch of these agents and the limited experience of their use in clinical practice, their adverse effects and pharmacological toxicities are not well established and call for their detailed registration and reporting.

A 26 year-old male was referred to our unit because of a stage III soft tissue sarcoma in the shoulder girdle-axillary area and reduced forearm-distal arm strength. Imaging studies revealed that the tumor encompassed the axillary artery and brachial plexus. We chemoembolized it using vincristine, adriamycin and cyclophosphamide (VAC) plus gel foam and performed limb salvage surgery (LSS) afterwards. The patient received adjuvant chemotherapy (ifosfamide/mesna, adriamycin, and dacarbazine/MAID) and finally radiation therapy (RT; 6500 cGy total dose). Thirty-six months after the operation the patient remains free of disease, without local recurrence and excellent neurological recovery and functional rehabilitation. In stage III soft tissue sarcomas, especially in proximity with major nerve/arterial bundles, a multimodality approach is mandatory; chemoembolization is very effective in shrinking the tumor and defining its margins so as to make feasible a LSS.

PURPOSE:To compare the postoperative outcomes of several techniques of reconstructive surgery for malignant and aggressive benign tumors of the proximal humerus.PATIENTS AND METHODS:Twenty-one shoulder reconstructions following tumor resection were studied. Nine cases with an intracompartmental tumor were treated with endoprosthetic reconstruction. Three cases with the tumor involving the glenoid were treated with a typical Malawer VB shoulder girdle resection. In 5 patients with extracompartmental resections including the rotator cuff or the deltoid muscle a modified Tikhoff-Linberg procedure using polypropylene mesh was performed. In 4 patients with extracompartmental excision the authors proceeded to skeletal reconstruction using a modular endoprosthesis, while soft tissue reconstruction was undertaken using monofilament polypropylene mesh in order to enforce joint stability.RESULTS:All patients achieved stable shoulders. In cases where the technique was modified with mesh the functional outcome was fairly improved and the cosmetic result was excellent.CONCLUSION:For extracompartmental excisions including the deltoid or the rotator cuff the authors recommend a modified Tikhoff-Linberg procedure. Using polypropylene mesh they aim to achieve a static suspension in order to avoid the excessive traction of the neurovascular bundle, which is the most common complication of this procedure. Substitutionally such cases may be treated by reconstruction with a modular endoprosthesis. They recommend stabilization of the prosthesis with the use of mesh implant, avoiding in this way instability.

Bevacizumab, a humanized monoclonal antibody against vascular endothelial factor (VEGF), is approved for the treatment of metastatic colon cancer, but it has also shown efficacy in first line therapy of non-squamous-cell non-small-cell lung cancer, breast cancer and clear-cell renal cancer. Antiangiogenic therapy severe toxic effects such as stroke, myocardial infraction, angina, arterial thromboembolism, pulmonary embolism or haemorrhage, gastrointestinal perforation, heart failure should be taken into account during treatment with bevacizumab. We describe and discuss two cases of cancer patients who developed fatal arterial thromboembolic episodes after administration of bevacizumab. Due to the recent launch of antiangiogenic agents and the limited experience with their use in clinical practice, their adverse effects and pharmacological toxicities, sometimes fatal, are not well-established and a detailed registration of them is needed.

Purpose: Topoisomerase II alpha (Topo IIa gene location 17q21) is a nucleic enzyme involved in the DNA replication, transcription and chromosome topological formation. Topo IIa inhibition strategies include specific chemotherapeutic agents such as anthracyclines. Our aim was to investigate potential protein alterations of the enzyme comparing them to ki 67 proliferation marker expression in papillary thyroid carcinoma (PTC). Materials and methods: Using tissue microarray (TMA) technology, 50 specimens consisting of histologically confirmed PTCs (n=20), multi-nodular goiters (n=20) and also normal thyroid epithelia (n=10) were cored and re-embedded in the final paraffin block. Immunohistochemical analysis was performed using monoclonal anti-Topo IIa and anti-ki 67 (MIB-1) antibodies. Digital image analysis assay was also applied for the evaluation of the protein expression results (Nuclear Labeling Index-NLI). Results: Topo IIa and ki 67 proteins were overerpressed in 4/20 (20%) and 14/20 (70%) cases, respectively Concerning multi-nodular goiters, overexpression was observed in 2120 and 4120 specimens, respectively Statistical association,was assessed correlating ki 67 expression to pathology type, capsular invasion and also to vascular infiltration (p=0.001, p=0.008, and p=0.012, respectively). Topo IIa protein expression was strongly correlated only to capsular invasion (p=0.004). Overall expression of the examined markers demonstrated a medium concordance (kappa=0.27), but a strong association (p=0.001). Conclusion: Topo IIa and also ki 67 overexpression are correlated to an aggressive phenotype in PTC. Topo IIa overexpression maybe is a reliable marker for a rational application of targeted chemotherapeutic strategies in some subgroups of patients.

Purpose: In earlier studies, this laboratory carried out research on the synthesis and anticancer evaluation of hybrid compounds, which combine two molecules in one such as homo-aza-steroidal esters (HASE) of carboxylic derivatives off N-bis (2-chloroethyl) aniline. In this combination, steroidal hormones are employed as carriers for transporting the alkylating agents to specific targeted tissues. Aiming to continue our research, we used alkylating agents, as nitrosoureas, instead of nitrogen mustards. In this work the N-[N(2-chloroethyl)-N-nitroso-carbomoyl]-L-alanine (CNC-ala) has been used and was bound to 7 newly synthesized modified steroidal esters (carrier molecule) of nitrosourea and the hybrid molecules were tested for antitumor activity against PANO2 murine pancreatic adenocarcinoma.Materials and methods: PANO2 adenocarcinoma was used in this study. C57Bl mice were used for chemotherapy evaluation. The activity was assessed from the inhibition Of tumor growth and the oncostatic parameter TIC %. Results: The antitumor activity displayed by 7 hybrid steroidal esters of nitrosourea was quite interesting. It was able to discern 4 of 7 compounds that exhibited considerable antitumor activity, increasing the lifespan of the tumor-bearing mice by inhibiting the tumor growth.Conclusion: The comparative study of 7 newly synthesized hybrid steroidal esters of nitrosourea shows that the antitumor effects of compound 7, which has an enlarged (7 carbon atoms) A-lactamic ring and nitrosourea esterfied at the position 17, which seems to be the most appropriate for the connection of a DNA cross-linking amino acid derivative is superior.

Results: Treatment of MCF-7/Arom-1 cells with L showed a reduction of testosteronedriven cell proliferation through inhibition of estradiol synthesis. Sorafenib alone reduced MCF-7/Arom-1 cell proliferation in a dose-dependent manner (IC50 3mM). The growth-inhibitory effect was associated with the induction of apoptosis, as indicated by FACS Annexin V-FITC assay and by confocal microscopy analysis. Apoptosis was not inhibited by the pan-caspase inhibitor z-VAD suggesting a caspaseindependent cell death. The combined effect of L and S was then investigated. 1mM letrozole and 0.1-2.5 mM Sorafenib significantly enhanced the anti-proliferative effect of a single agent treatment (P<0.001). The percentage of proliferative-inhibition was 42.9±4.8 for L alone, 35.7±2.9 for S alone and 78.7±6 for L-2.5 mM S combination (P<0.001). The association of 1 mM L with 2.5 mM S also significantly inhibited the colony formation (P<0.05); the inhibitory effect was 30%, 40% and 62% for L, S and L+S, respectively. However cell death was not increased further. Both drugs either alone or in association only slightly decreased ERK1/2 phosphorylation. At the dose of 10 mM, S completely blocked ERK1/2 activation, suggesting that the observed growthinhibitory effects could be associated with the inhibition of other survival/proliferation pathways.

The aim of this guideline is to provide a potential management strategy of women at high risk for breast cancer development. A summary of the available evidence is presented, including genetic risk assessment, chemoprevention, risk-reducing surgery and radiological screening, based on risk assessment of the individual. Recent progress in the diagnostic methods and therapeutic options for breast cancer does not prevent the death of at least one third of these patients from their disease. The focus on breast cancer prevention, especially for the group of women that is designated as high-risk, may reduce mortality. The determination of the group of women who are more likely to develop breast cancer will allow a targeted specific counselling and the application of preventative measures. All Cancer Centres and Units should develop an integrated network of breast cancer care using common clinical guidelines, management protocols and strategies of care (Recommendation grade D). All Breast Units should have a protocol for the management of women at high risk (Recommendation grade D).

PURPOSE:Deregulation of apoptotic pathways in cutaneous malignant melanoma appears to be correlated with chemoresistance and poor prognosis. Furthermore, telomerase (especially h-TERT) expression induces proliferation and also represents a potential target for vaccination regarding some types of malignancies.MATERIALS AND METHODS:Using tissue microarrays (TMA) technology, 25 paraffin-embedded tissue samples of histologically confirmed malignant melanomas were cored at a diameter of 2 mm and re-embedded into one recipient block (final TMA density 24/25-96%). Immunohistochemistry (IHC) was performed by the use of anti-bcl-2, anti-caspase 3, anti-caspase 8 and anti- h-TERT antibodies. Protein expression levels were evaluated using a computerized image analysis system (CIA). SPSS (chi square test and inter-rater kappa) was used for statistical analysis.RESULTS:Strong protein expression was observed in 1/24 (4.1%), 1/24 (4.1%), 2/24 (8.2%), and 4/24 (16.4%) cases regarding h-TERT, caspase 3, caspase 8 and bcl-2, respectively. Moderate was observed in 7/24 (29.1%), 8/24 (32.2%), 5/24 (20.2%), and 8/24(32.2%) cases, whereas reduced or absent expression demonstrated 16/24 (65%), 15/24 (60.2%), 17/24 (68.5%), and 12/24 (50 %) cases. Statistical significance was assessed correlating age to caspase 3 (p=0.05), Breslow's thickness to telomerase (p=0.013) and to bcl-2 (p=0.053), Clark's level to telomerase (p=0.008) and to bcl-2 (p=0.022), and finally ulceration to telomerase expression (p=0.007).CONCLUSION:bcl-2 and telomerase expression are correlated to critical parameters of malignant melanoma, affecting its biological behavior. Furthermore, downregulation of proteins such as caspases 3/8, which normally induce apoptosis, is perhaps associated with resistance of the applied chemotherapeutic strategies in this type of malignancy.

PURPOSE:In the development of rheumatic syndromes as well as of lymphoproliferative disorders it is probable that there are common genetic, environmental and immunoregulatory pathogenetic mechanisms. The purpose of this study was to determine the frequency of simultaneous presentation of both lymphoma or other lymphoproliferative diseases, and rheumatic syndromes.PATIENTS AND METHODS:In this study included were all patients with lymphoproliferative diseases (1920 patients) followed at our hospital during the last 5 years. 312/1920 (16.2%) patients presented with non-Hodgkin's lymphoma (NHL), 645/1920 (33.5%) had myeloma, 558/1920 (29%) had leukemia and miscellaneous other hematological malignancies (Hodgkin's lymphoma, cryoglogulinaemia etc) had 405/1920 patients (21%). Antinuclear antibodies (ANA), ribosome P and intermediate filament antibodies (IMF) were measured by immunofluorescence (IF). Anti-double-stranded DNA (ds-DNA) antibodies and extractable nuclear antigens (ENA: Sm, RNP, SSA, SSB, Scl70) were measured by ELISA and the rheumatoid factor (RF) by nephelometry.RESULTS:388/1920 (4.6%) patients were ANA positive (antibody titres>1/160). On the other hand, clinical symptoms attributed autoimmune diseases (arthralgias, morning stiffness etc) plus autoantibodies other than ANA were present only in 8/312 (2.56%) patients with NHL, among them one with anti-cardiolipin antibodies. It is interesting that from these 8 patients, 3 had MALT lymphoma and 3 diffuse B-cell large cell lymphoma. Also, we detected anti-IMF and IgM and lgG anti-CMV antibodies in 2/312 (0.42%) patients with NHL.CONCLUSION:We conclude that the simultaneous presence of lymphoproliferative diseases and rheumatic syndromes are more frequent among lymphoma patients than in other lymphoproliferative diseases. Therefore, the screening of antibodies in NHL patients may be useful for the discovery and the treatment of an underlying autoimmune disease.

Bilateral occurrence of a primary testicular tumor is unusual. The reported incidence of bilateral germ cell tumors of the testes has been between 0.5 and 7% and the majority of these cancers (90%) are metachronous. We report the case of a 27-year-old man with synchronous bilateral seminoma and discuss the value of the histopathological diagnosis in therapy and prognosis. The related literature is concisely reviewed.

PURPOSE Deregulation of cell cycle control molecules, such as cyclins and their inhibitors, is a crucial event in the carcinogenetic process. Our aim was to identify potential correlations between p16 and cyclin D1 expression in pancreatic ductal adenocarcinoma (PDAC) that affect the biological behavior of this neoplasm. MATERIALS AND METHODS Using tissue microarray (TMA) technology, 50 paraffin-embedded tissue samples of histologically confirmed primary PDACs were cored twice and re-embedded to the final recipient block. Immunohistochemistry (IHC) was performed using monoclonal anti-p16 and anti-cyclin D1 antibodies. Protein expression levels were determined by performing computerized image analysis (CIA; estimation of Nuclear Labeling Index-NLI). SPSS (chi square test and interrater Cohen's kappa) was used for statistical analysis. RESULTS Cyclin D1 overexpression was observed in 24/50 (48%) of the examined carcinomas, whereas p16 loss or reduced expression was detected in 40/50 (80%) cases. Statistical significance was noted when correlating grade to cyclin D1 (p=0.038), stage to p16 (p=0.012) and also to cyclin D1 (p=0.011). Interestingly, combined protein alterations (p16 loss and cyclin D1 overexpression) were observed in 23/50 (46%) cases associated with advanced stage (p=0.019). Overall combined expression of the two molecules demonstrated a significantly low value (kappa=0.012; 95% confidence interval-CI: 0.010-0.014). CONCLUSION A significant proportion of PDACs is characterized by simultaneous protein alterations regarding p16 and cyclin D1 genes. This mechanism of genetic deregulation in cell cycle potentially explains in part the aggressive phenotype of this neoplasm.

G.D. Geromichalos1, D.T. Trafalis2, G.A. Katsoulos3, A. Papageorgiou1, P. Dalezis1, E.B. Triandafi llidis4, C.C. Hadjikostas3, A. Athanassiou2 1Laboratory of Cell Culture Molecular Modeling and Drug Design, Symeonidio Research Center, Theagenio Cancer Hospital, Thessaloniki; 2Department of Medical Oncology, Metaxa Cancer Hospital, Piraeus; 3Department of Chemistry, Aristotle University of Thessaloniki; 4Department of Gynaecologic Oncology, Theagenio Cancer Hospital, Thessaloniki, Greece