Ilary Ruscito

Complete remission of ovarian cancer induced intractable malignant ascites with intraperitoneal bevacizumab. Immunological observations and a literature review

SummaryMalignant ascites resistant to conventional drugs frequently affects ovarian cancer patients at the end of life. Here we report the case of a patient who benefited from complete resolution of ascites after low dose intraperitoneal administration of bevacizumab. Immunological analyses showed an initial increase in proportion and function of CD8+ effector T cells and a reduction of circulating Treg cells. A review of the current literature regarding bevacizumab in ovarian cancer is reported. Bevacizumab has shown a high efficacy in the treatment of ovarian cancer. Intraperitoneal administration induces an immune activation and appears promising in the treatment of malignant ascites.

BRCA1 gene promoter methylation status in high-grade serous ovarian cancer patients - A study of the tumour Bank ovarian cancer (TOC) and ovarian cancer diagnosis consortium (OVCAD)

BACKGROUND Mutations in BRCA1/2 genes are involved in the pathogenesis of breast and ovarian cancer. Inactivation of these genes can also be mediated by hypermethylation of CpGs in the promoter regions. Aim of this study was to analyse the clinical impact of BRCA1 promoter gene methylation status in a homogenous cohort of high-grade serous ovarian cancer (HGSOC) patients. METHODS The cohort included 257 primary HGSOC patients treated by cytoreduction and platinum-based chemotherapy. DNA was extracted from fresh frozen tissue samples. BRCA1 gene promoter methylation rate was assessed using polymerase chain reaction (PCR). RESULTS 14.8% of patients presented hypermethylation within a selected region of the BRCA1 promoter. The rate of hypermethylation was significantly higher in younger patients (20.8% hypermethylation in the age group ⩽ 58 years versus 8.7% hypermethylation in the age group >58 years; p = 0.008). Optimal tumour debulking could be reached in 63% of patients, without significant differences in the extent of residual disease with respect to the methylation status. No impact of BRCA1 gene promoter methylation status on progression free- and overall-survival rates was found. No significant differences within BRCA1 promoter methylation status between primary and metastatic tissue could be observed. These results on BRCA1 promoter methylation status were also confirmed in a subgroup of 107 patients found negative for BRCA1 exon 11 mutations. CONCLUSIONS Our data suggest that BRCA1 methylation determines the earlier onset of HGSOC. Furthermore our study supports the idea that BRCAness is not only due to mutations but also to epigenetic changes in BRCA1 promoter gene.

Monoclonal Antibodies in Gynecological Cancer: A Critical Point of View

During the last decades, several improvements in treating gynecological malignancies have been achieved. In particular, target therapies, mostly monoclonal antibodies, have emerged as an attractive option for the treatment of these malignancies. In fact, various molecular-targeted agents have been developed for a variety of malignancies with the objective to interfere with a precise tumor associated receptor, essential for cancer cell survival or proliferation, blocking its function, of the cancer cells. Alternatively, monoclonal antibodies have been developed to block immune suppression or enhance functions of immune effector cells. So far, several monoclonal antibodies have been tested for clinical efficacy for the treatment of gynecological cancers. Antibodies against Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR) have been used in different neoplasms such as ovarian and cervical cancer. Catumazumab, a bivalent antibody against CD3 and EpCAM, is effective in the treatment of neoplastic ascites. Other antibodies are peculiar for specific cancer-associated antigen such as Oregovomab against CA125 or Farletuzumab against the folate receptor. Here we describe the preclinical and clinical experience gained up to now with monoclonal antibodies in tumors of the female genital tract and trace future therapeutic and research venues.

Current knowledge and open issues regarding Bevacizumab in gynaecological neoplasms

In the last fifty years the combining of different drugs has progressively improved response and survival rates in gynaecological malignancies. Results are, however, far from being satisfactory. Treatments used in cases of advanced or recurrent disease offer limited results in terms of long-term responses and the urgent need for new drugs has prompted researchers to investigate and propose new therapeutic modalities. One of the most important avenues that are being explored is represented by monoclonal antibodies (MoAb) directed against Vascular Endothelial Growth Factor (VEGF). Several antibodies against this target are now available and Bevacizumab appears to be one of the most promising agents. VEGF has been confirmed as an important therapeutic target in several clinical trials and in multiple disease settings, including gynaecological cancers, for its biological and clinical significance in tumour angiogenesis. The binding and blocking of VEGF growth factor is the basis of tumour growth inhibition, since angiogenesis is essential in the process of tumour growth and progression. Several clinical trials have utilized this agent successfully, either alone or in combination with other drugs. Despite initial concerns, adverse reactions have not been significant with side effects being more tolerable than those associated to conventional chemotherapy. Furthermore, the limited toxicity profile of this, as well as other target therapies, allows it to be combined with cytotoxic drugs without the requirement for a significant dose reduction of the latter. This review outlines the rationale for studying this anti-angiogenetic compound, summarizing the existing and emerging clinical evidence related to the use of Bevacizumab in the treatment of gynaecological malignancies, focusing on its potential benefits and adverse effects.

Monoclonal antibodies therapies for ovarian cancer

Introduction: Despite aggressive debulking surgery, intraperitoneal therapies and the use of new drugs for chemotherapy, patients with ovarian cancer (OC) still have poor prognosis and, therefore, new strategies for its management are needed. Molecular-targeted agents can be considered a new option in drug research. Several antigens related to OC have been isolated and they could be potential target of monoclonal antibodies (mAbs); therefore, different mAbs have been developed and are emerging as new potential OC treatments. Areas covered: This article aims to review the literature on the use of mAbs in the treatment of OC. The purposes of this manuscript are to offer a brief explanation of the mechanisms of action of mAbs and to help readers in understanding the current role of mAbs in the treatment of OC. Expert opinion: A deeper knowledge of the molecular biology of OC has brought new developments in targeted therapies. Among these therapies, bevacizumab demonstrated the higher clinical efficacy. Further larger trials are needed to better define the role of the other mAbs in OC treatment. There is a strong need to identify and validate robust biomarkers for a more focused patient selection and for tailoring therapies, optimizing dose and assessing response.

Vaginal Reconstruction with the Abbè-McIndoe Technique: From Dermal Grafts to Autologous in Vitro Cultured Vaginal Tissue Transplant

Vaginal agenesis represents the most common anomaly of the lower female genital tract. Surgical treatments have gradually evolved from aggressive procedures to minimally invasive techniques. The Abbè-McIndoe procedure is one of the most frequent surgical procedures used. The original Abbè-McIndoe procedure consisted of the surgical creation of a vagina in between the bladder and the rectum and the successive lining with a dermal graft. In the last decades different authors have introduced several modifications, mostly changing the lining material. Amniotic membranes, inert materials, and oral mucosa have all been used to improve the short- and long-term results. Recently, we have reported the use of autologous in vitro grown vaginal tissue as lining material with highly promising results. In this review, we discuss the improvements achieved using this minimally invasive procedure and discuss the advantages and disadvantages of the different materials.

Beyond circulating microRNA biomarkers: Urinary microRNAs in ovarian and breast cancer.

Breast cancer is the most common malignancy in women worldwide, and ovarian cancer is the most lethal gynecological malignancy. Women carrying a BRCA1/2 mutation have a very high lifetime risk of developing breast and ovarian cancer. The only effective risk-reducing strategy in BRCA-mutated women is a prophylactic surgery with bilateral mastectomy and bilateral salpingo-oophorectomy. However, many women are reluctant to undergo these prophylactic surgeries due to a consequent mutilated body perception, unfulfilled family planning, and precocious menopause. In these patients, an effective screening strategy is available only for breast cancer, but it only consists in close radiological exams with a significant burden for the health system and a significant distress to the patients. No biomarkers have been shown to effectively detect breast and ovarian cancer at an early stage. MicroRNAs (miRNAs) are key regulatory molecules operating in a post-transcriptional regulation of gene expression. Aberrant expression of miRNAs has been documented in several pathological conditions, including solid tumors, suggesting their involvement in tumorigenesis. miRNAs can be detected in blood and urine and could be used as biomarkers in solid tumors. Encouraging results are emerging in gynecological malignancy as well, and suggest a different pattern of expression of miRNAs in biological fluids of breast and ovarian cancer patients as compared to healthy control. Aim of this study is to highlight the role of the urinary miRNAs which are specifically associated with cancer and to investigate their role in early diagnosis and in determining the prognosis in breast and ovarian cancer.

Circulating tumor cells as trigger to hematogenous spreads and potential biomarkers to predict the prognosis in ovarian cancer.

Despite several improvements in the surgical field and in the systemic treatment, ovarian cancer (OC) is still characterized by high recurrence rates and consequently poor survival. In OC, there is still a great lack of knowledge with regard to cancer behavior and mechanisms of recurrence, progression, and drug resistance. The OC metastatization process mostly occurs via intracoelomatic spread. Recent evidences show that tumor cells generate a favorable microenvironment consisting in T regulatory cells, T infiltrating lymphocytes, and cytokines which are able to establish an “immuno-tolerance mileau” in which a tumor cell can become a resistant clone. When the disease responds to treatment, immunoediting processes and cancer progression have been stopped. A similar inhibition of the immunosuppressive microenvironment has been observed after optimal cytoreductive surgery as well. In this scenario, the early identification of circulating tumor cells could represent a precocious signal of loss of the immune balance that precedes cancer immunoediting and relapse. Supporting this hypothesis, circulating tumor cells have been demonstrated to be a prognostic factor in several solid tumors such as colorectal, pancreatic, gastric, breast, and genitourinary cancer. In OC, the role of circulating tumor cells is still to be defined. However, as opposed to healthy women, circulating tumor cells have been demonstrated in peripheral blood of OC patients, opening a new research field in OC diagnosis, treatment monitoring, and follow-up.

Past, Present and Future Strategies of Immunotherapy in Gynecological Malignancies

Recently, the combining of different drugs has greatly improved response and survival rates in gynecological malignancies. Results are however far from being satisfactory. Treatments used in case of advanced or recurrent disease offer limited results in terms of long-term responses. The urgent need for new and more effective treatments has prompted researchers to investigate and propose new therapeutic strategies. One of the most interesting approaches that are being explored is constituted by immunotherapy. Currently, immunotherapeutic strategies include vaccination with peptide, viral vectors, carbohydrates and antiidiotypic antibodies. In addition, cell based immunotherapy has been adopted in vitro activated lymphocytes and dendritic cells. Most experience has been acquired in ovarian cancer and cervical cancer. Little has been investigated in endometrial and rare gynecologic neoplasms.The clinical experiences and results achieved with immunotherapy in this setting of patients have been reviewed and the future avenues that are currently being explored have also been discussed.

Cediranib in ovarian cancer: state of the art and future perspectives.

Despite the dramatic improvements achieved in cancer treatment through a better understanding of the tumor biology, ovarian cancer is still characterized by a poor prognosis: most patients diagnosed with this disease will ultimately die from it. In various clinical trials conducted over a time span of two decades, new combinations of conventional chemotherapy regimens have failed to achieve significant improvements in oncologic outcome in ovarian cancer patients. We have now entered an era of “personalized medicine” in which new medications are designed to specifically target molecular pathways involved in carcinogenesis and cancer progression. Encouraging results in different tumor types have been reported, applying an increasing number of target therapies that are still under evaluation. In this setting, one of the most successfully targeted molecular pathways is tumor angiogenesis. Bevacizumab, a monoclonal antibody binding vascular endothelial growth factor (VEGF), has been recently incorporated in the treatment of primary and recurrent ovarian cancer patients after multiple phase III randomized controlled trials have proven its clinical benefit. Based on these positive results, more anti-angiogenic molecules using different mechanisms of action have been developed and are currently under investigation. Among these molecules, the tyrosine kinases inhibitors are probably the most promising ones. Cediranib is a tyrosine kinase inhibitor targeting VEGF receptors that has been tested in various trials with promising results. The aim of this manuscript is to review the current role of cediranib in the treatment of ovarian cancer and to present an overview of the ongoing clinical trials in this setting.