Hormone Molecular Biology and Clinical Investigation

Non-surgical prevention strategies in women with hereditary breast and ovarian cancer syndromes

Abstract Objectives To review non-surgical prevention strategies in women with hereditary breast and ovarian cancer syndromes. Content Women with a g BRCA1 or 2 mutations face a high cumulative breast and ovarian cancer risk. While bilateral mastectomy (PBM) and bilateral salpingo-oophrectomy (PBSO) profoundly reduce the respective cancer risks, they are also associated with considerable side effects. There is therefore an urgent need for alternative and non-surgical risk reduction options. Tamoxifen and aromatase inhibitors have both been evaluated in secondary prevention, but their benefit in primary prevention is currently unknown in BRCA mutation carriers. In addition, their use is compromised by their side effect profile which makes them less appealing for a use in chemoprevention. Summary and outlook Denosumab is a well-tolerated osteoprotective drug, which has been demonstrated to have a potential preventive effect particularly in BRCA1 -deficient models in vitro . The prospectively randomized double-blind BRCA-P trial is currently investigating the preventative effect of denosumab in healthy BRCA1 germ line mutation carriers.

Preface to special issue: update in the management of ovarian cancer

How to manage BRCA mutation carriers?

Abstract Inherited mutations in BRCA1 and BRCA2 genes increase the risk of development of cancer in organs especially in breast and ovary. Prevention and screening in BRCA mutation carriers are of high importance. Prophylactic surgeries are possible but are still insufficiently performed because they require surgical procedures in healthy patients. Guidelines for the management of BRCA mutations carriers must absolutely be part of the standard practice of all those involved in the management of these patients to increase the impact of the implementation of these preventive measures. There is no screening recommended for ovarian cancer. A risk-reducing bilateral salpingo-oophorectomy should be performed from age 35 to 40 years for BRCA1 mutation carriers and 40 to 45 years for BRCA2 mutation carriers. A screening for breast cancer should be performed annually from 30 years old by breast MRI and mammography. A risk-reducing bilateral mastectomy is recommended with nipple sparing mastectomy and immediate breast reconstruction from 30 years and before 40 years. A multidisciplinary care must be implemented for these patients with an important psychological support.

Hyperthermic intraperitoneal chemotherapy in ovarian cancer: an update

Abstract In the treatment of advanced-stage epithelial ovarian cancer (EOC)-associated surgery and chemotherapy with intravenous platinum/taxane-based therapy most patients had early or late recurrence. Prevention of progression and recurrence is a major objective for the management of EOC. Recently, many clinical studies have evaluated the strategy with hyperthermic intraoperative intraperitoneal (IP) drug delivery. This is an update of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) in EOC and a view for future strategies. Until recently studies on HIPEC in patients with EOC were mostly retrospective and heterogeneous. Thanks to recent clinical trials, it is reasonable to conclude that surgical cytoreduction and HIPEC is an interesting approach in the management of EOC without increasing morbidity.

Effects of iron-related compounds and bilirubin on redox homeostasis in endometriosis and its malignant transformations

Abstract Objectives The balance between oxidative stress and antioxidant defense has been reported to differ between women with endometriosis and patients with its malignant transformation. The aim of this study is to investigate changes in redox balance in endometriosis and endometriosis-related ovarian cancer (EAOC) by simultaneously measuring iron-related compounds and bilirubin. Methods This study included 235 patients with a histopathologically confirmed diagnosis of endometriosis (n=178) and EAOC (n=57). Cyst fluid samples were collected in Nara Medical University hospital from January 2013 to May 2019. The levels of iron-related compounds (total iron, heme iron, free iron, oxyhemoglobin [oxyHb], methemoglobin [metHb], and metHb/oxyHb ratio) and bilirubin were measured. Results Total iron, heme iron, free iron, metHb/oxyHb ratio, and bilirubin were significantly elevated in endometriosis compared to EAOC. In both endometriosis and EAOC, iron-related compounds in the cyst were correlated with each other. There was no statistically significant difference in oxyHb and metHb levels between the two groups, but the metHb/oxyHb ratio was significantly higher in endometriosis than in EAOC. Bilirubin was positively correlated with total iron and free iron in EAOC, but there was no correlation between bilirubin and iron-related compounds in endometriosis. Conclusions Iron-induced oxidative stress in endometriosis may exceed bilirubin-dependent antioxidant capability, while redox homeostasis in EAOC can be maintained by at least bilirubin.

Determinants of serum adiponectin levels: a cross-sectional study

Abstract Objectives To review non-surgical prevention strategies in women with hereditary breast and ovarian cancer syndromes. Content Women with a g BRCA1 or 2 mutations face a high cumulative breast and ovarian cancer risk. While bilateral mastectomy (PBM) and bilateral salpingo-oophrectomy (PBSO) profoundly reduce the respective cancer risks, they are also associated with considerable side effects. There is therefore an urgent need for alternative and non-surgical risk reduction options. Tamoxifen and aromatase inhibitors have both been evaluated in secondary prevention, but their benefit in primary prevention is currently unknown in BRCA mutation carriers. In addition, their use is compromised by their side effect profile which makes them less appealing for a use in chemoprevention. Summary and outlook Denosumab is a well-tolerated osteoprotective drug, which has been demonstrated to have a potential preventive effect particularly in BRCA1 -deficient models in vitro . The prospectively randomized double-blind BRCA-P trial is currently investigating the preventative effect of denosumab in healthy BRCA1 germ line mutation carriers.

PTEN protein expression has role in predicting disease-free-interval in endometrioid endometrial carcinoma

Abstract Objectives To determine the significance of tumour PTEN protein expression in endometrioid endometrial carcinoma (EEC) and it is correlation with tumour characteristics. Methods A total of 30 eligible archived paraffin-embedded tissue blocks from 61 EEC cases (January 2015–December 2017) were retrieved from the Histopathology Laboratory in Universiti Kebangsaan Malaysia Medical Centre (UKMMC) following institutional ethic approval. For PTEN protein detection, immunohistochemistry (IHC) staining was performed and the data was correlated with clinicopathologic parameters. Results Fourteen samples (46.7%) showed positive PTEN protein expression, while 16 (53.3%) were negative. The mean age was 62.00 ± 9.51 years old, while the mean Body Mass Index (BMI) was 27.28 ± 7.16 kg/m 2 . There was no significant difference between age (p=0.27, 95% CI: −10.98 to 3.21) and BMI (p=0.67, 95% CI: −4.30 to 6.58) with PTEN protein expression. There were significant correlation between PTEN protein expression with myometrial invasion (p=0.010), but not with lymphovascular space invasion (p=0.743), grade (p=0.532), stage (p=0.733) and CA-125 level (p=0.47). The higher stage correlates with the presence of LVSI (p=0.002). PTEN positive associated with longer disease-free-interval (p=0.025), but not improving the overall survival (p=0.38) Conclusions Positive PTEN protein expression correlates with less myometrial invasion.

Mature cystic ovarian teratoma with squamous cell carcinoma transformation: a case report and literature review

Abstract Objectives Cancerous transformation in mature cystic ovarian teratoma is rare. Herein, we reported a case of squamous cell carcinoma transformation in mature cystic ovarian teratoma and performed an in-depth literature review to highlight the risk factors, prognosis, and suggested treatment for these patients. Case presentation We report a 66-years old postmenopausal woman diagnosed with a 120×90 (mm) mass at the left adnexa compatible with mature cystic ovarian teratoma. Following resection, the histopathological investigations showed malignant transformation in her mature cystic ovarian teratoma, and the immunohistochemistry for cytokeratin (CK) 5/6 and tumor protein 63 (P63) indicated squamous cell carcinoma transformation. She has been observed for her stage IA tumor and has been cancer-free for 6 months. Conclusions Although malignant transformation in mature cystic ovarian teratoma is rare, it should be suspected if certain risk factors, e.g., elderly and high tumor size, exist. Stage IA patients’ prognosis is favorable, and chemotherapy is not recommended.

How do different histologic components of mixed endometrial carcinomas affect prognosis? Does it really matter?

Abstract The aim of this study is to evaluate and compare outcomes of patients with mixed and pure endometrial carcinomas (MEC). We reviewed data of patients with MEC, endometroid (EC), serous (SC), and clear cell (CC) carcinomas between 2002 and 2015. Overall survival (OS) and disease-free (DF) survival rates were evaluated, according to the percentage of histologic components. Clinicopathological variables and treatment strategies were assessed. Furthermore, χ 2 tests were used to compare proportions and Kaplan–Meier curves to compare recurrence and survival. Sample consisted of 302 cases with mean age 66.3 years. Early-stage disease was recorded in EC compared with CC and SC. Adnexal involvement was more frequent in MEC compared with EC (p=0.043). Extra uterine metastasis was more frequent in the SC compared to the EC group, while lymphovascular space involvement was more frequent in the MEC and CC compared to the SC (p=0.001). EC had less omentum involvement compared to CC (p=0.035) and SC (p<0.001). Furthermore, cervical involvement was more frequent in CC compared to EC (p=0.011). Recurrence (p=0.265) and OS (p=0.533) were found to be similar in MEC compared with CC, SC, and EC. Moreover, recurrence and OS were similar between EC-CC and EC-SC. There were no differences in recurrence and survival in MEC with a type II component larger than 10% or 20% (p>0.05).

WNT5A in ovarian physiology and pathology: from molecular mechanisms to therapeutic potential

Abstract Introduction As a pivotal molecule in tissue development and homeostasis, WNT5A regulates various aspects of ovarian physiology, including folliculogenesis, oocyte maturation, and hormonal responses. Content This review summarizes current knowledge on the molecular mechanisms of WNT5A signaling, its role in ovarian health, and its pathological involvement in disorders such as polycystic ovary syndrome (PCOS) and ovarian cancer. We discuss how WNT5A may be a double-edged sword in ovarian diseases and explore its therapeutic potential. Summary In PCOS, WNT5A exacerbates the inflammatory environment and insulin resistance, disrupting normal folliculogenesis and leading to impaired ovarian function. Moreover, in ovarian cancer, WNT5A presents challenges for therapeutic targeting, as it can either inhibit or facilitate tumor progression depending on the context. Outlook Continued research into the peripheral and central regulatory mechanisms of WNT5A, along with its interactions with other signaling pathways, will be instrumental in unlocking its full therapeutic potential.

Distant recurrence of endometrial cancer more than 10 years after hysterectomy: a case report

Abstract Objectives Endometrial cancer is the sixth most common cancer among women and recurrence of after 10 years is extremely rare. Case presentation We reported a comprehensive review of histopathology, investigations and treatment regarding a woman with distant recurrence of endometrial cancer to rectus abdominis muscle after 23 years from the primary surgery. Previous published literatures of similar case were included into the review analysis. A total of 11 similar cases had been reported. Overall, 9 (81.8%) cases were stage 1 disease and only 2 cases were classified as stage II disease. The majority, 6 (54.5%) cases were endometrial adenocarcinoma. Majority of the cases shared the similarity of low grade endometrial cancer with positive oestrogen receptor immunophynetype. Conclusions Thus, the phenomenon of ‘cell dormancy’ was hypothesized to explain the mechanism of late recurrence for these cases.