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As part of its mission to promote the best surgical care for cancer patients, the European Society of Surgical Oncology (ESSO) has been developing multiple programmes for clinical research along with its educational portfolio. This position paper describes the different research activities of the Society over the past decade and an action plan for the upcoming five years to lead innovative and high quality surgical oncology research. ESSO proposes to consider pragmatic research methodologies as a complement to randomised clinical trials (RCT), advocates for increased funding and operational support in conducting research and aims to enable young surgeons to be active in research and establish partnerships for translational research activities.

Georgios D Lianos,1 Konstantinos Vlachos,2 Odysseas Zoras,3 Christos Katsios,1 William C Cho,4 Dimitrios H Roukos11Centre for Biosystems and Genomic Network Medicine, Ioannina University, Ioannina, Greece; 2Department of Surgery, Ioannina University Hospital, Ioannina, Greece; 3Department of Surgical Oncology, Heraklion University Hospital, Crete, Greece; 4Department of Clinical Oncology, Queen Elizabeth Hospital, Hong KongAbstract: Progress in the treatment of cancer over the past decade has been slow. Targeting a mutated gene of an individual patient tumor, tumor-guided agents, and the first draft of the human genome sequence have created an overenthusiasm to achieve personalized medicine. However, we now know that this effort is misleading. Extreme interpatient and intratumor heterogeneity, scarce knowledge in how genome-wide mutational landscape and epigenetic changes affect transcriptional processes, gene expression, signaling transduction networks and cell regulation, and clinical assessment of temporary efficacy of targeted drugs explain the limitations of these currently available agents. Trastuzumab and a few other monoclonal antibodies or small-molecule tyrosine kinase inhibitors (TKIs) represent an exception to this rule. By blocking ligand-binding receptor in patients with human epidermal growth factor receptor 2 (HER2) amplification and overexpression, trastuzumab added to chemotherapy in HER2-positive patients has been proven to provide significant overall survival benefit in both metastatic and adjuvant settings. Lapatinib, a small-molecule dual inhibitor (TKI) of both HER2 and EGFR (epidermal growth factor receptor) pathways, has an antitumor activity translated into progression-free survival benefit in HER2-positive metastatic patients previously treated with a taxane, an anthracycline, and trastuzumab. Despite these advances, ~25% of patients with HER2-positive breast cancer experience recurrence in the adjuvant setting, while in the metastatic setting, median survival time is 25 months. In this review, we discuss the safety, efficacy, and limitations of the trastuzumab emtansine (T-DM1) conjugate in the treatment of HER2-positive metastatic breast cancer. We also highlight Phase III randomized trials, currently underway, using either the T-DM1 conjugate or various combinations of monoclonal antibodies and TKIs. Moreover, in contrast with all these agents developed on the basis of “central dogma” of simplified reductionist transcription and single gene–phenotype linear relationship, we summarize the emerging, amazing era of next-generation, transcriptional circuitry and intracellular signaling network-based drugs guided by the latest advances in genome science and dynamics of network biology.Keywords: trastuzumab emtansine, T-DM1, HER2 disease, targeted agents, cancer, genome, monoclonal antibodies

Item does not contain fulltext Desmoid tumor, or aggressive fibromatosis, is a rare, histologically benign, fibroblastic lesion that infrequently presents in the head and neck. Desmoid tumors often grow locally, invasively, and may, in rare instances, be fatal secondary to invasion into critical structures, such as airway or major vessels. The most common treatment is surgery, but desmoid tumors are characteristically associated with a high local recurrence rate after resection. Although the margin status seems to be of importance, operations that avoid function loss and esthetic disfigurement should be the primary goal. The efficacy of postoperative radiotherapy is controversial. Its potential benefit should be carefully balanced against possible radiation-induced adverse effects. Alternative treatment modalities, such as primary radiotherapy and medical treatment or a wait-and-see policy, may be preferable to mutilating surgery. Considering all the aforementioned, it seems obvious that desmoid tumors of the head and neck present a therapeutic challenge and require an individualized approach. (c) 2014 Wiley Periodicals, Inc. Head Neck, 36: 1517-1526, 2014.

Background: Although recent evidence has implicated viruses in the regulation of epithelial-to-mesenchymal transition and tumor progression, little is known regarding viral infections in thyroid malignancies. Thus the aim of this study was to detect sequences of 3 potentially oncogenic viruses – BK virus (BKV), Epstein-Barr virus (EBV) and human papillomavirus (HPV) – in a series of postoperative thyroid gland specimens. Methods: Thirty patients with thyroid nodules who underwent surgery for thyroid disease within a 3-year period were enrolled. Both nodular and adjacent normal thyroid tissue was surgically excised from each patient. Viral gene sequences of BKV (VP1), EBV (LMP1, EBNA2 and EBER1) and HPV were amplified by PCR. The PCR results were confirmed by direct sequencing analysis. Results: VP1 gene sequences were detected in 60% (18/30) of thyroid cancer or multinodular hyperplasia lesions compared with in 43.3% (13/30) of adjacent normal thyroid tissue specimens. Fifteen of thirty (50%) of thyroid cancer or multinodular hyperplasia samples revealed LMP1 sequences compared with 46.7% (14/30) of corresponding normal thyroid tissues. EBNA2 gene sequences were detected in 90% (27/30) of thyroid cancer or multinodular hyperplasia samples, compared with 90% (27/30) of adjacent normal thyroid tissue specimens. All samples were negative for EBER1 sequences, while HPV DNA was not detected in either nodular or normal thyroid tissue. Conclusions: This study suggests that BKV and EBV “infection” is an early event, occurring within normal tissue. Our findings do not show a clear role for the viruses examined, instead they suggest an “endemicity” pattern rather than a causal effect. © 2014 Wichtig Publishing - eISSN 1724-6008.

Background: Ten years after the first complete human genome sequencing, next-generation sequencing (NGS) technology has revolutionized genomics and biomedical research. Here we discuss potential emerging and future applications of NGS platforms and how cancer genome advances may change current surgical oncology practice. Materials and Methods: Publications in PubMed with partial or complete human and cancer genome sequencing over the last decade have been retrieved and analyzed. Recently launched international large-scale consortiums for systematic study of causal (driver) mutations underlying common complex diseases such as cancer and more recent opinion articles by leading scientists have been considered to predict the prospects of integration genomics data into surgical oncology. Results: Two dozen complete human genome sequences, and three full-genome sequencing in three cancer patients have recently been published. These studies and other cancer genome systematic studies evaluating genomic rearrangements and copy-number changes consistently reveal that cancer initiation and metastasis are much more complex than we thought. This high complexity and widespread variability of cancer genes, mutations, and deregulated signaling pathways among patients with the same cancer type, tumor stage, and clinicopathologic features explains the limited effectiveness of currently used biologically targeted agents. Conclusions: Yet the impact of genomics explosion in surgical oncology is little. Nevertheless, "big" biology consortiums such as the International Cancer Genome Project and other systematic studies in the areas of genetics, genomics, and epigenetics are now providing in-depth understanding of cancer, and shape new more rational ways towards novel therapeutics for improving oncologic outcomes of millions of patients worldwide. At the beginning of the second post-genomic decade, an explosion in genomic technology has revolutionized biomedical sciences. The ability of latest DNA sequencing technology to identify, in an unprecedented level, causal mutations driving cancer initiation and metastasis raises significant expectations for improving oncologic outcomes. Which are the challenges and perspectives to translate this genomic revolution into a surgical oncology-changing era? © 2012 Elsevier Inc. All rights reserved.

Expert Rev Anticancer Ther

BACKGROUND: Image analysis of tissue sections using RGB image profiling is a modern accepted technique. MATERIALS AND METHODS: A new method of RGB analysis, using the freeware ImageJ, is presented which can be applied to sections with either nuclear or cytoplasmic staining. The step-by-step process is presented and the method is tested using breast cancer specimens immunostained for CK-19 and estrogen receptors. RESULTS: This image analysis easily discriminates CK-19 and estrogen receptor positivity in prepared breast cancer specimens. The method is easy to perform, without the need for previous image transformations. CONCLUSION: Compared to previous methods, this method proved more accurate in estimating the actual colours that an observer recognizes as positive after immunostaining. Further studies are needed to evaluate whether this method is efficient enough to be applied in clinical practice. Anticancer Research

Actinic keratosis (AK) is a well-established pre-cancerous skin lesion that has the potential to progress to squamous cell carcinoma (SCC). We investigated the involvement of the CDKN2A, CDKN2B and p53 genes in AK and in the progression of AK to SCC. Mutational analysis on exons 1a, 1b and 2 of the CDKN2A locus and exon I of the CDKN2B locus as well as allelic imbalance was performed in 26 AK specimens. Expression levels of the genes p14(ARF), p15(INK4b), p16(INK4a) and p53 were examined in 16 AKs and 12 SCCs by real-time RT-PCR. A previously described polymorphism of p16(INK4a) (Ala148Thr) was detected at an allelic frequency of 12%. Six samples carried novel mutations at codon 71 of the CDKN2A locus and one sample presented an additional mutation at codon 65. Two AK samples carried a not-previously described non-UV type missense mutation at codon 184 (Val184Glu) of exon 1b in the p14(ARF) gene. Regarding the CDKN2B locus a new mutation at codon 50 (Ala50Thr) and another at codon 24 (Arg24Arg), were detected. Microsatellite instability (MSI) was found in 15% of AKs in at least one marker, indicating that genetic instability has some implication in the development of AK. Down-regulation of p16(INK4a) and p53 mRNA levels was noted in SCC compared to AK. TSGs expression levels in sun-exposed morphologically normal-appearing skin, suggests that abnormal growth stimuli might exist in these tissues as well. Furthermore, we suggest a possible role of p15(INK4b), independently from the intracellular pathway mediated by p16(INK4a), and of p14(ARF) in AK development, as well as in the progression of AK to SCC. The deregulation of the expression profiles of the CDKN2A, CDKN2B and p53 genes may, independently of mutations and LOH at 9p21, play a significant role in AK and progression of AK to SCC. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Background: The RAS/RAF/MEK/MAP kinase pathway is essential to intracellular signaling transduction regulating cell proliferation, differentiation and death. We investigated the occurrence of exon 15 BRAF and KRAS codon 12 mutations among Greek patients with colorectal cancer. Methods: Sixty-one samples from patients with sporadic colorectal adenocarcinomas were studied for exon 15 BRAF mutations. DNA from surgically resected specimens was analyzed by a combination of polymerase chain reaction and direct sequencing. KRAS codon 12 mutational analysis was technically possible in 58 samples (58/61) by a combination of polymerase chain reaction and restriction fragment length polymorphism. Results: No exon 15 BRAF mutations were detected in any of the colon cancer specimens. The frequency of KRAS codon 12 mutations was 29.3% (17/ 58). Patients aged ≤570 years more frequently presented carcinomas harboring KRAS codon 12 mutations than patients aged >70 years (p=0.028). Patients between 61 and 70 years of age were more likely to be carriers of this mutation (p=0.040). Conclusions: Despite the limited study sample, our data suggest that BRAF mutations might be present less frequently than KRAS mutations in Greek patients with colorectal carcinomas. Further research involving larger patient series will be necessary to confirm these findings and to assess possible ethnic, environmental and lifestyle influences on BRAF and KRAS mutagenesis. © 2007 Wichtig Editore.

In this study the EA.hy 926 endothelial cell line-simulating endothelial cells-was treated with imatinib in order to define a possible anti-angiogenic role for imatinib. Dose and time response experiments were performed. Cell morphology was studied, while migration efficiency, intercellular permeability and VE-cadherin expression were assayed, both in the presence and in the absence of imatinib. Imatinib-induced EA.hy 926 cell apoptosis was also examined. Results showed that imatinib reduced the endothelial cell population, changed cell monolayer morphology and reduced cell-to-cell cohesiveness. Migration efficiency was significantly decreased while intercellular permeability was 2.76-fold increased in the presence of imatinib. Indirect immunofluorescence microscopy showed nearly complete down-regulation of VE cadherin in imatinib-treated cells. Furthermore, apoptotic activity was detected in imatinib-treated cells. Altogether our results support an antiangiogenic profile for imatinib that possibly contributes to its therapeutic potential. © E.S.I.F.T. srl.

Background Nonmelanoma skin cancers [squamous cell carcinomas (SCC) and basal cell carcinomas (BCC)] are the most common neoplasias of the Caucasian population. Objectives The purpose of our study was to determine the involvement of CDKN2A genes in the development of sporadic nonmelanoma skin cancer in Greek patients. Patients and methods Allelic imbalance analysis was performed in 22 SCC and five Bowen’s disease specimens. Mutational analysis was performed on exons 1alpha, 1beta and 2 of the CDKN2A locus in 22 SCC, five Bowen’s disease and 39 BCC specimens. Exon 1alpha was additionally screened in 28 BCC specimens to complete the mutational analysis of a previous study. Results Overall, 52% (14 of 27) of the SCC and Bowen’s disease specimens exhibited loss of heterozygosity (LOH) in at least one microsatellite marker, whereas, only two of 27 (7%) exhibited microsatellite instability. LOH in 9p appears to be equally involved in both BCC and SCC tumours. Exons 1alpha, 1beta and 2 of the CDKN2A locus were screened for mutations. A Val28Gly substitution in exon 1alpha and a CCC–>TTT (Ala57Val and Arg58Ter) substitution in exon 2, resulting in a change in the amino acid sequence, are reported for the first time in two SCCs, the latter being indicative of a combination of an ultraviolet (UV) radiation-induced mutation and a point mutation. A previously described polymorphism of CDKN2A, the gene for p16(INK4a) , Ala148Thr, was also detected in an allelic frequency of 3.72%. No mutation was found in any of the five Bowen’s disease specimens, or in exon 1beta of CDKN2A , also the gene for p14(ARF) . Conclusions Mutations and the high incidence of 9p LOH detected in our SCC samples imply that inactivation of CDKN2A genes, via allelic loss and/or mutation (probably UV-induced) may play a significant role in nonmelanoma skin cancer development, particularly in the more aggressive SCC type.

Basal cell carcinoma of the skin is the most common neoplasia in humans. Previous studies have shown the existence of allelic imbalance (loss of heterozygosity and microsatellite instability) in BCC on several human chromosomes. Chromosome region 9p21-p22 harbors the CDKN2a/16(INK4a), p19(ARF), and p15(INK4b) tumor suppressor genes. To determine the contribution of these genes to the development of basal cell carcinomas we looked for evidence of allelic imbalance in 67 sporadic basal cell carcinoma specimens from Greek patients and screened 28 of them presenting loss of heterozygosity at 9p21-p22 for germline mutations in p16(INK4a) and p19(ARF) genes. Chromosome regions 17q21 and 17p13 were also screened for allelic imbalance in all the 67 basal cell carcinoma specimens. Overall, 69% (46 of 67) of the specimens displayed loss of heterozygosity in at least one microsatellite marker, whereas only six of the 67 (9%) exhibited microsatellite instability. For the 9p21-p22 locus the overall frequency of loss of heterozygosity reached 55% (37 of 67) and is the highest reported. The overall frequency of loss of heterozygosity for the 17q21 locus is 34% (22 of 64) and for the 17p13 locus is 11% (seven of 65). Two of the 28 loss of heterozygosity positive cases were heterozygous for a previously described polymorphism, Ala148Thr, in exon 2 of the CDKN2a gene. This is the first demonstration of polymorphism in the CDKN2a gene in human basal cell carcinomas. No sequence variation in exon 1 beta of the p19(ARF) gene was found. Our results provide evidence of a significantly high occurrence of loss of heterozygosity for the 9p21-p22 locus; however, lack of p16(INK4a)/p19(ARF) mutation suggests that these genes seem not to be implicated by mutational inactivation in the development of basal cell carcinoma. Other(s), yet unidentified, tumor suppressor gene(s) located in this locus may be related to this specific type of skin cancer.

Despite considerable improvement in the management of colon cancer, there is a great deal of variation in the outcomes among European countries, and in particular among different hospital centers in Greece and Cyprus. Discrepancy in the approach strategies and lack of adherence to guidelines for the management of colon cancer may explain the situation. The aim was to elaborate a consensus on the multidisciplinary management of colon cancer, based on European guidelines (ESMO and EURECCA), and also taking into account local special characteristics of our healthcare system. Following discussion and online communication among members of an executive team, a consensus was developed. Statements entered the Delphi voting system on two rounds to achieve consensus by multidisciplinary international experts. Statements with an agreement rate of ≥80% achieved a large consensus, while those with an agreement rate of 60-80% a moderate consensus. Statements achieving an agreement of

To study the relationship between the expressions of Ki-67, WT p53, Bcl-2 proteins and tumor grade, on fine needle aspiration biopsies (FNABs), in patients with invasive ductal breast carcinomas. One hundred (100) FNABs were performed from the same number of female patients, diagnosed cytologically and confirmed histologically after oncectomy. The same cases were studied immunocytochemically using the monoclonal antibodies Ki-67, WT p53 and Bcl-2 by the alkaline phosphatase (APAAP) method and correlated to the nuclear and histological grade of the tumors. An association and a relationship was found between the grade of the tumors and the immunoexpression of Ki-67, WT p53 and Bcl-2 proteins (p0.005). The relationship between Ki-67, WT p53 and Bcl-2 proteins and the grade of the invasive ductal breast carcinomas seems to be a significant prognostic factor and should be kept in mind in follow-up patients after previous treatment for breast cancer.