Evaluation of family history in individuals with heterozygous BRCA pathogenic variants diagnosed with breast or ovarian cancer in a single center in Italy.

BACKGROUND: BRCA1 and BRCA2 gene mutations are responsible for 5% of breast cancer (BC) and 10-15% of ovarian cancer (EOC). The presence of a germline mutation and therefore the identification of subjects at high risk of developing cancer should ideally precede the onset of the disease, so that appropriate surveillance and risk-reducing treatments can be proposed. In this study, we revisited the family history (FH) of women who tested positive for BRCA mutations after being diagnosed with BC or EOC. METHODS: The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®), and the Italian Association of Medical Oncology (AIOM) guidelines were applied to the FH of 157 women who were referred to San Gerardo Hospital for genetic counseling. RESULTS: Almost 85% of women had an FH of BRCA-related cancer. 63.7% and 52.2% of women could have undergone genetic testing according to NCCN and AIOM testing criteria (p < .05) before tumor diagnosis. An FH of EOC was the most frequent NCCN criterion, followed by BC diagnosed <45 years old. Sixty-five percent of deceased women could have undergone genetic testing before developing cancer. CONCLUSIONS: FH is a powerful tool to identify high-risk individuals eligible for genetic counseling and testing. Testing of healthy individuals should be considered when an appropriately affected family member is unavailable for testing.

Cancer Anxiety Mediates the Association Between Satisfaction With Medical Communication and Psychological Quality of Life After Prophylactic Bilateral Salpingo-Oophorectomy.

Background: Prophylactic Bilateral Salpingo-Oophorectomy (PBSO) reduces the risk of developing ovarian cancer. However, the psychological mechanisms that may affect post-surgery Quality of Life (QoL) among patients who underwent PBSO are still largely unknown. Thus, this study aimed at exploring the direct and indirect associations of satisfaction with medical communication and cancer anxiety on post-surgery QoL among women at high risk of developing ovarian cancer. Method: Fifty-nine women (mean age: 50.64 ± 6.7 years) who underwent PBSO took part in this cross-sectional study, filling out a sociodemographic and clinical questionnaire, a battery of validated psychological measures and an ad hoc developed scale for the assessment of cancer anxiety. We first examined the correlations among all variables of interest, and then tested if cancer anxiety mediated the association between satisfaction with medical communication and post-surgery psychological QoL, controlling both for time from surgery and education. Results: Post-surgery psychological QoL was unrelated from any sociodemographic or clinical variable. Cancer anxiety had a significant direct negative effect on psychological QoL, while satisfaction with medical communication had a significant positive direct effect on it. Finally, cancer anxiety significantly mediated the association between satisfaction with medical communication and post-surgery psychological QoL. Discussion: Results suggest that post-surgery psychological QoL of patients who underwent PBSO may be increased with interventions, delivered in a genetic counselling setting, targeting quality of medical communication and cancer anxiety.

Tubal histopathological abnormalities in BRCA1/2 mutation carriers undergoing prophylactic salpingo-oophorectomy: a case-control study.

OBJECTIVE: To describe tubal histopathological abnormalities in women with germline BRCA1/2 mutations and in controls. METHODS: Consecutive women with BRCA1/2 mutations undergoing bilateral salpingo-oophorectomy between 2010 and 2020 in two centers (San Gerardo Hospital, Monza and San Matteo Hospital, Pavia) were considered in this analysis and compared with controls who had the same surgical procedure for benign conditions. Frequency of p53 signature, serous tubal intraepithelial carcinoma, and high-grade serous ovarian cancer were compared between the two groups. RESULTS: A total of 194 women with pathogenic BRCA1/2 mutations underwent prophylactic salpingo-oophorectomy. Of these, 138 women (71%) had a completely negative histological examination, while in 56 (29%) patients an ovarian or tubal alteration was reported. Among controls, 84% of patients had a p53wt signature, while 16% had a p53 signature. There was no difference in the frequency of a p53 signature between cases and controls; however, women with BRCA1/2 mutations were more likely to have pre-malignant or invasive alterations of tubal or ovarian epithelium (p=0.015). Among mutation carriers, older age both at genetic testing and at surgery was associated with an increased risk of having malignancies (OR=1.07, p=0.006 and OR=1.08, p=0.004, respectively). The risk of malignancy seems to be increased in patients with a familial history of high-grade serous ovarian cancer. Previous therapy with tamoxifen was significantly more frequent in patients with malignant lesions (40.0% vs 21.3%, p=0.006). CONCLUSION: We found that a p53 signature is a frequent finding both in BRCA1/2 mutation carriers and in controls, while pre-invasive and invasive lesions are more frequent in BRCA1/2 mutation carriers. Genetic and clinical characteristics are likely to affect the progression to malignancy.

Prevalence of Human Papillomavirus (HPV) and Other Sexually Transmitted Infections (STIs) among Italian Women Referred for a Colposcopy.

Sexually transmitted infections (STIs) represent a major cause of morbidity in women and men worldwide. Human Papillomavirus (HPV) infections are among the most prevalent STIs and persistent infections with high-risk HPV (hrHPV) genotypes can cause cervical dysplasia and invasive cervical cancer. The association of other STIs with HPV cervical infection and/or dysplasia has however not yet been fully elucidated. The aim of this study was to assess the prevalence of HPV and other STIs among women presenting with an abnormal cervical cytology. Cervical infections with 28 HPV genotypes and seven other sexually transmitted pathogens were evaluated in 177 women referred for a colposcopy after an abnormal Pap smear. Positivity for at least one hrHPV genotype was shown in 87% of women; HPV 16 was the most prevalent (25.0%), followed by HPV 31 and HPV 51. The overall positivity for other STIs was 49.2%, with Ureaplasma parvum being the most prevalent microrganism (39.0%). Co-infections between hrHPV and other STIs were demonstrated in 17.5% of women; no significant association was demonstrated between multiple infections and the colposcopy findings. This study provides new epidemiological data on the prevalence of cervical infections associated with HPV and seven other common sexually transmitted pathogens in a population of women presenting with an abnormal cervical cytology.

Role of 18 F-fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in malignant ovarian germ cell tumors: a single-center experience with long term follow-up.

INTRODUCTION: 18F-fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is a diagnostic tool widely used in oncology, but to date there are no established recommendations for its use in malignant ovarian germ cell tumors. The aim of this study was to evaluate the role of 18F-FDG PET/CT in the clinical management of patients with malignant ovarian germ cell tumors. METHODS: This was a retrospective review of 18F-FDG PET/CT scans performed in patients diagnosed with malignant ovarian germ cell tumors treated at the gynecology department of San Gerardo Hospital (Monza, Italy) from June 2006 to December 2016. Data collected included clinical history, radiological, biochemical and pathological evaluation, treatment, follow-up, outcome, and clinical indication for the PET/CT scan. PET/CT findings were categorized as negative/normal (no abnormal FDG uptake or physiological uptake), positive/abnormal (FDG uptake considered to indicate active germ cell malignancy), or equivocal (FDG uptake of uncertain significance, not clearly correlated to neoplastic disease). RESULTS: A total of 69 PET/CT scans in 37 patients were evaluated. The mean age at diagnosis was 25 years (range 20-48). The majority of patients had International Federation of Gynecology and Obstetrics (FIGO) stage I (22/37) disease and had a diagnosis of dysgerminomas (18/37). Imaging indications were initial staging before treatment (4/69, 6%), staging after inadequate staging surgery (24/69, 35%), restaging after adjuvant chemotherapy (17/69, 25%), relapse suspect (9/69, 13%), and follow-up (15/69, 21%). Pathology confirmation of PET/CT results was available in 28/69 (40.5%) studies. All negative PET/CT (15/28) cases were confirmed with laparoscopy as true negative; among 13/28 positive PET cases, histopathology confirmed 7 (54%) as true positive and 6 (46%) as false positive (5 inflammatory and 1 mature teratoma implants). Patient-based analysis showed 100% sensitivity, 71% specificity, 54% positive predictive value, 100% negative predictive value, and 79% accuracy. Clinical follow-up was available in 41 (59.4%) of 69 PET/CT images: 28/41 studies were negative and 13/41 positive. A mean follow-up of 28 months (median 15, range 5-102) confirmed negative PET/CT studies. A total of 13 positive PET/CT patients underwent chemotherapy with subsequent evidence of disease response. DISCUSSION: PET/CT in malignant ovarian germ cell tumors was mainly performed for staging after inadequate staging surgery or for restaging after adjuvant chemotherapy. PET/CT was associated with high sensitivity and negative predictive value.

Oncologic and fertility impact of surgical approach for borderline ovarian tumours treated with fertility sparing surgery.

BACKGROUND: Even if borderline ovarian tumours (BOTs) in young women treated with fertility-sparing treatment (FST) have an excellent outcome, the type of surgery might affect relapse and fertility. We investigated the effect of surgical approach (open surgery vs. laparoscopy) and type of surgery (salpingo-oophorectomy [SO] vs. cystectomy [Cy]) on oncologic and fertility outcomes in patients with BOT. PATIENTS AND METHODS: Patients with BOT treated at San Gerardo Hospital, Monza, with FST in 1978-2013 period were included. Cox models, stratified by decade of surgery, were used to investigate the association between time to first recurrence or conception and clinical factors. RESULTS: Among 535 patients included, 271 underwent unilateral SO and 264 underwent Cy. Median follow-up was 13.5 years. Ten-year (10-yr) recurrence rate was 23% (95% confidence interval [CI]: 18-29%) for SO and 31% (95% CI: 24-38%) for Cy group (P = 0.10) in patients with unilateral tumour, whereas it was 62% (95% CI: 44-79%) and 72% (95% CI: 59-84%), respectively, (P = 0.35) in patients with bilateral tumour. Multivariable analysis showed no association between recurrence and surgical approach (P = 0.44), type of surgery (P = 0.06) and a negative association with advanced stage (hazard ratio [HR] = 3.18; 95% CI: 2.11-4.78; P < 0.001) and bilateral tumours (HR = 2.48; 95% CI: 1.78-3.47; P < 0.001). Among 252 patients (47.1%) with pregnancy desire, multivariable analysis showed no association between conception success and the type of surgery, surgical approach, histology and tumour laterality. Fertility after surgery was positively associated with prior pregnancy (HR = 1.68; 95% CI: 1.17-2.41; P = 0.005) and negatively associated with the number of surgical procedures (HR = 0.62; 95% CI: 0.53-0.73; P < 0.001). CONCLUSIONS: The type of surgical procedures did not influence recurrence rate or fertility. However, additional surgical procedures decreased the fertility potential. These data can support clinicians in tailoring the best strategy for FST in young patients with BOT.

Ovarian function, fertility, and menopause occurrence after fertility-sparing surgery and chemotherapy for ovarian neoplasms.

BACKGROUND: The effect of chemotherapy exposure (CE) on ovarian function in young women with ovarian neoplasms undergoing fertility-sparing treatment (FST) remains unclear. We investigated whether CE is correlated with the outcomes (1) during-treatment and (2) post-treatment amenorrhea, (3) conception rate, (4) pregnancy outcome, and (5) spontaneous menopausal age. PATIENTS AND METHODS: Eligibility criteria were patients with a diagnosis of epithelial (EOC) or nonepithelial (no-EOC) invasive ovarian neoplasm, premenopausal age, undergoing FST ±â€¯CE, histopathology confirmation, and adequate follow-up. The groups' outcomes were compared by logistic and linear regression analysis. RESULTS: A total of 548 patients diagnosed during 1980 and 2014 were included, 198 in the EOC group and 350 in the no-EOC group, and 44% received chemotherapy, with a median follow-up of 15.9 years. In no-EOC patients, CE conferred a higher risk for Outcomes 1 (adjusted OR [aOR] 27; 95% CI 12 to 61; P < .0001) and 2 (aOR 5.42; 95% CI 1 to 24; P = .0256) and was associated with a younger menopausal age (adjusted ß -5.52; 95% CI -10.53 to -0.52; P = .0313). Overall, 57% of patients attempted pregnancy, with a conception rate of 89%. In EOC patients, no association between CE and a decreased fertility was demonstrated (aOR, 3.05; 95% CI 0.72 to 12.88; P = .1298). CONCLUSIONS: CE in no-EOC was associated with an increased risk of during-treatment amenorrhea, post-treatment amenorrhea, and earlier spontaneous menopausal age; CE in EOC was not associated with any item at study. Patients undergoing FST had reassuringly high conception rates and low premature ovarian failure rates; however, in pretreatment counseling, the risks of this approach in such young population should be discussed.

Platinum sensitivity and DNA repair in a recently established panel of patient-derived ovarian carcinoma xenografts.

A xenobank of patient-derived (PDX) ovarian tumor samples has been established consisting of tumors with different sensitivity to cisplatin (DDP), from very responsive to resistant. As the DNA repair pathway is an important driver in tumor response to DDP, we analyzed the mRNA expression of 20 genes involved in the nucleotide excision repair, fanconi anemia, homologous recombination, base excision repair, mismatch repair and translesion repair pathways and the methylation patterns of some of these genes. We also investigated the correlation with the response to platinum-based therapy. The mRNA levels of the selected genes were evaluated by Real Time-PCR (RT-PCR) with ad hoc validated primers and gene promoter methylation by pyrosequencing. All the DNA repair genes were variably expressed in all 42 PDX samples analyzed, with no particular histotype-specific pattern of expression. In high-grade serous/endometrioid PDXs, the CDK12 mRNA expression levels positively correlated with the expression of TP53BP1, PALB2, XPF and POLB. High-grade serous/endometrioid PDXs with TP53 mutations had significantly higher levels of POLQ, FANCD2, RAD51 and POLB than high-grade TP53 wild type PDXs. The mRNA levels of CDK12, PALB2 and XPF inversely associated with the in vivo DDP antitumor activity; higher CDK12 mRNA levels were associated with a higher recurrence rate in ovarian patients with low residual tumor. These data support the important role of CDK12 in the response to a platinum based therapy in ovarian patients.

Laparoscopic Sentinel Node Mapping in Cervical and Endometrial Malignancies: A Case-Control Study Comparing Two Near-Infrared Fluorescence Systems.

STUDY OBJECTIVE: The goal of this study was to evaluate the intraoperative and perioperative surgical outcomes of 2 different florescence systems commonly used for sentinel lymph node (SLN) mapping in women with early-stage cervical cancer or endometrial cancer. DESIGN: Case-control study (Canadian Task Force classification II-2). SETTING: The Gynecology Oncology Surgical Unit of the San Gerardo Hospital, Italy. PATIENTS: Thirty-four consecutive women with early stage-cervical cancer (stage IA-1B1) or apparent confined stage I endometrial cancer were included in the study. INTERVENTIONS: Between October 2016 and May 2017, 34 patients underwent laparoscopic surgery with SLN mapping using indocyanine green dye: 22 women were mapped with the Storz 1S system (Karl Storz Endoscopy, Tuttlingen, Germany; Group A), whereas 12 women underwent planned surgery with the Novadaq PinPoint system (Novadaq, Mississauga, Ontario, Canada; Group B). MEASUREMENT AND MAIN RESULTS: We compared the surgical and perioperative outcomes of Group A and Group B. Patients in Group B had a shorter duration of the SLN mapping time than those in Group A (p = .0003). The median number of SLNs removed was 2 (range, 0-5) in Group A and 2 (range, 1-3) in Group B (p = .501). Bilateral mapping was 77.3% in Group A and 83.3% in Group B (p = .334), respectively. No differences were recorded in terms of body mass index, length of hospital stay, type of tumor, bilateral mapping, or number of lymph nodes removed. Body mass index was found to have no impact on the duration of the mapping (p = .353). CONCLUSION: From our preliminary experience we can conclude that both fluorescence systems are valid and applicable for SLN detection in the case of early-stage cervical or endometrial cancer. The PinPoint system seems to allow surgeons easier and faster identification of the SLNs, particularly in endometrial cancer patients.

Human papillomavirus DNA detection in plasma and cervical samples of women with a recent history of low grade or precancerous cervical dysplasia.

Circulating HPV DNA has been previously described in women with advanced stages of cervical cancer and has been suggested to be a prognostic marker of disease recurrences and metastases. Only a few studies have reported the presence of HPV DNA in bloodstream of patients with low grade or precancerous cervical lesions. This study aimed to define if HPV DNA could be detected in plasma samples of 120 women referred for a recent history of cervical dysplasia who presented with lesions ranging from High Squamous Intraepithelial Lesion (H-SIL) to regressed normal cytology. HPV DNA detection was carried out in both plasma and cervical samples using type-specific real-time quantitative PCR assays identifying oncogenic HPV 16, 18, 31, 33, 45, 51 and 52. Overall, 34.2% (41/120) of plasma samples were shown to be positive for HPV DNA detection; HPV 45 (46.3%), HPV-51 (29.6%), and HPV 16 (18.5%) were the most frequently identified genotypes. The rate of HPV detection in paired cervical and plasma samples increased with advancing disease stage, ranging from 15.4% in women with regressed lesions to 38.9% in women with HSIL; HPV 16 resulted the most common genotype identified in women found to be HPV DNA positive in both cervical and plasma samples. Moreover, HPV 16 showed the highest median viral load value in both cervical and plasma samples, with 48,313 copies/104 cells and 1,099 copies/ml, respectively. Results obtained in this study confirm that HPV DNA can be detected and quantified in plasma samples of women with asymptomatic cervical infection. Further knowledge on HPV dissemination through the blood stream of women with cervical lesions would be very important in better understanding the natural history of HPV infection as well as its potential role in other distant tumors.

Impact of Indocyanine Green for Sentinel Lymph Node Mapping in Early Stage Endometrial and Cervical Cancer: Comparison with Conventional Radiotracer (99m)Tc and/or Blue Dye.

PURPOSE: To compare the detection rate (DR) and bilateral optimal mapping (OM) of sentinel lymph nodes (SLNs) in women with endometrial and cervical cancer using indocyanine green (ICG) versus the standard technetium-99m radiocolloid ((99m)Tc) radiotracer plus methylene or isosulfan blue, or blue dye alone. METHODS: From October 2010 to May 2015, 163 women with stage I endometrial or cervical cancer (118 endometrial and 45 cervical cancer) underwent SLN mapping with (99m)Tc with blue dye, blue dye alone, or ICG. DR and bilateral OM of ICG were compared respectively with the results obtained using the standard (99m)Tc radiotracer with blue dye, or blue dye alone. RESULTS: SLN mapping with (99m)Tc radiotracer with blue dye was performed on 77 of 163 women, 38 with blue dye only and 48 with ICG. The overall DR of SLN mapping was 97, 89, and 100 % for (99m)Tc with blue dye, blue dye alone, and ICG, respectively. The bilateral OM rate for ICG was 85 %-significantly higher than the 58 % obtained with (99m)Tc with blue dye (p = 0.003) and the 54 % for blue dye (p = 0.001). Thirty-one women (19 %) had positive SLNs. Sensitivity and negative predictive value of SLN were 100 % for all techniques. CONCLUSIONS: SLNs mapping using ICG demonstrated higher DR compared to other modalities. In addition, ICG was significantly superior to (99m)Tc with blue dye in terms of bilateral OM in women with early stage endometrial and cervical cancer. The higher number of bilateral OM may consequently reduce the overall number of complete lymphadenectomies, reducing the duration and additional costs of surgical treatment.

Preoperative 18F-FDG PET/CT in the management of advanced epithelial ovarian cancer.

OBJECTIVE: The introduction of 18-FDG-PET/CT during preoperative evaluation of patients with epithelial ovarian cancer (EOC) has led to an increase of the detection of extra-abdominal metastases. However, the clinical impact of this upstage remains unclear. METHODS: Patients with suspected advanced EOC underwent 18-FDG-PET/CT within two weeks prior to debulking surgery. RESULTS: Between 2006 and 2011 95 patients met the inclusion criteria. Based on the concordance or the discrepancy of clinical and PET/CT stage, patients were divided into 3 groups (A: clinical and PET III; B: clinical III and PET IV; C: clinical and PET IV). Twenty-five patients were upstaged from FIGO stage III to stage IV by PET/CT. The proportion of patients who achieved a residual tumor <1cm in group B and C was similar, whereas it was significantly lower compared to group A. Similarly, complete response to adjuvant chemotherapy was achieved more frequently in patients in group A. PFS was similar in the three groups (17, 17 and 12 months in group A, B and C), as well as OS (51, 41 and 35 months). CONCLUSIONS: PET/CT is able to detect distant metastases in EOC patients. The presence of extra-abdominal disease probably indicates a more aggressive disease which also shows a lower response to standard chemotherapy. However, upstaged patients have a similar prognosis compared to stage III patients, probably because intra-abdominal disease is more likely to lead patients to death. This might also explain why residual tumor is the most important prognostic factor for advanced EOC patients.

ALDH enzymatic activity and CD133 positivity and response to chemotherapy in ovarian cancer patients.

The prognostic/predictive role of both CD133 and Aldehyde dehydrogenase (ALDH) expression in human ovarian cancer remains elusive. This is an observational study that investigated the expression of CD133 and of ALDH enzymatic activity in fresh ovarian cancer samples and their association with different clinic-pathological patient' characteristics and explored their possible predictive/prognostic role. We analyzed the expression of CD133 and ALDH enzymatic activity in 108 human ovarian cancer samples. We found that among the total patients analyzed, 13% of them was completely negative for ALDH activity and 26% was negative for CD133 staining. Both markers were variably expressed within the samples and when both studied in the same tumor sample, no statistically significant correlation between ALDH enzymatic activity and CD133 expression was found. No statistical significant correlation was found also between the percentage values of positive ALDH and CD133 cells and the number of serial passages patient's cultures underwent, suggesting that these markers do not confer by themselves a self-renewal growth advantage to the cultures. Lower levels of CD133 were associated with higher tumor grade. No correlation with response to therapy, progression free survival and overall survival was found. Our data suggest that neither ALDH enzymatic activity nor CD133 expression provide additional predictive/prognostic information in ovarian cancer patients.