Positive experiences of healthcare professionals with a mainstreaming approach of germline genetic testing for women with ovarian cancer

According to current guidelines, all women with epithelial ovarian cancer are eligible for genetic testing for BRCA germline pathogenic variants. Unfortunately, not all affected women are tested. We evaluated the acceptability and feasibility for non-genetic healthcare professionals to incorporate germline genetic testing into their daily practice. We developed and implemented a mainstreaming pathway, including a training module, in collaboration with various healthcare professionals and patient organizations. Healthcare professionals from 4 different hospitals were invited to participate. After completing the training module, gynecologic oncologists, gynecologists with a subspecialty training in oncology, and nurse specialists discussed and ordered genetic testing themselves. They received a questionnaire before completing the training module and 6 months after working according to the new pathway. We assessed healthcare professionals' attitudes, perceived knowledge, and self-efficacy, along with the feasibility of this new mainstream workflow in clinical practice, and evaluated the use and content of the training module. The participation rate for completing the training module was 90% (N = 19/21). At baseline and after 6 months, healthcare professionals had a positive attitude, high perceived knowledge and high self-efficacy toward discussing and ordering genetic testing. Knowledge had increased significantly after 6 months. The training module was rated with an average of 8.1 out of 10 and was considered useful. The majority of healthcare professionals (9/15) was able to discuss a genetic test in five to 10 min. After completion of a training module, non-genetic healthcare professionals feel motivated and competent to discuss and order genetic testing themselves

'We don't know for sure':discussion of uncertainty concerning multigene panel testing during initial cancer genetic consultations

Pre-test counseling about multigene panel testing involves many uncertainties. Ideally, counselees are informed about uncertainties in a way that enables them to make an informed decision about panel testing. It is presently unknown whether and how uncertainty is discussed during initial cancer genetic counseling. We therefore investigated whether and how counselors discuss and address uncertainty, and the extent of shared decision-making (SDM), and explored associations between counselors' communication and their characteristics in consultations on panel testing for cancer. For this purpose, consultations of counselors discussing a multigene panel with a simulated patient were videotaped. Simulated patients represented a counselee who had had multiple cancer types, according to a script. Before and afterwards, counselors completed a survey. Counselors' uncertainty expressions, initiating and the framing of expressions, and their verbal responses to scripted uncertainties of the simulated patient were coded by two researchers independently. Coding was done according to a pre-developed coding scheme using The Observer XT software for observational analysis. Additionally, the degree of SDM was assessed by two observers. Correlation and regression analyses were performed to assess associations of communicated uncertainties, responses and the extent of SDM, with counselors' background characteristics. In total, twenty-nine counselors, including clinical geneticists, genetic counselors, physician assistants-in-training, residents and interns, participated of whom working experience varied between 0 and 25 years. Counselors expressed uncertainties mainly regarding scientific topics (94%) and on their own initiative (95%). Most expressions were framed directly (77%), e.g. We don't know, and were emotionally neutral (59%; without a positive/negative value). Counselors mainly responded to uncertainties of the simulated patient by explicitly referring to the uncertainty (69%), without providing space for further disclosure (66%). More experienced counselors provided less space to further disclose uncertainty (p <0.02), and clinical geneticists scored lower on SDM compared with other types of counselors (p <0.03). Our findings that counselors mainly communicate scientific uncertainties and use space-reducing responses imply that the way counselors address counselees' personal uncertainties and concerns during initial cancer genetic counseling is suboptimal

The most efficient and effective BRCA1/2 testing strategy in epithelial ovarian cancer: Tumor-First or Germline-First?

OBJECTIVE: Genetic testing in epithelial ovarian cancer (OC) is essential to identify a hereditary cause like a germline BRCA1/2 pathogenic variant (PV). An efficient strategy for genetic testing in OC is highly desired. We evaluated costs and effects of two strategies; (i) Tumor-First strategy, using a tumor DNA test as prescreen to germline testing, and (ii) Germline-First strategy, referring all patients to the clinical geneticist for germline testing. METHODS: Tumor-First and Germline-First were compared in two scenarios; using real-world uptake of testing and setting implementation to 100%. Decision analytic models were built to analyze genetic testing costs (including counseling) per OC patient and per family as well as BRCA1/2 detection probabilities. With a Markov model, the life years gained among female relatives with a germline BRCA1/2 PV was investigated. RESULTS: Focusing on real-world uptake, with the Tumor-First strategy more OC patients and relatives with a germline BRCA1/2 PV are detected (70% versus 49%), at lower genetic testing costs (€1898 versus €2502 per patient, and €2511 versus €2930 per family). Thereby, female relatives with a germline BRCA1/2 PV can live on average 0.54 life years longer with Tumor-First compared to Germline-First. Focusing on 100% uptake, the genetic testing costs per OC patient are substantially lower in the Tumor-First strategy (€2257 versus €4986). CONCLUSIONS: The Tumor-First strategy in OC patients is more effective in identifying germline BRCA1/2 PV at lower genetic testing costs per patient and per family. Optimal implementation of Tumor-First can further improve detection of heredity in OC patients

Successful oxytocin-assisted nipple aspiration in women at increased risk for breast cancer

The high rate of interval malignancies urges for new screening methods for women at high risk for breast cancer. Nipple aspiration provides direct access to the breast tissue and its DNA, and therefore is a likely candidate, but clinical applications have been limited by the failure to obtain nipple aspiration fluid from most women. We performed oxytocin-assisted nipple aspiration in 90 women at increased risk for breast cancer based on family history or genetic test results (n = 63) and/or previous breast cancer (n = 34). Nipple fluid was obtained from 81/90 women (90%) and bilaterally in 77%. Mean discomfort rating was 0.6 (on a 0–10 scale), which was significantly lower than for mammography or MRI. These findings suggest that a new tool for biomarker detection in oxytocin-assisted nipple fluid of women at high risk for breast cancer is at hand

Модификации арефлюксного холедохоеюноанастомоза с восстановлением пассажа желчи в двенадцатиперстную кишку

Разработаны модификации формирования холедохоеюноанастомоза, способствующие восстановлению желчетока с пассажем желчи в двенадцатиперстную кишку, что предупреждает развитие в ней пептической язвы. Предложена специальная методика мобилизации отключенного по Ру сегмента тощей кишки, обеспечивающая его полноценную моторику.Modifications of forming choledochoanastomosis promoting restoration of bile passage to the duodenum, which prevented development of peptic ulcer, were worked out. A special technique for mobilization of the switched off segment of the jejunum according to Roux promoting an adequate motility was suggested

Repeated nipple fluid aspiration

Background: Despite intensive surveillance, a high rate of interval malignancies is still seen in women at increased breast cancer risk. Therefore, novel screening modalities aiming at early detection remain needed. The intraductal approach offers the possibility to directly sample fluid containing cells, DNA and proteins from the mammary ductal system where, in the majority of cases, breast cancer originates. Fluid from the breast can non-invasively be obtained by oxytocin-assisted vacuum aspiration, called nipple fluid aspiration (NFA). The goal of this feasibility study was to evaluate the potential of repeated NFA, which is a critical and essential step to evaluate its possible value as a breast cancer screening method. Methods: In this multicenter, prospective study, we annually collected nipple fluid for up to 5 consecutive years from women at increased breast cancer risk, and performed a questionnaire-based survey regarding discomfort of the aspiration. Endpoints of the current interim analyses were the feasibility and results of 994 NFA procedures in 451 women with total follow-up of 560 person years of observation. Results: In this large group of women at increased risk of breast cancer, repetitive NFA appeared to be feasible and safe. In 66.4% of aspirated breasts, nipple fluid was successfully obtained. Independent predictive factors for successful NFA were premenopausal status, spontaneous nipple discharge, smaller breast size, bilateral oophorectomy and previous use of hormone replacement therapy or anti-hormonal treatment. The procedure was well tolerated with low discomfort. Drop-out rate was 20%, which was mainly due to repeated unsuccessful aspiration attempts. Only 1.6% of women prematurely declined further participation because of side effects. Conclusions: Repeated NFA in women at increased breast cancer risk is feasible and safe. Therefore, NFA is a promising method to non-invasively obtain a valuable source of potential breast cancer specific biomarkers

Effects of chemotherapy on contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers:A nationwide cohort study

AIM: BRCA1/2 mutation carriers with primary breast cancer (PBC) are at high risk of contralateral breast cancer (CBC). In a nationwide cohort, we investigated the effects of chemotherapeutic agents given for PBC on CBC risk separately in BRCA1 and BRCA2 mutation carriers. PATIENTS AND METHODS: BRCA1 or BRCA2 mutation carriers with an invasive PBC diagnosis from 1990 to 2017 were selected from a Dutch cohort. We estimated cumulative CBC incidence using competing risks analysis. Hazard ratios (HR) for the effect of neo-adjuvant or adjuvant chemotherapy and different chemotherapeutic agents on CBC risk were estimated using Cox regression. RESULTS: We included 1090 BRCA1 and 568 BRCA2 mutation carriers; median follow-up was 8.9 and 8.4 years, respectively. Ten-year cumulative CBC incidence for treatment with and without chemotherapy was 6.7% [95%CI: 5.1–8.6] and 16.7% [95%CI: 10.8–23.7] in BRCA1 and 4.8% [95%CI: 2.7–7.8] and 16.0% [95%CI: 9.3–24.4] in BRCA2 mutation carriers, respectively. Chemotherapy was associated with reduced CBC risk in BRCA1 (multivariable HR: 0.46, 95%CI: 0.29–0.74); a similar trend was observed in BRCA2 mutation carriers (HR: 0.63, 95%CI: 0.29–1.39). In BRCA1, risk reduction was most pronounced in the first 5 years (HR: 0.32, 95%CI: 0.17–0.61). Anthracyclines and the combination of anthracyclines with taxanes were associated with substantial CBC risk reduction in BRCA1 carriers (HR: 0.34, 95%CI: 0.17–0.68 and HR: 0.22, 95%CI: 0.08–0.62, respectively). CONCLUSION: Risk-reducing effects of chemotherapy are substantial for at least 5 years and may be used in personalised CBC risk prediction in any case for BRCA1 mutation carriers

Определение скорости перемещения деформаций растяжений в массиве при подземной выемке угля

Приведена швидкість переміщення деформацій в непорушеному масиві. Встановлено, що швидкість в породах середнього ступеня метаморфізму складає 15 м/добу. Середня швидкість переміщення деформацій в сланцях – 10 м/добу, в піщаниках – 15 м/добу. При повторній підробці швидкість переміщення деформацій складає 17 м/добу.Deformation’s speed travel in the virgin rock massif is given in this article. It has been determined that deformation’s speed in the rocks of medium-scale metamorphism was 15 meters over the entire circadian period. The average speed of deformation’s travel in the shale rocks is 10 meters over the entire circadian period and in the sandstone is 15 meters over the entire circadian period. During the recurring undermining the speed travel of deformations is 17 meters over the entire circadian period

Long-Term Morbidity and Health After Early Menopause Due to Oophorectomy in Women at Increased Risk of Ovarian Cancer:Protocol for a Nationwide Cross-Sectional Study With Prospective Follow-Up (HARMOny Study)

Background: BRCA1/2 mutation carriers are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) at 35 to 45 years of age. RRSO substantially decreases ovarian cancer risk, but at the cost of immediate menopause. Knowledge about the potential adverse effects of premenopausal RRSO, such as increased risk of cardiovascular disease, osteoporosis, cognitive dysfunction, and reduced health-related quality of life (HRQoL), is limited. Objective: The aim of this study is to assess the long-term health effects of premenopausal RRSO on cardiovascular disease, bone health, cognitive functioning, urological complaints, sexual functioning, and HRQoL in women with high familial risk of breast or ovarian cancer. Methods: We will conduct a multicenter cross-sectional study with prospective follow-up, nested in a nationwide cohort of women at high familial risk of breast or ovarian cancer. A total of 500 women who have undergone RRSO before 45 years of age, with a follow-up period of at least 10 years, will be compared with 250 women (frequency matched on current age) who have not undergone RRSO or who have undergone RRSO at over 55 years of age. Participants will complete an online questionnaire on lifestyle, medical history, cardiovascular risk factors, osteoporosis, cognitive function, urological complaints, and HRQoL. A full cardiovascular assessment and assessment of bone mineral density will be performed. Blood samples will be obtained for marker analysis. Cognitive functioning will be assessed objectively with an online neuropsychological test battery. Results: This study was approved by the institutional review board in July 2018. In February 2019, we included our first participant. As of November 2020, we had enrolled 364 participants in our study. Conclusions: Knowledge from this study will contribute to counseling women with a high familial risk of breast/ovarian cancer about the long-term health effects of premenopausal RRSO. The results can also be used to offer health recommendations after RRSO