Mutations in genes encoding for proteins along the RAS-RAF-MEK-ERK pathway have been detected in a variety of tumor entities including ovarian carcinomas. In the recent years, several inhibitors of this pathway have been developed, whose antitumor potential is currently being assessed in different clinical trials. Low grade serous ovarian carcinoma, is a rare gynecological tumor which shows favorable overall survival, compared to the general ovarian cancer population, but worrying resistance to conventional chemotherapies. The clinical behavior of low grade serous ovarian carcinoma reflects the different gene profile compared to high-grade serous carcinoma: KRAS/BRAF mutations. BRAF inhibitors as single agents were approved for the treatment of BRAF mutated tumors. Nevertheless, many patients face progressive disease. The understanding of the mechanisms of resistance to BRAF inhibitors therapy and preclinical studies showing that BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors combined therapy delays the onset of resistance compared to BRAF inhibitor single agent, led to the clinical investigation of combined therapy. The aim of this paper is to review the efficacy and safety of the combination of BRAF plus MEK inhibitors on ovarian carcinomas, in particularly focusing on low grade serous ovarian carcinoma.

Objective: Early iatrogenic menopause in gynecological cancer survivors and BRCA mutation (BRCAm) carriers undergoing risk-reducing salpingo-oophorectomy (RRSO) is a major health concern. Hormone replacement therapy (HRT) is the most effective remedy, but remains underused in clinical practice. The Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) group promoted a national survey to investigate the knowledge and attitudes of healthcare professionals regarding the prescription of HRT. Methods: The survey consisted of a self-administered, multiple-choice 45-item questionnaire, available online to all MITO members for 2 months starting from January 2022. Results: A total of 61 participants completed the questionnaire (47 out of 180 MITO centers;compliance: 26.1%). Most respondents were female (73.8%), younger than 50 years (65.6%), and gynecologic oncologists (55.7%), working in public general hospitals (49.2%). An 84.4% of specialists actively discuss HRT with patients and 51.0% of patients ask the specialist for an opinion on HRT. The rate of specialists globally in favor of prescribing HRT was 22.9% for ovarian cancer, 49.1% for cervical cancer, and 8.2% for endometrial cancer patients. Most respondents (70.5%) believe HRT is safe for BRCA-mutated patients after RRSO. Nearly 70% of physicians prescribe systemic HRT, while 23.8% prefer local HRT. Most specialists recommend HRT for as long as there is a benefit and generally for up to 5 years. Conclusion Real-world data suggest that many healthcare professionals still do not easily prescribe HRT for gynecological cancer survivors and BRCA mutation carriers after RRSO.Further efforts are required to implement the use of HRT in clinical practice and to support both clinicians in recommending HRT and patients in accepting it.

Mutations in genes encoding for proteins along the RAS-RAF-MEK-ERK pathway have been detected in a variety of tumor entities including ovarian carcinomas. In the recent years, several inhibitors of this pathway have been developed, whose antitumor potential is currently being assessed in different clinical trials. Low grade serous ovarian carcinoma, is a rare gynecological tumor which shows favorable overall survival, compared to the general ovarian cancer population, but worrying resistance to conventional chemotherapies. The clinical behavior of low grade serous ovarian carcinoma reflects the different gene profile compared to high-grade serous carcinoma: KRAS/BRAF mutations. BRAF inhibitors as single agents were approved for the treatment of BRAF mutated tumors. Nevertheless, many patients face progressive disease. The understanding of the mechanisms of resistance to BRAF inhibitors therapy and preclinical studies showing that BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors combined therapy delays the onset of resistance compared to BRAF inhibitor single agent, led to the clinical investigation of combined therapy. The aim of this paper is to review the efficacy and safety of the combination of BRAF plus MEK inhibitors on ovarian carcinomas, in particularly focusing on low grade serous ovarian carcinoma.

Objective: Early iatrogenic menopause in gynecological cancer survivors and BRCA mutation (BRCAm) carriers undergoing risk-reducing salpingo-oophorectomy (RRSO) is a major health concern. Hormone replacement therapy (HRT) is the most effective remedy, but remains underused in clinical practice. The Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) group promoted a national survey to investigate the knowledge and attitudes of healthcare professionals regarding the prescription of HRT. Methods: The survey consisted of a self-administered, multiple-choice 45-item questionnaire, available online to all MITO members for 2 months starting from January 2022. Results: A total of 61 participants completed the questionnaire (47 out of 180 MITO centers;compliance: 26.1%). Most respondents were female (73.8%), younger than 50 years (65.6%), and gynecologic oncologists (55.7%), working in public general hospitals (49.2%). An 84.4% of specialists actively discuss HRT with patients and 51.0% of patients ask the specialist for an opinion on HRT. The rate of specialists globally in favor of prescribing HRT was 22.9% for ovarian cancer, 49.1% for cervical cancer, and 8.2% for endometrial cancer patients. Most respondents (70.5%) believe HRT is safe for BRCA-mutated patients after RRSO. Nearly 70% of physicians prescribe systemic HRT, while 23.8% prefer local HRT. Most specialists recommend HRT for as long as there is a benefit and generally for up to 5 years. Conclusion Real-world data suggest that many healthcare professionals still do not easily prescribe HRT for gynecological cancer survivors and BRCA mutation carriers after RRSO.Further efforts are required to implement the use of HRT in clinical practice and to support both clinicians in recommending HRT and patients in accepting it.

Mutations in genes encoding for proteins along the RAS-RAF-MEK-ERK pathway have been detected in a variety of tumor entities including ovarian carcinomas. In the recent years, several inhibitors of this pathway have been developed, whose antitumor potential is currently being assessed in different clinical trials. Low grade serous ovarian carcinoma, is a rare gynecological tumor which shows favorable overall survival, compared to the general ovarian cancer population, but worrying resistance to conventional chemotherapies. The clinical behavior of low grade serous ovarian carcinoma reflects the different gene profile compared to high-grade serous carcinoma: KRAS/BRAF mutations. BRAF inhibitors as single agents were approved for the treatment of BRAF mutated tumors. Nevertheless, many patients face progressive disease. The understanding of the mechanisms of resistance to BRAF inhibitors therapy and preclinical studies showing that BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors combined therapy delays the onset of resistance compared to BRAF inhibitor single agent, led to the clinical investigation of combined therapy. The aim of this paper is to review the efficacy and safety of the combination of BRAF plus MEK inhibitors on ovarian carcinomas, in particularly focusing on low grade serous ovarian carcinoma.

Objective: Early iatrogenic menopause in gynecological cancer survivors and BRCA mutation (BRCAm) carriers undergoing risk-reducing salpingo-oophorectomy (RRSO) is a major health concern. Hormone replacement therapy (HRT) is the most effective remedy, but remains underused in clinical practice. The Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) group promoted a national survey to investigate the knowledge and attitudes of healthcare professionals regarding the prescription of HRT. Methods: The survey consisted of a self-administered, multiple-choice 45-item questionnaire, available online to all MITO members for 2 months starting from January 2022. Results: A total of 61 participants completed the questionnaire (47 out of 180 MITO centers;compliance: 26.1%). Most respondents were female (73.8%), younger than 50 years (65.6%), and gynecologic oncologists (55.7%), working in public general hospitals (49.2%). An 84.4% of specialists actively discuss HRT with patients and 51.0% of patients ask the specialist for an opinion on HRT. The rate of specialists globally in favor of prescribing HRT was 22.9% for ovarian cancer, 49.1% for cervical cancer, and 8.2% for endometrial cancer patients. Most respondents (70.5%) believe HRT is safe for BRCA-mutated patients after RRSO. Nearly 70% of physicians prescribe systemic HRT, while 23.8% prefer local HRT. Most specialists recommend HRT for as long as there is a benefit and generally for up to 5 years. Conclusion Real-world data suggest that many healthcare professionals still do not easily prescribe HRT for gynecological cancer survivors and BRCA mutation carriers after RRSO.Further efforts are required to implement the use of HRT in clinical practice and to support both clinicians in recommending HRT and patients in accepting it.

Objective: Coronavirus disease 2019 (COVID-19) outbreak has correlated with the disruption of screening activities and diagnostic assessments. Endometrial cancer (EC) is one of the most common gynecological malignancies and it is often detected at an early stage, because it frequently produces symptoms. Here, we aim to investigate the impact of COVID-19 outbreak on patterns of presentation and treatment of EC patients. Methods: This is a retrospective study involving 54 centers in Italy. We evaluated patterns of presentation and treatment of EC patients before (period 1: March 1, 2019 to February 29, 2020) and during (period 2: April 1, 2020 to March 31, 2021) the COVID-19 outbreak. Results: Medical records of 5,164 EC patients have been retrieved: 2,718 and 2,446 women treated in period 1 and period 2, respectively. Surgery was the mainstay of treatment in both periods (p=0.356). Nodal assessment was omitted in 689 (27.3%) and 484 (21.2%) patients treated in period 1 and 2, respectively (p<0.001). While, the prevalence of patients undergoing sentinel node mapping (with or without backup lymphadenectomy) has increased during the COVID-19 pandemic (46.7% in period 1 vs. 52.8% in period 2; p<0.001). Overall, 1,280 (50.4%) and 1,021 (44.7%) patients had no adjuvant therapy in period 1 and 2, respectively (p<0.001). Adjuvant therapy use has increased during COVID-19 pandemic (p<0.001). Conclusion Our data suggest that the COVID-19 pandemic had a significant impact on the characteristics and patterns of care of EC patients. These findings highlight the need to implement healthcare services during the pandemic.

Objective: To evaluate the efficacy and safety of systematic lymph node dissection (SyLND) at the time of interval debulking surgery (IDS) for advanced epithelial ovarian cancer (AEOC). Methods: Systematic literature review of studies including AEOC patients undergoing SyLND versus selective lymph node dissection (SeLND) or no lymph node dissection (NoLND) after neoadjuvant chemotherapy (NACT). Primary endpoints included progression-free survival (PFS) and overall survival (OS). Secondary endpoints included severe postoperative complications, lymphocele, lymphedema, blood loss, blood transfusions, operative time, and hospital stay. Results: Nine retrospective studies met the eligibility criteria, involving a total of 1,660 patients: 827 (49.8%) SyLND, 490 (29.5%) SeLND, and 343 (20.7%) NoLND. The pooled estimated hazard ratios (HR) for PFS and OS were, respectively, 0.88 (95% confidence interval [CI]=0.65–1.20; p=0.43) and 0.80 (95% CI=0.50–1.30; p=0.37). The pooled estimated odds ratios (ORs) for severe postoperative complications, lymphocele, lymphedema, and blood transfusions were, respectively, 1.83 (95% CI=1.19–2.82; p=0.006), 3.38 (95% CI=1.71–6.70; p<0.001), 7.23 (95% CI=3.40–15.36; p<0.0001), and 1.22 (95% CI=0.50–2.96; p=0.67). Conclusion Despite the heterogeneity in the study designs, SyLND after NACT failed to demonstrate a significant improvement in PFS and OS and resulted in a higher risk of severe postoperative complications.

Objective: To investigate current evidence on oncological, fertility and obstetric outcomes of patients with stage I cervical cancer of 4 cm or larger undergoing fertility-sparing surgery (FSS). Methods: Systematic review of studies including women affected by stage I cervical cancer ≥4 cm who underwent FSS. Main outcome measures: disease-free survival (DFS), overall survival (OS), pregnancy rate, live birth rate, premature delivery rate. Results: Fifteen studies met all eligibility criteria for this systematic review, involving 48 patients affected by cervical cancer ≥4 cm who completed FSS. Three patients (6.3%) experienced a recurrence and one of them (2.1%) died of disease. The 5-year DFS rate was 92.4%. The 5-year OS rate was 97.6%. A significantly shorter 5-year DFS was reported for high-risk patients (G3, non-squamous histotype, diameter ≥5 cm) compared with low-risk (74.7% vs. 100%; log-rank test, p=0.024). Data about fertility outcomes were available for 12 patients. Five patients out of 12 (41.7%) attempted to conceive with an estimated pregnancy rate of 80%, a live birth rate of 83.3% and a premature delivery rate of 20%. Conclusion Women with high tumor grade, aggressive histology and tumor size ≥5 cm have a higher risk of recurrence. Oncologic outcomes are encouraging among low-risk patients; however, the lack of high-quality studies makes it difficult to draw any firm conclusions. Prospective multicentric clinical trials with a proper selection of inclusion/exclusion criteria should be conducted in women with low-risk factors, strong desire to preserve their fertility and high likelihood to conceive.

This extensive review summarizes clinical evidence on immunotherapy and targeted therapy currently available for endometrial cancer (EC) and reports the results of the clinical trials and ongoing studies. The research was carried out collecting preclinical and clinical findings using keywords such as immune environment, tumor infiltrating lymphocytes, programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) expression, immune checkpoint inhibitors, anti-PD-1/PD-L1 antibodies and others' on PubMed. Finally, we looked for the ongoing immunotherapy trials on ClinicalTrials.gov. EC is the fourth most common malignancy in women in developed countries. Despite medical and surgical treatments, survival has not improved in the last decade and death rates have increased for uterine cancer in women. Therefore, identification of clinically significant prognostic risk factors and formulation of new rational therapeutic regimens have great significance for enhancing the survival rate and improving the outcome in patients with advanced or metastatic disease. The identification of genetic alterations, including somatic mutations and microsatellite instability, and the definition of intracellular signaling pathways alterations that have a major role in in tumorigenesis is leading to the development of new therapeutic options for immunotherapy and targeted therapy.
Antibodies ; Biological Therapy ; Carcinogenesis ; Developed Countries ; Endometrial Neoplasms ; Female ; Humans ; Immunotherapy ; Lymphocytes, Tumor-Infiltrating ; Microsatellite Instability ; Molecular Targeted Therapy ; Mortality ; Risk Factors ; Survival Rate ; Uterine Neoplasms