Proteomic signature for detection of high-grade ovarian cancer in germline BRCA mutation carriers.

No current screening methods for high-grade ovarian cancer (HGOC) guarantee effective early detection for high-risk women such as germline BRCA mutation carriers. Therefore, the standard-of-care remains risk-reducing salpingo-oophorectomy (RRSO) around age 40. Proximal liquid biopsy is a promising source of biomarkers, but sensitivity has not yet qualified for clinical implementation. We aimed to develop a proteomic assay based on proximal liquid biopsy, as a decision support tool for monitoring high-risk population. Ninety Israeli BRCA1 or BRCA2 mutation carriers were included in the training set (17 HGOC patients and 73 asymptomatic women), (BEDOCA trial; ClinicalTrials.gov Identifier: NCT03150121). The proteome of the microvesicle fraction of the samples was profiled by mass spectrometry and a classifier was developed using logistic regression. An independent cohort of 98 BRCA mutation carriers was used for validation. Safety information was collected for all women who opted for uterine lavage in a clinic setting. We present a 7-protein diagnostic signature, with AUC >0.97 and a negative predictive value (NPV) of 100% for detecting HGOC. The AUC of the biomarker in the independent validation set was >0.94 and the NPV >99%. The sampling procedure was clinically acceptable, with favorable pain scores and safety. We conclude that the acquisition of Müllerian tract proximal liquid biopsies in women at high-risk for HGOC and the application of the BRCA-specific diagnostic assay demonstrates high sensitivity, specificity, technical feasibility and safety. Similar classifier for an average-risk population is warranted.

Breast cancer incidence in BRCA mutation carriers with ovarian cancer: A longitudal observational study.

OBJECTIVES: We evaluated the incidence of breast cancer and overall survival in a multi-center cohort of ovarian cancer patients carrying BRCA1/2 mutations in order to assess risks and formulate optimal preventive interventions and/or surveillance. METHODS: Medical records of 502 BRCA1/2 mutation carriers diagnosed with ovarian cancer between 2000 and 2018 at 7 medical centers in Israel and one in New York were retrospectively analyzed for breast cancer diagnosis. Data included demographics, type of BRCA mutations, surveillance methods, timing of breast cancer diagnosis, and family history of cancer. RESULTS: The median age at diagnosis of ovarian cancer was 55.8 years (range, 23.9-90.1). A third (31.5%) had a family history of breast cancer and 17.1% of ovarian cancer. Most patients (67.3%) were Ashkenazi Jews, 72.9% were BRCA1 carriers. Breast cancer preceded ovarian cancer in 17.5% and was diagnosed after ovarian cancer in 6.2%; an additional 2.2% had a synchronous presentation. Median time to breast cancer diagnosis after ovarian cancer was 46.0 months (range, 11-168). Of those diagnosed with both breast cancer and ovarian cancer (n = 31), 83.9% and 16.1% harbored BRCA1 and BRCA2 mutations, respectively. No deaths from breast cancer were recorded. Overall survival did not differ statistically between patients with an ovarian cancer diagnosis only and those diagnosed with breast cancer after ovarian cancer. CONCLUSION: The low incidence of breast cancer after ovarian cancer in women carrying BRCA1/2 mutations suggests that routine breast surveillance, rather than risk-reducing surgical interventions, may be sufficient in ovarian cancer survivors.

Ovarian size as a risk factor for recurrent adnexal torsion: Smaller is not better.

AIM: To investigate characteristics and risk factors for recurrent adnexal torsion (AT). METHODS: Retrospective cohort study in a university-affiliated medical center included 320 Women with AT verified by laparoscopy, from January 2005 through January 2017. Demographic data, clinical symptoms, surgical findings and treatment were retrospectively reviewed from patient records. Data from primary and secondary AT of patients in the recurrent torsion group was compared to those with single torsion, to evaluate risk factors for recurrent AT. RESULTS: Two hundred and sixty seven (83.4%) patients had a single event of AT and 53 (16.5%) had recurrent AT. Patients with recurrent torsion had significantly fewer previous non-gynecologic surgeries (4.3% and 9.8% of the study groups vs 32.2% of the control group, P = 0.001 for both). Ovarian size was significantly smaller in the recurrent torsion groups (47.5 mm and 48.3 mm vs 63.9 mm, P = 0.045 and P = 0.012, respectively). Polycystic ovary was significantly more common in the recurrent AT group (P = 0.028 and P = 0.005), with risk ratio 4.4 (95% confidence interval, 1.66 to 11.63). Ovaries without any specific findings were also more common among recurrent AT cases (P = 0.001 for both groups). Logistic regression analysis demonstrated that smaller ovarian size is an independent risk factor for recurrent AT. CONCLUSION: Recurrent torsion correlated with fewer previous surgeries, small ovarian mass, polycystic ovaries and ovaries without specific findings, which might indicate that additional pathophysiological factors contribute to the recurrent event. Ovarian fixation might be recommended in patients with primary torsion of normal or polycystic ovaries.

Adnexal Torsion during Pregnancy: Outcomes after Surgical Intervention-A Retrospective Case-Control Study.

STUDY OBJECTIVE: To investigate the pregnancy and neonatal outcomes of surgical treatment for adnexal torsion (AT) during pregnancy. DESIGN: A retrospective case-control study (Canadian Task Force classification II-2). SETTING: A tertiary care academic medical center. MEASUREMENTS AND MAIN RESULTS: The study group included all parturients who underwent surgery for suspected AT during pregnancy from January 2005 to January 2017. The control group included parturients with an uneventful pregnancy matched by maternal age, parity, multiple gestation, and pregnancy complications. The primary outcome was gestational age at delivery. Secondary outcomes were perinatal outcomes and intraoperative and immediate postoperative complications. Among 85 study group patients with suspected AT, 78 (91.7%) underwent laparoscopy and 7 (8.3%) laparotomy. Torsion was diagnosed in 84 patients (98.8%). The gestational age at delivery was similar between the study and control groups (38.7 ± 1.5 vs 38.6 ± 1.6 weeks, respectively; p = .908) as was preterm labor (5.8% in both groups, p = 1.00). There was no significant difference between the study and control groups in pregnancy and neonatal outcomes, including Apgar scores, mean cord blood pH (7.25 ± 0.1 and 7.26 ± 0.08, respectively), and birth weight (3040 ± 473 g and 3115 ± 584 g, respectively). In the study group, the mean gestational age at surgery was 11.2 ± 6 weeks (range, 4-34 weeks). The average operative time was 40.2 ± 22 minutes. In the postoperative follow-up, 3 (3.5%) patients had a first trimester miscarriage. A previous cesarean delivery was a risk factor for ovarian torsion during pregnancy (p = .012). CONCLUSION: Adnexal detorsion with or without additional surgical procedures during pregnancy did not affect the gestational age at delivery and did not appear to increase fetal or maternal complication rates.

The selenoenzyme type I iodothyronine deiodinase: a new tumor suppressor in ovarian cancer.

The selenoenzyme type I iodothyronine deiodinase (DIO1) catalyzes removal of iodine atoms from thyroid hormones. Although DIO1 action is reported to be disturbed in several malignancies, no work has been conducted in high-grade serous ovarian carcinoma (HGSOC), the most lethal gynecologic cancer. We studied DIO1 expression in HGSOC patients [The Cancer Genome Atlas (TCGA) data and tumor tissues], human cell lines (ES-2 and Kuramochi), normal Chinese hamster ovarian cells (CHO-K1), and normal human fallopian tube cells (FT282 and FT109). To study its functional role, DIO1 was overexpressed, inhibited [by propylthiouracil (PTU)], or knocked down (KD), and cell count, proliferation, apoptosis, cell viability, and proteomics analysis were performed. Lower DIO1 levels were observed in HGSOC compared to normal cells and tissues. TCGA analyses confirmed that low DIO1 mRNA expression correlated with worse survival and therapy resistance in patients. Silencing or inhibiting the enzyme led to enhanced ovarian cancer proliferation, while an opposite effect was shown following DIO1 ectopic expression. Proteomics analysis in DIO1-KD cells revealed global changes in proteins that facilitate tumor metabolism and progression. In conclusion, DIO1 expression and ovarian cancer progression are inversely correlated, highlighting a tumor suppressive role for this enzyme and its potential use as a biomarker in this disease.

Is post hysterectomy adnexal torsion a complication of laparoscopic approach? A retrospective cohort study.

OBJECTIVE: To investigate the correlation between the hysterectomy's surgical approach and post hysterectomy adnexal torsion. STUDY DESIGN: Retrospective cohort study of patients with diagnosed adnexal torsion after hysterectomy (abdominal, vaginal and laparoscopic approaches) in a tertiary care medical center from 2007 through 2017 was done. Demographic data, clinical symptoms, type of previous hysterectomy, surgical findings and treatment were retrospectively reviewed from patient records. To calculate the risk of post-hysterectomy adnexal torsion (PHAH) and evaluate its association with type of hysterectomy, we used a national hysterectomy registry that included all hysterectomy done in region of our medical centre. RESULTS: Eight cases of AT after hysterectomy were operated during the study period, seven after laparoscopic and one after vaginal hysterectomy. Torsion occurred a mean of 27.25 ±â€¯16.65 months (range 3-60 months) after surgery. Mean patient age at AT was 45 ±â€¯4.6 years. All patients presented with abdominal pain, five (62.5%) had nausea and vomiting and one had diarrhoea. Laparoscopic findings revealed ovarian torsion in 5 cases, fallopian tube torsion in one and torsion of the adnexa in two cases. The national hysterectomy registry in the geographic region of our hospital summarized 705 patients with laparoscopic hysterectomy with adnexal preservation. The prevalence of post-laparoscopic hysterectomy adnexal torsion was significant high than after other types of hysterectomy (P < 0.05). CONCLUSION: PHAT occurs more frequently after laparoscopic hysterectomy then after other approaches. Measures for prevention of adnexal torsion should be considered during the primary surgery.