Validation of the BOADICEA model in a prospective cohort of BRCA1/2 pathogenic variant carriers.

BACKGROUND: No validation has been conducted for the BOADICEA multifactorial breast cancer risk prediction model specifically in BRCA1/2 pathogenic variant (PV) carriers to date. Here, we evaluated the performance of BOADICEA in predicting 5-year breast cancer risks in a prospective cohort of BRCA1/2 PV carriers ascertained through clinical genetic centres. METHODS: We evaluated the model calibration and discriminatory ability in the prospective TRANsIBCCS cohort study comprising 1614 BRCA1 and 1365 BRCA2 PV carriers (209 incident cases). Study participants had lifestyle, reproductive, hormonal, anthropometric risk factor information, a polygenic risk score based on 313 SNPs and family history information. RESULTS: The full multifactorial model considering family history together with all other risk factors was well calibrated overall (E/O=1.07, 95% CI: 0.92 to 1.24) and in quintiles of predicted risk. Discrimination was maximised when all risk factors were considered (Harrell's C-index=0.70, 95% CI: 0.67 to 0.74; area under the curve=0.79, 95% CI: 0.76 to 0.82). The model performance was similar when evaluated separately in BRCA1 or BRCA2 PV carriers. The full model identified 5.8%, 12.9% and 24.0% of BRCA1/2 PV carriers with 5-year breast cancer risks of <1.65%, <3% and <5%, respectively, risk thresholds commonly used for different management and risk-reduction options. CONCLUSION: BOADICEA may be used to aid personalised cancer risk management and decision-making for BRCA1 and BRCA2 PV carriers. It is implemented in the free-access CanRisk tool (https://www.canrisk.org/).

Transformation of phenylarsenic chemical warfare agents and their effect on bacterial communities in Baltic Sea sediment.

During the World Wars large quantities of phenylarsenic chemical warfare agents (CWAs) were dumped in the Baltic Sea. Many transformation products of these chemicals have been identified, but the pathways that produce the found chemicals has not been investigated. Here we studied the biotic and abiotic transformation of phenylarsenic CWAs under oxic and anoxic conditions and investigated how the sediment bacterial communities are affected by CWA exposure. By chemical analysis we were able to identify seventeen CWA-related phenylarsenicals, four of which (methylphenylarsinic acid (MPAA), phenylthioarsinic acid (PTAA), phenyldithioarsinic acid (PDTAA) and diphenyldithioarsinic acid (DPDTAA)) have not been reported for marine sediments before. For the first time PTAA was verified from environmental samples. We also observed equilibrium reactions between the found transformation products, which may explain the occurrence of the chemicals. 16S rRNA-analysis showed that bacterial communities in sediments are affected by exposure to phenylarsenic CWAs. We observed increases in the amounts of arsenic-resistant and sulphur-metabolising bacteria. Different transformation products were found in biotic and abiotic samples, which suggests that bacteria participate in the transformation of phenylarsenic CWAs. We propose that methylated phenylarsenicals are produced in microbial metabolism and that chemical reactions with microbially produced sulphur species form sulphur-containing transformation products.

Use of electronic health record data mining for heart failure subtyping.

OBJECTIVE: To assess whether electronic health record (EHR) data text mining can be used to improve register-based heart failure (HF) subtyping. EHR data of 43,405 individuals from two Finnish hospital biobanks were mined for unstructured text mentions of ejection fraction (EF) and validated against clinical assessment in two sets of 100 randomly selected individuals. Structured laboratory data was then incorporated for a categorization by HF subtype (HF with mildly reduced EF, HFmrEF; HF with preserved EF, HFpEF; HF with reduced EF, HFrEF; and no HF). RESULTS: In 86% of the cases, the algorithm-identified EF belonged to the correct HF subtype range. Sensitivity, specificity, PPV and NPV of the algorithm were 94-100% for HFrEF, 85-100% for HFmrEF, and 96%, 67%, 53% and 98% for HFpEF. Survival analyses using the traditional diagnosis of HF were in concordance with the algorithm-based ones. Compared to healthy individuals, mortality increased from HFmrEF (hazard ratio [HR], 1.91; 95% confidence interval [CI], 1.24-2.95) to HFpEF (2.28; 1.80-2.88) to HFrEF group (2.63; 1.97-3.50) over a follow-up of 1.5 years. We conclude that quantitative EF data can be efficiently extracted from EHRs and used with laboratory data to subtype HF with reasonable accuracy, especially for HFrEF.

Oral Contraceptive Use in BRCA1 and BRCA2 Mutation Carriers: Absolute Cancer Risks and Benefits.

BACKGROUND: To help BRCA1 and 2 mutation carriers make informed decisions regarding use of combined-type oral contraceptive preparation (COCP), absolute risk-benefit estimates are needed for COCP-associated cancer. METHODS: For a hypothetical cohort of 10 000 women, we calculated the increased or decreased cumulative incidence of COCP-associated (breast, ovarian, endometrial) cancer, examining 18 scenarios with differences in duration and timing of COCP use, uptake of prophylactic surgeries, and menopausal hormone therapy. RESULTS: COCP use initially increased breast cancer risk and decreased ovarian and endometrial cancer risk long term. For 10 000 BRCA1 mutation carriers, 10 years of COCP use from age 20 to 30 years resulted in 66 additional COCP-associated cancer cases by the age of 35 years, in addition to 625 cases expected for never users. By the age of 70 years such COCP use resulted in 907 fewer cancer cases than the expected 9093 cases in never users. Triple-negative breast cancer estimates resulted in 196 additional COCP-associated cases by age 40 years, in addition to the 1454 expected. For 10 000 BRCA2 mutation carriers using COCP from age 20 to 30 years, 80 excess cancer cases were estimated by age 40 years in addition to 651 expected cases; by the age of 70 years, we calculated 382 fewer cases compared with the 6156 cases expected. The long-term benefit of COCP use diminished after risk-reducing bilateral salpingo-oophorectomy followed by menopausal hormone therapy use. CONCLUSION: Although COCP use in BRCA1 and BRCA2 mutation carriers initially increases breast, ovarian, and endometrial cancer risk, it strongly decreases lifetime cancer risk. Risk-reducing bilateral salpingo-oophorectomy and menopausal hormone therapy use appear to counteract the long-term COCP-benefit.

Osmolal and anion gaps after acute self-poisoning with agricultural formulations of the organophosphorus insecticides profenofos and diazinon: A pilot study.

Self-poisoning with organophosphorus (OP) insecticides is an important means of global self-harm. The insecticides are formulated with solvents that may also contribute to toxicity. We set up a study to detect changes in osmolal and anion gaps following ingestion of OP insecticides. We recruited consecutive patients admitted to a Teaching Hospital, Sri Lanka, with a history of OP self-poisoning. The osmolal and anion gaps were calculated on admission and at 4, 24 and 72 h post-ingestion together with ethanol concentration. Forty-nine patients were recruited (28 profenofos, 10 diazinon, one coumaphos, one chlorpyrifos, one phenthoate and eight unknown OP). Only modest increases in osmolal and anion gaps were noted. Small rises in osmolal gap above the upper limit of normal were noted in 16/49 (32.7%) of all cases, 9/28 (32.1%) profenofos cases and 4/10 (40.0%) diazinon cases. The anion gap was raised in 24/49 (49.0%) of all cases, 15/28 (53.6%) profenofos cases and 5/10 (50.0%) diazinon cases. We observed a trend for a fall in osmolal gap during the first 24 h, followed by an increase up to 72 h. There was no correlation between the anion gap and serum lactate concentration, indicating that a lactic acidosis was not responsible for the anion gap. Formate, which could have explained the increased gap, was not detected in any of the samples; ketoacids (beta-hydroxybutyrate and acetoacetate) were not measured. This pilot study found that profenofos and diazinon poisoning caused only modest increases in the osmolal and anion gaps in a minority of cases.

Diabetes status-related differences in risk factors and mediators of heart failure in the general population: results from the MORGAM/BiomarCaRE consortium.

BACKGROUND: The risk of heart failure among diabetic individuals is high, even under tight glycemic control. The correlates and mediators of heart failure risk in individuals with diabetes need more elucidation in large population-based cohorts with long follow-up times and a wide panel of biologically relevant biomarkers. METHODS: In a population-based sample of 3834 diabetic and 90,177 non-diabetic individuals, proportional hazards models and mediation analysis were used to assess the relation of conventional heart failure risk factors and biomarkers with incident heart failure. RESULTS: Over a median follow-up of 13.8 years, a total of 652 (17.0%) and 5524 (6.1%) cases of incident heart failure were observed in participants with and without diabetes, respectively. 51.4% were women and the mean age at baseline was 48.7 (standard deviation [SD] 12.5) years. The multivariable-adjusted hazard ratio (HR) for heart failure among diabetic individuals was 2.70 (95% confidence interval, 2.49-2.93) compared to non-diabetic participants. In the multivariable-adjusted Cox models, conventional cardiovascular disease risk factors, such as smoking (diabetes: HR 2.07 [1.59-2.69]; non-diabetes: HR 1.85 [1.68-2.02]), BMI (diabetes: HR 1.30 [1.18-1.42]; non-diabetes: HR 1.40 [1.35-1.47]), baseline myocardial infarction (diabetes: HR 2.06 [1.55-2.75]; non-diabetes: HR 2.86 [2.50-3.28]), and baseline atrial fibrillation (diabetes: HR 1.51 [0.82-2.80]; non-diabetes: HR 2.97 [2.21-4.00]) had the strongest associations with incident heart failure. In addition, biomarkers for cardiac strain (represented by nT-proBNP, diabetes: HR 1.26 [1.19-1.34]; non-diabetes: HR 1.43 [1.39-1.47]), myocardial injury (hs-TnI, diabetes: HR 1.10 [1.04-1.16]; non-diabetes: HR 1.13 [1.10-1.16]), and inflammation (hs-CRP, diabetes: HR 1.13 [1.03-1.24]; non-diabetes: HR 1.29 [1.25-1.34]) were also associated with incident heart failure. In general, all these associations were equally strong in non-diabetic and diabetic individuals. However, the strongest mediators of heart failure in diabetes were the direct effect of diabetes status itself (relative effect share 43.1% [33.9-52.3] and indirect effects (effect share 56.9% [47.7-66.1]) mediated by obesity (BMI, 13.2% [10.3-16.2]), cardiac strain/volume overload (nT-proBNP, 8.4% [-0.7-17.4]), and hyperglycemia (glucose, 12.0% [4.2-19.9]). CONCLUSIONS: The findings suggest that the main mediators of heart failure in diabetes are obesity, hyperglycemia, and cardiac strain/volume overload. Conventional cardiovascular risk factors are strongly related to incident heart failure, but these associations are not stronger in diabetic than in non-diabetic individuals. Active measurement of relevant biomarkers could potentially be used to improve prevention and prediction of heart failure in high-risk diabetic patients.

Hanguanadeflexa (Hanguanaceae), a new forest species from Sarawak, Borneo.

Hanguanadeflexa sp. nov. (Hanguanaceae) from Lawas district, Sarawak, Malaysia (northern Borneo) is described and illustrated, bringing the total number of species in Borneo to eight. The new species differs from all other recognized Hanguana species by a combination of flat leaf blade, deflexed infructescences, one-seeded dull red fruits with centrally positioned stigma and globose seed with wedge-shaped ostiole. Revised key for Bornean Hanguana species is presented.

Plastome evolution and organisation in the Hoya group (Apocynaceae).

The genus Hoya is highly diverse and many of its species are popular ornamental plants. However, the relationships between Hoya and related genera (the Hoya group) are not fully resolved. In this study, we report 20 newly sequenced plastomes of species in the Hoya group. The complete plastomes vary in length from 175,405 to 178,525 bp while the LSCs vary from 90,248 to 92,364 bp and the complete SSCs vary from 2,285 to 2,304 bp, making the SSC in the Hoya group one of the shortest known in the angiosperms. The plastome structure in the Hoya group is characterised by a massive increase in the size of the inverted repeats as compared to the outgroups. In all ingroup species, the IR/SSC boundary moved from ycf1 to ndhF while this was not observed in outgroup taxa, making it a synapomorphy for the Hoya group. We have also assembled the mitogenome of Hoya lithophytica, which, at 718,734 bp, is the longest reported in the family. The phylogenetic analysis using exons from 42 taxa in the Hoya group and three outgoups confirms that the earliest divergent genus in the Hoya group is Papuahoya, followed by Dischidia. The relationship between Dischidia and the clade which includes all Hoya and Oreosparte taxa, is not fully supported. Oreosparte is nested in Hoya making it paraphyletic unless Clemensiella is recognised as a separate genus.

Endometrial Cancer Risk in Women With Germline BRCA1 or BRCA2 Mutations: Multicenter Cohort Study.

BACKGROUND: Endometrial cancer (EC) risk in BReast CAncer gene 1/2 (BRCA1/2) mutation carriers is uncertain; therefore, we assessed this in a large Dutch nationwide cohort study. METHODS: We selected 5980 BRCA1/2 (3788 BRCA1, 2151 gBRCA2, 41 both BRCA1/BRCA2) and 8451 non-BRCA1/2 mutation carriers from the Hereditary Breast and Ovarian cancer study, the Netherlands cohort. Follow-up started at the date of the nationwide Dutch Pathology Registry coverage (January 1, 1989) or at the age of 25 years (whichever came last) and ended at date of EC diagnosis, last follow-up, or death (whichever came first). EC risk in BRCA1/2 mutation carriers was compared with 1) the general population, estimating standardized incidence ratios (SIRs) based on Dutch population-based incidence rates; and 2) non-BRCA1/2 mutation carriers, using Cox-regression analyses, expressed as hazard ratio (HR). Statistical tests were 2-sided. RESULTS: Fifty-eight BRCA1/2 and 33 non-BRCA1/2 mutation carriers developed EC over 119 296 and 160 841 person-years, respectively (SIR = 2.83, 95% confidence interval [CI] = 2.18 to 3.65; and HR = 2.37, 95% CI = 1.53 to 3.69, respectively). gBRCA1 mutation carriers showed increased risks for EC overall (SIR = 3.51, 95% CI = 2.61 to 4.72; HR = 2.91, 95% CI = 1.83 to 4.66), serous-like EC (SIR = 12.64, 95% CI = 7.62 to 20.96; HR = 10.48, 95% CI = 2.95 to 37.20), endometrioid EC (SIR = 2.63, 95% CI = 1.80 to 3.83; HR = 2.01, 95% CI = 1.18 to 3.45), and TP53-mutated EC (HR = 15.71, 95% CI = 4.62 to 53.40). For BRCA2 mutation carriers, overall (SIR = 1.70, 95% CI = 1.01 to 2.87) and serous-like EC risks (SIR = 5.11, 95% CI = 1.92 to 13.63) were increased compared with the general population. Absolute risks by 75 years remained low (overall EC = 3.0%; serous-like EC = 1.1%). CONCLUSIONS: BRCA1/2 mutation carriers have a two- to threefold increased risk for EC, with highest risk observed for the rare subgroups of serous-like and p53-abnormal EC in BRCA1 mutation carriers.

Rapid Quantification of Microalgae Growth with Hyperspectral Camera and Vegetation Indices.

Spectral cameras are traditionally used in remote sensing of microalgae, but increasingly also in laboratory-scale applications, to study and monitor algae biomass in cultures. Practical and cost-efficient protocols for collecting and analyzing hyperspectral data are currently needed. The purpose of this study was to test a commercial, easy-to-use hyperspectral camera to monitor the growth of different algae strains in liquid samples. Indices calculated from wavebands from transmission imaging were compared against algae abundance and wet biomass obtained from an electronic cell counter, chlorophyll a concentration, and chlorophyll fluorescence. A ratio of selected wavebands containing near-infrared and red turned out to be a powerful index because it was simple to calculate and interpret, yet it yielded strong correlations to abundances strain-specifically (0.85 < r < 0.96, p < 0.001). When all the indices formulated as A/B, A/(A + B) or (A - B)/(A + B), where A and B were wavebands of the spectral camera, were scrutinized, good correlations were found amongst them for biomass of each strain (0.66 < r < 0.98, p < 0.001). Comparison of near-infrared/red index to chlorophyll a concentration demonstrated that small-celled strains had higher chlorophyll absorbance compared to strains with larger cells. The comparison of spectral imaging to chlorophyll fluorescence was done for one strain of green algae and yielded strong correlations (near-infrared/red, r = 0.97, p < 0.001). Consequently, we described a simple imaging setup and information extraction based on vegetation indices that could be used to monitor algae cultures.

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. TRIAL REGISTRATION: ClinicalTrials.gov NCT03835793; https://clinicaltrials.gov/ct2/show/NCT03835793. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/24414.

Population genomics reveal apomixis in a novel system: uniclonal female populations dominate the tropical forest herb family, Hanguanaceae (Commelinales).

The abundance of apomixis in tropical plant genera is poorly understood, and this affects the understanding of speciation and evolution. Hanguanaceae is a tropical monogeneric, dioecious plant family. All but two species are solitary herbs with no capability to spread vegetatively. Viable seeds are often produced when males have not been observed. Our aim was to investigate the presence of apomixis in Hanguana. We used reduced representation genomics to study phylogenetics and genetic variability in all populations of Hanguana in Singapore. We measured genome sizes and estimated ploidy levels in 10 species. Almost all taxa tested were genetically uniform (uniclonal) regardless of the extent of their distribution. The distribution of single clones over distinct localities supports our hypothesis of apomictic reproduction. Only one sexually reproducing native species was detected. Triploid and pentaploid states support our hypothesis that the type of apomixis in Hanguana is gametophytic. Population genomics tools offer a quick and cost-effective way of detecting excess clonality and thereby inferring apomixis. In the case of Hanguana, the presence of male plants is a strong indicator of sexual reproduction, whereas genome triplication is indicative of apomictic reproduction.

Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants.

PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10-72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10-22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10-12) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

24-h urinary sodium excretion and the risk of adverse outcomes.

AIMS: The objective was to evaluate whether sodium intake, assessed with the gold standard 24-h urinary collections, was related to long-term incidence of death, cardiovascular disease (CVD) and diabetes mellitus (DM). METHODS: A cohort of 4630 individuals aged 25-64 years collected 24-h urine samples in 1979-2002 and were followed up to 14 years for the incidence of any CVD, coronary heart disease (CHD), stroke, heart failure (HF) and DM event, and death. Cox proportional hazards models were used to estimate the association between the baseline salt intake and incident events and adjusted for baseline age, body mass index, serum cholesterol, prevalent DM, and stratified by sex and cohort baseline year. RESULTS: During the follow-up, we observed 423 deaths, 424 CVD events (288 CHD events, 142 strokes, 139 HF events) and 161 DM events. Compared with the highest quartile of salt intake, persons in the lowest quartile had a lower incidence of CVD (hazard ratio [HR] 0.70; 95% confidence interval [CI], 0.51-0.95, p = .02), CHD (HR 0.63 [95% CI 0.42-0.94], p = .02) and DM (HR 0.52 [95% CI 0.31-0.87], p = .01). The results were non-significant for mortality, HF, and stroke. CONCLUSION: High sodium intake is associated with an increased incidence of CVD and DM.

Erratum: Multilabel segmentation of cancer cell culture on vascular structures with deep neural networks (Erratum).

[This corrects the article DOI: 10.1117/1.JMI.7.2.024001.].

Multilabel segmentation of cancer cell culture on vascular structures with deep neural networks.

New increasingly complex in vitro cancer cell models are being developed. These new models seem to represent the cell behavior in vivo more accurately and have better physiological relevance than prior models. An efficient testing method for selecting the most optimal drug treatment does not exist to date. One proposed solution to the problem involves isolation of cancer cells from the patients' cancer tissue, after which they are exposed to potential drugs alone or in combinations to find the most optimal medication. To achieve this goal, methods that can efficiently quantify and analyze changes in tested cell are needed. Our study aimed to detect and segment cells and structures from cancer cell cultures grown on vascular structures in phase-contrast microscope images using U-Net neural networks to enable future drug efficacy assessments. We cultivated prostate carcinoma cell lines PC3 and LNCaP on the top of a matrix containing vascular structures. The cells were imaged with a Cell-IQ phase-contrast microscope. Automatic analysis of microscope images could assess the efficacy of tested drugs. The dataset included 36 RGB images and ground-truth segmentations with mutually not exclusive classes. The used method could distinguish vascular structures, cells, spheroids, and cell matter around spheroids in the test images. Some invasive spikes were also detected, but the method could not distinguish the invasive cells in the test images.

The validity of heart failure diagnoses in the Finnish Hospital Discharge Register.

Background: Contemporary validation studies of register-based heart failure diagnoses based on current guidelines and complete clinical data are lacking in Finland and internationally. Our objective was to assess the positive and negative predictive values of heart failure diagnoses in a nationwide hospital discharge register. Methods: Using Finnish Hospital Discharge Register data from 2013-2015, we obtained the medical records for 120 patients with a register-based diagnosis for heart failure (cases) and for 120 patients with a predisposing condition for heart failure, but without a heart failure diagnosis (controls). The medical records of all patients were assessed by a physician who categorized each individual as having heart failure (with reduced or preserved ejection fraction) or no heart failure, based on the definition of current European Society of Cardiology heart failure guidelines. Unclear cases were assessed by a panel of three physicians. This classification was considered as the clinical gold standard, against which the registers were assessed. Results: Register-based heart failure diagnoses had a positive predictive value of 0.85 (95% CI 0.77-0.91) and a negative predictive value of 0.83 (95% CI 0.75-0.90). The positive predictive value decreased when we classified patients with transient heart failure (duration <6 months), dialysis/lung disease or heart failure with preserved ejection fraction as not having heart failure. Conclusions: Heart failure diagnoses of the Finnish Hospital Discharge Register have good positive predictive value and negative predictive value, even when patients with pre-existing heart conditions are used as healthy controls. Our results suggest that heart failure diagnoses based on register data can be reliably used for research purposes.

Germline BRCA-Associated Endometrial Carcinoma Is a Distinct Clinicopathologic Entity.

PURPOSE: Whether endometrial carcinoma (EC) should be considered part of the gBRCA1/2-associated hereditary breast and ovarian cancer (HBOC) syndrome is topic of debate. We sought to assess whether ECs occurring in gBRCA carriers are enriched for clinicopathologic and molecular characteristics, thereby supporting a causal relationship. EXPERIMENTAL DESIGN: Thirty-eight gBRCA carriers that developed EC were selected from the nationwide cohort study on hereditary breast and ovarian cancer in the Netherlands (HEBON), and these were supplemented with four institutional cases. Tumor tissue was retrieved via PALGA (Dutch Pathology Registry). Nineteen morphologic features were scored and histotype was determined by three expert gynecologic pathologists, blinded for molecular analyses (UCM-OncoPlus Assay including 1213 genes). ECs with LOH of the gBRCA-wild-type allele (gBRCA/LOHpos) were defined "gBRCA-associated," those without LOH (gBRCA/LOHneg) were defined "sporadic." RESULTS: LOH could be assessed for 40 ECs (30 gBRCA1, 10 gBRCA2), of which 60% were gBRCA/LOHpos. gBRCA/LOHpos ECs were more frequently of nonendometrioid (58%, P = 0.001) and grade 3 histology (79%, P < 0.001). All but two were in the TP53-mutated TCGA-subgroup (91.7%, P < 0.001). In contrast, gBRCA/LOHneg ECs were mainly grade 1 endometrioid EC (94%) and showed a more heterogeneous distribution of TCGA-molecular subgroups: POLE-mutated (6.3%), MSI-high (25%), NSMP (62.5%), and TP53-mutated (6.3%). CONCLUSIONS: We provide novel evidence in favor of EC being part of the gBRCA-associated HBOC-syndrome. gBRCA-associated ECs are enriched for EC subtypes associated with unfavorable clinical outcome. These findings have profound therapeutic consequences as these patients may benefit from treatment strategies such as PARP inhibitors. In addition, it should influence counseling and surveillance of gBRCA carriers.

Survival after bilateral risk-reducing mastectomy in healthy BRCA1 and BRCA2 mutation carriers.

BACKGROUND: In healthy BRCA1/2 mutation carriers, bilateral risk-reducing mastectomy (BRRM) strongly reduces the risk of developing breast cancer (BC); however, no clear survival benefit of BRRM over BC surveillance has been reported yet. METHODS: In this Dutch multicenter cohort study, we used multivariable Cox models with BRRM as a time-dependent covariable to estimate the associations between BRRM and the overall and BC-specific mortality rates, separately for BRCA1 and BRCA2 mutation carriers. RESULTS: During a mean follow-up of 10.3 years, 722 out of 1712 BRCA1 (42%) and 406 out of 1145 BRCA2 (35%) mutation carriers underwent BRRM. For BRCA1 mutation carriers, we observed 52 deaths (20 from BC) in the surveillance group, and 10 deaths (one from BC) after BRRM. The hazard ratios were 0.40 (95% CI 0.20-0.90) for overall mortality and 0.06 (95% CI 0.01-0.46) for BC-specific mortality. BC-specific survival at age 65 was 93% for surveillance and 99.7% for BRRM. For BRCA2 mutation carriers, we observed 29 deaths (7 from BC) in the surveillance group, and 4 deaths (no BC) after BRRM. The hazard ratio for overall mortality was 0.45 (95% CI 0.15-1.36). BC-specific survival at age 65 was 98% for surveillance and 100% for BRRM. CONCLUSION: BRRM was associated with lower mortality than surveillance for BRCA1 mutation carriers, but for BRCA2 mutation carriers, BRRM may lead to similar BC-specific survival as surveillance. Our findings support a more individualized counseling based on BRCA mutation type.