A Role of PET Agents Beyond FDG in Gynecology.

Gynecologic cancers comprise a varied group of malignancies with diverse clinical presentations and prognosis. Positron emission tomography (PET) with [18F]fluorodeoxyglucose (FDG), the most commonly used functional imaging for staging, treatment planning, and therapy response evaluation in gynecological cancers, is limited in providing information about the unique biological features of these tumors. There is an increasing need to noninvasively determine the patient's distinct tumor biological features in order to select the most appropriate therapy. This article presents an overview of the key PET biomarkers other than FDG that have been used for imaging of the three most common gynecological malignancies; cervical, endometrial, and ovarian cancers. These functional molecular imaging applications by PET have the potential to be translated to clinical practice for more complete evaluations of these cancers.

The role of bevacizumab on tumour angiogenesis and in the management of gynaecological cancers: A review.

OBJECTIVE: The study aims to analyze the effectiveness of bevacizumab in addressing the complications associated with gynecological cancers and evaluates effective treatments for various gynecological cancers. METHODS: The study follows a systematic review approach that has been implemented to analyze the qualitative published data from previous studies. Studies related with the trials of angiogenesis and bevacizumab were selected in the review. RESULTS: In general, the management of gynecological cancers include chemotherapy, surgery and radiation therapy. Results suggest bevacizumab as an effective treatment modality for cervical and several other cancers. Overall, bevacizumab showed promising results in improving the overall survival rate of gynecological cancer patients through the combination of bevacizumab with other chemotherapeutic agents. CONCLUSION: Bevacizumab possess less documented adverse effects when compared to other chemotherapeutic agents. The manifestation and severity of adverse effects reported varied according to the chemotherapeutic agent(s) that were used with bevacizumab in combination therapy. Overall, bevacizumab effectively improved the survival rate in patients with several gynaecological cancers.

Resectability and Vascular Management of Retroperitoneal Gynecological Malignancies: A Large Single-institution Case-Series.

BACKGROUND/AIM: To report on morbidity and oncological outcomes in a consecutive series of gynecological malignancies involving the vascular district. PATIENTS AND METHODS: We retrospectively evaluated a consecutive series between 1/2015 and 1/2017 with suspicious gynecological malignancies involving the vascular district. Peri-operative data and survival rates were computed. RESULTS: Eight-hundred-four women with gynecological malignancies were admitted for major oncologic surgery during the study period, and among them, 50 cases (6.2%) showed vascular involvement. Twenty-seven and 23 patients were submitted to minor and major vascular procedures, respectively. R0 resection was achieved in 44 patients. There were no perioperative mortalities. Major postoperative complications occurred in 6 patients (12.0%). The 2-year disease free survival (DFS) was 67% if R0 resection was achieved. In patients with positive pathological margins (n=2), the 2-year DFS was 33%. CONCLUSION: Vascular procedures can be safely performed with a proper pre-operative planning and may not be an impediment to major gynecological oncological surgery.

Angiogenesis Markers in Gynecological Tumors and Patents for Anti-Angiogenic Approach: Review.

The formation of a tumor-associated vascular network is an important step in understanding the stages of tumor progression. This review aims to highlight the main markers of induction, proliferation and inhibition of angiogenesis, as well as the quantification of microvessel density, correlated with preclinical and clinical research in gynecologic cancers and also discussed related patents. Studies show that in the most advanced cases of gynecological cancers, biomarkers such as VEGF (Vascular Endothelial Growth Factor), MMP (Matrix Metalloproteinase), CD105 (Endoglin), TIMP (tissue inhibitors of metalloproteinases) and VASH (Vasohibin) are more expressed compared to healthy individuals. Continuous evaluation of these biomarkers in cancer cases could serve in the future as a basis for development of new therapeutic approaches, leading to a good response to cancer treatment, and thus increase survival of cancer patients.

Improvements in progression-free and overall survival due to the use of anti-angiogenic agents in gynecologic cancers.

OPINION STATEMENT: In ovarian cancer (OC), the best established anti-angiogenic drug, bevacizumab, has demonstrated only modest prolonged progression free survival (PFS) and no increased overall survival (OS). The unanswered question is in which clinical situation bevacizumab might benefit ovarian cancer patients most. The cost-benefit analysis in the primary treatment was found not to be favorable but the use in the recurrent OC setting might be more compelling. Multi-targeted anti-angiogenic tyrosine kinase inhibitors (TKI) such as cediranib and pazopanib have shown some therapeutic benefits with improvements of PFS and OS in patients with platinum-sensitive as well as resistant OC, in whom there is a major need for novel therapies. Very promising is also the observed improvement of PFS in recurrent OC in patients when combining cediranib with the PARP inhibitor olaparib without giving additional chemotherapy. The anti-angiogenic agent trebananib has achieved similar results like TKI, but has a favorable toxicity profile which does not overlap with those of VEGF inhibitors. In cervical cancer the addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent or metastatic chemotherapy-naive disease results in a significant increase in OS. Considering the lack of therapeutic options in this difficult clinical setting, the inclusion of bevacizumab most likely will become a new standard for recurrent cervical cancer. In uterine sarcomas as very aggressive malignancies with a substantial need for better therapies the observed improved PFS with sorafenib warrants further investigation. No data showing a convincing improvement of survival in endometrial cancer have been presented yet. In view of the limited PFS and OS benefit observed with anti-angiogenics in gynecologic oncology, increased morbidity due to side effects of this treatment resulting in loss of quality of life and also substantial costs have to be taken into consideration. Thorough case selection based on molecular subgrouping of gynecologic cancers will therefore be a prerequisite for future anti-angiogenic therapy. This will require the integration of molecular diagnostics which still have to be developed and standardized.

Extravascular migratory metastasis in gynaecological carcinosarcoma.

AIMS: Extravascular migratory metastasis (EVMM) is a potential mechanism of tumour spread reported most extensively in cutaneous melanoma. It has not been described previously in gynaecological malignancies. We describe EVMM in four gynaecological carcinosarcomas. METHODS AND RESULTS: Extravascular migratory metastasis was observed in an ovarian carcinosarcoma during routine diagnostic assessment. Twenty-three additional, randomly selected gynaecological carcinosarcomas (11 tubo-ovarian and 12 endometrial) were examined retrospectively and EVMM was identified in three of these. Other than the index case, EVMM was a focal finding, identified in 12-18% of slides. The malignant cells demonstrating EVMM appeared sarcomatoid and were distributed abluminally, partly or completely surrounding the endothelium. Affected vessels often showed mural fibrin deposition. Immunohistochemistry for α-smooth muscle actin (SMA), CD31, CD34, D2-40, laminin and type IV collagen was performed on the EVMM-positive cases. The perivascular malignant cells showed more consistent SMA and laminin immunoreactivity than the non-vascular tumour elements. CONCLUSIONS: Extravascular migratory metastasis is a hitherto unrecognized mechanism of tumour spread in gynaecological carcinosarcomas. The perivascular tumour cells appear to adopt a pericytic phenotype, and this may represent a specific pattern of epithelial-mesenchymal transition. Further studies with pericyte-specific immunohistological markers may better demonstrate the presence and possible prognostic significance of EVMM in gynaecological tumours.

Anti-angiogenic drugs currently in Phase II clinical trials for gynecological cancer treatment.

INTRODUCTION: Numerous female patients suffer from gynecological cancers every year. When it comes to recurrent or chemoresistant cancers, there are limited treatment options. For decades, much enthusiasm has been shown for novel therapeutic strategies for cancers, and anti-angiogenesis agents appear to be a potential option. Since several promising angiogenesis inhibitors for certain cancers have been approved by Food and Drug Administration, more and more anti-angiogenic drugs are put into clinical trials. AREAS COVERED: In this review, the anti-angiogenic agents in Phase II clinical trials for gynecological cancer treatment are highlighted. This review mainly focuses on 5-year reports on angiogenesis inhibitors concerning ovarian cancer, cervical cancer, uterine leiomysarcoma and endometrial cancer. Inhibitors reviewed in this paper include bevacizumab, volociximab, aflibercept, temsirolimus, enzastaurin, trebananib, sunitinib, imatinib, pazopanib, sorafenib and nintedanib. EXPERT OPINION: These anti-angiogenic drugs while used either alone or in combination with chemotherapy, presented mixed results in treating gynecological cancers. The real challenge is how to take best advantage of the anti-angiogenesis hypothesis for therapeutic benefit. Much remains to be done before these molecules work efficaciously in treating gynecological cancer.

Translational predictive biomarker analysis of the phase 1b sorafenib and bevacizumab study expansion cohort.

Predictive biomarkers are needed to triage patients to the best therapy. We prospectively planned examination of sequential blood, biopsy, and functional imaging with which to confirm the mechanism and to identify potential predictive biomarkers in a phase Ib clinical trial expansion of patients with solid tumors receiving sorafenib/bevacizumab. The maximally tolerated doses of sorafenib at 200 mg twice daily with bevacizumab at 5 mg/kg every other week were given to biopsiable patients. Patients were randomized to receive either sorafenib or bevacizumab monotherapy for the first 28-day cycle with the second drug added with cycle 2. Biopsies, dynamic contrast-enhanced MRI, and fluorodeoxyglucose-proton emission tomography were done pre-therapy and at 2 and 6 weeks (2 weeks into combination therapy). Tumor and serum proteomics, Ras/Raf mutational analysis, and functional imaging results were examined individually and across the dataset to identify potential changes predictive of response to therapy and those that confirm the biochemical drug mechanism(s). Therapy with sorafenib/bevacizumab resulted in clinical benefit in 45% of this mixed solid tumor group. ERK activation and microvessel density were decreased with monotherapy treatment with sorafenib or bevacizumab, respectively; whereas a decreased signal over the group of total AKT, phospho(p)-VEGF receptor2, p-endothelial nitric-oxide synthase, b-RAF, and cleaved poly(ADP-ribose) polymerase was associated with earlier progression of disease. Tumor metabolic activity decreased in those patients with clinical benefits lasting longer than 4 months, and activity increased with progression of disease. Cleavage of caspase 3 and poly(ADP-ribose) polymerase was increased, and Ki67 expression decreased in patients with prolonged clinical benefits, consistent with decreased proliferation and increased apoptosis. The conglomerate analysis, incorporating pharmacodynamic and tumor biochemistry, demonstrated sorafenib/bevacizumab-targeted vascular activity in the tumor. Results suggest potential biomarkers for which changes, as a group, during early therapeutic exposure may predict clinical benefit.

Targeting angiogenesis in gynecologic cancers.

Gynecologic malignancies carry an estimated incidence of 83,750 cases per year and estimated mortality rate of more than 27,000 women per year. New therapies and therapeutic approaches are needed to improve the outlook for women with gynecologic cancers. Recent insights at the molecular and cellular levels are paving the way for a more directed approach to target mechanisms driving tumorigenesis. This article reviews the roles of new and emerging antiangiogenesis drugs, summarizes the data obtained from clinical trials of antiangiogenic agents, and discusses trials under way to address the role of such strategies in gynecologic cancers.

Retroperitoneal vascular aberrations increase the risk of vascular injury during lymphadenectomy in gynecologic cancers.

PURPOSE: To investigate the frequency of aberrations of retroperitoneal great vessels in patients with gynecologic cancers who were scheduled for pelvic and paraaortic lymphadenectomy, and to document the vascular complications which occurred during lymphadenectomy as well as the relationship of these vascular complications with vascular aberrations. METHODS: Patients with gynecologic cancers underwent a routine preoperative abdominal multi-detector computer tomography, and an intraoperative search for aberrations of the great vessels in the retroperitoneal region was undertaken. Intraoperative vascular complications were recorded and their relations to vascular aberrations were analyzed. RESULTS: The rate of vascular aberrations detected preoperatively by multi-detector computed tomography was 24.3 %. Vascular injuries occurred in six patients (16.2 %) during lymphadenectomy. Rate of intraoperative vascular injuries was significantly higher in patients who had vascular aberrations of retroperitoneal great vessels (44.4 vs. 7.1 %, p = 0.022). CONCLUSIONS: Aberrations of retroperitoneal vessels are not uncommon and may increase the risk of vascular complications during lymphadenectomy. The risk of these complications may be decreased if aberrations are detected preoperatively.

Moving beyond VEGF for anti-angiogenesis strategies in gynecologic cancer.

Gynecologic cancer is a major burden in both developed and developing countries. Almost a half million deaths from gynecologic cancer are reported each year. Understanding the molecular biology of cancer is a principle resource leading to the identification of new potential therapeutic targets, which may be parlayed into novel therapeutic options in gynecologic cancer. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase, which plays a pivotal role in many aspects of malignant growth including cancer cell survival, migration, invasion, angiogenesis and metastasis. Various human cancer tissues have demonstrated high expression of FAK or activated FAK, which has been correlated with survival of cancer patients. Among gynecologic cancers, reports have emerged demonstrating that FAK is involved in the pathogenesis of ovarian, endometrial, and cervical cancers. In addition, the polycomb group protein enhancer of Zeste homologue 2 (EZH2), Dll4/notch and EphA2 has also emerged as important regulators of endothelial cell biology and angiogenesis. Herein, we review the role of these new targets in tumor angiogenesis and the rationale for further clinical development.

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.

Dynamic MRI for imaging tumor microvasculature: comparison of susceptibility and relaxivity techniques in pelvic tumors.

PURPOSE: To assess the reproducibility of intrinsic relaxivity and both relaxivity- and susceptibility-based dynamic contrast enhanced (DCE) MRI in pelvic tumors; to correlate kinetic parameters obtained and to assess whether acute antivascular effects are seen in response to cisplatin- or taxane-based chemotherapy. MATERIALS AND METHODS: T1-weighted and T2*-weighted DCE-MRI and basal R2* measurements were performed on three consecutive days in women with gynecological tumors. The third scan was 21.0 (range 17.3-23.5) hours after the first cycle of chemotherapy. Kinetic parameter estimates were obtained and correlated between techniques. Test-retest reproducibility and response to treatment were assessed. RESULTS: Relative blood volume (rBV) and relative blood flow (rBF) correlated strongly with transfer constant (Ktrans), kep, and the initial area under the gadopentetate dimeglumine (Gd-DTPA) concentration-time curve (IAUGC) (all P<0.01). The group 95% confidence interval (CI) for change was -10.8 to +12.1%; +/-5.1%; -9.5 to +10.5%; +/-7.5%; for Ktrans, ve, kep, and IAUGC, respectively, and +/-13.6%, +/-2.4%, +/-11.6%, and +/-11.0%, for rBV, mean transit time (MTT), rBF, and R2*, respectively. There were no significant acute changes in kinetic parameter estimates in response to treatment on group analysis, apart from a small decrease in ve. CONCLUSION: The results confirm the dominant influence of flow on Ktrans in untreated gynecological tumors. There is no evidence of an acute, large magnitude antivascular effect caused by cisplatin- or taxane-based chemotherapy.

Vascular endothelial growth factor (VEGF) pathway as a therapeutic target in gynecologic malignancies.

Vascular endothelial growth factor (VEGF) plays a critical role in angiogenesis, which is required for tumor growth and metastasis. In this article, a review of the functional and biological roles of the VEGF pathway in driving angiogenesis and growth of gynecologic malignancies was performed. Based on the biological functions of VEGF, multiple approaches for targeting the VEGF/VEGF-receptor complex have been developed and many of these have demonstrated substantial activity in preclinical models. These promising data have led to rapid clinical development of VEGF-targeted agents. Therefore, we also assessed the status of VEGF-targeted therapies and associated toxicities in gynecologic malignancies. However, many questions remain related to optimal dosing, sequencing of therapies, management of toxicities, appropriate patient selection, and assessment of response, which will require further studies. Nevertheless, VEGF-targeted therapies offer hope for improving the outcome of cancer patients.

[The use of 2-dimensional and 3-dimensional color and power-Doppler in the diagnosis of blood flow indices of adnexal tumors]. / Zastosowanie ultrasonografii Dopplerowskiej i sonoangiografii trójwymiarowej w badaniu unaczynienia i przeplywu krwi w guzach przydatków macicy u kobiet.

OBJECTIVES: The purpose of this study was to compare 2-dimensional and 3-dimensional color and power-Doppler as measured with blood flow indices for the prediction of malignancy in complex adnexal masses. METHODS: Two hundred eighty women with complex adnexal masses (mean age, 46,3 years (range, 13-83 years) were evaluated by 2-dimensional and 3-dimensional power-Doppler imaging. Complex adnexal mass was defined as the presence of at least one of the following features: solid areas, thick papillary projections, thick septa, or purely solid echogenicity. Tumor volume, sonomorphology and Doppler indices (PI, RI), as well 3-dimensional power-Doppler assessment (VI, FI, VFI) were calculated. All tumors were surgically removed and definitive histological diagnosis was obtained in each case. Diagnostic accuracy and areas under ROC curve (AUROC's) were calculated for each test. RESULTS: Seventy one tumors (25.3%) were proved to be malignant, and 209 tumors (74.7%) were proved to be benign. Statistically significant differences between benign and malignant tumors were found for PI (1.06 vs 0.76; p = 0.001), RI (0.62 vs 0.51; p = 0.002), VI (0.55 vs 1.52; p = 0.002) oraz VFI (0.18 vs 0.49; p = 0.001). However, the highest sensitivity of 3D indices for malignant tumor detection was found for FI (42.9%). Specificity of 2D and 3D indices was between 93.6% for VI to 98.2% for RI. Accuracy and positive and negative predictive values were fund to be between 66.8% to 79.8%, respectively. AUROC's analysis indicated that the most useful test for the discrimination between benign and malignant tumors was VI followed by VFI and PI with RI. CONCLUSION: Three-dimensional power-Doppler imaging has diagnostic potential for the discrimination of benign and malignant complex adnexal masses, but specific, possibly most vascularised areas of each tumor have to be examined in detail to improve not yet satisfactory predictive values of this method.

Targeted therapies in gynecologic cancers.

With the rapid development of high-throughput techniques for identifying novel specific molecular targets in human cancer over the past few years, attention to targeted cancer therapy has dramatically increased. The term "targeted cancer therapy" refers to a new generation of drugs designed to interfere with a specific molecular target that is believed to play a critical role in tumor growth or progression, is not expressed significantly in normal cells, and is correlated with clinical outcome. There has been a rapid increase in the identification of targets that have potential therapeutic application. The clinical success of the small-molecule kinase inhibitor imatinib mesylate in chronic myeloid leukemia and gastrointestinal stromal tumors has accelerated the development of a new era of molecular targeted cancer therapy. The number of agents under preclinical and clinical investigation has grown accordingly. This emphasis on molecular biology and genetics has also resulted in significant changes in the treatment of gynecologic cancers. Several promising drugs targeting tyrosine kinases (EGFR and Her-2/Neu), mTOR, Raf kinase, proteasome, and histone deacetylases, as well as drugs affecting apoptosis and mitosis, are under development for clinical application. However, some clinical trials of p53 gene therapies and farnesyl transferase inhibitors have had limited success. In this review, we will focus on potential novel targets in gynecologic cancer and the development of targeted therapy and its clinical applications in gynecologic cancer.

The merits of vascular targeting for gynecologic malignancies.

Neovascularization is an early and critical step in tumor development and progression. Tumor vessels are distinct from their normal counterparts morphologically as well as at a molecular level. Recent studies on factors involved in tumor vascular development have identified new therapeutic targets for inhibiting tumor neovascularization and thus tumor progression. However, the process of tumor blood vessel formation is complex, and each tumor exhibits unique features in its vasculature. An understanding of the relative contribution of various pathways in the development of tumor vasculature is critical for developing effective and selective therapeutic approaches. Several such agents are currently in clinical trials, and many others are under development. In this review, the mechanisms and factors involved in tumor blood vessel formation are discussed. In addition, selected novel classes of antivascular therapies, including those targeting tumor endothelial cells and other components of the tumor vasculature, are summarized.

Angiogenesis in gynecological oncology-mechanism of tumor progression and therapeutic targets.

The purpose of this article is to review the current literature pertaining to various angiogenic stimulators and angiogenesis inhibitors in gynecological malignancies and the relevance of these markers in the prognosis of these diseases. We also summarize the antiangiogenic drugs currently in development and in clinical use in gynecological oncology. The information was obtained from a computer search of MEDLINE for studies published in the English language regarding angiogenesis and angiogenesis inhibitors in gynecological malignancies between 1970 and December 2003; additional sources were identified through cross-referencing. In ovarian cancer, various different angiogenic activators have been found to correlate with microvessed density (MVD), stage, lymph node and peritoneal metastasis, and survival. In cervical cancer, correlation has been seen between increased angiogenic markers and stage, grade, tumor size, and survival. Studies in endometriat cancer show correlation of angiogenic markers with stage, grade, MVD, and survival. Whereas, in gestational trophoblastic neoplasm (GTD) only few markers have been studied, and some correlated with progression. Information on anti angiogenic drugs currently in ongoing and upcoming trials in gynecological malignancies is also presented. Angiogenesis factors may have a prognostic role to play in patients with gynecological cancers and should continue to be investigated as clinically useful tumor markers. Antiangiogenic-targeted therapies offer an attractive strategy for clinical investigation in gynecologic oncology.