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Abstract: After more than 30 years of clinical and translational research, and having contributed to large randomized international clinical trials in gynecologic cancer, the multidisciplinary EORTC Gynecologic Cancer Group (GCG) currently is dealing with one of the greatest challenges in cancer research, which is to discover and establish clinically useful predictive and prognostic factors, to identify subgroups of patients based on genomic patterns and activated pathways and to design clinical trials appropriate for such subgroups. EORTC GCG current and future research has to include the validation of prognostic and predictive markers, the identification of novel therapies that target specific pathways, and a better understanding of the molecular basis for resistance. These studies will require the collection of large numbers of biologic specimens, both at time of diagnosis and at time of recurrence and, whenever possible, during treatment. These objectives can only be reached with transversal cooperation within the EORTC framework (Pathobiology group, Imaging group, etc.), as well as international cooperation. Support from private industry will also be important in the context of a high-standard cooperation among industry and academia. The EORTC with its unique multidisciplinary infrastructure and long experience in cancer research is taking part through the EORTC GCG in international networks focused on gynecological cancer research on a large scale. Intergroup collaboration and international contribution to establish the current and future world-wide standards of care is also a priority for the GCG. The GCG also has a good track record in rare tumors and will continue working on rare diseases along with international partners. [Copyright &y& Elsevier]

Abstract: Genital tract neoplasms account for approximately 10% of female cancers and are the fourth cause of death after lung, breast and colon malignancies. Cancer prevention, early diagnosis, adequate management, with an eventually tailored treatment can improve both survival and quality of life in patients affected by gynecologic cancers. We will focus attention on the main aspects of epidemiology, prevention, diagnosis and treatment of the major gynecological neoplasms: ovarian, cervical and endometrial cancer. An overview of current treatment regimens and their evolution is provided, with particular emphasis on the interdependence of surgery and chemotherapy in the optimal management of these diseases. Attention is also focused on novel biomarkers, new preventive anticancer vaccinations and new molecular targeted treatments with a view to future developments. [Copyright &y& Elsevier]

Objective: Kallikrein 10 is a secreted serine protease recently implicated in the growth and invasion of several human tumors. The goal of this study was to investigate the expression and secretion levels in vitro and in vivo of kallikrein 10 in uterine serous papillary carcinoma, a highly aggressive variant of endometrial tumor. Study design: Human kallikrein 10 gene expression levels were evaluated in 11 snap-frozen uterine serous papillary carcinoma biopsies and 6 normal endometrial cell biopsies by real-time polymerase chain reaction. Secretion of kallikrein 10 protein by 10 primary tumor cultures including 3 uterine serous papillary carcinomas, 2 endometrioid carcinomas, and 5 ovarian serous papillary tumors was measured using a sensitive ELISA. Finally, kallikrein 10 concentration in 75 serum and plasma samples from 22 healthy women, 20 women with benign diseases, 21 women with endometrioid carcinomas, and 12 uterine serous papillary carcinoma patients was studied. Results: Kallikrein 10 gene expression levels were significantly higher in uterine serous papillary carcinoma when compared with normal endometrial cell biopsies (mean copy number by real time polymerase chain reaction = 743 versus 1.4; uterine serous papillary carcinoma versus endometrioid carcinoma: P < .02). In vitro kallikrein 10 secretion was detected in all primary uterine serous papillary carcinoma cell lines tested (mean = 2.7 μg/L), and the secretion levels were not significantly different to those found in primary ovarian serous papillary tumor cultures (mean 4.2 μg/L), in contrast, no kallikrein 10 secretion was detectable in primary endometrioid carcinomas. Kallikrein 10 serum and plasma concentrations (μg/L; mean ± SEM) among normal healthy females (0.6 ± 0.04), patients with benign diseases (0.6 ± 0.06), and patients with endometrioid carcinomas (0.7 ± 0.06) were not significantly different. In contrast, serum and plasma kallikrein 10 values in uterine serous papillary carcinoma patients (1.2 ± 0.1) were significantly higher than those in the non-cancer group (P = .002), benign group (P = .002), and endometrioid carcinoma patients (P = .005). Conclusion: Kallikrein 10 is highly expressed in uterine serous papillary carcinoma, and it is released in the plasma and serum of uterine serous papillary carcinoma patients. Kallikrein 10 may represent a novel biomarker for uterine serous papillary carcinoma. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Clear cell carcinoma of the ovary is a distinct subtype of epithelial cancer associated with chemoresistance and poor outcome compared with serous papillary carcinomas. Resistance to paclitaxel has been linked to serous papillary overexpression of class III β-tubulin in several human cancers but inadequately characterized among clear cell carcinoma of the ovary. Chemoresistance has also been variably linked to the drug efflux pump p-glycoprotein. Epothilones are microtubule-stabilizing agents with putative activity in paclitaxel-resistant malignancies. In this study, we clarify the relationship between class III β-tubulin and p-glycoprotein expression in clear cell carcinoma of the ovary, clinical outcome, and in vitro responsiveness to patupilone and paclitaxel. STUDY DESIGN: Class III β-tubulin and p-glycoprotein were quantified by real time polymerase chain reaction in 61 fresh-frozen tissue samples and 11 cell lines. Expression by polymerase chain reaction was correlated with immunohistochemistry and overall survival. IC50 was determined using viability/metabolic assays. Impact of class III β-tubulin down-regulation on IC50 was assessed with small interfering RNAs, RESULTS: Clear cell carcinoma of the ovary overexpressed class III β-tubulin and p-glycoprotein relative to serous papillary carcinomas carcinomas in fresh-frozen tissues and cell lines. Class III β-tubulin immunohistochemistry reflected real time polymerase chain reaction results and overexpression stratified patients by overall survival, P-glycoprotein correlated with in vitro paclitaxel resistance, but not clinical outcome. Clear cell carcinoma of the ovary were exquisitely sensitive to patupilone in a manner that correlated with class III β-tubulin expression. CONCLUSION: Class III β-tubulin overexpression in clear cell carcinoma of the ovary discriminates poor prognosis, serves as a marker for sensitivity to patupilone, and may contribute to paclitaxel resistance. Immunohistochemistry reliably identifies tumors with overexpression of class III β-tubulin, and accordingly a subset of individuals likely to respond to patupilone. [ABSTRACT FROM AUTHOR]

The author sought t0 identity metastasis-associated genes In ovarian serious papillary carcinomas as groundwork for the development of more effective treatment modalities than are article currently. [ABSTRACT FROM PUBLISHER]

Objective: To evaluate PIK3CA mutational status and c-erbB2 gene amplification in a series of primary uterine serous carcinomas (USC) cell lines. To assess the efficacy of GDC-0980, a potent inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2), against primary USC harboring HER2/neu gene amplification and/or PIK3CA mutations. Study Design: Twenty-two primary USC cell lines were evaluated for c-erbB2 oncogene amplification by fluorescence in situ hybridization (FISH) assays and for PIK3CA gene mutations by direct DNA sequencing of exons 9 and 20. In vitro sensitivity to GDC-0980 was evaluated by flow-cytometry-based viability and proliferation assays. Downstream cellular responses to GDC-0980 were assessed by measuring phosphorylation of the 4-EBP1 protein by flow-cytometry. Results: Five of 22 (22.7%) USC cell lines contained oncogenic PIK3CA mutations although 9 (40.9%) harbored c-erbB2 gene amplification by FISH. GDC-0980 caused a strong differential growth inhibition in FISH+ USC when compared with FISH− (GDC-0980 IC50 mean ± SEM = 0.29 ± 0.05 μM in FISH+ vs 1.09 ± 0.20 μM in FISH− tumors, P = .02). FISH+ USC harboring PIK3CA mutations were significantly more sensitive to GDC-0980 exposure when compared with USC cell lines harboring wild-type PIK3CA (P = .03). GDC-0980 growth-inhibition was associated with a significant and dose-dependent decline in phosphorylated 4-EBP1 levels. Conclusion: Oncogenic PIK3CA mutations and c-erbB2 gene amplification may represent biomarkers to identify patients harboring USC who may benefit most from the use of GDC-0980. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Clear cell carcinoma of the ovary is a distinct subtype of epithelial cancer associated with chemoresistance and poor outcome compared with serous papillary carcinomas. Resistance to paclitaxel has been linked to serous papillary overexpression of class III [beta]-tubulin in several human cancers but inadequately characterized among clear cell carcinoma of the ovary. Chemoresistance has also been variably linked to the drug efflux pump p-glycoprotein. Epothilones are microtubule-stabilizing agents with putative activity in paclitaxel-resistant malignancies. In this study, we clarify the relationship between class III [beta]-tubulin and p-glycoprotein expression in clear cell carcinoma of the ovary, clinical outcome, and in vitro responsiveness to patupilone and paclitaxel. STUDY DESIGN: Class III [beta]-tubulin and p-glycoprotein were quantified by real time polymerase chain reaction in 61 fresh-frozen tissue samples and 11 cell lines. Expression by polymerase chain reaction was correlated with immunohistochemistry and overall survival. IC50 was determined using viability/metabolic assays. Impact of class III [beta]-tubulin down-regulation on IC50 was assessed with small interfering RNAs. RESULTS: Clear cell carcinoma of the ovary overexpressed class III [beta]-tubulin and p-glycoprotein relative to serous papillary carcinomas carcinomas in fresh-frozen tissues and cell lines. Class III [beta]-tubulin immunohistochemistry reflected real time polymerase chain reaction results and overexpression stratified patients by overall survival. P-glycoprotein correlated with in vitro paclitaxel resistance, but not clinical outcome. Clear cell carcinoma of the ovary were exquisitely sensitive to patupilone in a manner that correlated with class III [beta]-tubulin expression. CONCLUSION: Class III [beta]-tubulin overexpression in clear cell carcinoma of the ovary discriminates poor prognosis, serves as a marker for sensitivity to patupilone, and may contribute to paclitaxel resistance. Immunohistochemistry reliably identifies tumors with overexpression of class III [beta]-tubulin, and accordingly a subset of individuals likely to respond to patupilone. [ABSTRACT FROM AUTHOR]

Objective: We evaluated the expression of human trophoblast cell-surface marker (Trop-2) and the potential of hRS7, a humanized monoclonal anti-Trop-2 antibody, against treatment-refractory cervical cancer. Study Design: Trop-2 expression was evaluated by immunohistochemistry, real-time polymerase chain reaction, and flow cytometry. Sensitivity to hRS7 antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity was tested in 5-hour chromium release assays. The effect of interleukin (IL)-2 on hRS7 ADCC was also investigated. Results: Membrane Trop-2 expression was observed in 8 of 8 (100%) of the cancer samples tested by immunohistochemistry, but not in normal cervix. High messenger RNA expression by real-time polymerase chain reaction and high Trop-2 surface expression by flow cytometry were detected in 80% of cervical cancers (4 of 5 cell lines). Although these tumors were resistant to natural killer cell–dependent cytotoxicity in vitro (mean killing, 6.0%), Trop-2-positive cell lines showed high sensitivity to hRS7 ADCC (range of killing, 30.6–73.2%). Incubation with IL-2 further increased the level of cytotoxicity against Trop-2-positive tumors. Conclusion: hRS7 may represent a novel treatment option for patients with cervical cancer refractory to conventional treatment modalities. [ABSTRACT FROM AUTHOR]

Objective: We evaluated the expression of epithelial cell adhesion molecule (EpCAM) and the potential of MT201 (adecatumumab), a human-monoclonal-antibody that targets EpCAM against chemotherapy-resistant ovarian disease. Study Design: EpCAM expression was evaluated by real-time polymerase chain reaction and flow cytometry. Sensitivity to MT201 antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity was tested in 4-hour chromium-release assays. The effect of interleukin-2 on MT201 ADCC was also studied. Results: High messenger RNA expression by real-time polymerase chain reaction and high EpCAM surface expression by flow cytometry was detected in 71% of ovarian cancers (5 of 7 cell lines). Although these cell lines were highly resistant to complement-dependent cytotoxicity and natural killer-dependent cytotoxicity in vitro (range of killing, 0–7%), EpCAM-positive cell lines showed high sensitivity to MT201 ADCC (range of killing, 27–66%). Incubation with interleukin-2 further increased the cytotoxic activity against EpCAM-positive ovarian cancer cell lines. Conclusion: MT201 may represent a novel, potentially highly effective treatment option for patients with ovarian carcinoma whose body is harboring disease refractory to chemotherapy. [Copyright &y& Elsevier]

Objective: The purpose of this study was to develop and characterize a human antibody in a single-chain antibody fragment format (scFv) that is directed specifically against claudin-3 (CLDN3). Study Design: The synthetic ETH-2 Gold human antibody phage display library was used to select scFv specific against CLDN3. scFv binding properties were analyzed by surface plasmon resonance; specificity was confirmed with enzyme-linked immunosorbent assay, immunofluorescence, and flow cytometry on a panel of ovarian and uterine serous carcinoma cell lines. Results: Surface plasmon resonance studies indicated scFv H6 to be the clone with the highest affinity against CLDN3 (KD of 23.60 nmol/L). scFv H6 efficiently stained CLDN3-expressing cells and recognized its epitope in enzyme-linked immunosorbent assay that was performed with uterine serous papillary carcinoma native protein extract, which suggested that a conformational epitope is recognized by this antibody. Cell surface immunofluorescence with laser scanning confocal microscopy confirmed the specific binding to the native membrane CLDN3. Conclusion: scFv H6 may represent a novel antitumor agent against chemotherapy-resistant ovarian and serous papillary carcinomas and other human malignancies that overexpress CLDN3. [Copyright &y& Elsevier]

Objective: To identify potential immunogenic peptides derived from CA125. Study Design: A bioinformatics approach was used to identify peptides derived from CA125 that bind to human leukocyte antigen A2.1 and elicit peptide-specific human cytotoxic T-lymphocyte responses in healthy individuals and patients with ovarian carcinoma. Results: CD8+ cytotoxic T-lymphocyte populations generated against 4 CA125-derived peptides were able to induce lysis of autologous peptide-loaded target cells. CA125 YTLDrDSLYV peptide-specific cytotoxic T lymphocytes were found to effectively kill ovarian tumors expressing CA125. Cytotoxicity was inhibited by antihuman leukocyte antigen A2.1 (BB7-2) and antihuman leukocyte antigen class I (W6/32) antibodies, whereas natural killer-sensitive targets were not lysed. YTLDrDSLYV peptide-specific cytotoxic T lymphocyte precursor frequency was low in peripheral blood leukocytes of normal donors and patients with ovarian cancer as determined by interferon-gamma production in ELISPOT assays. Intracellular cytokine expression measured by flow cytometry showed a type 1 cytokine profile in YTLDrDSLYV peptide-specific cytotoxic T lymphocytes. Conclusion: The CA125 YTLDrDSLYV peptide is an immunogenic epitope and may represent an attractive target for immunotherapy of ovarian cancer. [Copyright &y& Elsevier]

Background In older adults co-occurrence of multiple diseases often leads to use of multiple medications (polypharmacy). The aim of the present study is to describe how prescription of medications varies across age groups, with specific focus on the oldest old. Methods We performed a cross-sectional study using 2013 data from the OsMed Health-DB database (mean number of medicines and defined daily doses prescribed in 15,931,642 individuals). There were 3,378,725 individuals age 65 years or older (21.2% of the study sample). Results The mean number of prescribed medications progressively rose from 1.9 in the age group <65 years to 7.4 in the age group 80–84 years and then declined, with a more marked reduction in the age group 95 years or older with a mean number of 2.8 medications. A similar pattern was observed for the mean number of defined daily doses. Among participants age ≥65 years, proton pump inhibitors were the most commonly prescribed medication (40.9% of individuals ≥65 years), followed by platelet aggregation inhibitors (32.8%) and hydroxy-methylglutaryl-coenzyme A reductase inhibitors (26.1%). A decline in prescription was observed among individuals age 90 years or older, but this reduction was less consistent for medications used to treat acute conditions (ie, antibiotics and glucocorticoids) rather than preventive medicines commonly used to treat chronic diseases (ie, antihypertensive medications and hydroxy-methylglutaryl-coenzyme A reductase inhibitors). Conclusions The burden of medication treatment progressively increases till age 85 and substantially declines after age of 90 years. Patterns of medication prescription widely vary across age groups. [ABSTRACT FROM AUTHOR]

Background The story of Human Papillomavirus vaccination demands reflection not only for its public health impact on the prophylactic management of HPV disease, but also for its relevant economic and social outcomes. Greater than ever data confirm the efficacy and support the urge for effective vaccination plans for both genders before sexual debut. Methods A review of previous experience in gender-restricted vaccination programs has demonstrated a lower effectiveness. Limiting vaccination to women might increase the psychological burden on women by confirming a perceived inequality between genders; and even if all women were immunized, the HPV chain of transmission would still be maintained through men. Results The cost-effectiveness of including boys into HPV vaccination programs should be re-assessed in view of the progressive drop of the economic burden of HPV-related diseases in men and women due to universal vaccination. The cost of the remarkable increase in anal and oropharyngeal HPV driven cancers in both sexes has been grossly underestimated or ignored. Conclusions Steps must be taken by relevant bodies to achieve the target of universal vaccination. The analysis of HPV vaccination's clinical effectiveness vs. economic efficacy are supportive of the economic sustainability of vaccination programs both in women and men. In Europe, these achievements demand urgent attention to the social equity for both genders in healthcare. There is sufficient ethical, scientific, strategic and economic evidence to urge the European Community to develop and implement a coordinated and comprehensive strategy aimed at both genders and geographically balanced, to eradicate cervical cancer and other diseases caused by HPV in Europe. Policymakers must take into consideration effective vaccination programs in the prevention of cancers. [ABSTRACT FROM AUTHOR]

Background: Prognostic factors currently available are insufficient to predict the clinical course of epithelial ovarian cancer (EOC). In a previous microarray study we identified the human trophoblast cell surface antigen Trop-2 as one of the top differentially expressed genes in serous papillary EOCs compared to normal human ovarian surface epithelial (HOSE) short-term cultures. The aim of the present investigation was to analyse Trop-2 expression at mRNA and protein level and to assess its prognostic significance in EOC. Methods: Using quantitative real-time PCR we tested a total of 104 fresh-frozen EOC tissues and 24 HOSE for Trop-2 mRNA expression. Trop-2 protein expression was then examined by immunohistochemistry in matched formalin-fixed paraffin-embedded EOC samples and in 13 normal ovaries. Finally, we correlated Trop-2 expression to EOC conventional clinicopathological features and patient outcomes. Results: We found a significant Trop-2 mRNA and protein upregulation in EOCs compared to normal controls (p <0.001). Trop-2 protein overexpression was significantly associated with the presence of ascites (p =0.04) and lymph node metastases (p =0.04). By univariate survival analysis, Trop-2 protein overexpression was significantly associated with decreased progression-free (p =0.02) and overall survival (p =0.01). Importantly, Trop-2 protein overexpression was an independent prognostic marker for shortened survival time in multivariate Cox regression analysis (p =0.04, HR=2.35, CI95% =1.03–5.34). Conclusions: Our results indicate, for the first time, that Trop-2 protein overexpression correlates with an aggressive malignant phenotype and may constitute a novel prognostic factor for EOC. The targeting of Trop-2 overexpression by immunotherapeutic strategies may represent an attractive and potentially effective approach in patients harbouring EOC. [Copyright &y& Elsevier]

Purpose: To analyze prospectively the effects of blood transfusion administered during radiotherapy (RT) on the immune function of patients with locally advanced cervical cancer.Methods and Materials: In a total of 15 patients, 7 transfused and 8 untransfused, lymphocyte populations, including CD3+, CD4+, and CD8+ T-cell subsets, B cells (CD19+), and natural killer (NK) cells (CD56+, CD16+, CD3−) were studied before (i.e., time 0), during (i.e., times 1 and 2), and after (i.e., time 3) therapy. Expression of the early (CD25) and late (HLA-DR) activation markers on CD3+ T cells, the intracellular levels of perforin in CD8+ and CD56+ cells, and interferon (IFN)-γ, interleukin (IL)-2, and IL-4 in CD4+ and CD8+ T cells were also measured. NK cell cytotoxicity against the NK-sensitive target K-562 cells and CD8+ T-cell-directed cytotoxicity against OKT3 hybridoma cells were also assessed. Finally, the plasma levels of the immunoregulatory cytokine IL-10 were analyzed by enzyme-linked immunosorbent assay.Results: The mean absolute number of all lymphocyte subsets compared with pretreatment levels decreased significantly during RT of both transfused and untransfused patients (p >0.001), with no detectable differences between the two groups in terms of total lymphocytes or relative numbers of CD3+ and CD4+ T cells, CD56+ NK cells, or CD19+ B cells. In contrast, concomitant with an inversion of the CD4/CD8 ratio, a significant increase in the number of CD8+ T cells at time 2 and CD3+ T cells, CD8+ T cells, and NK cells at time 3 was found in the transfused patients compared with the untransfused group. The percentages of CD25+/CD3+ T cells and HLA-DR+/CD3+ T cells increased during RT of the untransfused patients, but CD3+ T cells showed decreased CD25 expression and increased HLA-DR expression in the transfused group. An increase of CD8+ IFN-γ+ T cells with a concomitant decrease in CD8+ IL-2+ T cells was found in the transfused vs. untransfused group, and no differences were noted in the percentage of CD4+ IFN-γ+ T cells and CD4+ IL-2+ T cells. The proportion of perforin-positive CD8+ and CD56+ cells was higher in the transfused group than in the untransfused group. However, CD56+ cells and CD8+ T cells from the transfused patients showed markedly diminished cytotoxic function. Finally, IL-10 was detected only in the plasma of the transfused patients.Conclusion: Blood transfusion during primary RT for cervical cancer profoundly alters the magnitude and characteristics of radiation-induced immunosuppression. Elevated serum IL-10 in transfused patients may play a role in the disregulation of lymphocyte function, in particular, the depression of NK- and T-cell cytotoxicity. Investigation of alternatives to blood transfusion during RT that do not diminish host immunity is warranted. [Copyright &y& Elsevier]

Research on multimorbidity has rapidly increased in the last decade, but evidence on the effectiveness of interventions to improve outcomes in patients with multimorbidity is limited. The European Commission is co-funding a large collaborative project named Joint Action on Chronic Diseases and Promoting Healthy Ageing across the Life Cycle (JA-CHRODIS) in the context of the 2nd EU Health Programme 2008–2013. The present manuscript summarizes first results of the JA-CHRODIS, focuses on the identification of a population with multimorbidity who has a high or very high care demand. Identification of characteristics of multimorbid patients associated with a high rate of resource consumption and negative health outcomes is necessary to define a target population who can benefit from interventions. Indeed, multimorbidity alone cannot explain the complexity of care needs and further, stratification of the general population based on care needs is necessary for allocating resources and developing personalized, cost-efficient, and patient-centered care plans. Based on analyses of large databases from European countries a profile of the most care-demanding patients with multimorbidity is defined. Several factors associated with adverse health outcomes and resource consumption among patients with multimorbidity were identified in these analyses, including disease patterns, physical function, mental health, and socioeconomic status. These results underline that a global assessment is needed to identify patients with multimorbidity who are at risk of negative health outcomes and that a comprehensive approach, targeting not only diseases, but also social, cognitive, and functional problems should be adopted for these patients. [ABSTRACT FROM AUTHOR]

Abstract: In Italy, prescription drug costs represent approximately 17% of total public health expenditures. Older adults commonly use multiple drugs and, for this reason, this population is responsible for a large portion of drug-related costs. In 2012, public expenditure for pharmaceuticals in primary care exceeded 11 billion Euros (approximately 15.2 billion US $), and older adults aged 65 or older accounted for more than 60% of these costs. Recently, increased attention has been focused on studies aimed at monitoring drug use and evaluating the appropriateness of drug prescribing in older adults. In this article, we examined studies that assessed these issues in different settings at a national level. Specifically, results of surveys of prescription drug use in primary care (OsMED), hospital (GIFA, CRIME, and REPOSI) and long-term care (ULISSE and SHELTER) settings are reviewed. Overall, these studies showed that the quality of drug prescribing in older patients is far from optimal. This leads to an increased risk of negative health outcomes and increased health care costs. Data from these studies are valuable, not only to monitor drug use, but also to target interventions aimed at improving the quality of prescribing. Translating the findings of clinical research and monitoring programs will be challenging, but it will lead to quantifiable improvements in the quality of drug prescribing at a national level. [Copyright &y& Elsevier]