Evangelos C Briasoulis

Abstract: To explore the impact of dose intensity (DI) in the adjuvant setting of breast cancer, a randomized phase III trial was conducted comparing postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel, and cyclophosphamide, methotrexate and fluorouracil (CMF)in high-risk breast cancer patients. From Oct 2000 to June 2005, 1,121 node-positive patients were randomized to dose-dense sequential epirubicin 110 mg/m(2) and paclitaxel (Taxol((R)), Bristol Myers-Squibb, Princeton, NJ) 250 mg/m(2) (group A), or concurrent epirubicin 83 mg/m(2) and paclitaxel 187 mg/m(2) (group B), both followed by three cycles of "intensified" combination chemotherapy with CMF. By protocol design total cumulative dose and duration of treatment were identical in both groups. Dose intensity of epirubicin and paclitaxel was double in the dose-dense arm. Prophylactic treatment with granulocyte colony-stimulating factor was given with the dose-dense treatments. Disease-free survival (DFS) was the primary endpoint. At a median follow-up of 76 months, 253 patients (23%) had documented disease relapse (123 vs. 130 in groups A and B, respectively) and 208 deaths (101, group A and 107, group B) had been observed. The 5-year DFS rate of 74 and 74% and OS rate of 86 and 85% were observed for group A and group B, respectively. No differences were found in DFS or OS between the two treatment groups (P = 0.78 and P = 0.45 for DFS and OS, respectively). Safety analysis results showing that both regimens were well tolerated and safe have been previously published (Fountzilas et al. Ann Oncol 2008). No DFS or OS benefit from the dose-dense sequential epirubicin and paclitaxel was detected when compared to the concurrent administration of the same drugs. No additional safety issues were raised with long-term follow-up.

Abstract: ABSTRACT: BACKGROUND: : To investigate the expression of E-cadherin, beta-catenin and topoisomerase-II alpha and examine their clinical relevance in liposarcomas . MATERIALS AND METHOD: S: The expression of E-cadherin, beta-catenin and topoisomerase II alpha was examined immunohistochemically on formalin-fixed paraffin-embedded tissue specimens from 71 patients who underwent surgical treatment for liposarcomas of the extremities or the retroperitoneum in two major cancer reference centres between 1990 and 2000. Detailed medical notes were available for all patients who were followed for median 82 months (range 5 to 215 months). Obtained expression data were weighted against clinical and pathology parameters of clinical relevance. RESULTS: : Patients were mostly male (59%), median age was 56 years for the liposarcomas of the extremities and 60 years for the retroperitoneal liposarcomas. The tumours were of diverse histology, grade and size (median diameters 7 and 17 cm for tumours of the extremities and retroperitoneum respectively). Expression of -catenin protein was weakly detected in 15 cases (21.1%). Similarly weak expression of topoisomerase II-alpha was detected in 14 (19.7%) cases of which only two had more than 20% of tumor cells stained positive. E-cadherin was not detected in the studied cohort of liposarcomas. We did not detect associations between the expression of the above proteins by liposarcoma cells and clinical outcome. CONCLUSIONS: : Liposarcomas do not express E-cadherin, which matches the absence of epithelioid differentiation in this sarcoma subtype, and have low topoisomerase II-alpha expression, which justifies to some extend their resistance to anthracycline-based chemotherapy.

Abstract: Thrombospondin (TSP-1) is a 450-kd adhesive glycoprotein that was initially discovered in platelets and subsequently in a variety of cell types. Several reports suggest that TSP-1 possesses tumour suppressor function, through its ability to inhibit tumour neovascularization. In this study we investigated tissue sections from 124 breast carcinomas for the immuno-histochemical expression of TSP-1 protein and its relationship to several clinicopathological parameters. The possible relationship to hormone receptors content, p53 protein, proliferation associated indices, angiogenesis, VEGF expression and extracellular matrix components (tenascin, fibronectin, laminin, collagen type IV and syndecan-1) was also estimated. TSP-1 was detected in the perivascular tissue, at the epithelial-stromal junction, in the stroma and in the tumour cells. High tumour cell TSP-1 expression was observed in 9.7%, moderate in 17.7%, mild in 10.5%, while 62.1% of the cases were negative for TSP-1 expression. The survival analysis showed an increased risk of recurrence associated with low TSP-1 tumour cell expression. High stromal TSP-1 expression was observed in 3.2% of the cases, moderate in 3.3%, mild in 27.4%, while 63.6% of the cases showed absence of TSP-1 expression. This expression was higher in invasive lobular type of breast cancer and inversely correlated with the lymph node involvement and the estrogen receptor content. Stromal TSP-1 expression was also positively correlated with extracellular matrix components expression, tenascin, fibronectin, collagen type IV, laminin, and syndecan-1. The relationship of TSP-1 expression with tumor angiogenesis, growth fraction and p53 protein expression was not significant. Our data suggest that TSP-1 expression seems to be associated with favorable biological behavior and may have clinical value in terms of predicting the risk of recurrence. In addition, TSP-1 might not be a direct anti-angiogenic factor, although it seems to be implicated in the remodeling of breast cancer tissue through interaction with other extracellular matrix components.

Abstract: Various cyanobacterial species have the capacity to produce different types of toxins. Microcystins, the most prominent cyanotoxins are considered health hazards because of their potential hepatotoxic effects. They are well known to contaminate freshwater ecosystems but their presence in marine ecosystems has been reported only occasionally. We investigated seasonal changes of microcystin concentrations both in water and in the edible species of mussels Mytilus galloprovincialis collected from Amvrakikos Gulf (salinity ranging from 30� to 34�), the biggest semi-enclosed basin in Greece. The microcystin concentrations in the water ranging from 0.003 to 19.8 ng*l^-1, were below the World Health Organization (WHO) upper limit for recreational activities. In contrast, we found that microcystin concentrations in M. galloprovincialis mussels (ranging from 45 to 141.5 ng*g^-1) exceeded the upper limit of the tolerable daily intake (TDI) of microcystin as determined by WHO. Genotype composition of the total cyanobacterial community of the Gulf was analyzed by using denaturing gradient gel electrophoresis (DGGE) profiling of the rRNA internal transcribed spacer region (rRNA-ITS). The cyanobacterial community was found to be dominated almost exclusively by the cosmopolitan species Synechococcus � Synechocystis. In order to determine genes involved in the production of microcystins, a range of both specific and degenerate molecular primers against microcystin synthetase gene cluster (mcyS) was used. To our knowledge this is the first report of the presence of the hepatotoxic microcystins in the Mediterranean Sea, the first study on the accumulation of these toxins in mussels from a Mediterranean marine ecosystem and one of the few published works suggesting a potential association of microcystins with Synechococcus and/or Synechocystis cyanobacteria. The importance of our study is strengthened by the fact that Amvrakikos Gulf is among the most productive Greek �seafood� areas and a Mediterranean wetland of international significance according to Ramsar Convention. xD;

Abstract: BACKGROUND: Taxanes are established in the treatment of metastatic beast cancer (MBC) and early breast cancer (EBC) as potent chemotherapy agents. However, their therapeutic usefulness is limited by de-novo refractoriness or acquired resistance, which are common drawbacks to most anti-cancer cytotoxics. Considering that the taxanes will remain principle chemotherapeutic agents for the treatment of breast cancer, we reviewed known mechanisms of resistance in with an outlook of optimizing their clinical use. METHODS: We searched the PubMed and MEDLINE databases for articles (from inception through to 9th January 2012; last search 10/01/2012) and journals known to publish information relevant to taxane chemotherapy. We imposed no language restrictions. Search terms included: cancer, breast cancer, response, resistance, taxane, paclitaxel, docetaxel, taxol. Due to the possibility of alternative mechanisms of resistance all combination chemotherapy treated data sets were removed from our overview. RESULTS: Over-expression of the MDR-1 gene product Pgp was extensively studied in vitro in association with taxane resistance, but data are conflicting. Similarly, the target components microtubules, which are thought to mediate refractoriness through alterations of the expression pattern of tubulins or microtubule associated proteins and the expression of alternative tubulin isoforms, failed to confirm such associations. Little consensus has been generated for reported associations between taxane-sensitivity and mutated p53, or taxane-resistance and overexpression of Bcl-2, Bcl-xL or NFkB. In contrary sufficient in vitro data support an association of spindle assembly checkpoint (SAC) defects with resistance. Clinical data have been limited and inconsistent, which relate to the variety of methods used, lack of standardization of cut-offs for quantitation, differences in clinical endpoints measured and in methods of tissue collection preparation and storage, and study/patient heterogeneity. The most prominent finding is that pharmaceutical down-regulation of HER-2 appears to reverse the taxane resistance. CONCLUSIONS: Currently no valid practical biomarkers exist that can predict resistance to the taxanes in breast cancer supporting the principle of individualized cancer therapy. The incorporation of several biomarker analyses into prospectively designed studies in this setting are needed.

Abstract: We show using pyrosequencing, bisulphite sequencing and methylation specific PCR that NT5E (5'-nucleotidase, ecto; CD73) is subject to epigenetic regulation in melanoma. NT5E mRNA is down-regulated by methylation-dependent transcriptional silencing in melanoma cell lines Sk-Mel2, Sk-Mel123, WM35, Mel501, Mel505 and C81-61 and expression can be reactivated by azacytidine (AZA). In contrast, the CpG island is unmethylated and the gene expressed in cultured normal melanocytes. In clinical cases, we demonstrate using quantitative pyrosequencing and methylation specific PCR that methylation in the NT5E CpG island occurs in both primary and metastatic melanoma and correlates with transcriptional down-regulation of NT5E mRNA. Relapse with metastatic disease, particularly to visceral sites and to brain, is more common in primary melanomas lacking NT5E methylation., whereas melanomas with methylated �Τ5� show limited metastatic potential or tend to metastasise to bone. In analysis of sequential lesions from individual patients, we show quantitative changes in methylation in the NT5E CpG island with malignant progression, implying that deregulation of NT5E expression occurs via epigenetic changes in the NT5E promoter and suggesting that inhibition of NT5E may have therapeutic potential

Abstract: Abstract BIK (bcl2-interacting killer) is the founding member of the BH3-only BCL-2 family of pro-apoptotic proteins, which is found suppressed in various cancers. In multiple myeloma (MM), BIK has been shown to be epigenetically silenced in vitro but there is lack of clinical data. We investigated CpG methylation status of BIK promoter in a well-characterized clinical series of multiple myeloma (MM) patients and analyzed for clinical relevance. Forty MM patients (21 male, 19 female, mean age 66) were studied. According to International Staging System (ISS) there were classified to stage-I 16 patients, stage-II 12 patients and stage-III 12 patients. Methylation in the BIK CpG island was assessed by methylation-specific PCR (MSP) assay. Logistic regression analysis was used to investigate for associations between gene methylation and age, ISS stage, performance status, extramedullary disease, bone disease, anemia (Hb10<mg/dl), serum albumin, beta 2 microglobulin levels and relapsed/refractory disease. Methylation in the BIK CpG Island was detected in 16 patients (40%) with a trend favouring male gender (OR=3.08, p=0.09) and the development of bone disease and extramedullary disease (OR=1.6, p=0.35 and OR=3, p=0.14 respectively). MM patients with methylated the BIK CpG island had a statistically significant risk for evolving into relapsed/refractory disease (OR=5.4, p=0.03). This study provides clinical evidence that methylation-induced transcriptional silencing of BIK pro-apoptotic gene may occur in MM, which might serve as a predictor of developing relapsed/refractory MM. These findings warrant validation in larger cohorts of patients and suggest therapeutic utility for agents that enhance BIK expression.

Abstract: Non-Small-Cell Lung Cancer (NSCLC) with somatic mutations of the epidermal growth factor receptor (EGFR) is anticipated to respond to small-molecule tyrosine kinase inhibitors (TKIs) of the EGFR tyrosine kinase. There are, however, patients with EGFR mutated tumors who do not demonstrate tumor response. The most widely accepted mechanism of 'de novo' (inherent) resistance to these TKIs involves mutations of the KRAS gene. KRAS is a downstream mediator of EGFR-induced cell signaling, such mutations appear to be mutually exclusive from EGFR mutations in lung cancer. The first molecular modifier of resistance identified in patients who developed resistance (termed 'acquired resistance') to TK inhibition was a new acquired somatic EGFR mutation (T790M). Today there is an ever-growing series of molecular events that have recently come to the forefront to explain other instances of TKI resistance not attributable to T790M or KRAS. These include a number of molecules that interact with EGFR or form part of its downstream signaling pathway such as HER-2, IGFR-1, MET and B-RAF. Considering that the majority of studies carried out to date with respect to the identification of resistant clones have not used highly sensitive techniques (e.g. allelic discrimination to identify somatic mutations), coupled with the relatively low number of studies examining multiple molecular markers and the accepted molecular heterogeneity of NSCLC raise question as to the existence of 'acquired' versus 'de-novo' resistance. By examining the current knowledge base with respect to mechanisms of resistance to EGFR TKIs in NSCLC, we explore whether 'acquired' resistance is 'de-novo' resistance in disguise, and discuss the promises and limitations of molecular stratification with respect to strategies incorporating TKIs in the treatment of NSCLC.

Abstract: Rheumatoid arthritis (RA) in patients suffering from hemoglobinopathies is an important clinical problem, but the correlation between these diseases is still imperfectly known. The aim of this study was to analyze the clinical, serological and radiological characteristics of RA occurring in patients with hemoglobinopathies (thalassemia major, thalassemia intermedia and sickle-cell disease). In a single institution, in an adult cohort of 90 patients with hemoglobinopathies, we investigated retrospectively medical records of the patients. We evaluated the clinical findings, the autoantibodies and the radiological progression of patients who were diagnosed with RA according the American College of Rheumatology (ACR) criteria for RA. There were found 4 patients, with thalassemia major, who fulfilling the ACR criteria for RA. The clinical picture of the patients revealed a mild form of arthritis of the knees, shoulders, wrist and hands, while one patient had episcleritis. All patients had radiological damage compatible with RA (Larsen's score, 28.75 +/- 29). All had positive rheumatoid factor, while anti-cyclic citrullinated peptide antibodies were positive in 1 patient. Three patients received steroid treatment and one immunosuppressive agent (methotrexate). True RA with low frequency of extra-articular manifestations is described. The diagnosis of RA must be suspected in patients with hemoglobinopathies picture and chronic arthritis of small joints.

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Abstract: To explore the impact of dose intensity (DI) in the adjuvant setting of breast cancer, a randomized phase III trial was conducted comparing postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel, and cyclophosphamide, methotrexate and fluorouracil (CMF)in high-risk breast cancer patients. From Oct 2000 to June 2005, 1,121 node-positive patients were randomized to dose-dense sequential epirubicin 110 mg/m(2) and paclitaxel (Taxol((R)), Bristol Myers-Squibb, Princeton, NJ) 250 mg/m(2) (group A), or concurrent epirubicin 83 mg/m(2) and paclitaxel 187 mg/m(2) (group B), both followed by three cycles of "intensified" combination chemotherapy with CMF. By protocol design total cumulative dose and duration of treatment were identical in both groups. Dose intensity of epirubicin and paclitaxel was double in the dose-dense arm. Prophylactic treatment with granulocyte colony-stimulating factor was given with the dose-dense treatments. Disease-free survival (DFS) was the primary endpoint. At a median follow-up of 76 months, 253 patients (23%) had documented disease relapse (123 vs. 130 in groups A and B, respectively) and 208 deaths (101, group A and 107, group B) had been observed. The 5-year DFS rate of 74 and 74% and OS rate of 86 and 85% were observed for group A and group B, respectively. No differences were found in DFS or OS between the two treatment groups (P = 0.78 and P = 0.45 for DFS and OS, respectively). Safety analysis results showing that both regimens were well tolerated and safe have been previously published (Fountzilas et al. Ann Oncol 2008). No DFS or OS benefit from the dose-dense sequential epirubicin and paclitaxel was detected when compared to the concurrent administration of the same drugs. No additional safety issues were raised with long-term follow-up.

Abstract: The aim of the study was to evaluate the association of vascular endothelial growth factor (VEGF) genotypes with treatment efficacy in a randomized trial. This study compared two chemotherapy regimens (FOLFIRI versus XELIRI) combined with bevacizumab, as first-line treatment for metastatic colorectal cancer. DNA was extracted from blood samples of 173 patients participating in the trial. Genotyping was performed for selected SNPs (VEGF-1154, +936, -634, -2578 and -1498). All candidate genotypes were evaluated for associations with overall survival (OS), progression-free survival (PFS) and response rate (RR). There were no significant differences with respect to the distribution of genotypes in the treatment groups. The VEGF-1154 GG genotype was more frequent in patients not responding to treatment compared with responders (65.5 versus 39.8%, P=0.032). Furthermore, the VEGF-1154 GG genotype was associated with inferior median OS compared with GA (hazards ratio=1.68; 95% confidence interval: 1.10-2.57; P=0.016) or with the alternative genotypes (GA and AA) combined (hazards ratio=1.62; 95% confidence interval: 1.09-2.40; P=0.017). In multivariate analysis, the VEGF-1154 GG genotype remained a significant adverse factor for OS. Our results support the potential predictive ability of VEGF genotypes in patients with metastatic colorectal cancer receiving irinotecan-based chemotherapy plus bevacizumab, in terms of RR and OS. However, current results should be validated prospectively, in larger cohorts.The Pharmacogenomics Journal advance online publication, 16 August 2011; doi:10.1038/tpj.2011.37.

Abstract: We are currently witnessing a decline in the development of efficient new anticancer drugs, despite the salient efforts made on all fronts of cancer drug discovery. This trend presumably relates to the substantial heterogeneity and the inherent biological complexity of cancer, which hinder drug development success. Protein-protein interactions (PPIs) are key players in numerous cellular processes and aberrant interruption of this complex network provides a basis for various disease states, including cancer. Thus, it is now believed that cancer drug discovery, in addition to the design of single-targeted bioactive compounds, should also incorporate diversity-oriented synthesis (DOS) and other combinatorial strategies in order to exploit the ability of multi-functional scaffolds to modulate multiple protein-protein interactions (biological hubs). Throughout the review, we highlight the chemistry driven approaches to access diversity space for the discovery of small molecules that disrupt oncogenic PPIs, namely the p53-Mdm2, Bcl-2/Bcl-xL-BH3, Myc-Max, and p53-Mdmx/Mdm2 interactions.

Abstract: The KRAS oncogene has been extensively studied for more than three decades, however, it is only recently that it attained a central role in the clinical decision-making process for the practicing oncologist. Recently, based on retrospective analyses of large randomized clinical trials, the use of anti-epidermal growth factor (EGFR) monoclonal antibodies, cetuximab and panitumumab, was restricted to patients with metastatic colorectal cancer that carry the "wild-type"KRAS genotype. Challenges remain in the laboratory implementation of KRAS mutational testing and the clinical application of the test for treatment planning. This review attempts to offer a global view of KRAS biology, its functional role in cell signaling, mechanisms of resistance to anti-EGFR agents and its predictive potential in metastatic colorectal cancer. We also survey the growing list of candidate biomarkers that may shortly supplement KRAS in routine clinical patient stratification. Finally, we discuss practical aspects of KRAS testing that may be useful for those involved in mutational screening in their centers. This general overview of KRAS for clinical oncology practice aims to assist in data interpretation and offer insight into potential pitfalls of mutational testing. KRAS is a prime example of how translational research can fulfill the promises of personalized medicine for tailoring treatment to match the underlying tumor biology.

Abstract: BACKGROUND: Organic anion-transporting polypeptides (OATPs) are influx transporters that mediate intracellular uptake of selective endogenous and xenobiotic compounds. Identification of new molecular targets and discovery of novel targeted therapies is top priority for pancreatic cancer, which lacks any effective therapy. MATERIALS AND METHODS: We studied expression of OATP 1A2, 1B1, and 1B3 in pancreatic cancer tissue and in cell lines. Formalin-fixed paraffin-embedded biopsy material of 12 human pancreatic cancers was immunohistochemically assessed for protein expression of the three studied influx transporters. Immunohistochemistry was evaluated by experienced pathologists and quantified by use of an automated image analysis system. BxPC-3 and MIA PaCa-2 pancreatic cancer cell lines were used to quantify transcripts of OATP 1B1 and 1B3. RESULTS: OATP 1A2, 1B1, and 1B3 proteins were found ubiquitously expressed in all studied cases. Quantification performed by HistoQuest system revealed that mean intensity was 53 for 1A2, 45 for 1B1, and 167 for OATP 1B1/1B3 on a range scale 0-250 units. At mRNA level, 1B1 and 1B3 were overexpressed in both studied cancer cell lines but not in normal pancreatic tissue. CONCLUSION: OATPs 1A2, 1B1, and 1B3 are highly expressed in pancreatic adenocarcinoma. We suggest that expression of these transporters in pancreatic cancer justify research efforts towards discovery of novel therapeutics targeting OATPs.

Abstract: Currently we are witnessing an exponential increase in cancer biology achievements and molecular target knowledge, but at the same time we are seeing unnecessarily slow improvements in the therapy of advanced/ metastatic cancer. �is discrepancy is largely attributed to inherent di culties of clinical cancer research to follow the more rapidly developing biotechnological advances that are occurring, or in handling the accelerated accumulation of basic research data. Impressive discoveries of basic research hazily reported by news agencies and disseminated by the media lead to misconceptions and promote false expectations among the public. The missing link between basic/ preclinical and clinical science is the low performance of clinical trials. Both the UN and the WHO have identified this as a signifficant defficiency and are now undertaking, for the frst time, initiatives to demystify and promote such research among member states. Clinical trials in oncology are costly and often slowly progressive. Moreover, they demand large competences in know-how, recourses and specialists. Furthermore, several categories of players with di erent professional backgrounds and interests need to continuously collaborate and cross- interact over prolonged periods of time to see completion of these studies. Poor accrual is the single most important negative factor that intervenes with clinical trials achieving their timely goals. Connected to that are trial unavailability, lack of clinical research education and promotion in the community and between health professionals alike. A relatively poor understanding, poor know-how, ine ciencies of involved medical sta , a reluctance of physicians to engage in accrual, and poor co-operation and underpowered regulatory mechanisms are all aspects of a poor reality. These obstacles are evidently more pronounced in low outcome countries xD;We can do better! From a medical associations perspective, such as MOFF, we need to shape interregional and international scientific working collaborations and networks, and to promote public education on clinical research in regard to regulations, basic concepts, mechanisms and procedures. Only in such forums can we join together all the specialties necessary to accomplish our goals.

Abstract: Background: Taxanes are established in the treatment of metastatic beast cancer (MBC) and early breast cancer (eBC) as potent chemotherapy agents. However, their therapeutic usefulness is limited by de-novo refractoriness or acquired resistance, which are common drawbacks to most anti-cancer cytotoxics. Considering that the taxanes will remain principle chemotherapeutic agents for the treatment of breast cancer, we reviewed known mechanisms of resistance to these drugs with an outlook of optimizing their clinical use. xD;Methods: We searched the PubMed and MeDLINe databases for articles (from inception through to 30th June 2011; last search 17th July 2011) and journals known to publish information relevant to taxane chemotherapy. We imposed no language restrictions. Search terms included: cancer, breast cancer, response, resistance, taxane, paclitaxel, docetaxel, taxol. Due to the possibility of alternative mechanisms of resistance all combination chemotherapy treated data sets were removed from our overview. xD;Results: Over-expression of the mdR1 gene product Pgp was extensively studied in vitro in association with taxane resistance, but data are conflicting. Similarly, the target components microtubules, which are thought to mediate refractoriness through alterations of the expression pattern of tubulins or microtubule associated proteins and the expression of alternative tubulin isoforms, failed to confirm such associations. Little consensus has been generated for reported associations between taxane-sensitivity and mutated p53, or taxane-resistance and overexpression of Bcl-2, Bcl-xL or NFkB. On the contrary sufficient in vitro data support an association of spindle assembly checkpoint (SAC) defects with resistance. Clinical data have been limited and inconsistent, which relate to the variety of methods used, lack of standardization of cut-offs for quantitation, differences in clinical endpoints measured and in methods of tissue collection preparation and storage, and study/ patient heterogeneity. The most prominent finding is that pharmaceutical down-regulation of HeR2 appears to reverse taxane resistance. xD;Conclusions: Currently no valid practical biomarkers exist that can predict resistance to the taxanes in breast cancer supporting the principle of individualized cancer therapy. The incorporation of several biomarker analyses into prospectively designed studies in this setting are needed. MOJ 2011, 1:14-29

Abstract: BACKGROUND: To analyse the discriminative impact of osteopontin (OPN) and activated leukocyte cell adhesion molecule (ALCAM), combined with human epidermal growth factor 2 (HER2) and oestrogen receptor (ER) in breast cancer. METHODS: Osteopontin, ALCAM, HER2 and ER mRNA expression in breast cancer tissues of 481 patients were analysed (mRNA microarray analysis, kinetic RT-PCR). Hierarchical clustering was performed in training cohort A (N=100, adjuvant treatment) and validation cohorts B (N=200, no adjuvant treatment, low-risk) and C (N=181, adjuvant treatment, high-risk). RESULTS: Negative/low ER and HER2, high OPN and low ALCAM mRNA expression helped to identify patients at particularly high risk, showing shorter DFS, P<0.001, and OAS, P=0.001. Although both validation cohorts showed diverse risk and treatment profiles, this marker constellation was concordantly associated with shorter DFS and OAS (P<0.001 and P=0.075 for cohort B and P=0.043 and P<0.001 for cohort C, respectively). In multivariate analysis, this algorithm was the main independent prognostic factor. Cohort B: DFS, P=0.0065, OAS, not significant; cohort C: DFS, P=0.026, OAS, P<0.001. CONCLUSION: Activated leukocyte cell adhesion molecule and OPN mRNA expression has a strong discriminative impact on survival within cancer patients with low or negative expression of ER and HER2, so called 'high-risk' breast cancers, and might help in identifying patients who could benefit from new treatment approaches like targeted therapies in the adjuvant setting.

Abstract: MicroRNAs (miRNAs) are evolutionarily conserved, naturally abundant, small, regulatory non-coding RNAs that inhibit gene expression at the post-transcriptional level in a sequence-specific manner. Each miRNA represses the protein expression of several coding genes in a manner proportional to the sequence complementarity with the target transcripts. MicroRNAs play key regulatory roles in organismal development and homeostasis. They control fundamental biological processes, such as stem-cell regulation and cellular metabolism, proliferation, differentiation, stress resistance, and apoptosis. Differential miRNA expression is found in malignant tumors in comparison to normal tissue counterparts. This indicates that miRNA deregulation contributes to the initiation and progression of cancer. Currently, miRNA expression signatures are being rigorously investigated in various tumor types, with the aim of developing novel, efficient biomarkers that can improve clinical management of cancer patients. This review discusses deregulated miRNAs in solid tumors, and focuses on their emerging prognostic potential.

Abstract: This trial aimed to define a recommended safe dose (RSD) of weekly paclitaxel and irinotecan combined with carboplatin in patients with advanced cancer. Patients with advanced cancer were eligible for this trial. Dose-limiting toxicity (DLT) was considered to be any grade greater than or equal to 3 (G> or =3) nonhematological toxicity except nausea/vomiting, G4 hematological toxicity of more than 4 days without recombinant human granulocyte colony-stimulating factor support, concurrent diarrhea G> or =2 and neutropenia G> or =3, and a treatment delay for more than 14 days because of toxicity. Patients were given carboplatin area under the curve (AUC) 5 mg*min/ml on day 1 combined with irinotecan and paclitaxel on days 1 and 8, every 3 weeks. The starting dose of both irinotecan and paclitaxel was 50 mg/m and a toxicity-guided escalation/de-escalation was planned by 10 mg/m steps. Sixteen patients were enrolled. DLTs occurred in three of the four patients treated at the starting dose level, which defined that dose as the maximum tolerated dose. Accrual continued with irinotecan and paclitaxel doses, which were de-escalated by one step. At this dose level, two of the 12 patients developed DLT, which defined that dose as the RSD. We concluded that the maximum tolerated dose of weekly irinotecan and paclitaxel when given in combination with carboplatin AUC 5 mg*min/ml was 50 mg/m and the RSD 40 mg/m. DLTs were febrile neutropenia, concurrent neutropenia (G3) and diarrhea (G3), and prolonged treatment delay because of toxicity. The most common non-DLT G3/G4 toxicity was leukopenia and neutropenia (18%), and thrombocytopenia and diarrhea (6%). A patient with metastatic endometrial carcinoma treated at the RSD had a compete response of retroperitoneal lymph node metastases, lasting for more than 3 years. Two other patients had their minimal tumor shrinkage documented. Paclitaxel (40 mg/m) and irinotecan (40 mg/m) can safely be administered on days 1 and 8 in combination with carboplatin AUC 5 mg*min/ml given on day 1. At the recommended doses this is a well-tolerated regimen with noticeable antitumor activity and warrants further investigation in phase II studies.

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Abstract: BACKGROUND: Platinum-based combinations are the standard second-line treatment for platinum-sensitive ovarian cancer (OC). This randomized phase II study was undertaken in order to compare the combination of carboplatin and pegylated liposomal doxorubicin (LD) with carboplatin and paclitaxel (CP) in this setting. METHODS: Patients with histologically confirmed recurrent OC, at the time of or more than 6 months after platinum-based chemotherapy, were randomized to six cycles of CP (carboplatin AUC5 + paclitaxel 175 mg/m2, d1q21) or CLD (carboplatin AUC5 + pegylated LD 45 mg/m2, d1q28). RESULTS: A total of 189 eligible patients (CP 96, CLD 93), with a median age of 63 years, median Performance Status (PS) 0 and a median platinum free interval (PFI) of 16.5 months, entered the study. Discontinuation due to toxicity was higher in the CP patients (13.5% versus 3%, P = 0.016). The overall response rate was similar: CP 58% versus CLD 51%, P = 0.309 (Complete Response; CR 34% versus 23%) and there was no statistical difference in time-to-progression (TTP) or overall survival (OS; TTP 10.8 months CP versus 11.8 CLD, P = 0.904; OS 29.4 months CP versus 24.7 CLD, P = 0.454). No toxic deaths were recorded. Neutropenia was the most commonly seen severe toxicity (CP 30% versus CLD 35%). More frequent in CLD were severe thrombocytopenia (11% versus 2%, P = 0.016), skin toxicity and Palmar-plantar erythrodysesthesia (PPE) grade 1-2 (38% versus 9%, P< 0.001), while grade 3 neurotoxicity and alopecia were higher in CP (7% versus 0%, P = 0.029, 20% versus 5%, P = 0.003). PS and PFI were independent prognostic factors for TTP and OS. CONCLUSIONS: The combination of pegylated LD with carboplatin is effective, showing less neurotoxicity and alopecia than paclitaxel-carboplatin. It thus warrants a further phase III evaluation as an alternative treatment option for platinum-sensitive OC patients. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12609000436279.

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Abstract: Cyanobacterial cyclopeptides, including microcystins and nodularins, are considered a health hazard to humans due to the possible toxic effects of high consumption. From a pharmacological standpoint, microcystins are stable hydrophilic cyclic heptapeptides with a potential to cause cellular damage following uptake via organic anion-transporting polypeptides (OATP). Their intracellular biological effects involve inhibition of catalytic subunits of protein phosphatase 1 (PP1) and PP2, glutathione depletion and generation of reactive oxygen species (ROS). Interestingly, certain OATPs are prominently expressed in cancers as compared to normal tissues, qualifying MC as potential candidates for cancer drug development. In the era of targeted cancer therapy, cyanotoxins comprise a rich source of natural cytotoxic compounds with a potential to target cancers expressing specific uptake transporters. Moreover, their structure offers opportunities for combinatorial engineering to enhance the therapeutic index and resolve organ-specific toxicity issues. In this article, we revisit cyanobacterial cyclopeptides as potential novel targets for anticancer drugs by summarizing existing biomedical evidence, presenting structure-activity data and discussing developmental perspectives.

Abstract: This study aimed to investigate the efficacy of prophylactic amifostine in reducing the risk of severe radiation colitis in cancer patients receiving radical radiotherapy to the pelvis.

Abstract: The aim of this retrospective study was to present the epidemiological, pathological and clinical characteristics and treatment results of Greek women with epithelial ovarian cancer (EOC).

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Abstract: Major advances in cancer research, escalating improvements in cancer management and epidemic increase of cancer incidence drive today Clinical Oncology disciplines into most appealing and challenging medical practices. In reflection, medical schools worldwide consider upgrading their curricula on cancer education. In this article we portray the current situation of undergraduate cancer education and professional training in Clinical Oncology in Greece. In this country the need of systemic education in Oncology was early realized by pioneer oncologists two decades ago and since then it gets steadily improving. Today, intra- and extra-curriculum education activities are intense and offer advanced teaching and training opportunities at both undergraduate and postgraduate levels. Medical and Radiation Oncology are two officially recognized specialties of Medicine in Greece and have both contemporary education curricula which are officially portrayed in the establishment acts. Centers accredited as training centers for Clinical Oncology have regular commitments to teaching and develop structured training programs; however, the burden of service commitments and shortage in senior staff compromise in some cases the educational activities. Finally, generous training and research grants offered by National and European scientific bodies provide now advanced educational opportunities to willing young oncologists.

Abstract: Combination of trastuzumab and anthracyclines in metastatic breast cancer (MBC) is precluded due to cardiotoxicity. Pegylated liposomal doxorubicin (PLD) is the least cardiotoxic among the anthracyclines. We performed a phase II study of trastuzumab and PLD with biomarker evaluation.

Abstract: To determine the safe dose range and pharmacokinetics of metronomic oral vinorelbine and obtain preliminary data on biomarkers and efficacy in patients with advanced cancer.

Abstract: Cyanobacterial blooms are a frequent phenomenon in eutrophic freshwaters worldwide, and are considered as potential hazards to ecosystems and human health, while it has been shown that on average 60% of these cyanobacterial blooms are toxic. Hepatotoxic blooms are more common than neurotoxic ones and microcystins have been found to be the most prevalent cyanobacterial hepatotoxins. Lake Pamvotis is an ancient (having been in continual existence throughout the Plio-Pleistocene period) suburban Mediterranean Lake used for recreation, fishing and irrigation purposes which has suffered eutrophication for the last three decades. We investigated cyanobacterial species composition and microcystin loads in this lake over a 16-month period. The highest microcystin concentrations were recorded in autumn, one to two months after the midsummer severe bloom. With the exception of the winter months, microcystin concentrations exceed the WHO upper limits for drinking water but not for recreational waters. Seasonal changes of microcystin bioaccumulation in edible species were also investigated. Microcystin concentrations never exceed the WHO upper limits in those species with the exception of bivalves. For a detailed characterization of the cyanobacterial species composition of the lake, we used polymerase chain reaction (PCR) amplification of the internal transcribed spacer (ITS) between 16S and 23S rRNA genes, in combination with denaturing gradient gel electrophoresis (DGGE). ITS sequences from Lake Pamvotis revealed that the cyanobacterial community of this lake is made of two major populations. A population well defined both microscopically and molecularly as Microcystis sp. dominated during autumn, and another population of filamentous cyanobacteria microscopically characterized as Anabaena sp./Aphanizomenon sp. dominated during midsummer blooms. Sequences of filamentous cyanobacteria from Lake Pamvotis revealed that this cyanobacterial population is homogeneous, although divergent from other populations worldwide. Finally, by using a combination of general and genus specific primer sets against the mcyE gene, we identified Microcystis as the only genus responsible for microcystin production in Lake Pamvotis.

Abstract: Effective anthracycline-free combinations need to be evaluated in metastatic breast cancer (MBC), due to the increased number of patients treated with anthracycline-based adjuvant chemotherapy.

Abstract: Olive oil compounds is a dynamic research area because Mediterranean diet has been shown to protect against cardiovascular disease and cancer. Olive leaves, an easily available natural material of low cost, share possibly a similar wealth of health benefiting bioactive phytochemicals. In this work, we investigated the antioxidant potency and antiproliferative activity against cancer and endothelial cells of water and methanol olive leaves extracts and analyzed their content in phytochemicals using LC-MS and LC-UV-SPE-NMR hyphenated techniques. Olive-leaf crude extracts were found to inhibit cell proliferation of human breast adenocarcinoma (MCF-7), human urinary bladder carcinoma (T-24) and bovine brain capillary endothelial (BBCE). The dominant compound of the extracts was oleuropein; phenols and flavonoids were also identified. These phytochemicals demonstrated strong antioxidant potency and inhibited cancer and endothelial cell proliferation at low micromolar concentrations, which is significant considering their high abundance in fruits and vegetables. The antiproliferative activity of crude extracts and phytochemicals against the cell lines used in this study is demonstrated for the first time.

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Abstract: The epidermal growth factor receptor (EGFR) is over-expressed in 70-75% of colorectal adenocarcinomas (CRC). The anti-EGFR monoclonal antibody cetuximab has been approved for the treatment of metastatic CRC, however tumor response to cetuximab has not been found to be associated with EGFR over-expression by immunohistochemistry (IHC). The aim of this study was to explore EGFR and the downstream effector phosphatase and tensin homologue deleted on chromosome 10 (PTEN) as potential predictors of response to cetuximab.

Abstract: The combination of Carboplatin and Paclitaxel is considered the standard of care as initial chemotherapy for Advanced Ovarian Cancer (AOC). We compared this regimen with the combination of Cisplatin, Paclitaxel and Doxorubicin.

Abstract: Peroxisome proliferator-activated receptor-gamma (PPARgamma), one of three ligand-activated transcription factors named PPAR, has been identified as a molecular target for cancer chemopreventive agents. PPARgamma was initially understood as a regulator of adipocyte differentiation and glucose homeostasis while later on, it became evident that it is also involved in cell differentiation, apoptosis, and angiogenesis, biological processes which are deregulated in cancer. It is now established that PPARgamma ligands can induce cell differentiation and yield early antineoplastic effects in several tumor types. Moreover, several bioactive natural products with cancer protecting potential are shown to operate through activation of PPARgamma. Overall, PPARgamma appears to be a prevalent target ally to cancer chemopreventive agents and therefore pursuing research in this area is of great relevance.

Abstract: The aim of the study was to evaluate the prognostic ability of the transcriptional profiling of the HER family genes in early breast cancer, as well as to investigate the predictive value of HER2 mRNA expression for adjuvant treatment with paclitaxel. RNA was extracted from 268 formalin-fixed paraffin-embedded (FFPE) tumour tissue samples of high-risk breast cancer patients enrolled in the randomised HE10/97 trial, evaluating the effect of dose-dense anthracycline-based sequential adjuvant chemotherapy with or without paclitaxel. The mRNA expression of all four HER family members was assessed by kinetic reverse transcription-polymerase chain reaction (kRT-PCR). The overall concordance between kRT-PCR and IHC/FISH for HER2 status determination was 74%. At a median follow-up of 8 years, multivariate analysis showed that EGFR and HER2 mRNA expression was associated with reduced overall survival (OS). HER3 and HER4 mRNA level had a favourable prognostic value in terms of OS and disease-free survival (DFS), respectively. Adjusting for HER2 mRNA expression, OS and DFS did not differ between treatment groups. These data indicate that EGFR as well as HER2 are prognostic factors of worse clinical outcomes, whereas HER3 and HER4 gene transcription is associated with better prognosis in high-risk early breast cancer. However, HER2 mRNA expression did not predict clinical benefit from paclitaxel. Kinetic RT-PCR represents an alternative method for evaluating the expression of HER family members in FFPE breast carcinomas.

Abstract: A number of studies have shown that absence of myelotoxicity during chemotherapy is associated with worse outcome for various types of cancer, including carcinoma of the breast. The aim of this study was to determine whether myelosuppression in patients being treated with chemotherapy for advanced breast cancer has an impact on their prognosis.

Abstract: Taxane/platinum combinations exhibit synergistic cytotoxicity and activity against a broad range of solid tumours. We sought to optimise the regimen as a suitable outpatient palliative treatment for cancer of unknown primary (CUP).

Abstract: Hereditary cancer syndromes comprise approximately 5-10% of diagnosed carcinomas. They are caused by mutations in specific genes. Carriers of mutations in these genes are at an increased risk of developing cancer at a young age. When there is a suspicion of a hereditary cancer predisposition syndrome a detailed family tree of the patient requesting screening is constructed. DNA is isolated from all available members of the family. Mutation detection is carried out on DNA from an affected family member. If a mutation is found the remaining family is screened. The genetic basis of a large number of inherited cancer predisposition syndromes is known. In this paper the focus is on mutations in genes responsible for colorectal cancer, meaning adenomatous polyposis coli (APC), which is involved in familial adenomatous polyposis and homo sapiens mutL homolog 1 (hMLH1) and homo sapiens mutS homolog 2 (hMSH2), involved in hereditary non-polyposis colorectal cancer. In addition, the genes responsible for inherited breast and/or ovarian cancer, breast cancer genes 1 and 2 (BRCA1 and BRCA2), and the rearranged during transfection protooncogene RET which is responsible for multiple endocrine neoplasia type 2 are discussed. In all cases emphasis is given to the data available on the Greek population.

Abstract: We report on a small-cell lung cancer case that was heralded by the presence of CENP-B specific anti-centromere autoantibodies (ACA) detected well before the diagnosis of cancer. The patient received chemotherapy plus radiotherapy, which resulted in complete remission of the tumor. Serum ACA levels were zeroed at the time of radiological documentation of tumor response and remained undetected at serial follow-up assessments until they rose again along with documentation of tumor recurrence which occurred 12 months later. We review in brief published research and discuss anti-centromere autoantibodies as potential biomarkers in small-cell lung cancer, a highly proliferative tumor which lacks sensitive serum markers.

Abstract: A randomized phase III trial in high-risk breast cancer patients was conducted, to further explore the impact of dose-density in the adjuvant treatment for breast cancer. The safety analysis is presented.

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Abstract: Cancer of unknown primary (CUP) lacks established therapy although it affects 3% of cancer patients. We evaluated the irinotecan-oxaliplatin combination (IROX regimen) in previously untreated patients with non-favorable subsets of unknown primary carcinomas.

Abstract: The continuous flow of molecular genetic information has cautiously started integrating into clinical practice changing the future landscape of the clinical management of cancer. Germline mutation analysis for individuals at familial risk and testing result-based surgical or nonsurgical preventive intervention can protect from hereditary breast-ovarian, colorectal and stomach cancer and reduce mortality. Research is focusing now on the development of effective chemoprevention to replace prophylactic surgery for improving quality of life and to provide novel targeted therapies for hereditary cancer patients. The TNM staging system and conventional clinicopathologic factors have led clinical decisions on adjuvant therapy for decades improving survival in patients with early-stage tumors. However, current staging methods and therapeutic decisions remain suboptimal. Patients with early-stage cancer who are at low risk of recurrence could be spared the toxicity of systemic treatment if clearly distinguished, while others at high risk of distant recurrence could get maximal benefit if therapy matched the molecular genetic profile of either the host or the tumor. With the establishment of validated molecular analysis techniques it is believed that clinical biomarkers will gradually overtake TNM by their capacity to form more accurate prognostic systems and delineate better predictors of response to specific therapies. Areas of cancer research such as germ-cell mutation analysis, tumor gene-signature identification, gene expression profile linked targeted therapy, cancer stem cells, circulating cancer cells and single-nucleotide polymorphism keep on producing promising data which is believed to refine future preventive and early intervention strategies on an individual basis. Today these gene-based strategies are in a transition phase prior to full implementation into clinical practice. At present they wait for the results of large-scale prospective validation studies which compare molecular against "classic" markers. It is anticipated that molecular genetic biomarkers when implemented in clinical practice will considerably improve both biologically guided therapeutic decisions and clinical outcomes.

Abstract: The purpose of this study was to evaluate the efficacy and toxicity of cisplatin, etoposide and irinotecan as first-line treatment in patients with extensive small-cell lung cancer (E-SCLC).

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Abstract: Cancer of unknown primary site (CUP) ranks as the fourth most common cause of cancer deaths and represents both a diagnostic and a management challenge. In CUP, the regression or dormancy of the primary tumor, the development of early, uncommon, systemic metastases, and the resistance to therapy are hallmarks of this heterogeneous clinical entity. Still, no consensus exists on whether CUP is simply a group of metastatic tumors with unidentified primaries or a distinct entity with specific genetic/phenotypic aberrations that define it as "primary metastatic disease." In this review, we present karyotypic analyses as well as the single-gene, single-protein studies done on the expression of oncogenes, tumor- or metastasis-suppressor genes, as well as angiogenesis effectors. These studies show frequent expression of oncoproteins, lack of activating epidermal growth factor receptor/c-Kit mutations or amplification, uncommon presence of tumor- or metastasis-suppressor gene mutations and highly active angiogenesis in CUP. Informative as they may be, these data have been observed in several solid tumors of known primary and failed to identify a CUP-specific molecular signature. The latter, if it exists, probably consists of a multigene expression pattern not captured by single-gene studies. Gene and protein microarray technologies offer promise for the unraveling of complex genetic programs that would either identify each CUP's primary tissue of origin or instead define the CUP-specific molecular signature. Confirmation of one of the two hypotheses would either improve primary disease-oriented therapy or develop CUP-oriented treatments targeting molecular aberrations that drive neoplastic growth/dissemination.

Abstract: We retrospectively investigated the outcome of epithelial ovarian cancer (EOC) in women less than 45 years and over 70 years treated with cisplatin-based chemotherapy. We also investigated the impact of various factors on patients' survival. The tumor registry of the Hellenic Cooperative Oncology Group was used to identify women less than 45 years and over 70 years with EOC diagnosed between 1979 and 2004. Survival was calculated by the Kaplan-Meier method, and Cox proportional hazard models were used to determine the independent effect of each variable on survival. Of 1748 EOC patients, 200 were 45 or younger and 282 were over 70 years old. In the univariate analysis, younger age (P < 0.001), better performance status (PS) (P < 0.001), early stage (P < 0.001), 0-2 cm residual disease (P < 0.001), and well or moderate differentiation grade (P= 0.004) were significant prognostic factors for improved survival. In the multivariate analysis, older age (hazard ratio [HR]: 1.88, 95% CI: 1.27-2.77, P= 0.002), advanced stage (HR: 2.87, 95% CI: 1.49-5.52, P= 0.002), PS >1 (HR: 1.91, 95% CI: 1.18-3.08, P= 0.008), and residual disease (HR: 1.46, 95% CI: 1.01-2.13, P= 0.046) were independently associated with inferior survival. With a median follow-up of 45 months (range 0.1-197 months), median survival (118.5 months) of younger patients differed significantly compared to that of older patients (33 months) (P < 0.001). In conclusion, younger women with EOC have significantly improved survival compared to older patients. Age, PS, stage of the disease at diagnosis, and residual disease are important independent predictors for survival.

Abstract: Life-saving, risk-reducing medical interventions are required for women with a BRCA1/2 mutation. Interventions comprise a four-stage approach that involves risk assessment, genetic counseling, gene-mutation analysis and medical intervention strategies. Genetic counseling should be offered at specialized familial breast-cancer clinics and gene-mutation analysis should be recommended on the basis of personal and family-history-based risk criteria. Prophylactic bilateral salpingo-oophorectomy appears to offer the optimal benefit-risk ratio compared with prophylactic bilateral mastectomy, chemoprevention, or intensified surveillance. Tamoxifen is an alternative approach only for BRCA2 mutation carriers. The comprehensive, clinical decision-making Ioannina algorithm provided here can facilitate the complex preventive strategic approach. Newly diagnosed BRCA1/2 carriers might benefit from extensive surgery and a specific pharmacological treatment, but data to support this strategy are limited. Microarray gene-expression studies show that breast tumors from BRCA1 carriers are predominantly of basal subtype (i.e. triple negative) and BRCA2 carriers are of luminal subtype (i.e. estrogen-receptor-positive). Although optimum management of women with familial susceptibility to breast and ovarian cancer has not yet been prospectively validated, data indicate substantial benefits when an individualized evidence-based prevention strategy is provided by an experienced team.

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Abstract: Paclitaxel and carboplatin are frequently used in advanced ovarian cancer following cytoreductive surgery. Threshold models have been used to predict paclitaxel pharmacokinetic-pharmacodynamics, whereas the time above paclitaxel plasma concentration of 0.05 to 0.2 micromol/L (t(C > 0.05-0.2)) predicts neutropenia. The objective of this study was to build a population pharmacokinetic-pharmacodynamic model of paclitaxel/carboplatin in ovarian cancer patients.

Abstract: To investigate the population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients.

Abstract: To assess the prognostic and predictive significance of HER-1/EGFR protein levels in high-risk patients with breast cancer treated with dose-dense sequential adjuvant chemotherapy.

Abstract: 'Classical' mutations in the EGFR tyrosine kinase domain (exons 18, 19 and 21) have been associated with sensitivity to tyrosine kinase inhibitors (TKIs) in patients with NSCLC. The aim of the current study was to evaluate whether other than the classical G719X, DEL19 and L858R mutations of EGFR confer sensitivity to TKIs. Genomic DNA was extracted from microdissected formalin-fixed paraffin-embedded tumour tissue from 86 patients treated with gefitinib. Exons 18, 19 and 21 were amplified and subjected to direct sequencing. Eleven (13%) patients harboured the classical exon's 18, 19 and 21 mutations, while 14 (16%) had 'other' variants. There was a significantly higher percentage of 'never-smoker' patients with 'classical' EGFR mutations (P=0.002). Among patients with 'classical' mutations 3 patients achieved PR and 7 SD, while in the 'other' mutations group 10 patients had SD as best response. In the wild-type group, there were 3 patients with PR and 25 with SD. Median TTP was 16, 64 (P=0.002) and 21 weeks and median survival was 36, 78 and 67 weeks for patients with wild-type, 'classical' and 'other' EGFR mutations, respectively. The clinical relevance of 'other' EGFR mutation variants remains uncertain and requires further assessment in a prospective study.

Abstract: This study is a presentation of our department's experience in the treatment of localized prostate cancer with either radical or postoperative radiotherapy (RT). Fifty-five patients with clinical localized prostate cancer were reviewed. Thirty-three patients (T1-T2AN0M0 stage) were treated with radical RT and 22 (T2B-T3N0M0 stage) with postoperative RT. All patients received hormonal therapy. Primary end points of the study were the incidence of clinical and biochemical recurrences and death in the whole group and according to treatment modality. Within a median follow-up of 18 months the overall incidence of clinical relapse was 16.9%, of biochemical relapse 12.7% and of death 10.9%. Both treatment options achieved similar outcomes despite the fact that the patients in the postoperative RT group were of higher stage. Radical RT group tended to have better overall and disease-free survival compared to postoperative RT group, but there was no statistically significant evidence. Long-term toxicity was negligible.

Abstract: Although the very high locoregional recurrence rates reported with limited D0/D1 surgery can be reduced with extended D2 gastrectomy for operable gastric cancer, overall relapse and survival rates remain poor and can only be improved with adequate perioperative adjuvant treatment. However, despite intensive research, no regimen has been established as standard. Meta-analyses have demonstrated a marginal survival benefit with adjuvant chemotherapy. Two recent large randomized trials for operable gastric cancer, the MAGIC trial and the INT-0116 trial, provide evidence that some patients may benefit from perioperative chemotherapy and chemoradiation, respectively. However, while both trials suggest an overall survival benefit with adjuvant treatment, they don't provide the harm-benefit ratio for specific subsets of patients wih different extent of surgery (D1 or D2) and tumor stage (early [T1,2]/advanced [T3,4]). This lack of evidence complicates current therapeutic adjuvant decisions. Estimating the risk of local and distant recurrence (high, moderate or low) after D1 or D2 surgery in various tumor stages and the expected harm-benefit ratio, the authors provide useful information for decisions on adjuvant chemotherapy with or withour radiotherapy in individual patients. Research on newer cytotoxic and targeted agents may improve treatment efficacy. Simultaneously, advances with microarray-based gene-expression profiling signatures may improve individualized treatment decisions. However, the validation and translation of these genomic classifiers as biomarkers into a completed 'bench-to-bedside' cycle for tailoring treatment to individuals is a major challenge and limits inflated expectations.

Abstract: The aim of this study is to investigate the feasibility and determine the pharmacokinetics of low-dose paclitaxel in cancer patients with severe hepatic dysfunction. This was a prospective study. Patients with liver metastases who had either transaminase serum levels higher than 10 times the upper normal limit or bilirubin serum levels higher than 5 times the upper normal limit were eligible. All patients underwent pharmacokinetic evaluation during the first course of treatment. Pharmacokinetics in severe hepatic dysfunction patients were compared with data from a reference group of patients with normal hepatic function who participated in a phase I study. Nine severe hepatic dysfunction patients were treated with paclitaxel 70 mg/m administered as a 1-h infusion every 2 weeks. They received a median three treatment courses (range 1-9) without clinically relevant toxicity. The area under the concentration-time curve of paclitaxel was markedly higher in severe hepatic dysfunction patients when compared with the normal hepatic function control group treated with the same dose (98% increase, P<0.001). Area under the concentration-time curve and the time above 0.1 micromol/l (T>0.1) concentration threshold in the severe hepatic dysfunction patients who received paclitaxel 70 mg/m approximated pharmacokinetics of paclitaxel in patients with normal liver function who received 130 mg/m. Maximum plasma concentration (Cmax) did not differ between the two groups. In conclusion, paclitaxel 70 mg/m was safely delivered every 2 weeks in patients with severe hepatic dysfunction and resulted in adequate plasma concentrations. Paclitaxel at this dosage can be taken as an option for severe hepatic dysfunction patients who are expected to get clinical benefits from taxanes.

Abstract: The aim of the study was to investigate angiogenesis in patients with advanced-stage ovarian carcinoma. We used paraffin-embedded tumor tissues from 33 patients diagnosed with FIGO III ovarian cancer who had optimal surgery and received platinum-based chemotherapy. The tissue expression of CD34, vascular endothelial growth factor (VEGF), and thrombospondin-1 (TSP-1) was assessed immunohistochemically. CD34 stained hot spot areas were used to evaluate tumor microvessel density (MVD). VEGF and TSP-1 were assessed by semiquantitative methods. The studied molecules were investigated for relationship with standard clinicopathologic parameters. MVD count was high: median value of 39, range 12-143 microvessels/mm2. VEGF was present in all cases and stained strong in 91%. Stroma staining for TSP-1 was weak in 79% of the cases, strong in 6%, and absent in five (15%). We did not find correlations between the three studied markers and histologic type or tumor grade. MVD score did not relate to VEGF or TSP-1. We only observed a trend toward a longer survival in patients with tumors expressing high TSP-1 (60 vs. 36 months, P= 0.1). Proangiogenetic factor VEGF is highly expressed in advanced-stage ovarian carcinomas. The findings of this study may offer support for considering VEGF-targeted therapeutics in ovarian cancer treatment research.

Abstract: We present the case of a 35-year-old man with Crohn's disease diagnosed at the age of 27, several months after an operation for small-bowel adenocarcinoma. Seven years after the adenocarcinoma diagnosis, the patient presented with severe continuous anal pain and diarrhea. In parallel with antibiotic administration, the patient was given treatment with Infliximab, but without clinical symptom amelioration. Sigmoidoscopy and subsequent biopsies from an ulcerated rectal area supported the diagnosis of Epstein-Barr virus-positive (EBV+) primary Hodgkin's lymphoma. Infliximab administration was immediately discontinued and the patient underwent oncological follow-up and began a course of chemotherapy. Only a few cases with primary gastrointestinal Hodgkin's lymphoma in Crohn's disease patients have so far been reported, including a variety of scenarios on the causal relationship including disease duration, presence of EBV, long-term immunosuppressive treatment and, recently, anti-TNFalpha administration.

Abstract: Metallothioneins (MTs) are a family of cystein-rich metal-binding proteins, which are expressed in normal cells during fetal and postnatal life but also in a variety of human neoplasms. MT expression in human tumors has been linked to resistance to anticancer drugs and differentiation and progression in some types of tumors. This study examined the immunohistochemical expression of MTs in benign, borderline and malignant tumors of ovarian surface epithelium and the possible correlations with clinicopathological parameters and survival. A total of 87 cases with diagnosis of ovarian surface epithelial tumors were included. Specifically, 21 cases of benign cystadenomas (11 serous and 10 mucinous), 14 borderline (low malignant potential tumors, 8 mucinous and 6 serous) and 52 cases of ovarian cancer were analysed. Immunohistochemical expression of MT (cut-off level > 10% of tumor cells) was clearly associated with malignancy. A statistically significant correlation was found between the expression of MT in cancer cases and benign tumors (p < 0.0001) and cancer cases and borderline tumors p = 0.003. In cancer cases a difference was observed between grade I and III (p = 0.002). There was no correlation of MT overexpression with survival in the small number of ovarian carcinoma patients where it was analysed. MT constitutes a marker that characterizes aggressiveness and a high malignant potential in ovarian epithelial tumors. In diagnostic problems MT may help distinguish between benign, borderline and malignant tumors.

Abstract: To assess the safety and efficacy of a 3-day schedule of cisplatin and topotecan in patients with recurrent small-cell lung cancer (SCLC).

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Abstract: We performed a phase I study of two fixed dosing schemes of cisplatin, a DNA cross-linker, with intravenous escalating topotecan, a DNA-topoisomerase I inhibitor.

Abstract: The irinotecan-cisplatin combination has emerged as a new standard for the treatment of advanced-stage small-cell lung cancer (AS-SCLC). To move forward we developed a 3-day regimen of cisplatin, etoposide and irinotecan.

Abstract: Paclitaxel (Taxol) and carboplatin are an effective combination regimen for treating advanced breast cancer. Gefitinib (IRESSA) is the first epidermal growth factor receptor tyrosine kinase inhibitor to be approved for cancer treatment. This multicenter phase II trial treated 68 patients with advanced breast cancer with paclitaxel (175 mg/m(2) over 3 h) and 3-weekly carboplatin (area under the curve of 6) for six cycles, and 250 mg/day gefitinib orally. Median age was 57 (range 35-77) years, patients had performance status 0 (69.1%), 1 (27.9%) 2 (2.9%), 82.4% of patients had visceral metastases and 63.2% had received adjuvant chemotherapy. Forty-eight (70.6%) patients completed six cycles of chemotherapy and 20 (29.4%) patients discontinued treatment (seven [10.3%] due to disease progression, seven [10.3%] due to toxicity, five [7.4%] withdrew consent and one [1.5%] died after the first cycle). Sixty-three (92.7%) patients were evaluable for response; nine (13.2%) had complete responses, 30 (44.1%) had partial responses, 21 (30.9%) had stable disease and three (4.4%) had disease progression. Grade 3/4 adverse events in > or =5% of patients except of alopecia, included neutropenia (17.7%), anemia (10.3%), diarrhea (7.4%), thrombocytopenia (5.9%) and peripheral neuropathy (5.9%). Of those tumor biopsies available for immunohistochemical analysis (n=60), 5.0% were positive and 35.0% negative for expression of all HER-family receptors. Comparable numbers of tumor biopsies were nuclear p27(kipl) positive and negative (39.7 and 42.7%, respectively), with the majority (72.1%) negative for cytoplasmic p27(kipl). The observed efficacy data in this study were similar to those reported for the combination of paclitaxel and carboplatin alone.

Abstract: Therapeutic options for metastatic insular thyroid carcinoma (ITC) are very limited. We present the case of a 39-year-old woman with refractory metastatic ITC who responded to oxaliplatin plus irinotecan chemotherapy. She was initially diagnosed with a locally advanced and metastatic to lung ITC and underwent near-total thyroidectomy. After surgery she was treated and failed to respond first to radioiodine and subsequently to liposomal doxorubicin plus paclitaxel combination chemotherapy and was offered palliative external irradiation for metastases to bone and the brain. Eleven months postdiagnosis the patient became severely dyspnoic as a result of progression of lung metastases and elected to be treated with oxaliplatin plus irinotecan as a secondline chemotherapy. She experienced relief of her dyspnea shortly after treatment initiation and an objective response of her lung metastases was documented after the third course of treatment. Treatment continued for six cycles and tumor remission lasted for 5 months. Toxicity was mild. Confirmatory testing of oxaliplatin-irinotecan combination in case series or single cases of metastatic ITC is warranted.

Abstract: To evaluate the pharmacokinetics of imatinib mesylate (Glivec) and its main metabolite (CGP74588) in a patient with end stage renal disease on hemodialysis and compare it with published data from subjects with normal renal function.

Abstract: Mucinous epithelial ovarian cancer (mEOC) representing about 10% of all EOC are known to be possibly resistant to platinum-based chemotherapy and bear a poorer prognosis with respect to other subtypes of EOC. This study was undertaken to compare response and survival to platinum-based chemotherapy between patients with advanced stages III and IV mEOC and serous EOC (sEOC).

Abstract: This is a retrospective analysis of 150 patients with advanced non-small cell lung cancer who had failed prior treatment or were unfit for chemotherapy and were treated with oral gefitinib ('Iressa', ZD1839; AstraZeneca) 250 mg/day. Thirty-two patients who received gefitinib for 3 weeks or less were not included in the analysis. For the remaining 118 evaluable patients, the mean age was 63.1 years; most patients had received prior chemotherapy (97.5%), Eastern Cooperative Oncology Group performance status scores 0-2 (97.4%) and stage IV disease (64.4%). The majority were symptomatic (84.6%). Disease control was observed in 30 patients (25.4%), of whom five had a partial response and 25 had stable disease; 18 (15.3%) were not evaluable. Median duration of treatment was 29.9 weeks in responding patients and 11.5 in patients with progressive disease (p<0.0001). Median overall survival was 7.3 months (15.2 months for disease control) and median progression-free survival was 3.2 months. Gefitinib was well tolerated, with grade 3/4 skin rash and diarrhea seen in 2.5 and 4.2% of patients, respectively. Clinical benefit was evaluated using questionnaires before and following treatment with gefitinib. In 82 patients with completed questionnaires, evaluation revealed symptom improvement in 40.1% and improvement in general feeling in 31.4%. Epidermal growth factor receptor (EGFR) analysis found that efficacy did not correlate with tumor EGFR overexpression. Therefore, in this retrospective analysis, gefitinib treatment provided disease control in 25% of patients who derived significant palliative benefit.

Abstract: Hyponatremia is a common metabolic disorder in clinical practice and is associated with significant morbidity and mortality, especially among the elderly. Hyponatremia resulting from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has been reported in association with neoplasia (including a few reports in patients with head and neck malignancies) and may represent a paraneoplastic condition. Patients with SIADH present with signs and symptoms that cannot be explained by the primary tumour mass effect or its metastases. We describe a 67-year-old male patient with oral squamous-cell carcinoma of recent recurrence admitted because of symptomatic severe hyponatremia resulting from SIADH and discuss the principles of the diagnostic approach and appropriate management.

Abstract: The purpose was to study proteolysis-related molecules, matrix metalloproteinase-2 (MMP-2) and MMP-9 and tissue inhibitor of metalloproteinases-1 (TIMP-1), in carcinoma of unknown primary (CUP).

Abstract: Cancer of unknown primary remains a mallignancy of elusive biology and grim prognosis that lacks effective therapeutic options. We investigated angiogenesis in cancer of unknown primary to expand our knowledge on the biology of these tumors and identify potential therapeutic targets.

Abstract: Carcinoma of unknown primary (CUP) is characterized by dismal patient survival. The outcome of patients with two favourable risk CUP subsets was studied. Eighty patients diagnosed with either midline lymph node metastases (n=33) or peritoneal carcinomatosis (n=47) were analysed retrospectively. The majority had poorly differentiated adenocarcinoma or undifferentiated carcinoma, treated with platinum-taxane based chemotherapy from 1996 till 2002. Females with peritoneal carcinomatosis also underwent surgical debulking. Objective tumour regression was present in 44% of patients (nodal group 30% versus peritoneal group 53%, p=0.066). Complete responses were seen more often in peritoneal carcinomatosis patients (nodal group 9%, peritoneal group 36%, p=0.008). At a median follow up of 60 months, median progression-free and overall survival were 5 and 10 months respectively in the nodal group, 7 and 15 months in the peritoneal group. Five-year survival was 7% (nodal group 0% vs. peritoneal group 10%, p=0.05). Complete responders fared better than non-CR patients. Fewer than four metastatic sites, elevated CA 125, and normal CA 19-9 levels were favourable prognostic factors for survival. Modern combination chemotherapy has satisfactory activity, with a minority of CUP patients enjoying long-term responses. Research efforts towards complete remission consolidation and molecular profiling are imperative.

Abstract: The aim of this study was to explore the effect of dose-dense sequential chemotherapy with or without paclitaxel primarily on disease-free survival (DFS) and secondarily on overall survival (OS) in patients with high-risk operable breast cancer.

Abstract: Patients with resected breast carcinoma who received granulocyte-colony-stimulating factor (G-CSF)-supported adjuvant chemotherapy exhibited an increase in their serum CA 15-3 levels. The authors investigated the role of G-CSF-induced neutrophil MUC1 expression in this setting.

Abstract: Estrogen receptors (ER) are members of the nuclear receptor superfamily of ligand-activated transcription factors and mediate the effects of estrogen on target tissues. ERalpha was the first estrogen receptor to be characterized, and ERbeta was identified ten years later. The role of ERbeta in breast cancer pathobiology is largely unknown because specific antibodies have not been available until recently. The purpose of this study was to explore the expression of ERbeta in breast neoplasms and to correlate it with ERalpha and prognosis. ERa and ERbeta expression was monitored immunohistochemically in 59 breast carcinomas. We found no correlation between ERalpha and ERbeta expression, between ERbeta expression and the known prognostic indicators such as tumor size, grade or lymph node status, or between ERbeta expression and survival. Our findings contribute to the better understanding of the role of ERbeta in breast cancer.

Abstract: The current study was performed to study metastatic breast carcinoma that remains confined to bone.

Abstract: The most important cellular protective mechanisms against oxidative stress are antioxidant enzymes. Their action is based on decomposal of reactive oxygen species (ROS) and their transformation to H2O2. Within the mitochondria manganese superoxide dismutase (MnSOD) affords the major defense against ROS. In this study we investigated tissue sections from 101 breast carcinomas for the immunohistochemical expression of MnSOD protein and these results were assessed in relation to various clinicopathological parameters, in order to clarify the prognostic value of this enzyme. The possible relationship to hormone receptor content, anti-apoptotic protein bcl-2, p53 and cell proliferation was also estimated. High expression levels were observed, as 79/101 (78,2%) cases expressed strong immunoreactivity. In this study MnSOD increased in a direct relationship with tumor grade and is therefore inversely correlated with differentiation (p=0.0004). Furthermore, there was a strong positive correlation between MnSOD expression and p53 protein immunoreactivity (p=0.0029). The prognostic impact of MnSOD expression in determining the risk of recurrence and overall survival with both univariate (long-rang test) and multivariate (Cox regression) methods of analysis was statistically not significant. These results indicate that neoplastic cells in breast carcinomas retain their capability to produce MnSOD and thus protected from the possible cellular damage provoked by reactive oxygen species. In addition, MnSOD content varies according to the degree of differentiation of breast carcinoma.

Abstract: To investigate the pharmacokinetics of polyethylene glycol-coated liposomal doxorubicin (PLD, Caelyx) when given as a single agent and in combination with the taxanes paclitaxel or docetaxel in humans.

Abstract: The activity of glufosfamide (beta-D-glucosylisophosphoramide mustard) was tested in a multicentre phase II clinical trial in patients with advanced non-small cell lung cancer (NSCLC) who had received one prior line of platinum-based chemotherapy. Patients were treated with 5000 mg/m(2) glufosfamide by a 1-h intravenous (i.v.) infusion every 3 weeks following registration at the European Organisation for Research and Treatment of Cancer (EORTC) Data Center. Patients were randomised between hydration and no hydration to evaluate the nephroprotective effects of forced diuresis. Patients experiencing >/= 35 micromol/l increase of serum creatinine compared with baseline values were taken off the treatment. The Response evaluation criteria in solid tumours (RECIST) criteria were applied for the response assessment. Blood sampling was performed for a pharmacokinetic analysis. 39 patients from seven institutions were registered and a median of three cycles was given (range 0-6) cycles; 20 patients were randomised to the hydration arm. Haematological toxicity was mild, but treatment-related metabolic and electrolytic abnormalities and increases of serum creatinine occurred in several patients. Hydration did not have any significant influence on the plasma pharmacokinetics of glufosfamide and did not show any nephroprotective effect. Only one confirmed partial remission was observed (response rate 3%; 95% (Confidence Interval (CI) 0-14) and 18 cases with stable disease (49%) were recorded as assessed by an independent panel. Median survival of all patients treated was 5.8 months (95% CI 4.2-7.9). In conclusion, glufosfamide administered by a 1-h infusion every 3 weeks has modest activity in advanced NSCLC patients after one prior platinum-based chemotherapy.

Abstract: To compare survival between patients with advanced breast cancer (ABC) treated with epirubicin/paclitaxel (Taxol) or paclitaxel/carboplatin (Cp) chemotherapy.

Abstract: To investigate the role of CD44s in the biological behavior of surface epithelial ovarian tumors and its correlation with clinicopathological parameters, prognosis, p53, steroid receptor status and proliferative indices (PCNA, MIB1).

Abstract: We aimed to define the maximum tolerated dose (MTD) and characterize the toxicity of the combination of pegylated liposomal doxorubicin (PLD; Caelyx trade mark ) and weekly paclitaxel (wPTX), and to investigate pharmacokinetics of PLD in this combination.

Abstract: Syndecan-1, a cell surface proteoglycan found predominantly on epithelia of mature tissues, binds both extracellular matrix (ECM) components and basic fibroblast growth factor (bFGF) and is implicated in the restriction of growth and invasiveness of neoplastic cells, as it induces the adhesion capacity of neoplastic cells with the stroma. In this study we investigated breast carcinomas for the immunohistochemical expression of syndecan-1 protein and these results were assessed in relation to clinicopathological parameters, in order to clarify its prognostic value. The possible relationship with hormone receptors content, p53, cell proliferation markers, and extracellular matrix components was also estimated. Tissue sections from 102 breast carcinomas were used and immunostainings were performed on formalin-fixed, paraffin-embedded tissue sections by the labelled streptavidin avidin biotin (LSAB) method. High expression levels were observed, as 75/102 (73.5%) cases expressed immunoreactivity in more than 80% of neoplastic cells, while 67/102 (65.7%) exhibited high staining intensity. The survival analysis showed an increased mortality risk associated with high syndecan-1 staining intensity with borderline significance (p=0.041). In addition, there was a strong negative correlation between syndecan-1 protein expression and ECM, specifically collagen IV (p=0.026) and tenascin (p=0.0067). The results of the present study show the implication of this protein in the remodeling of breast cancer tissue, through the interaction with other extracellular matrix components, probably influences the tumour progression.

Abstract: To evaluate the efficacy and toxicity of the combination of vinorelbine and interleukin (IL)-2 in patients with metastatic melanoma as second-line chemotherapy.

Abstract: We developed a chemotherapy combination regimen based on preclinical data suggesting synchronization of cancer cells in G2/M phase when exposed to irinotecan over a protracted period. This phase I study aimed to determine the toxicity spectrum, and define the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended optimal dose (ROD) of irinotecan infused over 24 h and followed by a 1-h infusion of 30 mg/m2 docetaxel. Starting dose for irinotecan was 30 mg/m2 and escalation proceeded at 30 mg/m2 increments, in cohorts of three to six patients until the MTD was reached. A dose between the MTD and the previous level was explored to further define the ROD. Thirty-two patients with advanced refractory cancers (median age 64, 19 male) received 190 treatment courses at five dosing levels of irinotecan: 30 mg/m2 (n=6 patients), 60 (n=3), 90 (n=7), 120 (n=8) and 105 (n=8). The MTD and ROD was 120/30 and 105/30 mg/m2. DLTs were diarrhea and neutropenia. Antitumor activity was modest. The ROD of biweekly administration of 24-h irinotecan followed by 1-h docetaxel is 105 and 30 mg/m2, respectively. The low hematological toxicity and modest activity observed leave questions concerning the optimal timing of this combination.

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Abstract: The risk of secondary leukemia in breast cancer patients who receive adjuvant chemotherapy is an open question. We describe the case a 38-year-old woman who developed acute leukemia 18 months after completion of intense adjuvant chemotherapy with prophylactic granulocyte colony-stimulating factor (G-CSF) support and chest wall irradiation. The diagnosis of biphenotypic T-cell acute myeloid leukemia (AML) was based on morphologic and immunophenotypic criteria. Chromosomal analysis of blasts revealed multiple trisomies and tetrasomies. The patient failed to respond to induction and salvage chemotherapy and died 4 months later. This case of acute leukemia occurred in a cohort of 65 high-risk breast cancer patients who were given intense adjuvant chemotherapy during the last 5 years in our hospital. This is the first case reported in the literature of acute leukemia following intense adjuvant chemotherapy with continuous prophylactic G-CSF, which is an actively investigated therapeutic strategy. Vigilance and investigation are needed to determine the leukemogenic potential of intense adjuvant chemotherapy plus radiotherapy in breast cancer patients. A brief review of the literature that deals with acute leukemia that develops after adjuvant chemotherapy for breast cancer and with secondary biphenotypic acute leukemia is presented.

Abstract: Expression of the hormone-related proteins hsp27, pS2, and also of cathepsin D (CD) and metallothionein (MT) was studied by immunohistochemistry and analyzed against clinical data in breast cancer. Archived material of paraffin-embedded breast carcinoma tissues from a cohort of 134 patients with primary invasive breast cancer was used. Hsp27 and pS2 (>10% of tumor cells stained) were found to be expressed in 63.6% and 37.6% of cases, respectively, and were correlated negatively with grading (P=0.006 and 0.01) and positively with estrogen receptors (ER) (P=0.04 and 0.04). pS2 expression was correlated with lymph node status (P=0.02), tumor size (P=0.01), progesterone receptor (PR) content (P=0.02), hsp27 (P=0.015) and bcl-2 protein (P=0.001). An inverse relationship between pS2 expression and the expression of p53 protein (P=0.005) and proliferation-associated index MIB1 (P<0.0001) was noted. Stromal cathepsin D was positively correlated with tumor grade (P=0.01), PCNA (P=0.007), MIB1 (P=0.001) and p53 (P=0.01), and negatively with ER (P=0.04) and bcl-2 (P<0.0001). MT was correlated positively with stromal CD (P=0.007) and inversely with PgR (P=0.04). Univariate analysis showed CD expression to be a positive prognostic factor for survival (P=0.035), with borderline significance, while MT was more strongly positive (P=0.01). However, none of the proteins studied was found to be related to disease outcome in univariate analysis. Our data show that hsp27, pS2 and stromal CD expression may reflect tumor differentiation and the functional status of ER in breast cancer, but stromal CD and tumor MT expression were the only factors found that may be of limited prognostic value.

Abstract: Metastatic Cancer of Unknown Primary Site (CUP) accounts for approximately 3% of all malignant neoplasms and is therefore one of the 10 most frequent cancer diagnoses in man. Patients with CUP present with metastatic disease for which the site of origin cannot be identified at the time of diagnosis. It is now accepted that CUP represents a heterogeneous group of malignancies that share a unique clinical behaviour and, presumably, unique biology. The following clinicopathological entities have been recognised: (i) metastatic CUP primarily to the liver or to multiple sites, (ii) metastatic CUP to lymph nodes including the sub-sets involving primarily the mediastinal-retroperitoneal, the axillary, the cervical or the inguinal nodes, (iii) metastatic CUP of peritoneal cavity including the peritoneal papillary serous carcinomatosis in females and the peritoneal non-papillary carcinomatosis in males or females, (iv) metastatic CUP to the lungs with parenchymal metastases or isolated malignant pleural effusion, (v) metastatic CUP to the bones, (vi) metastatic CUP to the brain, (vii) metastatic neuroendocrine carcinomas and (viii) metastatic melanoma of an unknown primary. Extensive work-up with specific pathology investigations (immunohistochemistry, electron microscopy, molecular diagnosis) and modern imaging technology (computed tomography (CT), mammography, Positron Emission Tomography (PET) scan) have resulted in some improvements in diagnosis; however, the primary site remains unknown in most patients, even on autopsy. The most frequently detected primaries are carcinomas hidden in the lung or pancreas. Several favourable sub-sets of CUP have been identified, which are responsive to systemic chemotherapy and/or locoregional treatment. Identification and treatment of these patients is of paramount importance. The considered responsive sub-sets to platinum-based chemotherapy are the poorly differentiated carcinomas involving the mediastinal-retroperitoneal nodes, the peritoneal papillary serous adenocarcinomatosis in females and the poorly differentiated neuroendocrine carcinomas. Other tumours successfully managed by locoregional treatment with surgery and/or irradiation are the metastatic adenocarcinoma of isolated axillary nodes, metastatic squamous cell carcinoma of cervical nodes, or any other single metastatic site. Empirical chemotherapy benefits some of the patients who do not fit into any favourable sub-set, and should be considered in patients with a good performance status.

Abstract: The aim of this study was to present the Ioannina Radiation Therapy Department experience in the treatment of postoperative recurrent prostate cancer with postoperative external beam radiotherapy (EBRT) in initially low-risk patients for recurrence.

Abstract: The activity of glufosfamide (beta-D-glucopyranosyl-N,N'-di-(2-chloroethyl)-phosphoric acid diamide) against pancreatic cancer was investigated in a multicentre, phase II clinical study. Chemotherapy-nai;ve patients with advanced or metastatic disease were treated with glufosfamide (5 g/m(2)) using a 1-h intravenous (i.v.) infusion every 3 weeks. Patients were randomised between active-hydration and normal fluids to evaluate the nephroprotective effect of forced diuresis. Patients experiencing >0.4 mg/dl (>35 micromol/l) increase in serum creatinine compared with their baseline value were taken off treatment for safety reasons. The evaluation of response was according to the Response evaluation criteria in solid tumours (RECIST). Blood sampling was performed for pharmacokinetic analyses. 35 patients from 13 institutions were registered over a 13-month period. A total of 114 treatment cycles (median 3, range 1-8) were administered to 34 patients; 18 patients were allocated to the hydration arm. Overall haematological toxicity was mild. Metabolic acidosis occurred in 2 patients treated in the active-hydration arm, grade 3 hypokalaemia was recorded in 5 patients and grade 3 hypophosphataemia in 4 patients. One patient had a grade 4 increase in serum creatinine level, concomitantly to disease progression. Active-hydration did not show a nephroprotective effect and the plasma pharmacokinetics (Pk) of glufosfamide was not significantly influenced by hydration. Two confirmed partial remissions (PR) were reported (response rate 5.9%, 95% Confidence Interval (CI) 0.7-19.7%) and 11 cases obtained disease stabilisation (32.4%). An extra mural review panel confirmed all of the responses. Median overall survival was 5.3 months (95% CI 3.9-7.1) and time to progression (TTP) was 1.4 months (95% CI 1.3-2.7). In conclusion, glufosfamide administered using a 1-h infusion every 3 weeks has a modest activity in advanced pancreatic adenocarcinoma. Haematological toxicity is particularly mild, but regular monitoring of renal function is recommended.

Abstract: Taxane-based chemotherapy has shown activity but also toxicity when administered at standard doses in patients with hormone-resistant prostate cancer (HRPC). In this pilot study, we investigated biweekly low-dose docetaxel in patients with HRPC as a convenient regimen with low toxicity. Sixteen patients with metastatic HRPC entered the study. Median age was 73 years, median performance status (PS) was 2, and median Gleason score was 9. All patients had undergone and failed combined androgen-blockade therapy (luteinizing hormone-releasing hormone analogue plus antiandrogen) for their metastatic disease; 3 had also been treated with mitoxantrone. Treatment consisted of docetaxel 30 mg/m2 administered every 2 weeks. Prostate-specific antigen (PSA) response, characterized by a 50% decrease of PSA level confirmed 4 weeks later, was the primary endpoint. Durations of PSA response and toxicity assessment were secondary endpoints. A total of 136 biweekly docetaxel doses were administered, with a median of 8.5 doses per patient (range, 2-24). Six patients (38%; 95% confidence interval, 25%-43%) fulfilled the criteria of PSA response. Median duration of PSA response was 4.5 months (range, 3-12). Toxicity was negligible: myelotoxicity was practically absent, whereas 3 patients developed grade 1 alopecia and 1 patient developed dacryorrhea. We conclude that our study provides evidence that biweekly docetaxel at 30 mg/m2 can be considered an effective nontoxic therapeutic option for patients with HRPC. Confirmation of these preliminary data in larger-scale trials is justified

Abstract: The number of agents that are active in patients with metastatic melanoma is limited and cure is not a realistic objective for treatment at this stage. The aim of the study was to evaluate the efficacy and safety of new combination regimen cosisting of docetaxel and dacarbazine (DTIC), as first-line chemotherapy, in patients with advanced melanoma.

Abstract: We characterized the toxicity and determined the maximum tolerated dose of non-break weekly paclitaxel (Taxol) in chemotherapy-naive cancer patients, and studied pharmacokinetics of the formulation vehicle Cremophor-EL with this schedule. Twenty-three patients with primary refractory solid tumors received weekly paclitaxel at the dose range of 70-200 mg/m2. As dose-limiting toxicity we defined granulocytopenia grade > or =2 causing a treatment delay for more than 2 weeks, or febrile neutropenia or grade >2 organ-specific toxicity. Plasma kinetics of Cremophor-EL were analyzed over the first five courses of treatment. Non-break weekly paclitaxel was feasible at doses up to 110 mg/m2, while granulocytopenia precluded scheduled administration of doses > or =130 mg/m2. Clinically relevant peripheral neurotoxicity tended to occur at around 1500 mg/m2 cumulative dosage at weekly doses > or =110 mg/m2. Detectable Cremophor-EL levels were found in all pre-dose samples, but there was no evidence of accumulation up to the sixth course. Our results, discussed in the light of an overview of published data, suggest that chronic weekly administration of paclitaxel is feasible and with a lack of significant accumulation of Cremophor-EL levels at doses up to 90 mg/m2.

Abstract: The immunohistochemical expression of the extracellular matrix (ECM) components tenascin (TN), fibronectin (FN), collagen type IV (Coll) and laminin (LN), and their possible relationships were studied in a series of 134 operable breast cancer cases. Their expression was also compared with the expression of the proteolytic enzyme cathepsin D (CD), the adhesion molecule CD44 standard form (CD44s) and other known factors to clarify the prognostic value and role of these molecules in tumour progression and metastasis. TN expression in the tumour stroma was positively correlated with tumour grade and size, CD44s expression, tumour and stromal CD expression as well as with FN, laminin and Coll expression in the same areas. TN expression was inverse correlated with ER status. Its expression at the invasion front was only positively correlated with the lymph node status. Survival analysis showed an increased mortality risk associated with high levels of TN expression. In multivariate analysis, among the ECM proteins, only TN expression was independently correlated with patients' survival. FN expression was positively correlated with lymph node involvement, with the proliferation-associated index Ki-67 and stromal CD expression. Survival analysis showed an increased mortality risk associated with a high level of FN expression. Coll expression was positively correlated with the tumour size and LN expression. An inverse relationship of Coll expression with ER and PgR receptor status was also found. LN expression was positively correlated with tumour and stromal CD expression, with the proliferation-associated index Ki-67 and inversely with ER receptor status. The observed alterations in the expression of ECM proteins in breast cancer tissue and their correlations with the proteolytic enzyme CD and the adhesion molecule CD44s, suggest an involvement in cancer progression. In addition, overexpression of stromal TN and FN seems to have negative prognostic value in breast cancer patients.

Abstract: Invasive thymoma is a rare mediastinal tumor. Clinicopathological characteristics that influence survival of patients with this tumor are under debate. Treatment is based on tumor resection. The benefice of therapies, such as radiation therapy (RT) and/or chemotherapy (CT) as adjuvant treatments to surgery, or palliative therapy to unresectable or recurrent thymoma are discussed.

Abstract: Noncardiogenic pulmonary edema (NCPE) is a rare and less well-recognizable pulmonotoxic syndrome of anticancer therapy than pneumonitis/fibrosis. NCPE is a clinical syndrome characterized by simultaneous presence of severe hypoxemia, bilateral alveolar infiltrates on chest radiograph, and no evidence of left atrial hypertension/congestive heart failure. The diagnosis of drug-related NCPE relies upon documented exclusion of any infectious, metabolic, or cancer-related causes. The time proximity to therapy with drugs that are known to precipitate NCPE, any preceding episodes of flu-like symptoms during previous chemotherapy courses and possible response to corticosteroids may further support such a diagnosis. Cancer therapeutic agents clearly associated with NCPE are cytarabine, gemcitabine, and interleukin-2, as well as all-trans retinoic acid in acute promyelocytic leukemia patients, while a few other compounds have rarely or occasionally been implicated. The pathophysiology of lung injury in drug-induced NCPE remains unclear. There are indications suggesting that both a direct cytotoxic insult to the lung epithelial cells and induction of a cytokine-triggered inflammatory response may be involved in its pathogenesis. By distinction to drug-induced pulmonary pneumonitis that may lead to permanent pulmonary fibrosis, NCPE if not fatal, can be reversed upon prompt recognition, following immediate discontinuation of the offensive drug and start of intensive supportive treatment and intravenous corticosteroids.

Abstract: We evaluated the efficacy and tolerance of the combination of docetaxel and vinorelbine as first line treatment in metastatic breast cancer (MBC). These agents have different mechanisms of action and both are active in advanced breast cancer. Thirty-nine chemotherapy-naive for metastatic disease patients were treated on an out-patient basis with vinorelbine 20 mg/m2 i.v. on days 1 and 8 and docetaxel 85 mg/m2 i.v. on day 8, every 3 weeks. Twenty-one (53.8%) patients had locoregional disease, 30 (76.9%) had distant metastases and 20 (51.3%) had visceral metastases. The intent-to-treat objective response rate (RR) was 48.75% (19 out of 39 patients; 95% confidence interval (CI), 32.4% to 65.2%). Four patients (10.25%) achieved a complete response (CR) (95% CI, 2.9% to 24.2%) and 15 (38.5%) a partial response (PR) (95% CI, 23.4% to 55.4%). The median duration of response was 4 months, the median time to progression (TTP) was 6 months and the median survival-time was 11.3 months. Grade 3 and/or 4 (3/4) anemia and thrombocytopenia occurred in 7.7% and 5.1% of patients, respectively. Twelve (30.7%) patients developed grade 3/4 neutropenia and 7 (17.9 %) were complicated with fever. Grade 3/4 diarrhea, nausea-vomiting, fatigue and constipation were not a problem. Alopecia was universal. Grade 3/4 neurotoxicity was evident in 2.6% of patients. None of the patients developed allergic reaction or fluid retention. There was one treatment-related death due to grade 4 neutropenia and sepsis. CONCLUSION: This combination of docetaxel and vinorelbine, a non-anthracycline-containing regimen, is a moderately effective regimen for the treatment of chemotherapy-naive breast cancer patients with metastases, causing only mild to moderate toxicity.

Abstract: Cancer antigen 15-3 (CA 15-3), a circulating marker that determines secreted products of the polymorphic MUC1 gene, has been established as a convenient tool for monitoring breast carcinoma patients.

Abstract: The clinical relevance of quantitative assessment of tumor-tissue expression of the bcl-2 protein in operated stage II breast cancer was investigated in this study. Thirty-five cases were studied by immunohistochemistry for the expression of bcl-2 protein and analyzed for disease outcome. One fourth (25%) of the cases were negative and 57% demonstrated near-absolute expression of the bcl-2 protein. No association was found between immunohistochemical detection of the protein with age, hormonal receptor status and tumor grading other than between bcl-2 and estrogen receptor expression (p=0.01). An impressively positive impact of near-absolute expression of bcl-2 on clinical outcome was identified. Our results provide evidence that quantitative assessment of bcl-2 expression constitutes a new approach in early breast cancer with potential clinical implications. We consider that molecular sub-staging of patients with stage II breast cancer by level of bcl-2 expression provides additional important prognostic information and prompts for investigation of its clinical significance on the issue of adjuvant systemic therapy.

Abstract: Long-term cancer survivors are at increased risk for the development of second primary malignancies. This is usually associated with common genetic and etiologic factors and the treatment modality used for the primary cancer. In this paper we describe the case of a patient who developed a leiomyosarcoma in his left arm 5 years after he had a colon adenocarcinoma resected. Both primary tumours were treated successfully with surgical resection alone. The literature regarding second primary neoplasms, specifically focused on sarcomas, is briefly reviewed.

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Abstract: To evaluate the efficacy of the carboplatin/paclitaxel combination in patients with carcinoma of unknown primary site (CUP).

Abstract: To determine the maximum-tolerated dose (MTD), the principal toxicities, and the pharmacokinetics of 6-hour infusion of glufosfamide (beta-D-glucosylisophosphoramide mustard; D-19575), a novel alkylating agent with the potential to target the glucose transporter system.

Abstract: Several cancer therapeutic agents have been associated with pulmonary toxicity. Herein, we describe the case of a 73-year-old woman with breast cancer metastatic to the liver, who developed noncardiogenic pulmonary edema (NPE) while on treatment with gemcitabine plus docetaxel combination with granulocyte colony-stimulating factor (G-CSF) support. Gemcitabine, a deoxycytidine analogue, is reported to produce mild self-limiting and only occasionally severe pulmonary toxicity. The microtubule stabilizer docetaxel has been associated with water retention complications. The combination of these two agents has shown promising activity in several solid tumors and is in a phase of clinical development with prophylactic G-CSF in most of the trials due to the high rate of dose-limiting neutropenia observed with this combination. In our case pulmonary toxicity resolved rapidly following the administration of corticosteroids. A possible deleterious synergy of the compounds involved in this case is discussed and the medical literature on NPE related to cancer therapy is shortly reviewed. We conclude that NPE should always be considered in patients with respiratory function deterioration while on therapy with the gemcitabine-docetaxel combination and G-CSF. Corticosteroids can provide maximum benefit if started early upon diagnosis coupled with withdrawal of the causative drugs.

Abstract: Randomized studies have shown that postoperative chemotherapy with or without radiation therapy (RT) improved local control and survival of patients with stages II or III rectal cancer. However, the optimal sequence of treatments and the optimal chemotherapeutic regimen have not been defined. Modulation of fluorouracil (FU) by leucovorin (LV) has yielded a highly significant difference in response rate from that of FU monotherapy, as suggested by an overview of randomized trials in patients with advanced colorectal cancer. However, this difference in response rate did not translate into a survival benefit.

Abstract: Docetaxel is an agent with impressive clinical activity but a rather poor profile of toxicity when given every three weeks. Therefore, optimisation of its clinical use is highly warranted. This is a dose-escalation study of weekly docetaxel particularly focused on the feasibility of long-term administration and characterisation of cumulative toxicity.

Abstract: The encouraging results that have been reported for cisplatin combination chemotherapy in a minority of patients with cancer of unknown primary (CUP) together with the previously shown equal activity of carboplatin in this setting, prompted us to investigate the effectiveness of a carboplatin-containing regimen in a phase II clinical trial. Sixty-two evaluable CUP patients entered the protocol. The chemotherapy regimen consisted of carboplatin 300 mg/m2 IV D1, epirubicin 45 mg/m2 IV D1 and etoposide 120 mg/m2 IV D1-3 (CEE regimen) administered every 3 weeks. The median age of the patients was 61 years and 36 were male. Thirty-one diagnosed as poorly differentiated carcinomas (pdc) and the rest as adenocarcinomas. By clinicopathological criteria, 14 patients had a predominately nodal disease with pdc or poorly differentiated adenocarcinomas (pda), 3 women peritoneal carcinomatosis, and the remaining 46 patients had a predominately splanchnic involvement (24 pdc, 22 pda). Twenty-three patients responded to chemotherapy with 4 (6.5%) complete and 19 (30.5%) partial responders (RR 37%, 95% CI 25-49%). An equal activity of the regimen was observed between the two major histopathological types, the pdc and the adenocarcinomas. Nevertheless, significant differences were seen when the CEE regimen was assessed for its activity in the distinct clinicopathological subsets of CUP. Patients with predominately nodal disease of midline distribution with pdc or pda, and women with peritoneal carcinomatosis, achieved a response rate of 64 and 62% respectively, as compared with a 26% response rate for those with predominately splanchnic involvement. Overall median survival was 10 months and for patients with midline distribution 15 months. The regimen was well tolerated. It is concluded that CEE is a relatively nontoxic chemotherapy regimen and easily administered on an outpatient basis. This prospective phase II study confirmed the activity of carboplatin in the chemosensitive subsets of the predominately nodal disease of midline distribution and peritoneal carcinomatosis in women in the CUP syndrome.

Abstract: Six patients with multiple myeloma (MM) and a second non-hematological neoplasm (solid tumor) are documented in this study. Two patients had a previous history of adenocarcinoma of the colon prior to MM diagnosis; in three patients a second neoplasm (lung cancer, adenocarcinoma of the urinary bladder and adenocarcinoma of the colon) appeared at the time of MM diagnosis; one patient, a woman with a six-year history of MM, developed hepatoma. The two patients who had had a neoplasm of the colon ten years before and the patient with bladder carcinoma, responded to MM therapy. The patient with lung cancer and the patient with adenocarcinoma of the colon died; the last patient, with MM and liver cancer, is alive but with aggressive disease. In conclusion we have found that in MM patients a second neoplasm may develop or co-exist, in greater frequency than that of the general population.

Abstract: We have previously shown that metastatic carcinomas of unknown primary site overexpress several tumor markers as well as the products of the oncogenes c-myc, ras and c-erbB2. We analyzed the tissue expression of the protein products of the apoptosis modulation genes p53 and bcl-2 in 47 CUP cases. Formalin-fixed, paraffin embedded tumor specimens were stained with commercially available antibodies to p53 (DO7) and bcl-2 after antigen retrieval by the microwave method. Staining was evaluated by intensity (1+ to 3+), percentage of positive cells (1-100%), and the 'intensity times percentage' product defined as the immunoreactivity index with values ranging from 0 to 300. Immunoreactivity index values higher than 150 were considered to characterize protein over-expression. Expression of p53 was identified in 70.2% of tumors while 53% of them showed a high immunoreactivity index. Bcl-2 expression was detected in 65% of tumors and overexpressed in 40%. Overexpression of both proteins was detected in 20% of tumors. The detection of either protein was not associated with any of the major clinicopathological variables studied. Nevertheless, a trend towards a more favourable response to platin based chemotherapy was seen in the cases that showed a strong expression of both proteins, when analysed by immunoreactivity index and percentage of positive cells. We conclude that CUP overexpress at a high percentage the p53 and the bcl2 proteins. The observed weak association of strong expression of these proteins with response to platin-based chemotherapy deserves further evaluation in the CUP setting.

Abstract: About 3% of all cancer patients suffer from cancer of unknown primary origin. These patients present with metastatic disease for which a primary site cannot be detected at the time of diagnosis. Sophisticated diagnostic techniques and operational procedures have failed to improve the diagnostic efficacy in this group of patients. Consequently, a limited diagnostic procedure with basic laboratory tests and imaging studies is sufficient for the diagnosis of this syndrome. The use of immunohistochemistry, as well as serum tumor markers of high specificity that may help to identify other tumors, is highly suggested. Although the prognosis for the majority of these patients still remains poor, several subsets of favorable outcome to treatment have been recognized. Nevertheless, promising in vitro data and new drugs on trials, paralleled with a better knowledge of the underlying pathogenetic molecular mechanisms, offer a more optimistic look to the future therapeutic management of these patients.

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Abstract: 37 patients with advanced breast cancer resistant to anthracyclines were treated with paclitaxel 200 mg/m2 by 3-h infusion and carboplatin at an area under the curve of 7 mg.min/ml every 4 weeks with G-CSF support. There were 5 (14%, 95% CI 3-25%) complete and 11 (30%, 95% CI 15-45%) partial responders. Median duration of response was 11.5 months (range 5.2-16.8+), median time to progression 8 months (range 0.26-16.8+) and median survival 12 months (range 0.5-19.6+). Grade 3-4 leucopenia (27%), thrombocytopenia (10%) and diarrhoea (5%) were noted. In conclusion, the combination of paclitaxel and carboplatin is active and well tolerated in patients with advanced breast cancer resistant to anthracyclines.

Abstract: To evaluate the impact on the response rate in patients with advanced breast cancer (ABC) of the doubling of the dose intensity (DI) of epirubicin monotherapy.

Abstract: Paclitaxel has been demonstrated to have significant activity in recurrent or metastatic head and neck cancer (HNC). In addition, the combination of paclitaxel and cisplatin is active in untreated patients with inoperable HNC. Substitution of carboplatin for cisplatin allows the treatment to be delivered on an outpatient basis.

Abstract: The orally administered tubulin-binding agent 1069C85 was developed with the hope of overcoming the multidrug resistance associated with existing anti-tubulin agents, such as the vinca alkaloids. A phase I study was performed using a single oral dose every 3 weeks, administered as a suspension reconstituted in 0.1% Tween 80 and 0.9% saline. The starting dose was 2.8 mg m-2, and dose doubling was permitted until the area under curve (AUC) was > or = 40% of that at the mouse LD10; thereafter, a modified Fibonacci scheme was used. The formulation proved to be unsatisfactory, resulting in inconsistent absorption. The terminal elimination half-life was prolonged (range 18-73.5 h). Sporadic central neurotoxicity was observed, which was grade 3 in one patient treated at 200 mg m-2. A revised formulation with micronized drug was more easily suspended and appeared to increase the bioavailability by a factor of 2-4. Severe central neurotoxicity, up to grade 4, was then observed at doses of 50-100 mg m-2. Unfortunately, toxicity was not predictable and one patient, with a previous history of partial intestinal obstruction, treated at 50 mg m-2, cleared the drug very slowly, possibly because of prolonged, delayed absorption. This patient died from pancytopenia and severe gastrointestinal damage. It was concluded that such unpredictable behaviour would be incompatible with safe evaluation in phase II studies; the trial was closed and further clinical development abandoned.

Abstract: PURPOSE: To investigate if double modulation of fluorouracil (5-FU) with leucovorin (folinic acid [FA]) and interferon alfa-2b (IFN 2b) improves responses and survival in comparison to single modulation of 5-FU with FA. PATIENTS AND METHODS: One hundred six patients with histologically confirmed advanced colorectal cancer, measurable disease, and without previous chemotherapy were prospectively randomized into two groups. Patients in group A received 5-FU 450 mg/m2 as an intravenous bolus in the midinfusion of FA weekly. FA was given at a dose of 200 mg/m2 in 500 mL 0.9% normal saline solution in 2-hour infusion. Patients in group B received exactly the same regimen plus IFN 2b 5 million units subcutaneously three times weekly. RESULTS: All patients were well balanced in both groups regarding age, sex, performance status, number, and site of metastasis. One hundred two patients were assessable. All patients have died. There was no difference in response between the two groups (7.8% v 9.8%). Median survival was 10.1 months in group A, and 7.2 months in group B (P = .00189). Median time to progression was 8.4 and 5.2 months, respectively (P = .00196). Overall, better performance status and older age had a positive impact on survival. Toxicity was the most important and catastrophic aspect of this study. Patients who received IFN 2b had significantly worse anemia, neutropenia, diarrhea, anorexia, weight loss, flu-like syndrome, and psychological reactions. CONCLUSION: Based on this final analysis, the addition of IFN 2b to the combination of 5-FU and FA enhances toxicity and contributes to decreased survival.

Abstract: The role of oncogenes in carcinoma of unknown primary site (CUP) has not yet been elucidated. In the present study the expression of the c-myc p62, ras p21 and c-erB-2 p185 oncoproteins were studied by a 3-step immunoperoxidase technique in 26 cases of CUP. Positive immunoreactivity was observed in 96% of the cases for c-myc, 92% for ras and in 65% for c-erb-2, with at least half of tumor cells labelled in 85%, 92% and 58% respectively. The degree of staining intensity was considered moderate or strong in more than half of the cases for all oncogene products. In conclusion, our results showed that patients with CUP have an extremely high overexpression of all three oncogenes studied. Nevertheless, the biological role of these overexpressed oncoproteins, their relationship with different histological or clinical parameters and their diagnostic or prognostic value need further evaluation.

Abstract: The risk and the type of second malignancies (SM) developing in 217 treated Hodgkin's disease (HD) patients were studied. The median age of the patients was 35 years (range 14-83) and the M/F ratio 1.8. Treatment consisted of radiotherapy alone (24 patients, 11%), chemotherapy alone (96 patients, 44.3%), or a combination of both modalities (43 patients, 19.8%), while 54 patients (24.9%) received salvage treatment. The median follow-up time was 67 months (range 12-224). Ten patients developed a SM with a 5-year and 10-year actuarial risk of 3.3% and 5.4%, respectively. There were 3 cases of ANLL and MDS (actuarial risk of 2.4% at 6 years), 1 case of non-Hodgkin's lymphoma and 6 cases of solid tumors (actuarial risk of 2.4% at 6 years). The risk of developing SM was higher in males and older patients (> 40 years). SM represent a serious late side effect of successful treatment for HD. The possibility of developing a SM must be taken into consideration in the initial treatment of the disease.

Abstract: From June 1985 to March 1993, 20 consecutive patients with histologically proven malignant mesothelioma were treated with cisplatin 100 mg/m2 i.v. infusion on day 1 and vinblastine 6 mg/m2 i.v. on day 1 and 8. Treatment was repeated every 4 weeks until progression. All patients were evaluated clinically and by CT-scan and were staged (Stage IV), according to Butchard's criteria, on entry to the study. None had prior surgical excision. Eighty-one chemotherapy cycles were administered to 20 patients. One complete response, four partial responses, nine stable diseases and six progressions were noted. One partial responder entered complete response following an operation. Toxicity was acceptable and no treatment-related deaths occurred. The median survival for responders was 19.3 months; for patients with stable disease 15.7 months and for non-responders, 5.2 months. The mean duration of response was 13 months. We conclude that for this small group of patients, the combination cisplatin-vinblastine is effective, with acceptable toxicity in malignant mesothelioma. Further study with a larger number of patients is necessary.

Abstract: The current study has prospectively investigated the incidence and course of ocular toxicity after low-dose tamoxifen treatment. Sixty-three patients with cancer who could be examined were analyzed. Tamoxifen was administered on a 20-mg daily dose. Median duration of treatment was 25 months. Median total tamoxifen dose was 14.4 gr. Four patients had retinopathy and/or keratopathy 10, 27, 31, and 35 months, respectively, after tamoxifen initiation (an incidence of 6.3%). Ophthalmologic findings consisted of decreased visual acuity, bilateral macular edema, yellow-white dots in the paramacular and fovea areas in all patients as well as corneal opacities in one patient. After tamoxifen withdrawal almost all ocular abnormalities were found to be reversible, except for the retinal opacities. This is the first prospective study in the literature indicating that even conventional low-dose tamoxifen treatment can induce ocular toxicity. In addition, the authors review and discuss the literature of the last decades.

Abstract: