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Innovative therapies in cervical cancer (CC) remain a priority. Recent data indicate that human immunodeficiency virus (HIV)-protease inhibitors used in highly active antiretroviral therapy can exert direct antitumor activities also in HIV-free preclinical and clinical models. The aim of the present study was to evaluate the antineoplastic effects of various HIV-protease inhibitors (indinavir, ritonavir and saquinavir) on primary and established CC cell lines. Two CC cell lines established in our laboratory and four commercially available CC cell lines were treated with indinavir, ritonavir and saquinavir at different concentrations and for different times. Proliferation, clonogenicity and radiosensitivity were evaluated by crystal violet staining. Proteasomal activities were assessed using a cell-based assay and immunoblotting. Cell cycle was analyzed by propidium iodide staining and flow cytometric analysis. Invasion was tested with Matrigel chambers. A t-test for paired samples was used for statistical analysis. In all cell lines, saquinavir was more effective than ritonavir in reducing cell proliferation and inhibiting proteasomal activities (P=0.05). Conversely, indinavir exerted a negligible effect. The saquinavir concentrations required to modulate the proteasome activities were higher than those observed to be effective in inhibiting cell proliferation. In HeLa cells, saquinavir was strongly effective in inhibiting cell invasion and clonogenicity (P≤0.05) at concentrations much lower than those required to perturb proteasomal activities. Saquinavir did not contribute to increase the sensitivity of HeLa cells to X-rays. In conclusion, the present results demonstrate that saquinavir is able to significantly reduce cell proliferation, cell invasion and clonogenicity in a proteasome-independent manner in in vitro models of CC, and suggest that saquinavir could be a promising CC therapeutic agent. [ABSTRACT FROM AUTHOR]

Background: The Human Papillomavirus (HPV) is generally recognized to be the direct cause of cervical cancer. The development of effective anti-HPV vaccines, included in the portfolio of recommended vaccinations for any given community, led to the consolidation in many countries of immunization programs to prevent HPV-related cervical cancers. In recent years, increasing evidence in epidemiology and molecular biology have supported the oncogenic role of HPV in the development of other neoplasm including condylomas and penile, anal, vulvar, vaginal, and oro-pharyngeal cancers. Men play a key role in the paradigm of HPV infection: both as patients and as part of the mechanisms of transmission. Data show they are affected almost as often as women. Moreover, no screening procedures for HPV-related disease prevention are applied in men, who fail to undergo routine medical testing by any medical specialist at all. They also do not benefit from government prevention strategies. Discussion: A panel of experts convened to focus on scientific, medical, and economic studies, and on the achievements from health organizations' intervention programs on the matter. One of the goals was to discuss on the critical issues emerging from the ongoing global implementation of HPV vaccination. A second goal was to identify contributions which could overcome the barriers that impede or delay effective vaccination programs whose purpose is to eradicate the HPV infection both in women and men. Summary: The reviewed studies on the natural history of HPV infection and related diseases in women and men, the increasing experience of HPV vaccination in women, the analysis of clinical effectiveness vs economic efficacy of HPV vaccination, are even more supportive of the economic sustainability of vaccination programs both in women and men. Those achievements address increasing and needed attention to the issue of social equity in healthcare for both genders. [ABSTRACT FROM AUTHOR]

Epithelial cell adhesion molecule (EpCAM) is a surface glycoprotein highly differentially expressed in many epithelial malignancies. The goal of this study was to evaluate the expression of EpCAM and the potential of MT201 (adecatumumab), a human monoclonal antibody targeting EpCAM, against multiple primary cervical carcinoma cell lines.Epithelial cell adhesion molecule expression was evaluated by real-time polymerase chain reaction and flow cytometry in a total of 8 primary cervical cancer cell lines. Sensitivity to MT201-mediated cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity was tested in standard 4-hour 51Cr release assays. To investigate the effect of interleukin-2 (IL-2) on MT201-mediated ADCC, 4-hour 51Cr release assays were also conducted in the presence of low doses of IL-2.High messenger RNA expression by real-time polymerase chain reaction and high EpCAM surface expression by flow cytometry were detected in 4 (50%) of 8 primary cervical carcinoma cell lines. With no exception, the primary cell lines derived from clinically aggressive tumors showed EpCAM overexpression. Whereas these cell lines were highly resistant to complement-dependent cytotoxicity and natural killer (NK)-dependent cytotoxicity in vitro (range of killing, 4%-19%), EpCAM-positive cell lines showed high sensitivity to MT201-mediated ADCC (range of killing, 23%-59%). Incubation with IL-2 in addition to MT201 significantly increased the cytotoxic activity against EpCAM-positive cervical cancer cell lines (P = 0.007). Addition of human serum also further increased the MT201-mediated killing of EpCAM-positive cell lines (P = 0.03).Epithelial cell adhesion molecule is highly expressed in primary cervical carcinoma cell lines, and these biologically aggressive tumors are highly sensitive to MT201-mediated cytotoxicity in vitro. MT201 may represent a novel, potentially highly effective treatment option for patients with cervical carcinoma, especially for those with advanced, recurrent, or metastatic disease refractory to standard salvage therapy. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) vaccines represent a major advance in the prevention of cervical cancer and other HPV-related diseases. The availability of HPV vaccination and cervical cancer screening creates the unique opportunity to combine primary and secondary prevention of a cancer. HPV vaccination is currently being adopted in Europe at a faster rate than has been seen with most previous vaccines. This article analyses the reasons for the rapid and broad access to this cancer prevention measure to illustrate the new sociopolitical environment that drives vaccination policies in the 21st century. The promise of this intervention to prevent infection by the virus that can cause these diseases in young women created an environment receptive to vaccination. However, it was robust data generated by research specifically targeted to public health needs that have convinced various stakeholders to advocate, license, recommend, and fund vaccination. It was not just the usual host of actors who rallied to this process: early support for decision-making came from experts and scientific societies, patient and women’s groups, and policy makers at the EU and national levels. Implementation now looms as the greatest challenge to vaccine uptake, in particular in the adolescent target group. Determinants of successful implementation include well-informed healthcare professionals who in turn can educate parents and adolescents on the infectious disease, its consequences, and the efficacy and safety of vaccination, and successful provision of equitable access to vaccination. The integration of vaccination and screening must also be carefully managed and adapted to the situation in each country. Inevitably, the impact of this promising public health intervention will depend upon the continuing engagement of all stakeholders to maintain interest and confidence in vaccination. [ABSTRACT FROM AUTHOR]

Cervical cancer is the second leading cause of cancer death among women worldwide and remains an important health problem for women, especially in underserved and minority groups in industrially developed nations. Although radical surgery and radiotherapy represent effective modalities of treatment for invasive cervical cancer, up to 35% of these patients overall will develop recurrent/metastatic disease for which treatment results remain poor. Novel therapeutic strategies that are effective in reducing the risk of recurrence/metastatic disease are still needed desperately. Human papillomavirus (HPV) infection represents the most important risk factor for the development of cervical dysplasia and cervical cancer. Since HPVE6 and E7 oncoproteins are constantly expressed in these lesions, these foreign proteins represent ideal tumor-specific target antigens for immunotherapy of cervical cancer. Recently, the recognition of dendritic cells (DC) as powerful antigen-presenting cells, capable of inducing primary T-cell responses in vitro and in vivo, has generated widespread interest in DC-based immunotherapy of several human malignancies. This review summarizes the therapeutic clinical trials and the different preclinical research strategies that are under investigation, with a particular emphasis on the use of autologous DC-pulsed HPV16 or 18 E7 oncoproteins as therapeutic vaccines against cervical cancer. [ABSTRACT FROM AUTHOR]

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]

The "International Classification of the Stages of Carcinoma of the Uterine Cervix" dates back to 1950; since then, seven changes have been made to the staging system for cervical cancer (almost all were made to Stage I), the most recent being in 1995. The FIGO system of classification of cervical cancer is originally based on the results of clinical examination, essentially of the anatomical extent of disease, and is determined at the time of primary diagnosis. Only if the rules for clinical staging are strictly observed is it possible to compare results using different modalities of treatment. Cervical cancer remains a clinically staged malignancy according to the FIGO staging system. Surgical-pathologic staging would not be feasible for advanced-stage disease or in early-stage patients treated primarily with radiation, especially in nations that do not routinely offer surgical extirpation due to different or limited health care resources. However, surgical and pathological data are important for precise analysis of survival and prognostic risk factors. [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]

Abstract: Objectives. : To evaluate and compare epidermal growth factor type-1 receptor (EGF-R1) expression in short term and established cervical cancer cell lines generated from primary and metastatic/recurrent sites of disease. To evaluate the sensitivity of cervical cancer cell lines to treatment with a chimeric MAb against EGFR-1 (Cetuximab). Methods. : EGFR-1 expression was evaluated by flow cytometry on 22 cervical cancer cell lines including 14 primary cervical cancer cell lines obtained from cervical biopsies (11 patients) and recurrent sites of disease (three patients) as well as eight established cell lines. Tumor cell lines were tested for sensitivity to Cetuximab-mediated complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) in 51Cr release assays. Finally, Cetuximab-mediated inhibition of cell proliferation was also tested. Results. : Fourteen out of fourteen (100%) primary tumors and seven out of eight (87.5%) established cervical cancer cell lines expressed EGFR-1 by flow cytometry. Cell lines from recurrent/metastatic sites of disease expressed higher levels of EGFR-1 when compared to those obtained from primary sites (p >0.05). Minimal CDC was detected in the majority of cervical cancer cell lines exposed to complement±Cetuximab in the absence of peripheral blood lymphocytes (PBL). In contrast, cervical tumor cell lines were found highly sensitive to Cetuximab-mediated ADCC when challenged with PBL from either healthy donors or cervical cancer patients. Importantly, ADCC was further increased in the presence of complement. Finally, tumor proliferation was significantly inhibited by Cetuximab in all cervical tumors tested. Conclusions. : EGFR-1 is highly expressed in primary and recurrent cervical tumors. Cetuximab might be a novel and attractive therapeutic strategy in patients harboring chemotherapy-resistant, recurrent, or metastatic cervical cancer. [Copyright &y& Elsevier]

Abstract: Objective. : To evaluate the potential of human papillomavirus (HPV) type 16 and 18 E7 antigen-loaded autologous dendritic cells (DC) as a therapeutic cellular vaccine in a case series of cervical cancer patients harboring recurrent/metastatic disease refractory to standard treatment modalities. Methods. : Autologous monocyte-derived DC were pulsed with recombinant HPV16 E7 or HPV18 E7 oncoproteins and administered to 4 cervical cancer patients. Vaccinations were followed by subcutaneous administration twice daily of low doses of human recombinant interleukin-2 (1 × 106 IU/m2) from day 3 to day 7. Safety, toxicity, delayed type hypersensitivity reactions (DTH), clinical responses, and induction of serological and cellular immunity against HPV16/18 E7 were monitored. Results. : The vaccine was well-tolerated in all patients and no local or systemic side effects or toxicity were recorded. Three out of four patients were found to be significantly immunocompromised before starting the vaccination treatment, as assessed by DTH with a panel of recall antigens. Specific humoral and cellular CD4+ T cell responses to the E7 vaccine were detected in 2 patients, as detected by ELISA and by IFN-γ ELISpot assays, respectively. Increased numbers of E7-specific IFN-γ secreting CD8+ T cells were detected in all patients after vaccination. Swelling and induration (i.e., a positive DTH response) to the intradermal injection of HPV E7 oncoprotein and/or irradiated autologous tumor cells were detected in two patients after six vaccinations. No objective clinical responses were observed. However, both patients who developed a positive DTH to the vaccine experienced a slow tumor progression (i.e., 13 months survival) while DTH unresponsive patients died within 5 months from the beginning of therapy. Conclusions. : Autologous DC pulsed with HPV16/18 E7 proteins can induce systemic B and T cell responses in patients unresponsive to standard treatment modalities. However, treatment-induced immunosuppression may impose severe limitations on the efficacy of active vaccination strategies in late stage cervical cancer patients. DC-based vaccination trials are warranted in immunocompetent cervical cancer patients with early stage disease and/or limited tumor burden, and at significant risk for tumor recurrence or disease progression. [Copyright &y& Elsevier]

Objective. To determine whether the Stratum Corneum Chymotryptic Enzyme (SCCE), a novel serine protease known to contribute to the cell shedding process by catalyzing the degradation of intercellular cohesive structures at the skin surface, is overexpressed in human cervical tumors.Methods. SCCE expression was evaluated in 18 cervical cancer cell lines (i.e., 10 primary and 8 established cell lines) as well as in 8 normal cervical keratinocyte cultures by RT-PCR. In addition, SCCE expression was evaluated by immunohistochemistry on paraffin-embedded tumor tissue.Results. Normal cervical keratinocytes did not express SCCE. In contrast, 50% of the primary and 50% of the established cervical cancer cell lines expressed SCCE by RT-PCR. Eighty percent (i.e., four of five) of primary squamous cervical tumors and 20% (i.e., one of five) of primary adenocarcinomas expressed SCCE. Five out of five (100%) of the patients harboring SCCE-positive tumors were found to have metastatic involvement of the pelvic tumor draining lymph nodes. Immunohistochemistry staining of paraffin-embedded cervical cancer specimens confirmed SCCE expression in tumor cells and its absence on normal cervical epithelial cells.Conclusion. Squamous cervical cancer expressed high levels of SCCE, suggesting that this protease may play an important role in invasion and metastasis. Because SCCE appears only in abundance in tumor tissue and contains a secretion signal sequence, suggesting that SCCE is secreted, it may prove to be a useful diagnostic/prognostic tool for the detection of metastatic or recurrent disease or as a novel molecular target for cervical cancer therapy. [Copyright &y& Elsevier]

: ObjectivesThe purpose of this study was to compare HER-2/neu expression on biopsies obtained from early stage cervical cancer, primary cell lines established therefrom, established cervical cancer cell lines, and metastatic or recurrent sites of disease; and to evaluate the sensitivity of primary cervical cancer cell lines to treatment with a humanized MAb against HER-2/neu (Herceptin).: MethodsSurface HER-2/neu expression on 18 cervical cancer cell lines was compared to HER-2/neu detection by immunohistochemistry on biopsies obtained from the original tumors (10 patients) and sites of recurrence (2 patients). Primary cell lines were tested for sensitivity to Herceptin-mediated antibody-dependent cellular cytotoxicity (ADCC) and sensitivity to Herceptin-mediated inhibition of proliferation.: ResultsNine out of 10 primary (90%) and 8 out of 8 (100%) established cervical cancer cell lines expressed HER-2/neu by flow cytometry. Surprisingly, all HER-2/neu-positive primary cell lines were derived from tumor biopsies that scored negative (i.e., 0 to 1+) for HER-2/neu expression by immunohistochemistry. Heavy staining for HER-2/neu (i.e., 3+) was found in the recurrent/metastatic lesions of the two relapsed patients. Importantly, all HER-2/neu-positive primary cell lines were highly sensitive to Herceptin-mediated ADCC, and their proliferation was also significantly inhibited by Herceptin. A significant enhancement of Herceptin-mediated ADCC was demonstrated when effector cells were exposed to low doses of IL-2 in vitro.: ConclusionsEarly stage cervical cancer may develop a population of HER-2/neu-positive cells with a selective growth advantage over HER-2/neu-negative cells. Therapy which targets HER-2/neu may be more effective in patients with cervical cancer than indicated by the commonly low expression of HER-2/neu in tumors removed at the time of primary treatment. [Copyright &y& Elsevier]

: ObjectiveTo evaluate the potential of autologous dendritic cells (DC) pulsed with HPV16 and HPV18 E7 oncoprotein in restoring tumor-specific cytotoxicity in populations of tumor infiltrating lymphocytes (TIL) for adoptive immunotherapy of cervical cancer patients.: MethodsFull-length E7-pulsed DC-stimulated CD8+ T cells derived from peripheral blood (PBL) and from tumor tissues (TIL) were tested and compared for their ability to induce a HLA class-I-restricted cytotoxic T lymphocyte (CTL) response against autologous tumor cells. In addition, in order to correlate cytotoxic activity by CTL with a particular lymphoid subset, analysis of surface antigens and intracellular CD3 ζ chain and two-color flow cytometric analysis of intracellular cytokine expression (IFN-γ vs IL-4) at the single cell level were performed.: ResultsDC stimulation induced powerful cytotoxicity against autologous tumor target cells by TIL-derived CD8+ T cells from all three cervical cancer patients, while autologous Epstein–Barr virus-transformed lymphoblastoid cell lines were not lysed. Killing of autologous tumor cells was higher by CD8+ T cells from TIL compared to PBL (P > 0.01) and was more strongly inhibited by anti-HLA class I MAb (P > 0.05). Phenotypically, all CTL populations were CD3+/CD8+, with higher levels of CD56 expression by TIL-derived CTL. Finally, although a marked Type 1 cytokine bias (i.e., IFN-γhigh/IL-4low) was observable in both PBL- and TIL-derived DC-stimulated CD8+ T cell populations, TIL-derived CD8+ T cells showed a higher percentage of IFN-γ-positive cells compared to PBL.: ConclusionsFull-length E7-pulsed DC can consistently restore strong CD8+ CTL responses against autologous HPV16- and HPV18-infected cervical cancer cells. DC-stimulated TIL may represent a superior source of tumor-specific CTL compared to PBL for adoptive T cell immunotherapy of patients harboring metastatic or recurrent cervical cancer refractory to standard treatment modalities. [ABSTRACT FROM AUTHOR]

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]