BRCA Mutation Patients: Are There Other Predisposing Factors for Ovarian Cancer Occurrence? A Multicenter Retrospective Study.

OBJECTIVES: The objective of this multicenter retrospective study aimed to evaluate the association of clinical variables and the incidence of ovarian cancer in patients with BRCA 1-2 mutation carriers who underwent risk-reducing salpingo-oophorectomy (RRSO). DESIGN: Patients with a pathogenic mutation of BRCA 1-2 genes and with no evidence of disease are considered eligible. The exclusion criterion was the refusal to undergo the surgery. The retrospective study included all RRSO performed from May 2015 to April 2022 in the three gynecological Institutions of Southern Italy for were included in this retrospective study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Age, menarche age, BMI, menopause at time of RRSO, breast cancer first- and second-degree relatives, ovarian cancer first- and second-degree relatives, estroprogestin use, pregnancy normal full-term delivery, history of endometriosis, previous breast cancer and histologic type, previous abdominal/pelvic surgery, BRCA 1 or BRCA 2 status, preoperative serum CA-125 levels (IU/mL), age at time of RRSO and histological analysis were collected. RESULTS: 184 were recruited. One was excluded. To assess cancer risk, the outcome variable was classified into three classes: no event, cancer, and other conditions excluding cancer. 14 women presented ovarian cancer and tubal intraepithelial carcinoma (STIC) on histopathologic final report. Ovarian cancer was found in 8 patients, whereas the presence of STIC was found in 6 of them. LIMITATIONS: The low incidence of patients diagnosed with ovarian cancer or STIC compared with the total number of patients undergoing RRSO is a potential bias. CONCLUSIONS: Our study did not demonstrate a correlation between clinical features and the occurrence of precancerous or cancerous lesions in BRCA mutation carrier patients.

A human-interpretable machine learning pipeline based on ultrasound to support leiomyosarcoma diagnosis.

The preoperative evaluation of myometrial tumors is essential to avoid delayed treatment and to establish the appropriate surgical approach. Specifically, the differential diagnosis of leiomyosarcoma (LMS) is particularly challenging due to the overlapping of clinical, laboratory and ultrasound features between fibroids and LMS. In this work, we present a human-interpretable machine learning (ML) pipeline to support the preoperative differential diagnosis of LMS from leiomyomas, based on both clinical data and gynecological ultrasound assessment of 68 patients (8 with LMS diagnosis). The pipeline provides the following novel contributions: (i) end-users have been involved both in the definition of the ML tasks and in the evaluation of the overall approach; (ii) clinical specialists get a full understanding of both the decision-making mechanisms of the ML algorithms and the impact of the features on each automatic decision. Moreover, the proposed pipeline addresses some of the problems concerning both the imbalance of the two classes by analyzing and selecting the best combination of the synthetic oversampling strategy of the minority class and the classification algorithm among different choices, and the explainability of the features at global and local levels. The results show very high performance of the best strategy (AUC = 0.99, F1 = 0.87) and the strong and stable impact of two ultrasound-based features (i.e., tumor borders and consistency of the lesions). Furthermore, the SHAP algorithm was exploited to quantify the impact of the features at the local level and a specific module was developed to provide a template-based natural language (NL) translation of the explanations for enhancing their interpretability and fostering the use of ML in the clinical setting.

An explainable machine learning ensemble model to predict the risk of ovarian cancer in BRCA-mutated patients undergoing risk-reducing salpingo-oophorectomy.

Introduction: It has been estimated that 19,880 new cases of ovarian cancer had been diagnosed in 2022. Most epithelial ovarian cancer are sporadic, while in 15%-25% of cases, there is evidence of a familial or inherited component. Approximately 20%-25% of high-grade serous carcinoma cases are caused by germline mutations in the BRCA1 and BRCA2 genes. However, owing to a lack of effective early detection methods, women with BRCA mutations are recommended to undergo bilateral risk-reducing salpingo-oophorectomy (RRSO) after childbearing. Determining the right timing for this procedure is a difficult decision. It is crucial to find a clinical signature to identify high-risk BRCA-mutated patients and determine the appropriate timing for performing RRSO. Methods: In this work, clinical data referred to a cohort of 184 patients, of whom 7.6% were affected by adnexal tumors including invasive carcinomas and intraepithelial lesions after RSSO has been analyzed. Thus, we proposed an explainable machine learning (ML) ensemble approach using clinical data commonly collected in clinical practice to early identify BRCA-mutated patients at high risk of ovarian cancer and consequentially establish the correct timing for RRSO. Results: The ensemble model was able to handle imbalanced data achieving an accuracy value of 83.2%, a specificity value of 85.3%, a sensitivity value of 57.1%, a G-mean value of 69.8%, and an AUC value of 71.1%. Discussion: In agreement with the promising results achieved, the application of suitable ML techniques could play a key role in the definition of a BRCA-mutated patient-centric clinical signature for ovarian cancer risk and consequently personalize the management of these patients. As far as we know, this is the first work addressing this task from an ML perspective.

Overlap of Suspicious and Non-Suspicious Features in the Ultrasound Evaluations of Leiomyosarcoma: A Single-Center Experience.

Leiomyosarcoma (LMS) is a rare type of mesenchymal tumor. Suspecting LMS before surgery is crucial for proper patient management. Ultrasound is the primary method for assessing myometrial lesions. The overlapping of clinical, laboratory, as well as ultrasound features between fibroids and LMS makes differential diagnosis difficult. We report our single-center experience in ultrasound imaging assessment of LMS patients, highlighting that misleading findings such as shadowing and absent or minimal vascularization may also occur in LMS. To avoid mistakes, a comprehensive evaluation of potentially overlapping ultrasound features is necessary in preoperative ultrasound evaluations of all myometrial tumors.

The Role of Hormonal Replacement Therapy in BRCA Mutated Patients: Lights and Shadows.

All cancers develop as a result of mutations in genes. DNA damage induces genomic instability and subsequently increases susceptibility to tumorigenesis. Women who carry mutations of BRCA 1 and BRCA2 genes have an augmented risk of breast and ovarian cancer and a markedly augmented probability of dying because of cancer compared to the general population. As a result, international guidelines recommend that all BRCA1\2 mutation carriers be offered risk-reducing bilateral salpingo-oophorectomy at an early age to reduce the risk of cancer and decrease the mortality rate of this high-risk population. NCCN guidelines recommend risk-reducing bilateral salpingo-oophorectomy in pre-menopausal women, between 35-40 years in BRCA1 mutation carriers and between 40-45 years in BRCA2 mutation carriers. Unfortunately, the well-documented reduction of cancer risk is counterbalanced by early sterility and premature ovarian failure with an early onset of secondary menopausal syndromes such as neuromotor, cardiovascular, cognitive and urogenital deficiency. Hormonal replacement therapy significantly compensates for hormonal deprivation and counteracts menopausal syndrome morbidity and mortality; however, some data suggest a possible correlation between hormonal medications and cancer risk, especially in BRCA1\2 carriers who undergo long-term regimens. Conversely, short-term treatment before the age of natural menopause does not appear to increase the cancer risk in BRCA1 mutation carriers without a personal history of breast cancer after prophylactic surgery. Few data are available on BRCA2 mutation carriers and more well-designed studies are needed. In conclusion, clinicians should propose short-term hormone replacement therapy to BRCA 1 carriers to counteract hormonal deprivation; personalized counselling should be offered to BRCA2 mutation carriers for a balance between the risks and benefits of the treatment.

Machine learning applied to MRI evaluation for the detection of lymph node metastasis in patients with locally advanced cervical cancer treated with neoadjuvant chemotherapy.

PURPOSE: Concurrent cisplatin-based chemotherapy and radiotherapy (CCRT) plus brachytherapy is the standard treatment for locally advanced cervical cancer (LACC). Platinum-based neoadjuvant chemotherapy (NACT) followed by radical hysterectomy is an alternative for patients with stage IB2-IIB disease. Therefore, the correct pre-treatment staging is essential to the proper management of this disease. Pelvic magnetic resonance imaging (MRI) is the gold standard examination but studies about MRI accuracy in the detection of lymph node metastasis (LNM) in LACC patients show conflicting data. Machine learning (ML) is emerging as a promising tool for unraveling complex non-linear relationships between patient attributes that cannot be solved by traditional statistical methods. Here we investigated whether ML might improve the accuracy of MRI in the detection of LNM in LACC patients. METHODS: We analyzed retrospectively LACC patients who underwent NACT and radical hysterectomy from 2015 to 2020. Demographic, clinical and MRI characteristics before and after NACT were collected, as well as information about post-surgery histopathology. Random features elimination wrapper was used to determine an attribute core set. A ML algorithm, namely Extreme Gradient Boosting (XGBoost) was trained and validated with tenfold cross-validation. The performances of the algorithm were assessed. RESULTS: Our analysis included n.92 patients. FIGO stage was IB2 in n.4/92 (4.3%), IB3 in n.42/92 (45%), IIA1 in n.1/92 (1.1%), IIA2 in n.16/92 (17.4%) and IIB in n.29/92 (31.5%). Despite detected neither at pre-treatment and post-treatment MRI in any patients, LNM occurred in n.16/92 (17%) patients. The attribute core set used to train ML algorithms included grading, histotypes, age, parity, largest diameter of lesion at either pre- and post-treatment MRI, presence/absence of fornix infiltration at pre-treatment MRI and FIGO stage. XGBoost showed a good performance (accuracy 89%, precision 83%, recall 78%, AUROC 0.79). CONCLUSIONS: We developed an accurate model to predict LNM in LACC patients in NACT, based on a ML algorithm requiring few easy-to-collect attributes.

A prospective multicentric study of risk-reducing salpingo-oophorectomy in BRCA mutation patients.

BACKGROUND AND AIM OF THE WORK: BRCA1/2 are tumour-suppressor genes involved in DNA homologous recombination and ovarian cancer development.  The study evaluated the risk of tumor cancer in women presenting the BRCA mutations. METHODS: Risk-reducing surgery (RRS) was performed in 100 patients carrying BRCA1 (aged between 30-73 years, median age was 51 years) and BRCA 2 mutation (aged between 36-70 years, median age was 53 years). Fifty-eight patients had previous history of breast cancer. RESULTS: Between the 100 patients, 82 women underwent risk-reducing salpingo-oophorectomy (RRSO) through a laparoscopic minimally invasive approach, 7 (7 %) underwent laparoscopic RRSO and contextual hysterectomy, 1 woman (1 %) underwent RRSO through a laparotomic approach and 10 women (10 %) laparotomic RRSO and hysterectomy. During 5 (5 %) laparoscopic RRSO, prophylactic bilateral mastectomy was also performed. Early and late complication occurred in 3 patients (3 %). Two patients (2 %) were found to have occult Serous Tubal Intraepithelial Carcinoma (STIC) and three patients (3 %) occult cancer. CONCLUSIONS: RRSO is safe and feasible in BRCA mutation carriers. The procedure is effective for genetic prevention of ovarian cancer.

Characteristics and outcome of BRCA mutated epithelial ovarian cancer patients in Italy: A retrospective multicenter study (MITO 21).

OBJECTIVE: Around 15% of epithelial ovarian cancer (EOC) patients (pts) harbor a germline BRCA1 or 2 mutation, showing different features than BRCA wild-type pts. The clinical and pathological features of an Italian BRCA mutated EOC cohort were described. METHODS: We retrospectively analyzed clinical, pathological and mutational data from a cohort of Italian BRCA mutated EOC pts. treated in 15 MITO centers between 1995 and 2017. RESULTS: Three-hundred thirty-one pts. were recorded. Two-hundred forty (72%) and 91 (27.5%) pts. harbored a BRCA1 and BRCA2 mutation, respectively. Median age at diagnosis was 52 years. The most frequent diagnosis was a high grade serous FIGO III or IV EOC and platinum doublet in first-line was administered to almost all pts. Fifty-three % of them had no residual disease (R = 0) at surgery. Median progression-free-survival (mPFS) after first-line chemotherapy was 29 months. Expected percentage of pts. alive at 5 years was 72.5% (CI 60.2-80.8%) and R = 0 predicted a significantly longer overall survival (OS). Sixty-six pts. (19,9%) had both an EOC and a breast cancer (BC) diagnosis. The first diagnosis was BC in 81,8% of cases with a mean interval between the two diagnoses (IBTDs) of 132.4 months. Mutational data show that the founder mutation c.5266dupC in BRCA1 was the most frequently recorded. CONCLUSIONS: This is the largest Italian BRCA mutEOC cohort. The only predictor of longer OS was R = 0. EOC pts. that developed subsequently a BC are long-term survivors.

PARP inhibitors and epithelial ovarian cancer: Molecular mechanisms, clinical development and future prospective.

Epithelial ovarian cancer (EOC) has a poor prognosis. Since the introduction of paclitaxel as antineoplastic agent >20 years ago, only a few phase III randomized trials have shown challenging data regarding different therapeutic options for facing its aggressive clinical course and granting active therapies to patients. Different studies have shown the utility of poly(ADP-ribose) polymerase (PARP) inhibitors in women with EOC with or without BRCA mutations, both germline and somatic. Three PARP inhibitors, olaparib, rucaparib and niraparib, have been recently approved by the Food and Drug Administration for clinical use in EOC patients, though with different clinical indications and profiles of toxicity, while two other molecules, veliparib and talazoparib, are still under clinical investigation. The aim of the present paper is to evaluate the current status of PARP inhibitors in terms of molecular activity, pharmacodynamic properties and clinical applications.

In Vitro Generation of Oocytes from Ovarian Stem Cells (OSCs): In Search of Major Evidence.

The existence of ovarian stem cells (OSCs) in women as well as their physiological role in post-menopausal age are disputed. However, accumulating evidence demonstrated that, besides the animal models including primarily mice, even in adult women putative OSCs obtained from ovarian cortex are capable to differentiate in vitro into oocyte-like cells (OLCs) expressing molecular markers typical of terminal stage of oogonial cell lineage. Recent studies describe that, similarly to mature oocytes, the OSC-derived OLCs also contain haploid karyotype. As proof of concept of their stem commitment, OSCs from mice differentiated to oocytes in vitro are suitable to be fertilized and implanted in sterilized animals resulting in embryo development. Despite enthusiasm for these data, which definitely require extended confirmation before considering potential application in humans for treatment of ovarian insufficiency, OSCs appear suitable for other clinical uses, restoring the endocrine derangements in premature ovarian failure or for fertility preservation in oncologic patients after anti-cancer treatments. In this context, the selection of viable oocytes generated from OSCs before chemotherapy protocols would overcome the potential adjunct oncogenic risk in women bearing hormone-dependent tumors who are repeatedly stimulated with high dose estrogens to induce oocyte maturation for their egg recruitment and cryopreservation.

Paget disease of the vulva an analysis of 24 cases.

Paget's disease can arise in the breast (mammary Paget disease) or in other locations (extramammary Paget disease) such as anogenital skin in both males and females (Paget disease of the vulva [PDV]). Underlying adenocarcinoma can be found in some cases. This study aims to report clinical aspects, surgical procedures, outcomes, and recurrences of patients with PDV.A retrospective chart review was conducted on patients with pathologically confirmed diagnosis of PDV managed at the Department of Obstetrics and Gynecology, University of Bari, and the "Giovanni Paolo II" National Cancer Institute in Bari, between 1998 and 2018.Records of 24 cases of PDV were examined. Median age of the patients at diagnosis was 69.3 (range 38-84), diagnosis of synchronous cancer was made in 2 cases and in 2 other cases of metachronous disease. Three patients had previously been diagnosed with other oncological diseases. All patients underwent surgery including wide local excision (6), simple vulvectomy (8), and extended vulvectomy (10). Lymphadenectomy was performed in 2 cases and reconstructions with advancement flaps in 7 cases. Four patients were found to have invasive disease and 1 had inguinal node involvement. Positive margins were found in 11 patients. Wound dehiscence and urethral stenosis were found in 4 and 1 case each. Eight recurrences (33.33%) were observed, regardless of positive surgical margins.PDV has a low rate of malignancy but a high rate of recurrence. It should be diagnosed early to avoid repeated surgery and to reduce symptoms and morbidity.

Hysteroscopy as a valid tool for endometrial pathology in patients with postmenopausal bleeding or asymptomatic patients with a thickened endometrium: hysteroscopic and histological results.

OBJECTIVE: This study compares hysteroscopic and histopathological results in postmenopausal women with abnormal uterine bleeding (AUB) and asymptomatic postmenopausal women with a thickened endometrium. MATERIALS AND METHODS: This is a retrospective study of 570 cases hysteroscopically examined between January 2008 and July 2012. The patients were followed up at the Istituto Tumori 'Giovanni Paolo II', Bari, Italy. RESULTS: A total of 320 of the 570 cases were selected. The inclusion criteria were transvaginal ultrasound, hysteroscopy and endometrial biopsy. In the AUB group, if the hysteroscopy results were normal, a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 100, 95, 71 and 100%, respectively, were achieved, while in the asymptomatic group these values were 100, 97, 90 and 100%, respectively. For both the group with polyps and that with myomas, the sensitivity, specificity, PPV and NPV were 100%. For endometrial hyperplasia, hysteroscopy showed a sensitivity, specificity, PPV and NPV of 81, 96, 87 and 93%, respectively, in the AUB group, while in the asymptomatic group, the sensitivity was 60%, the specificity and PPV were 100%, and the NPV was 98%. The sensitivity of hysteroscopy for endometrial cancer was 63%, the specificity 97%, the PPV 77%, and the NPV 95%. CONCLUSIONS: In postmenopausal women with a thickened endometrium with or without AUB, hysteroscopy allows for an accurate diagnosis in benign endometrial pathology. Hysteroscopy also allows directed biopsies of suspicious lesions, which is useful in malignant endometrial pathology.

BRCA1/2 and clinical outcome in a monoinstitutional cohort of women with hereditary breast cancer.

The clinical outcome of BRCA mutation carriers and non-carriers still remains a topic of discussion. In order to interpret controversial data, in the present study, we analyzed a large consecutive monoinstitutional series of breast cancer patients and relatives with familial features carrying or not carrying BRCA mutations. The intense research in recent years regarding the clinical genetics of patients with breast or ovarian cancer and their relatives has allowed the organization of a unique database comprising anamnestic, clinical, pathological and molecular data. Families with two or more cases of breast cancer under the age of 50 years, or with three cases at any age, were identified. From June, 2003 to June, 2010, a total of 202 patients (136 probands + 66 relatives) from 45 families were included in the analysis. A total of 136 (49 carrier and 87 non-carrier) cases had a cancer diagnosis at the time of their genetic testing. Twenty and 24 events were observed in the carrier and control group, respectively. The 10-year disease-free suvival rate was 57% for patients in the control group compared with 50% for patients carrying a BRCA mutation (P=0.15 by log-rank test). Finally, 66 (32 genetic and 34 control) cases were unaffected at the time of molecular analysis, and 6 new cases of cancer were observed in the carriers, while no new cases were detected in the control cohort. Thus, at age 50, 40% of carriers had a high risk of disease (P=0.0069 by log-rank test). Our data support the hypothesis that the presence of BRCA mutations does not alter the clinical outcome for hereditary breast cancer patients. Conversely, BRCA mutations are proven to be crucial for prediction of risk in healthy relatives from carrier families.

Benign granular cell tumor of the vulva: first report of multiple cases in a family.

Granular cell tumors (GCTs) are uncommon soft tissue tumors of neural derivation, as supported by immunohistochemical and ultrastructural evidence. Vulvar involvement has been reported in 7-16%. This paper presents the cases of a 60-year-old woman and her 32-year-old niece with a strong family history of cancer, both presenting with an enlarging mass on their left labia majora. The lesions were treated by simple surgical excision. Histopathological examination revealed a benign vulvar GCT in both lesions. This is the first reported case of GCT of the vulva in the same family. The possible familial component of GCT needs further investigation. A systematic review of the literature on vulvar GCTs is carried out, the most complete one to date. This review unexpectedly reveals that there have been more than 130 cases of GCT of the vulva reported to date, only 7 of which were malignant. Since 5-25% of patients have multiple lesions, before planning treatment, clinicians should exclude multicentric lesions. After surgical treatment, if there is any evidence of tumor in the surgical margin, wider local excision should be performed. Regular follow-up is important for diagnosing a possible recurrence or a new lesion.