Roberta Tana

Serum and tissue biomarkers as predictive and prognostic variables in epithelial ovarian cancer

Tumour stage, residual disease after initial surgery, histological type and tumour grade are the most important clinical-pathological factors related to the clinical outcome of patients with epithelial ovarian cancer. In the last years, several investigations have assessed different biological variables in sera and in tissue samples from patients with this malignancy in order to detect biomarkers able to reflect either the response to chemotherapy or survival. The present paper reviewed the literature data about the predictive or prognostic relevance of serum CA 125, soluble cytokeratin fragments, serum human kallikreins, serum cytokines, serum vascular endothelial growth factor and plasma d-dimer as well as of tissue expression of cell cycle- and apoptosis-regulatory proteins, human telomerase reverse transcriptase, membrane tyrosine kinase receptors and matrix metalloproteinases. A next future microarray technology will hopefully offer interesting perspectives of translational research for the identification of novel predictive and prognostic biomarkers for epithelial ovarian cancer.

Molecular target therapies in endometrial cancer: from the basic research to the clinic.

Molecular targeted therapies represent an interesting field of pharmacological research in endometrial cancer. The loss of PTEN (phosphatase and tensin homolog deleted on chromosome 10) function, with consequent activation of the PI3K (phosphatidylinositol-3-kinase)–AKT (serine/threonine-specific protein kinase)–mTOR (mammalian target of rapamycin) signaling pathway, occurs in 32–83% of endometrioid-type endometrial carcinomas, thus suggesting a role for mTOR inhibition in this malignancy. Some analogues of rapamycin (CCI-799, RAD-001, AP-23573) have been developed and tested in different tumors including endometrioid-type endometrial carcinoma. For example, AP-23573 achieved a clinical benefit response in 33% of 27 heavily pretreated patients, and CCI-799 obtained a 26% partial response rate and a 63% stable disease rate in 19 patients. Overexpression of ErbB-2 (epidermal growth factor type II receptor) has been detected in 18–80% of uterine papillary serous carcinomas (UPSCs), thus providing a biological rationale for the use of trastuzumab in these aggressive tumors. UPSC often overexpresses claudin-3 and claudin-4, which represent the epithelial receptors for Clostridium perfringens enterotoxin (CPE). CPE-mediated therapy might be a novel treatment modality for UPSC resistant to chemotherapy. A better understanding of the signaling transduction pathways that are dysregulated in endometrioid-type endometrial carcinoma and UPSC will allow the development of novel molecular targeted therapies.

The fertility-sparing treatment in patients with endometrial atypical hyperplasia and early endometrial cancer: A debated therapeutic option

Fertility-sparing treatment may represent a realist option for accurately selected young patients with endometrial atypical hyperplasia or well differentiated, early endometrial cancer. Oral progestins, and especially medroxyprogesterone acetate (MPA) and megestrol acetate with different doses and schedules, represent the most commonly used hormone agents in this clinical setting. Approximately three fourths of the women achieve a histologically documented complete response, with an mean response time of 12 weeks, but about one third of these subsequently developed a recurrence after a mean time of 20 months. The expression of receptor for progesterone receptor (PR), PTEN gene, DNA mismatch repair gene MLH1 and phospho-AKT on tissue specimens may be useful for selecting patients fit for a conservative management. Several successful pregnancies have occurred after a fertility-sparing treatment of endometrial atypical hyperplasia or endometrial cancer, more frequently with assisted reproductive technologies. The implementation of in vitro fertilisation techniques not only increases the chance of conception, but it may also decrease the interval to conception. The opportunity of a demolitive surgery after delivery or after childbearing being no longer required is a still debated issue. Large multicenter trials are strongly warranted to better define the selection criteria for a conservative treatment, endocrine regimen of choice, the optimal dosing, the duration of treatment and follow-up protocols. In any case, the patient should be accurately informed about the relatively high recurrence rates after complete response to hormone treatment and expectations for pregnancy.

Clinico-pathological and biological prognostic variables in squamous cell carcinoma of the vulva

Several clinical-pathological parameters have been related to survival of patients with invasive squamous cell carcinoma of the vulva, whereas few studies have investigated the ability of biological variables to predict the clinical outcome of these patients. The present paper reviews the literature data on the prognostic relevance of lymph node-related parameters, primary tumor-related parameters, FIGO stage, blood variables, and tissue biological variables. Regarding these latter, the paper takes into account the analysis of DNA content, cell cycle-regulatory proteins, apoptosis-related proteins, epidermal growth factor receptor [EGFR], and proteins that are involved in tumor invasiveness, metastasis and angiogenesis. At present, the lymph node status and FIGO stage according to the new 2009 classification system are the main predictors for vulvar squamous cell carcinoma, whereas biological variables do not have yet a clinical relevance and their role is still investigational.

Fertility and endocrine outcome after robot-assisted laparoscopic myomectomy (RALM)

Introduction: Laparoscopic myomectomy has recently gained wide acceptance but this procedure remains technically highly demanding and concerns have been raised about the increased blood loss and an higher risk of postoperative uterine rupture of the pregnant uterus. Objective: The aim of the present study is to evaluate the fertility and endocrine outcome in women underwent robot-assisted laparoscopic myomectomy (RALM). Methods: Data from 48 RALM performed in our department between the years 2007 and 2011 have been collected. Conception rate, abortion rate, incidence of feto-maternal morbidity or severe pregnancy and labor-related complications were reported; FSH and AMH levels and ultrasound valuation of AFC has been made before and 6 months after operation. Number of cesarean sections and vaginal deliveries were described. Results: The average age of the patients was 35 years and median Body Mass Index was 23 kg/m2 (range 18–35 kg/m2). Seven women (13%) became pregnant after RALM with eight pregnancies. One pregnancy is actually on going; there were six deliveries with caesarian section and one spontaneous delivery. No spontaneous abortions. No uterine ruptures occurred. No significant modification of ovarian function was found after myomectomy. Conclusion: RALM seems to have a favorable impact on the reproductive outcome of young patients with no impact on the ovarian function.

Novel insights on the malignant transformation of endometriosis into ovarian carcinoma

Abstract The malignant transformation of endometriosis is an uncommon event, which happens in 0.7–2.5% of the cases, and, when occurs, it usually involves the ovary. A 2 to 3-fold higher risk of ovarian endometrioid and clear cell carcinoma has been reported in women with endometriosis. Pathological studies have detected a morphological continuum of sequential steps from normal endometriotic cyst epithelium to atypical endometriosis and finally to invasive carcinoma. Ovarian endometrioid carcinoma harbors mutations of CTNNB1 in 16–53.3%, of PTEN in 14–20% and of ARID1A in 30–55% of the cases. Ovarian clear cell carcinoma harbors mutations of PIK3CA in 20–40% and of ARID1 in 15–75% of the cases. Whereas estrogen receptors and progesterone receptors are quite always absent, HNF-1b is often over-expressed in this histotype. Atypical endometriosis and endometriosis-related ovarian neoplasms share molecular alterations, such as PTEN mutations, ARID1A mutations and up-regulation of HNF-1b. Moreover, ARID1A mutations have been noted in clear cell tumors and contiguous atypical endometriosis, but not in distant endometriotic lesions. The loss of BAF250a protein expression is suggestive for the presence of ARID1A mutations, and represents an useful marker of malignant transformation of endometriosis. Chinese abstract 子宫内膜异位症的恶性转化属于不常见事件，它的发生率大约为0.7%-2.5%，并且这种情况通常发生在卵巢中。患有子宫内膜异位症的女性，其卵巢组织中出现异位病灶以及透明细胞癌的风险升高2-3倍。病理学研究指出从正常子宫内膜异位症囊性上皮，到非典型子宫内膜异位改变，直至发展成为浸润癌,这是一系列连续性的形态学改变。卵巢子宫内膜样癌灶通常16%-53.3%伴有CTNNB1突变，14%-20%有PTEN突变，30%-55%有ARID1A突变。卵巢透明细胞癌中20%-40%有PIK3CA突变，15%-75%有ARID1突变。然而通常此时雌激素受体及孕激素受体表达缺失，HNF-1b通常在这些组织型中过表达。非典型子宫内膜异位灶以及子宫内膜异位症相关的卵巢肿瘤通常有共同的分子学改变，例如PTEN突变，ARID1A突变，以及HNF-1b表达上调。此外，人们发现在透明细胞肿瘤以及邻近的非典型子宫内膜异位灶中有ARID1A突变，在较远的子宫内膜异位病灶中无此变化。BAF250a蛋白表达的缺失提示存在ARID1A突变，同时也是子宫内膜异位灶恶性转化的一个有效标志物。

Metformin use and gynecological cancers: A novel treatment option emerging from drug repositioning

Metformin exerts antitumor effects mainly through AMP-activated protein kinase [AMPK] activation and phosphatidylinositol 3-kinase [PI3K]-Akt-mammalian target of rapamycin [mTOR] inhibition. This drug leads to activation of the cellular energy-sensing liver kinase B1 [LKB1]/AMPK pathway. LKB1 is implicated as a tumor suppressor gene in molecular pathogenesis of different malignancies. AMPK is a serine/threonine protein kinase that acts as an ultra-sensitive cellular energy sensor maintaining the energy balance within the cell. AMPK activation inhibits mRNA translation and proliferation in cancer cells via down-regulation of PI3K/Akt/mTOR pathway. Moreover, metformin decreases the production of insulin, insulin-like growth factor, inflammatory cytokines and vascular endothelial growth factor, and therefore it exerts anti-mitotic, anti-inflammatory and anti-angiogenetic effects. Recent in vitro and experimental data suggest that metformin electively targets cancer stem cells, and acts together with chemotherapy to block tumor growth in different cancers. Several epidemiological studies and meta-analysis have shown that metformin use is associated with decreased cancer risk and/or reduced cancer mortality for different malignancies. The present review analyzes the recent biological and clinical data suggesting a possible growth-static effect of metformin also in gynecological cancers. The large majority of available clinical data on the anti-cancer potential of metformin are based on observational studies. Therefore long-term phase II-III clinical trials are strongly warranted to further investigate metformin activity in gynecological cancers.

Alternatives to risk-reducing surgery for ovarian cancer

BRCA1 and BRCA2 mutation carriers have an 18%-60% and 11%-27% lifetime risk of developing ovarian carcinoma, respectively. Prophylactic bilateral salpingo-oophorectomy reduces the risk of this malignancy by up to 96%. Gynecological screening programs with periodical trans-vaginal ultrasound and serum CA125 assay have been widely used in women at hereditary high risk of ovarian carcinoma, but clinical results have been conflicting. These surveillance protocols have often fallen short of expectations because of the advanced stage of ovarian carcinoma in the identified screened women. Several investigations have been addressed to the detection of additional tumor markers able to generate more reliable screening tools. The combined serum assay of leptin, prolactin, osteopontin, CA125, macrophage inhibiting factor and insulin-like growth factor-II appears to have a significant better diagnostic reliability compared with serum CA125 alone in discriminating healthy individuals from ovarian carcinoma patients, and therefore, it could have a role in the screening of women at high risk for this malignancy. As far as chemoprevention is concerned, oral contraceptives significantly reduce the ovarian carcinoma risk also in BRCA mutation carriers, whereas the efficacy of fenretinide is still under investigation.

Menstrual function and childbearing potential after fertility-sparing surgery and platinum-based chemotherapy for malignant ovarian germ cell tumours.

Abstract Malignant ovarian germ cell tumours (MOGCT) account for 5% of all ovarian malignancies. Their elevated chemosensitivity, the frequent unilaterality and the young age of patients have strongly supported the conservative surgery as the standard approach, often followed by adjuvant platinum-based chemotherapy. The risk for recurrence is not affected by the performance of conservative versus radical surgery. During chemotherapy 50% of patients become amenorrhoeic but more than 95% of them resume normal menses after treatment completion. Literature has reported several healthy babies born after fertility-sparing surgery with or without chemotherapy for MOGCT. The incidence of miscarriages is in the normal range, whereas malformation rate is slightly higher compared to general population, without any difference between chemotherapy-treated and -untreated patients. Therefore, young women with MOGCT must be reassured of their excellent chances of survival and fertility preservation following conservative surgery and adjuvant platinum-based chemotherapy.

Acute and late vaginal toxicity after adjuvant high-dose-rate vaginal brachytherapy in patients with intermediate risk endometrial cancer: is local therapy with hyaluronic acid of clinical benefit?

Purpose The aim of the present study was to evaluate the effectiveness of hyaluronic acid (HA) in the prevention of acute and late vaginal toxicities after high-dose-rate (HDR) vaginal brachytherapy (BT). Material and methods Between January 2011 and January 2015, we retrospectively analyzed 126 patients with endometrial cancer who underwent extrafascial hysterectomy with or without lymphadenectomy and adjuvant HDR-vaginal BT +/– adjuvant chemotherapy. The total dose prescription was 21 Gy in 3 fractions (one fraction for week). Vaginal ovules containing 5 mg of HA were given for whole duration of vaginal BT and for the two following weeks. Acute and late toxicities were evaluated according to CTCAE vs 4.02. Results According to the revised FIGO 2009 classification, most tumors were in stage IA (30.9%) and in stage IB (57.9%). Thirty-three patients (26.2%) received adjuvant chemotherapy before vaginal BT. Five-year disease-free survival (DFS) and five-year overall survival (OS) were 88% and 93%, respectively. The most common grade 1-2 acute toxicities were vaginal inflammation (18 patients, 14.3%) and dyspareunia (7 patients, 5.5%). Two patients (1.6%) had more than one toxicity. Late toxicity occurred in 20 patients (15.9%). Grade 1-2 late toxicities were fibrosis (14 patients, 11.1%) and telangiectasias (7 patients, 5.5%). Six patients (4.8%) had more than one late toxicity. No grade 3 or higher acute or late toxicities were observed. Conclusions These results appear to suggest that the local therapy with HA is of clinical benefit for intermediate risk endometrial cancer patients who receive adjuvant HDR-vaginal BT after surgery. A randomized trial comparing HA treatment vs. no local treatment in this clinical setting is warranted to further evaluate the efficacy of HA in preventing vaginal BT-related vaginal toxicity.