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.

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.

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.

A randomized comparison of intrauterine and intraperitoneal insemination in the treatment of infertility.

OBJECTIVE: To compare the pregnancy rates (PRs) between intrauterine insemination (IUI) and intraperitoneal insemination (IPI) in women receiving comparable ovarian stimulation in couples who were infertile for various infertility conditions. METHOD: Fifty-four couples were treated. Of these, 25 were diagnosed as having unexplained infertility, 21 as having male infertility and 8 as having cervical mucus hostility. RESULT: Nine pregnancies occurred with 89 cycles of IUI and 6 pregnancies with 85 cycles of IPI, giving an overall PR of 28%. Twelve of the 15 pregnancies occurred during the first treatment cycle and three during the second treatment cycle. There was no significant difference in the (PRs) between the IUI and IPI (P > 0.25). CONCLUSION: Both procedures combined with superovulation proved to be simple, inexpensive safe and worthwhile for infertile couples with unexplained infertility, male infertility and cervical mucus hostility.

Treatment of idiopathic infertility with testosterone undecanoate. A double blind study.

This study refers to 50 couples treated for subfertility. Twenty five of these patients were treated with TU (Testosterone Ur econoate), the remaining 25 received placebo. Sperm characteristics, including ejaculate volume, pH, sperm density, morphology, motility, total testosterone, FSH, LH, DHT and E2 were evaluated both before and after treatment. A statistically significant increase of DHT levels was noticed after TU administration, whereas a marginally significant improvement of sperm morphology was present. Serum FSH concentrations, decreased significantly in the TU group whereas serum LH presented a slight but not statistically significant decrease; 4 pregnancies were achieved by the TU group whereas none were achieved by the patients belonging to the placebo group. The administration of TU per os to patients with idiopathic oligospermia presents a demonstrably positive effect.