Targeting histone deacetylases in endometrial cancer: a paradigm-shifting therapeutic strategy?

OBJECTIVE: Endometrial cancer is increasingly prevalent in western societies and affects mainly postmenopausal women; notably incidence rates have been rising by 1.9% per year on average since 2005. Although the early-stage endometrial cancer can be effectively managed with surgery, more advanced stages of the disease require multimodality treatment with varying results. In recent years, endometrial cancer has been extensively studied at the molecular level in an attempt to develop effective therapies. Recently, a family of compounds that alter epigenetic expression, namely histone deacetylase inhibitors, have shown promise as possible therapeutic agents in endometrial cancer. The present review aims to discuss the therapeutic potential of these agents. MATERIALS AND METHODS: This literature review was performed using the MEDLINE database; the search terms histone, deacetylase, inhibitors, endometrial, targeted therapies for endometrial cancer were employed to identify relevant studies. We only reviewed English language publications and also considered studies that were not entirely focused on endometrial cancer. Ultimately, sixty-four articles published until January 2018 were incorporated into our review. RESULTS: Studies in cell cultures have demonstrated that histone deacetylase inhibitors exert their antineoplastic activity by promoting expression of p21WAF1 and p27KIP1, cyclin-dependent kinase inhibitors, that have important roles in cell cycle regulation; importantly, the transcription of specific genes (e.g., E-cadherin, PTEN) that are commonly silenced in endometrial cancer is also enhanced. In addition to these abstracts effects, novel compounds with histone deacetylase inhibitor activity (e.g., scriptaid, trichostatin, entinostat) have also demonstrated significant antineoplastic activity both in vitro and in vivo, by liming tumor growth, inducing apoptosis, inhibiting angiogenesis and potentiating the effects of chemotherapy. CONCLUSIONS: The applications of histone deacetylase inhibitors in endometrial cancer appear promising; nonetheless, additional trials are necessary to establish the therapeutic role, clinical utility, and safety of these promising compounds.

Trocar metastases in laparoscopic approach for gynecologic malignancies. A short review of the literature.

INTRODUCTION: Compared to laparotomy, laparoscopy has many benefits for patients, such as shorter recovery and lower morbidity rates. Port site metastases after laparoscopic approach in the treatment of gynecologic malignancies are uncommon. The purpose of this review is to identify and summarize possible risk factors for port-site metastases in patients undergoing laparoscopic surgery in the ambit of gynecologic oncology. DISCUSSION: The precise incidence of port-site metastases is not well known because many patients are not followed-up during the whole postoperative period. Possible risk factors that can increase the risk of port-site metastases can be the presence of large masses in the abdomen, especially in the presence of concomitant ascites and in patients treated for ovarian carcinomas. Different theories have been postulated in order to explain the development of port site metastases during laparoscopy for oncological patients. CONCLUSIONS: Patient selection is an essential factor that can influence the incidence of port site metastases in gynecological patients. Robust data regarding port site metastases in gynecologic oncology are needed.

IVF/ICSI frozen replacement cycles; every cycle? Opinion expressed after a systematic review of the literature.

OBJECTIVE: To determine whether in vitro fertilization (IVF), frozen replacement cycles offer better outcomes than fresh cycles in order to support, or not, a possible shift towards total replacement of fresh IVF/intracytoplasmic sperm injection (ICSI) cycles from frozen elective transfers (FETs). STUDY DESIGN: Systematic review; opinion paper. RESULTS: Initial results seem to support a shift in current practice towards frozen cycles. CONCLUSION: Initial results may support replacement all fresh IVF/ICSI cycles with FETs, as this could be a safer and equally effective strategy. However, robust evidence from randomized controlled trials is needed if this will be generally applied.

A rare case report of squamous-cell carcinoma arising from mature cystic teratoma of ovary.

The most frequent ovarian germ cell tumors are mature cystic teratomas (MCTs), composing 10-25% of all ovarian neoplasms. MCTs have the potential of undergoing malignant transformation, typically in postmenopausal women, with a frequency of 0.17-3%, with squamous cell carcinoma being the most common malignant tumor arising from MCT. We present the rare clinical entity of a squamous cell carcinoma arising from a mature cystic teratoma in a 56-year-old premenopausal woman as well as diagnostic and therapeutic route followed.

Primary fallopian tube carcinoma: a case report and mini-review of the literature.

Primary fallopian tube carcinoma (PFTC) is an uncommon gynecologic tumor, responsible for 0.14% to 1.8% of genital malignancies, with a mean incidence of 3.6 per million women per annum. The factors that contribute to its appearance are not well-known. Overall survival percentages for patients with PFTC are generally low. Although the preoperative diagnosis rarely occurs and it is usually first confirmed by the pathologist, an earlier diagnosis occurs with early clinical manifestation and prompt investigation leading to better prognosis. Both PFTC and epithelial ovarian cancer (EOC) are treated with similar surgical and chemotherapy methods. The authors report a case of a patient with bilateral high grade serous carcinoma of the fallopian tube, whose initial presentation was bilateral cystic adnexal masses and serosanguinous discharge, with no other pelvic involvement. This article also reviews in brief and presents updates of this rare gynecological malignancy.

Fertility preservation in women with early stage cervical cancer. Review of the literature.

Within the last decades, the percentage of diagnosed cervical cancer in women of reproductive age has increased. The possibility of diagnosing small cervical tumors (< or = twocm) in childbearing age, can be explained due to the fact that many women, are aware of the benefits of Pap smear or colposcopy examination. Many demand a more conservative policy to handle such lesions in order to have an uneventful pregnancy in the near future.

Homeopathy for infertility treatment: a case series.

Homeopathy has been used in the past for treating a broad aspect of diseases. In gynecology, its use remains limited. Taking under consideration its clinical aspects, the authors attempted to use it for treating female sub fertility problems. With this study, the authors present five cases of female infertility treated successfully with the use of homeopathic treatment in a large obstetrics-gynecology Hospital in Athens.

Morbus Bourneville: a case report and review of the literature.

Tuberous sclerosis (TS) or tuberous sclerosis complex (TSC), also known as Bourneville disease or Bourneville-Pringle disease, is an autosomal dominant disorder classically characterized by the presence of hamartomatous growths in multiple organs. A combination of symptoms may include seizures, developmental delay, behavioral problems, skin abnormalities, and lung and kidney diseases. The authors present a case of a 18 year-old female patient with a history of TS, epileptic episodes, mental retardation, and papillary formations in multiple organs located at the abdominal, axillary, cervical, facial, and genital region.

Effect of tamoxifen on postmenopausal endometrium.

PURPOSE: The objective of this study was to evaluate the effect oftamoxifen on the endometrium of45 postmenopausal women with breast cancer, as evidenced by hysteroscopic, ultrasound, histological methods, and by immunohistochemical investigation of the expression of Bcl-2 and Ki67. MATERIALS AND METHODS: Forty-five postmenopausal women with breast cancer (ER and/or PgR positive) undergoing tamoxifen therapy for six to 48 months, were selected from the files of the 2nd Department of Obstetrics and Gynecology, University of Athens Aretaieion Hospital, among a total of 120 patients treated from 2004-2009. RESULTS: The ultrasound findings during the follow-up period revealed 18 cases of thickened endometrium, 14 cases of suspected polyps, one case with accumulation of endometrial fluid, and 12 cases of heterogeneous endometrial echo texture. The patients had undergone hysteroscopy because of thickened endometrium (18/45 patients), postmenopausal bleeding (14/45 patients), and polyps (13/45 patients). The endometrial tissue samples were examined in the Pathology Department of Aretaieion Hospital and showed in 23 cases with adenomatous endometrial polyps, 15 cases with endometrial cystic atrophy, two cases with adenomatous hyperplasia, and five cases with mucosal endometrial adhesions. Immunohistochemical investigation of Bcl-2 and KJ67 expression was undertaken on paraffin blocks and showed elevated expression in the cases with endometrial polyps and hyperplasia, in contrast to atrophic endometria. CONCLUSION: Long-term tamoxifen therapy of postmenopausal women with breast cancer is associated with uterine pathology. Ultrasonography alone is useful in asymptomatic patients selecting cases with increased endometrial thickness for further investigation. Hysteroscopy is an accurate method for diagnosing endometrial disease because it provides a direct view of the uterine cavity, reveals focal lesions, and enables targeted biopsies to be performed at the same time. Pathological findings show elevated expression of Ki67 and Bcl-2 in hyperplastic endometria and adenomatous polyps, consistent with an elevated glandular cell proliferation due to tamoxifen effect.

Bioethical issues on the role of contemporary gynecologists concerning HPV vaccination.

UNLABELLED: Debate is heating up whether or not to require girls to be vaccinated against the human papillomavirus (HPV), a leading cause of cervical cancer (CC). Prolepsis against this plague is mainly focused on early detection with Pap test (screening) and recently with administrating HPV vaccines in youths. OBJECTIVE: To discuss the increased bioethical role of contemporary gynecologist in the young population, with the aim to contribute to the decrease of this malignancy. MATERIALS AND METHODS: The authors searched the web (data-warehouse: articles, forums, etc., and data-mining: sequence analysis and classification) for HPV vaccination and related bioethical issues. RESULTS: HPV vaccines have already caused debates on whether they must be mandatory and on whether they cause a pseudo-safeness mental state, making youths "forget" necessary annual Pap tests or even worse, urging them in promiscuity, resulting in an increased occurrence of CC. CONCLUSIONS: Greece, in order to appropriately apply the Constitutional Law 5 Section 5 (All persons have the right to the protection of their health...), needs to train contemporary gynecologists in adequate youth consultation and proper family approaches regarding HPV vaccination issues. Enhancing the gynecologist's role, vaccination's effectiveness (sensitivity and specificity) will be increased and on the other hand, a rule of social law will be established in the country.

Primary fallopian tube carcinoma.

Primary fallopian tube carcinoma (PFTC) is a rare gynaecological tumour that accounts for 0.14-1.8% of genital malignancies. The most common age of occurrence is between 40 and 65 years, and the mean age is 55 years. The factors that contribute to its appearance are not well known. Population studies show that the mean incidence of PFTC is 3.6 per million women per annum. Overall survival percentages for patients with PFTC are generally low, in the range of 22-57%. Pre-operative diagnosis is rare and PFTC is usually confirmed by a pathologist, but earlier diagnosis with early clinical manifestation and prompt investigation improves the prognosis. Both PFTC and epithelial ovarian cancer (EOC) are treated with similar surgical and chemotherapy methods. Studies have shown that the prognosis for PFTC is worse than that for EOC or other primary gynaecological tumours. This article reviews and presents the current updates of this rare gynaecological malignancy.

Clinicopathological study of 112 cases of benign, pre-invasive and invasive lesions of the vagina: a 15-year review.

OBJECTIVE: Benign vaginal lesions are mainly asymptomatic and often diagnosed during routine screening gynecological examinations. Additionally, vaginal intraepithelial lesions are asymptomatic and diagnosis is often confirmed after vaginal biopsy under colposcopic evaluation in cases of abnormal cytological Papanicolaou examination or synchronous cervical intraepithelial neoplasia. On the other hand, primary vaginal cancer is rare representing approximately 1-2% of all gynecological cancers. Metastatic invasion of the vagina is common especially in cases of advanced stage cervical cancer. The aim of this study was to examine the diagnostic approach, the management strategy, and the pathological findings in cases of benign, pre-invasive and invasive vaginal lesions that were diagnosed and treated in our Department. MATERIALS AND METHODS: This was a 15-year retrospective study. Cases of benign, pre-invasive, and invasive vaginal lesions diagnosed during the last fifteen years at Aretaieion Hospital of the University of Athens, were analyzed. RESULTS: During this study period 40 cases of vaginal cysts (35.7% of all vaginal lesions) were diagnosed. Surgical excision of the lesions was decided in all cases and histology showed that the most frequent cyst type was mucus-secreting Mullerian (30%). During the study period, 23 cases of vaginal intraepithelial neoplasia (VAIN, 20.5% of all vaginal lesions) were detected. In 43.5% of the cases, histological diagnosis revealed low grade VAIN, while the remaining cases were classified as high grade VAIN. Furthermore, 11 cases of primary vaginal cancer (9.8% of all vaginal lesions) were diagnosed. The vast majority of them (91%) were squamous cell carcinomas. Additionally, histology confirmed the diagnosis of metastatic invasion of the vaginal wall in 38 cases (34% of all vaginal lesions). In the majority of these cases (55.2%), primary cancer was located in the cervix. DISCUSSION: Benign, pre-invasive and invasive vaginal lesions are relatively uncommon and usually accompany lesions in other sites of the lower genital tract. Their diagnosis is based on gynecological or colposcopical examination. Treatment depends on the type of the lesion and the progression of the disease.

Comparing transvaginally defined endometrial thickness with hysteroscopic and histopathologic findings in asyptomatic postmenopausal women.

PURPOSE: To assess the diagnostic value of transvaginal sonography (TVS) measurement of the endometrium compared to hysteroscopic findings and histopathologic reports in order to facilitate clinical management in asymptomatic postmenopausal women with thickened endometrium. METHODS: During the period between January 2000 and December 2008, a retrospective analysis was performed including cases of women who were preoperatively diagnosed with a sonographically thickened endometrium, while asymptomatic, and therefore underwent hysteroscopic and fractionated dilatation and curettage (D & C) under general anesthesia at the Second Department of Obstetrics and Gynecology at Aretaieion Hospital in Athens, Greece. In the present study we compare US, hysteroscopic and pathologic findings. RESULTS: The mean age of the patients ranged between 54-74 years (mean age 65.2 +/- 6.8 years). In 108 cases, sonographically measured endometrial thickness ranged between 5 and 10 mm. In 59 cases, endometrial thickness ranged between 11 and 15 mm, whereas in 22 cases, between 16 and 20 mm and finally, in 13 cases endometrial thickness was more than 20 mm. Hysteroscopic examination revealed endometrial polyps in 161 cases, focal hyperplastic lesions in 28 cases, complete hyperplastic lesions in five cases while atrophy was found in five and cancer in three cases, respectively. Pathological results of the samples taken after hysteroscopy are as follows: in 169 cases (83.67%) in women with asymptomatic abnormal endometrial thickness, an endometrial polyp was present. Endometrial thickness in these cases patients was 10.9 +/- 7.5 mm. In patients with focal hyperplasia (22 cases), endometrial thickness was 7.2 +/- 0.5 mm but in patients with complete hyperplasia (5 cases) endometrial thickness was higher (12.3 +/- 5.1 mm). Finally, in three cases with endometrial carcinoma endometrial thickness was 15.5 +/- 7.8 mm. Six cases out of 28 described in our study were diagnosed as focal hyperplasia and two out of five cases as complete hyperplasia, whereas histological reports classified these cases as endometrial polyps. The other histological diagnoses confirmed hysteroscopic findings and thus provided the same results. CONCLUSIONS: We recommend hysteroscopy to follow gynecological TVS when a thickened endometrium is found in asyptomatic postmenopausal women for better diagnostic and, in a later stage, therapeutic efficacy.

Endometrial polyps and their relationship in the pregnancy rates of patients undergoing intrauterine insemination.

PURPOSE: To evaluate the effect of the presence of endometrial polyps (EP) on pregnancy rates and how polypectomy could affect pregnancy rates in women scheduled for intrauterine insemination (IUI). METHODS: The study included patients who had attended the Second Department of Obstetrics and Gynecology of the University of Athens from April 2003 to October 2008 for infertility treatment and were candidates for IUI. In these women the presence of an endometrial polyp had been already diagnosed during the infertility evaluation. The study group consisted of 86 women who, following the diagnosis of endometrial polyp, had agreed to have the polyps removed hysteroscopically prior to the IUI. The control group consisted of 85 women, who despite the fact that the presence of an endometrial polyp had been previously diagnosed and its removal suggested, elected not to have the polyp removed. We used statistical analysis to check what effect the removal of the polyp had on the total number of pregnancies. RESULTS: There was a statistically significant difference in cumulative pregnancy rates between the two groups. The group that underwent polyp removal had higher pregnancy rates as compared to the one that the polyps were left intact. CONCLUSIONS: We propose that hysteroscopic polypectomy of any size appears to improve fertility in women with otherwise unexplained infertility.

Endometrial stromal sarcoma in a 29-year-old patient. Case report and review of the literature.

OBJECTIVE: Endometrial stromal sarcomas are rare tumors accounting for about 0.2% of all genital tract malignancies. They are considered to occur more often in premenopausal women. Endometrial stromal sarcomas are hormone sensitive tumors. A state of hyper-estrogenemia could act as a growth stimulus. Given the rarity of these tumors there are limited reports in the literature referring to the clinical management and final outcome of these cases. CASE: The patient, a 29-year-old woman, had a surgical history of myomectomy in another hospital three months before her referal to our department. The histological examination of the removed myoma showed an endometrial stromal sarcoma. Total abdominal hysterectomy, with bilateral salpingo-oophorectomy, omentectomy and elective pelvic lymphadenectomy were then performed as a second radical surgical approach. CONCLUSION: Endometrial stromal sarcomas are uncommon and their differential diagnosis from typical submucosal uterine myomas or benign endometrial polyps could be difficult. The hysteroscopic features of uterine sarcomas are often similar to those of endometrial polyps or submucosal myomas. The histological examination of the specimen is necessary to exclude malignancy and establish the final diagnosis. Total abdominal hysterectomy, bilateral salpingo-oopherectomy with pelvic lymphadenectomy is the optimal treatment in cases of endometrial stromal sarcomas.

Management of hematocolpos in adolescents with transverse vaginal septum.

AIM: The aim of this study was to underline the significance of premenarcheal gynecological examination in patients with transverse vaginal septum that could possibly be complicated with endometriosis. DESIGN: Retrospective study including the period between January 2008 and December 2010. SETTING: Second Department of Obstetrics and Gynecology. PATIENTS: We searched our databases regarding cases of hematocolpos caused by transverse vaginal septum. MAIN OUTCOME: Among the patients presented with hematocolpos we identified 4 cases caused by transverse vaginal septum. RESULTS: We present the management of these cases regarding diagnosis, differential diagnosis, and treatment. The mean age of the patients was 13.1 years. All patients presented in our department with hypogastric abdominal pain and hematocolpos. No problems in adrenarche or thelarche were mentioned. The U/S and MRI revealed a normal cystic in the upper part of the vagina--hematocolpos varying from 42 × 26 × 30 to 73 × 55 × 32 mm. Three of the patients had an upper transverse vaginal septum while one had a middle transverse vaginal septum. Only one patient had a concomitant anomaly of the urinary system (ectopic kidney). In our patients, after laparoscopic examination 3 out of 4 patients had findings of endometriosis (2/3 with stage I-minimal endometriosis and 1/3 with stage II-mild endometriosis). CONCLUSION: Physicians should be aware of transverse vaginal septum in the differential diagnosis of hematocolpos with abdominal pain and primary amenorrhea in the early adolescent years. Early diagnosis could be based on premenarcheal gynecological examination and could lead to correct management in order to avoid the complications of endometriosis (dysmenorrhea or infertility).

The role of oral contraception use in the occurrence of breast cancer. A retrospective study of 405 patients.

UNLABELLED: The investigation of potential predisposing factors of breast cancer, a disease accounting for almost one-third of malignancies in women, is necessary in order to reduce the incidence. MATERIALS AND METHOD: We interviewed 405 female patients who had been diagnosed with breast cancer and who also reported having used oral contraceptive pills before. They were categorized into two groups (group A < 7 years OC use and group B > 7 years OC use). RESULTS: Statistical analysis revealed a small (p < 0.02) but significant increased risk of the disease to BRCA mutation carriers, as well as to the women with a significant medical or family history of breast, ovarian or colon cancer who had also previously used oral contraceptive pills for more than seven years. DISCUSSION: Breast cancer seems to be positively dependent on prolonged oral contraceptive use. CONCLUSION: More research is needed to establish the hypothesis that the human genome is vulnerable to oral contraceptives.

Primary mixed epithelial and germ cell tumors of the ovary. Two case reports and literature review.

Two cases of mixed germ cell and epithelial primary ovarian tumors which developed in women 47 and 57 years of age are reported. In both cases, large teratomas measuring 20 and 21 cm were observed in combination with carcinoids and malignant mucinous neoplasms. A possible common oncogenic mechanism is discussed and a literature review is presented.

Unwanted pregnancy and induced abortion among young women 16-22 years old in Greece: a retrospective study of the risk factors.

UNLABELLED: Unwanted pregnancies and the subsequent induced abortions are common problems of our youths in modern Greece. The aim of this study was to recognize the risk factors of the problem in an effort to find the best possible solution out of this social dead end. MATERIALS AND METHOD: We interviewed 1,320 young female individuals and analyzed their answers using statistical analysis. RESULTS: Several useful conclusions were reached concerning the forces that are involved in unwanted pregnancy/induced abortions. DISCUSSION: We have tried to underline the strategy to combat the problem. CONCLUSION: Sexual education and the proper use of contraception remain the essential tools in this effort.