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Objectives Cerebrospinal fluid α-synuclein (CSF α-syn) represents a possible biomarker in Parkinson’s disease (PD) diagnosis. CSF blood contamination can introduce a bias in α-syn measurement. To date, CSF samples with a red blood cells (RBC) count >50 RBC × 106/L or haemoglobin (Hb) concentration >200 μg/L are excluded from biomarker studies. However, investigations for defining reliable cut-off values are missing. Methods We evaluated the effect of blood contamination on CSF α-syn measurement by a systematic approach in a cohort of 42 patients with different neurological conditions who underwent lumbar puncture (LP) for diagnostic reasons. CSF samples were spiked with whole blood and serially diluted to 800, 400, 200, 100, 75, 50, 25, 5, 0 RBC × 106/L. CSF α-syn and Hb levels were measured by ELISA. Results In neat CSF, the average concentration of α-syn was 1,936 ± 636 ng/L. This value increased gradually in spiked CSF samples, up to 4,817 ± 1,456 ng/L (+149% α-syn variation) in samples with 800 RBC × 106/L. We established different cut-offs for discriminating samples with α-syn level above 5, 10, and 20% variation, corresponding to a Hb (RBC) concentration of 1,569 μg/L (37 RBC × 106/L), 2,082 μg/L (62 RBC × 106/L), and 3,118 μg/L (87 RBC × 106/L), respectively. Conclusions Our data show the high impact of CSF blood contamination on CSF α-syn levels, highlighting the measurement of Hb concentration as mandatory when assessing CSF α-syn. The thresholds we calculated are useful to classify CSF samples for blood contamination, considering as reliable only those showing a Hb concentration

Objective The present work was undertaken to study the genetic contribution to the start of Alzheimer's disease (AD) with amyloid and tau biomarkers in cognitively intact older identical twins.Methods We studied in 96 monozygotic twin-pairs relationships between amyloid-beta (A beta) aggregation as measured by the A beta 1-42/1-40 ratio in cerebrospinal fluid (CSF; n = 126) and positron emission tomography (PET, n = 194), and CSF markers for A beta production (beta-secretase 1, A beta 1-40, and A beta 1-38) and CSF tau. Associations among markers were tested with generalized estimating equations including a random effect for twin status, adjusted for age, gender, and apolipoprotein E epsilon 4 genotype. We used twin analyses to determine relative contributions of genetic and/or environmental factors to AD pathophysiological processes.Results Twenty-seven individuals (14%) had an abnormal amyloid PET, and 14 twin-pairs (15%) showed discordant amyloid PET scans. Within twin-pairs, A beta production markers and total-tau (t-tau) levels strongly correlated (r range = 0.73-0.86, all p < 0.0001), and A beta aggregation markers and 181-phosphorylated-tau (p-tau) levels correlated moderately strongly (r range = 0.50-0.64, all p < 0.0001). Cross-twin cross-trait analysis showed that A beta 1-38 in one twin correlated with A beta 1-42/1-40 ratios, and t-tau and p-tau levels in their cotwins (r range = -0.28 to 0.58, all p < .007). Within-pair differences in A beta production markers related to differences in tau levels (r range = 0.49-0.61, all p < 0.0001). Twin discordance analyses suggest that A beta production and tau levels show coordinated increases in very early AD.Interpretation Our results suggest a substantial genetic/shared environmental background contributes to both A beta and tau increases, suggesting that modulation of environmental risk factors may aid in delaying the onset of AD pathophysiological processes. ANN NEUROL 2021

Background CSF biomarkers are well-established for routine clinical use, yet a paucity of comparative assessment exists regarding CSF extraction methods during lumbar puncture. Here, we compare in detail biomarker profiles in CSF extracted using either gravity drip or aspiration. Methods Biomarkers for β-amyloidopathy (Aβ1–42, Aβ1–40), tauopathy (total tau), or synapse pathology (BACE1, Neurogranin Trunc-p75, α-synuclein) were assessed between gravity or aspiration extraction methods in a sub-population of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study (cognitively normal, N = 36; mild cognitive impairment, N = 8; Alzheimer’s disease, N = 6). Results High biomarker concordance between extraction methods was seen (concordance correlation > 0.85). Passing Bablock regression defined low beta coefficients indicating high scalability. Conclusions Levels of these commonly assessed CSF biomarkers are not influenced by extraction method. Results of this study should be incorporated into new consensus guidelines for CSF collection, storage, and analysis of biomarkers.

Objective To estimate the diagnostic value of tumor and immune related proteins in the discrimination between benign and malignant adnexal masses, and between different subgroups of tumors. Methods In this exploratory diagnostic study, 254 patients with an adnexal mass scheduled for surgery were consecutively enrolled at the University Hospitals Leuven (128 benign, 42 borderline, 22 stage I, 55 stage II-IV, and 7 secondary metastatic tumors). The quantification of 33 serum proteins was done preoperatively, using multiplex high throughput immunoassays (Luminex) and electrochemiluminescence immuno-assay (ECLIA). We calculated univariable areas under the Receiver Operating Characteristic Curves (AUCs). To discriminate malignant from benign tumors, multivariable ridge logistic regression with backward elimination was performed, using bootstrapping to validate the resulting AUCs. Results CA125 had the highest univariable AUC to discriminate malignant from benign tumors (0.85, 95% confidence interval 0.79-0.89). Combining CA125 with CA72.4 and HE4 increased the AUC to 0.87. For benign vs borderline tumors, CA125 had the highest univariable AUC (0.74). For borderline vs stage I malignancy, no proteins were promising. For stage I vs II-IV malignancy, CA125, HE4, CA72.4, CA15.3 and LAP had univariable AUCs ≥0.80. Conclusions The results confirm the dominant role of CA125 for identifying malignancy, and suggest that other markers (HE4, CA72.4, CA15.3 and LAP) may help to distinguish between stage I and stage II-IV malignancies. However, further research is needed, also to investigate the added value over clinical and ultrasound predictors of malignancy, focusing on the differentiation between subtypes of malignancy.

Background The presynaptic protein neuregulin1 (NRG1) is cleaved by beta-site APP cleaving enzyme 1 (BACE1) in a similar way as amyloid precursor protein (APP) NRG1 can activate post-synaptic receptor tyrosine-protein kinase erbB4 (ErbB4) and was linked to schizophrenia. The NRG1/ErbB4 complex is neuroprotective, can trigger synaptogenesis and plasticity, increases the expression of NMDA and GABA receptors, and can induce neuroinflammation. This complex can reduce memory formation. In Alzheimer’s disease (AD) brains, NRG1 accumulates in neuritic plaques. It is difficult to determine if NRG1 has beneficial and/or detrimental effects in AD. BACE1 levels are increased in AD brains and cerebrospinal fluid (CSF) and may lead to enhanced NRG1 secretion, but no study has assessed CSF NRG1 levels in AD and mild cognitive impairment (MCI) patients. Methods This retrospective study included 162 patients suffering from AD dementia (54), MCI with progression to AD dementia (MCI-AD) (27), non-AD MCI (30), non-AD dementias (30), and neurological controls (27). All patients had neurological examinations, brain MRI, and neuropsychological evaluations. After written informed consent and using enzyme-linked immunosorbent assays (ELISAs), CSF samples were evaluated for Aβ1–42, Aβ1–40, total tau (T-tau), phosphorylated tau on threonine 181 (P-tau), BACE1, growth-associated protein 43 (GAP 43), neurogranin (Ng), and NRG1. Results Levels of NRG1 were significantly increased in the CSF of AD (+ 36%) and MCI-AD (+ 28%) patients compared to neurological controls and also non-AD MCI and non-AD dementias. In addition, in AD and MCI-AD patients, NRG1 levels positively correlated with Aβ1–42 but not with T-tau, P-tau, and BACE1 levels and negatively correlated with MMSE scores. A longitudinal follow-up study of AD patients revealed a trend (p = 0.08) between CSF NRG1 levels and cognitive decline. In the overall population, NRG1 correlated with MMSE and the synaptic biomarkers GAP 43 and neurogranin. Conclusions Our results showed that CSF NRG1 levels are increased in AD and MCI-AD as compared to controls and other dementias. CSF NRG1 levels are associated with cognitive evolution, and a major outcome of our findings is that synaptic NRG1 could be involved in the pathophysiology of AD. Modulating brain NRG1 activity may represent a new therapeutic target in AD.

Background Dementia with Lewy bodies (DLB) is more prevalent in men than in women. In addition, post-mortem studies found sex differences in underlying pathology. It remains unclear whether these differences are also present antemortem in in vivo biomarkers, and whether sex differences translate to variability in clinical manifestation. The objective of this study was to evaluate sex differences in cerebrospinal fluid (CSF) biomarker concentrations (i.e., alpha-synuclein (α-syn), amyloid β1-42 (Aβ42), total tau (Tau), phosphorylated tau at threonine 181 (pTau)) and clinical characteristics in DLB. Methods We included 223 DLB patients from the Amsterdam Dementia Cohort, of which 39 were women (17%, age 70 ± 6, MMSE 21 ± 6) and 184 men (83%, age 68 ± 7, MMSE 23 ± 4). Sex differences in CSF biomarker concentrations (i.e., α-syn, Aβ42, Tau, and pTau) were evaluated using age-corrected general linear models (GLM). In addition, we analyzed sex differences in core clinical features (i.e., visual hallucinations, parkinsonism, cognitive fluctuations, and REM sleep behavior disorder (RBD) and cognitive test scores using age- and education-adjusted GLM. Results Women had lower CSF α-syn levels (F 1429 ± 164 vs M 1831 ± 60, p = 0.02) and CSF Aβ42 levels (F 712 ± 39 vs M 821 ± 18, p = 0.01) compared to men. There were no sex differences for (p) Tau concentrations (p > 0.05). Clinically, women were older, had a shorter duration of complaints (F 2 ± 1 vs M 4 ± 3, p p = 0.02), and scored lower on MMSE and a fluency task (MMSE, p = 0.02; animal fluency, p = 0.006). Men and women did not differ on fluctuations, RBD, parkinsonism, or other cognitive tests. Conclusions Women had lower Aβ42 and α-syn levels than men, alongside a shorter duration of complaints. Moreover, at the time of diagnosis, women had lower cognitive test scores and more frequent hallucinations. Based on our findings, one could hypothesize that women have a more aggressive disease course in DLB compared to men. Future research should investigate whether women and men with DLB might benefit from sex-specific treatment strategies.

This contribution discusses legal design in the development of legal analytical tools for dispute resolution, starting from a study using a legal knowledge graph in the creation of an algorithm to predict the legal ground in criminal cases. Legal Analytics are legal information tools that ultimately influence how law is made and administered in disputes. As such, Legal Analytics are design hybrids, encompassing principles of information design and product design. The chapter proposes to extend the definition of legal design to encompass the creation of Legal Analytics. Furthermore, it is claimed that, by applying design principles, a debate about the data, the questions and the choices for the natural language and machine learning algorithm can be facilitated, thus enhancing the Rule of Law in onlife societies. The arguments are based on concepts of the philosophy of information and the logic of design.

The core cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers amyloid beta (Aβ42 and Aβ40), total tau, and phosphorylated tau, have been extensively clinically validated, with very high diagnostic performance for AD, including the early phases of the disease. However, between-center differences in pre-analytical procedures may contribute to variability in measurements across laboratories. To resolve this issue, a workgroup was led by the Alzheimer's Association with experts from both academia and industry. The aim of the group was to develop a simplified and standardized pre-analytical protocol for CSF collection and handling before analysis for routine clinical use, and ultimately to ensure high diagnostic performance and minimize patient misclassification rates. Widespread application of the protocol would help minimize variability in measurements, which would facilitate the implementation of unified cut-off levels across laboratories, and foster the use of CSF biomarkers in AD diagnostics for the benefit of the patients.

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Altres ajuts: The Catalan frontotemporal initiative (CATFI) is funded by the Health Department of the Government of Catalonia (grant PERIS SLT002/16/00408 to Alberto Lleó and Raquel Sánchez-Valle). This work was also supported by research grants from the CIBERNED Program (Program 1, Alzheimer Disease to Alberto Lleó and SIGNAL study, file://www.signalstudy.es), partly funded by Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, "Una manera de hacer Europa." This work has also been supported by a "Marató TV3" grant (20141210 to Juan Fortea, 044412 to Rafael Blesa, 20143710 to Ricard Rojas-García and 20143810 to Raquel Sánchez-Valle) and Fundación BBVA (grant to A. Lleó) and a grant from the Fundació Bancaria La Caixa to Rafael Blesa. Ignacio Illán-Gala and Sergi Borrego-Écija are supported by the Rio Hortega grant from "Acción estratégica en Salud 2013-2016" and the European Social Fund. Ignacio Illán-Gala is supported by the Global Brain Health Institute (Atlantic Fellow for Equity in Brain Health). We acknowledge all the participants in this study and all the collaborators of the SPIN cohort. We also acknowledge Soraya Torres and Laia Muñoz for technical assistance. We thank EUROIMMUN for providing Aβ1-38 and Aβ1-40 ELISA assays for this study. Objective: We aimed to investigate the relationship between cerebrospinal fluid levels (CSF) of amyloid precursor protein (APP)-derived peptides related to the amyloidogenic pathway, cortical thickness, neuropsychological performance, and cortical gene expression profiles in frontotemporal lobar degeneration (FTLD)-related syndromes, Alzheimer's disease (AD), and healthy controls. Methods: We included 214 participants with CSF available recruited at two centers: 93 with FTLD-related syndromes, 57 patients with AD, and 64 healthy controls. CSF levels of amyloid β (Aβ)1-42, Aβ1-40, Aβ1-38, and soluble β fragment of APP (sAPPβ) were centrally analyzed. We compared CSF levels of APP-derived peptides between groups and, we studied the correlation between CSF biomarkers, cortical thickness, and domain-specific cognitive composites in each group. Then, we explored the relationship between cortical thickness, CSF levels of APP-derived peptides, and regional gene expression profile using a brain-wide regional gene expression data in combination with gene set enrichment analysis. Results: The CSF levels of Aβ1-40, Aβ1-38, and sAPPβ were lower in the FTLD-related syndromes group than in the AD and healthy controls group. CSF levels of all APP-derived peptides showed a positive correlation with cortical thickness and the executive cognitive composite in the FTLD-related syndromes group but not in the healthy control or AD groups. In the cortical regions where we observed a significant association between cortical thickness and CSF levels of APP-derived peptides, we found a reduced expression of genes related to synaptic function. Interpretation: APP-derived peptides in CSF may reflect FTLD-related neurodegeneration. This observation has important implications as Aβ1-42 levels are considered an indirect biomarker of cerebral amyloidosis.

Resume L’endometrite du post-partum est frequente et represente 2 % des infections du post-partum dans les pays a bon niveau socioeconomique. En France, 2,3 % des deces sont imputes aux infections puerperales. Le facteur de risque le plus important est l’accouchement par cesarienne, d’autant plus lorsque celle-ci est effectuee apres le debut du travail. Les bacteries du microbiote vaginal sont associees a l’endometrite du post-partum. Les signes d’appel sont l’apparition de douleurs abdominopelviennes, une hyperthermie, des lochies anormales. Le diagnostic est clinique, confirme par une douleur a la mobilisation uterine. L’antibiotherapie probabiliste de premiere intention est l’amoxicilline–acide clavulanique, 3 a 6 grammes par jour selon le poids par voie intraveineuse ou per os. En cas de contre-indication aux penicillines (anaphylaxie par exemple), l’association clindamycine 600 mg × 4/j plus gentamicine 5 mg/kg × 1/j sera utilisee, elle doit relever d’un avis specialise en cas d’allaitement maternel. Le traitement est poursuivi jusqu’a l’obtention de 48 heures d’apyrexie et la disparition des douleurs provoquees. En cas de persistance de la fievre et/ou des douleurs pelviennes apres 72 heures d’antibiotherapie, une imagerie pelvienne devra etre realisee pour rechercher une retention placentaire, une thrombophlebite pelvienne septique, un abces profond ou tout autre complication chirurgicale, et eliminer les diagnostics differentiels. Il est important de souligner les difficultes d’interpretation des images endo-uterines en echographie. Une heparinotherapie a posologie hypocoagulante doit etre debutee en cas de thrombophlebite pelvienne septique pour une duree de 6 semaines, ou plus s’il existe des complications a type d’embols ou des facteurs de risque thrombotique. Concernant la prevention, lors d’une cesarienne, un badigeonnage vaginal avec de la polividone-iodee ou de la chlorhexidine est recommande avant la cesarienne si possible, et la delivrance du placenta doit etre spontanee.

The main pathophysiological alterations of Alzheimer's disease (AD) include loss of neuronal and synaptic integrity, amyloidogenic processing, and neuroinflammation. Similar alterations can, however, also be observed in cognitively intact older subjects and may prelude the clinical manifestation of AD. The objectives of this prospective cross-sectional study in a cohort of 38 cognitively intact older adults were twofold: (i) to investigate the latent relationship among cerebrospinal fluid (CSF) biomarkers reflecting the main pathophysiological processes of AD, and (ii) to assess the correlation between these biomarkers and gray matter volume as well as amyloid load. All subjects underwent extensive neuropsychological examinations, CSF sampling, [18 F]-flutemetamol amyloid positron emission tomography, and T1 -weighted magnetic resonance imaging. A factor analysis revealed one factor that explained most of the variance in the CSF biomarker dataset clustering t-tau, α-synuclein, p-tau181 , neurogranin, BACE1, visinin-like protein 1, chitinase-3-like protein 1 (YKL-40), Aβ1-40 and Aβ1-38 . Higher scores on this factor correlated with lower gray matter volume and with higher amyloid load in the precuneus. At the level of individual CSF biomarkers, levels of visinin-like protein 1, neurogranin, BACE1, Aβ1-40 , Aβ1-38, and YKL-40 all correlated inversely with gray matter volume of the precuneus. These findings demonstrate that in cognitively intact older subjects, CSF levels of synaptic and neuronal integrity biomarkers, amyloidogenic processing and measures of innate immunity (YKL-40) display a latent structure of common variance, which is associated with loss of structural integrity of brain regions implicated in the earliest stages of AD. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript, and for *Preregistration* because the study was pre-registered at https://osf.io/7qm9t/. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Glial fibrillary acidic protein (GFAP), an astrocytic cytoskeletal protein, can be measured in blood samples, and has been associated with Alzheimer’s disease (AD). However, plasma GFAP has not been investigated in cognitively normal older adults at risk of AD, based on brain amyloid-β (Aβ) load. Cross-sectional analyses were carried out for plasma GFAP and plasma Aβ1–42/Aβ1–40 ratio, a blood-based marker associated with brain Aβ load, in participants (65–90 years) categorised into low (Aβ−,n = 63) and high (Aβ+,n = 33) brain Aβ load groups via Aβ positron emission tomography. Plasma GFAP, Aβ1–42, and Aβ1–40 were measured using the Single molecule array (Simoa) platform. Plasma GFAP levels were significantly higher (p p

IntroductionLong-term survivors of ovarian cancer are a unique group of patients in whom prognostic factors for long-term survival have been poorly described. Such factors may provide information for a more personalized therapeutic approach. The objective of this study is to determine further characteristics of long-term survivors with high-grade serous ovarian cancer.MethodsLong-term survivors were defined as patients living longer than 8 years after first diagnosis and were recruited within seven high volume centers across Europe from November 1988 to November 2008. The control group included patients with high-grade serous ovarian cancer with less than 5 years' survival identified from the systematic ‘Tumorbank ovarian cancer’ database. A subanalysis of Charité patients only was performed separately for in-depth analysis of tumor dissemination. Propensity score matching with nearest-neighbor caliper width was used to match long-term survivors and the control group regarding age, FIGO stage, and residual tumor.ResultsA total of 276 patients with high-grade serous ovarian cancer were included, divided into 131 long-term survivors and 145 control group patients. After propensity score matching and multivariable adjustment, platinum sensitivity (p=0.002) was an independent favorable prognostic factor whereas recurrence (pConclusionPlatinum sensitivity constitutes a favorable factor for long-term survival whereas tumor involvement of the upper abdomen, ascites, and recurrence have a negative impact. Based on clinical estimation, long-term survival is associated with combinations of clinical, surgical, and molecular factors.

BackgroundBlood-based amyloid biomarkers may provide a non-invasive, cost-effective and scalable manner for detecting cerebral amyloidosis in early disease stages.MethodsIn this prospective cross-sectional study, we quantified plasma Aβ1–42/Aβ1–40ratios with both routinely available ELISAs and novel SIMOA Amyblood assays, and provided a head-to-head comparison of their performances to detect cerebral amyloidosis in a nondemented elderly cohort (n = 199). Participants were stratified according to amyloid-PET status, and the performance of plasma Aβ1–42/Aβ1–40to detect cerebral amyloidosis was assessed using receiver operating characteristic analysis. We additionally investigated the correlations of plasma Aβ ratios with amyloid-PET and CSF Alzheimer’s disease biomarkers, as well as platform agreement using Passing-Bablok regression and Bland-Altman analysis for both Aβ isoforms.ResultsELISA and SIMOA plasma Aβ1–42/Aβ1–40detected cerebral amyloidosis with identical accuracy (ELISA: area under curve (AUC) 0.78, 95% CI 0.72–0.84; SIMOA: AUC 0.79, 95% CI 0.73–0.85), and both increased the performance of a basic demographic model including only age andAPOE-ε4genotype (p ≤ 0.02). ELISA and SIMOA had positive predictive values of respectively 41% and 36% in cognitively normal elderly and negative predictive values all exceeding 88%. Plasma Aβ1–42/Aβ1–40correlated similarly with amyloid-PET for both platforms (Spearmanρ = − 0.32,p 1–42/t-tau were stronger for ELISA (ρ = 0.41,p = 0.002) than for SIMOA (ρ = 0.29,p = 0.03). Plasma Aβ levels demonstrated poor agreement between ELISA and SIMOA with concentrations of both Aβ1–42and Aβ1–40measured by SIMOA consistently underestimating those measured by ELISA.ConclusionsELISA and SIMOA demonstrated equivalent performances in detecting cerebral amyloidosis through plasma Aβ1–42/Aβ1–40, both with high negative predictive values, making them equally suitable non-invasive prescreening tools for clinical trials by reducing the number of necessary PET scans for clinical trial recruitment.Trial registrationEudraCT 2009-014475-45 (registered on 23 Sept 2009) and EudraCT 2013-004671-12 (registered on 20 May 2014,https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-004671-12/BE).

Among the strategies to encourage pregnant women to be vaccinated against pertussis in the postpartum period, that of giving them a prescription has been evaluated only sparsely.To measure the effect of giving women who are not immunized against pertussis a prescription for the vaccine at discharge from the maternity unit.Single-center before-and-after study (2011: before; 2015: after). All women received both oral and written information about vaccination against pertussis. During the after period, they were also specifically asked their immunization status during pregnancy. Those currently unimmunized received a written prescription for it at discharge.Among the women unimmunized at delivery, the percentage who were vaccinated postpartum climbed from 17 to 42% between 2011 and 2015 (p0.001), while the percentage of their unimmunized partners who were vaccinated remained stable (27 and 29%, p = 0.74). During this time, the percentage of women immunized against pertussis at the beginning of pregnancy rose from 32 to 52% (p0.001). Finally, the percentage of all women protected against this disease postpartum climbed from 44 to 72% between these two periods (p0.001).In the postpartum period, giving a prescription for pertussis vaccine to women unimmunized is accompanied by a significant elevation in their vaccination rate. Nevertheless, this rate remains low and better strategies have to be implemented.

Background Blood-based biomarkers for Alzheimer’s disease (AD) might facilitate identification of participants for clinical trials targeting amyloid beta (Abeta) accumulation, and aid in AD diagnostics. We examined the potential of plasma markers Abeta(1-42/1-40), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) to identify cerebral amyloidosis and/or disease severity. Methods We included individuals with a positive (n = 176: 63 ± 7 years, 87 (49%) females) or negative (n = 76: 61 ± 9 years, 27 (36%) females) amyloid PET status, with syndrome diagnosis subjective cognitive decline (18 PET+, 25 PET−), mild cognitive impairment (26 PET+, 24 PET−), or AD-dementia (132 PET+). Plasma Abeta(1-42/1-40), GFAP, and NfL were measured by Simoa. We applied two-way ANOVA adjusted for age and sex to investigate the associations of the plasma markers with amyloid PET status and syndrome diagnosis; logistic regression analysis with Wald’s backward selection to identify an optimal panel that identifies amyloid PET positivity; age, sex, and education-adjusted linear regression analysis to investigate associations between the plasma markers and neuropsychological test performance; and Spearman’s correlation analysis to investigate associations between the plasma markers and medial temporal lobe atrophy (MTA). Results Abeta(1-42/1-40) and GFAP independently associated with amyloid PET status (p = 0.009 and p p = 0.001 and p = 0.048 respectively). The optimal panel identifying a positive amyloid status included Abeta(1-42/1-40) and GFAP, alongside age and APOE (AUC = 88% (95% CI 83–93%), 82% sensitivity, 86% specificity), while excluding NfL and sex. GFAP and NfL robustly associated with cognitive performance on global cognition and all major cognitive domains (GFAP: range standardized β (sβ) = − 0.40 to − 0.26; NfL: range sβ = − 0.35 to − 0.18; all: p (1-42/1-40) associated with global cognition, memory, attention, and executive functioning (range sβ = 0.22 – 0.11; all: p 0.33, p (1-42/1-40) showed a moderate negative correlation with MTA (Spearman’s rho = − 0.24, p = 0.001). Discussion and conclusions Combination of plasma Abeta(1-42/1-40) and GFAP provides a valuable tool for the identification of amyloid PET status. Furthermore, plasma GFAP and NfL associate with various disease severity measures suggesting potential for disease monitoring.

ObjectiveTo study the genetic contribution to the start of Alzheimer’s disease as signified by abnormalities in amyloid and tau biomarkers in cognitively intact older identical twins.MethodsWe studied in 96 monozygotic twin-pairs relationships between Aβ aggregation as measured by the ratio Aβ1-42/1-40 in cerebrospinal fluid (CSF) and positron emission tomography (PET), and CSF markers for Aβ production (BACE1, Aβ1-40 and 1-38) and tau. Associations amongst markers were tested with Generalized Estimating Equations including a random effect for twin status, adjusted for age, gender, and APOE ε4 genotype. We used twin analyses to determine relative contributions of genetic and/or environmental factors to AD pathophysiological processes.ResultsTwenty-seven individuals (14%) had an abnormal amyloid-PET, and 14 twin-pairs (15%) showed discordant amyloid status. Within twin-pairs, Aβ production markers and total-tau (t-tau) levels strongly correlated (r range 0.76, 0.88; all pInterpretationOur results suggest a substantial genetic/shared environmental background contributes to both Aβ and tau increases, suggesting that modulation of environmental risk factors may aid in delaying the onset of AD pathophysiological processes.

Accumulating evidence suggests a relationship between endometrial cancer and epithelial ovarian cancer. For example, endometrial cancer and epithelial ovarian cancer share epidemiological risk factors and molecular features observed across histotypes are held in common (e.g. serous, endometrioid and clear cell). Independent genome-wide association studies (GWAS) for endometrial cancer and epithelial ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. Using GWAS summary statistics, we explored the shared genetic etiology between endometrial cancer and epithelial ovarian cancer. Genetic correlation analysis using LD Score regression revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e. inverse-variance meta-analysis, co-localization, and M-values), and performed analyses by stratified by subtype. We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10−9). In addition, four novel regions at 7p22.2, 7q22.1, 9p12 and 11q13.3 were identified at a sub-genome wide threshold (P < 5 × 10−7). Integration with promoter-associated HiChIP chromatin loops from immortalized endometrium and epithelial ovarian cell lines, and expression quantitative trait loci (eQTL) data highlighted candidate target genes for further investigation.

Introduction Amyloid, Tau, and neurodegeneration biomarkers can stage Alzheimer's Disease (AD). Synaptic biomarkers may help track cognition. Methods In cognitively normal controls, Mild Cognitive Impairment (MCI) and AD, we investigated CSF biomarkers in relation to cognitive measures and as predictors of cognitive and global decline. Results There were 90 normal controls (mean age 73.0, 58% women), 57 MCI (mean age 74.3, 35% women), and 46 AD (mean age 70.7, 41% women). CSF Aβ1-42 and Neuronal Pentraxin 2 (NPTX2) were decreased, and CSF Tau, neurogranin, and SNAP25 increased in AD versus controls. Aβ1-42/Tau or NPTX2/Tau discriminated AD and controls best. NPTX2/Tau correlated strongly with cognition in AD and MCI and predicted a 2–3-year decline. We replicated findings in the ADNI cohort. Discussion CSF synaptic biomarkers, particularly NPTX2, which regulates synaptic homeostasis, relate to cognition and predict progression in AD beyond Aβ1-42 and Tau. This is relevant for prognosis and clinical trials., Highlights • CSF levels of synaptic biomarkers and their ratios to CSF Tau improved AD diagnosis • CSF synaptic biomarkers, particularly NPTX2, predicted cognitive decline. • Combining CSF biomarkers of neurodegeneration may improve diagnosis or prognosis. • NPTX2 relates to interneuron-dependent circuit homeostasis, likely impaired in AD.

Ovarian cancer (OC) accounts for the most gynecological cancer-related deaths in developed countries. Unfortunately, the lack of both evident early symptoms and effective asymptomatic population screening results in late diagnosis and inevitably poor prognosis. Hence, it is urgent to identify novel molecular markers to support personalized prognosis. In the present study, we have analyzed the clinical significance of miR-203 in OC using two institutionally independent cohorts. miR-203 levels were quantified in a screening (n = 125) and a validation cohort (n = 100, OVCAD multicenter study). Survival analysis was performed using progression and death as clinical endpoint events. Internal validation was conducted by bootstrap analysis, and decision curve analysis was used to evaluate the clinical benefit. Increased miR-203 levels in OC patients were correlated with unfavorable prognosis and higher risk for disease progression, independently of FIGO stage, tumor grade, residual tumor after surgery, chemotherapy response and age. The analysis of the institutionally independent validation cohort (OVCAD study) clearly confirmed the shorter survival outcome of the patients overexpressing miR-203. Additionally, integration of miR-203 levels with the established disease prognostic markers led to a superior stratification of OC patients that can ameliorate prognosis and benefit patient clinical management. In this regard, miR-203 expression constitutes a novel independent molecular marker to improve patients' prognosis in OC. ispartof: CARCINOGENESIS vol:41 issue:4 pages:442-451 ispartof: location:England status: published

ObjectivesPoor survival of high-grade serous pelvic cancer is caused by a lack of effective screening measures. The detection of exfoliated cells from high-grade serous pelvic cancer, or precursor lesions, is a promising concept for earlier diagnosis. However, collecting those cells in the most efficient way while fulfilling all requirements for a screening approach is a challenge. We introduce a new catheter for uterine and tubal lavage (UtL) and the clinical evaluation of its performance.Methods/MaterialsIn study I, the clinical feasibility of the UtL using the new catheter was examined in 93 patients admitted for gynecologic surgery under general anesthesia. In study II, the safety of the UtL procedure was assessed. The pain during and after the UtL performed under local anesthesia was rated on a visual analog scale by 22 healthy women.ResultsIn study I, the UtL was carried out successfully in 92 (98.9%) of 93 cases by 16 different gynecologists. It was rated as easy to perform in 84.8% of patients but as rather difficult in cancer patients (odds ratio, 5.559; 95% confidence interval, 1.434–21.546; P = 0.007). For benign conditions, dilatation before UtL was associated with menopause status (odds ratio, 4.929; 95% confidence interval, 1.439–16.884; P = 0.016). In study II, the pain during UtL was rated with a median visual analog scale score of 1.6. During a period of 4 weeks after UtL, none of the participants had to use medication or developed symptoms requiring medical attention. The UtL took 6.5 minutes on average. The amount of extracted DNA was above the lower limit for a sensitive, deep-sequencing mutation analysis in all cases.ConclusionsOur studies demonstrate that the UtL, using the new catheter, is a safe, reliable, and well-tolerated procedure, which does not require elaborate training. Therefore, UtL fulfils all prerequisites to be used in a potential screening setting.

High levels of total α-synuclein (t-α-synuclein) in the cerebrospinal fluid (CSF) were reported in sporadic Creutzfeldt-Jakob disease (sCJD). The potential use of t-α-synuclein in the discrimination of Lewy body dementias (i.e., Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB)) is still under investigation. In addition, phospho-serine-129 α-synuclein (p-α-synuclein) has been described to be slightly increased in the CSF of synucleinopathies. Here, we analyzed t-α-synuclein and p-α-synuclein concentrations and their ratio in the context of differential diagnosis of neurodegenerative diseases. We quantified the levels of CSF t-α-synuclein and p-α-synuclein in a cohort of samples composed of neurological controls (NC), sCJD, PDD, and DLB by means of newly developed specific enzyme-linked immunosorbent assays. T-α-synuclein and p-α-synuclein were specifically elevated in sCJD compared to other disease groups. The area under the curve (AUC) values for t-α-synuclein were higher for the discrimination of sCJD from dementias associated to Lewy bodies as compared to the use of p-α-synuclein. A combination of both markers even increased the diagnostic accuracy. An inverse correlation was observed in CSF between t-α-synuclein and p-α-synuclein, especially in the DLB group, indicating a disease-relevant association between both markers. In conclusion, our data confirm t-α-synuclein and p-α-synuclein as robust biomarkers for sCJD and indicate the potential use of colorimetric t-α-synuclein ELISAs for differential diagnosis of dementia types.

Mucinous (goblet cell) carcinoids are a rare type of ovarian carcinoid tumors. Only a limited number of primary mucinous carcinoids of the ovary have been reported in the literature. We describe the case of a 55-year-old woman with a diffusely metastasized adenocarcinoma arising in a primary ovarian mucinous carcinoid. The differential diagnosis with a metastatic goblet cell carcinoid from the appendix or elsewhere can be very challenging. In our case, especially the immunohistochemical profile of the tumor with diffuse positivity for cytokeratin 7 and PAX8, and no expression of cytokeratin 20 and CDX2, directed us toward a primary ovarian origin. Expression of PAX8 in ovarian mucinous carcinoid has never been reported before.

Antiangiogenic compounds were the first active targeted agents implemented in the treatment of ovarian cancer. Bevacizumab and tyrosine kinase inhibitors such as pazopanib, nintedanib and cediranib target the VEGF pathway, while trebananib was developed as an inhibitor of the angiopoietin pathway. All these compounds have been extensively evaluated and, in this review, we provide a structured overview of the randomized trials that have been performed in both primary and relapsed ovarian cancer. From this data, it is evident that antiangiogenic therapy has its place in ovarian cancer. If not during first-line treatment, then at least at some point for the treatment of relapsed disease. In addition, we address and summarize the trials designed to address the remaining issues related to treatment duration, continuation beyond progression and optimal combination. The future clinical development of angiogenesis inhibitors in ovarian cancer indeed looks at combinations with poly (ADP-ribose) polymerase (PARP) inhibitors, immune checkpoint inhibitors and vascular disrupting agents. Finally, an overview is given of the retrospective translational studies that were performed on the samples of the two pivotal first-line trials GOG(Gynecologic Oncology Group)-218 and ICON(International Collaborative Ovarian Neoplasm study)7, with initial evidence for the predictive value of the BRCA status, some molecular subtypes and histological assessment of microvessel density. If confirmed, these biomarkers could further improve the implementation of antiangiogenic therapy in ovarian cancer.

Background and Purpose— Inflammation is involved in the pathogenesis of large artery atherosclerosis, ischemic stroke, and Alzheimer dementia. However, the role of inflammation in cerebral small vessel disease and neurodegeneration remains poorly understood. We hypothesize that CRP (C-reactive protein) is associated with brain structural changes and may interact with amyloid to produce vascular and degenerative damage. We examined the association of CRP levels with imaging markers of cerebral small vessel disease and neurodegeneration. Furthermore, we studied the association of CRP with plasma Aβ (amyloid-β) levels and their joint effects with imaging markers. Methods— We included 2814 persons (mean age, 56.9 years; 44.8% women) from the Rotterdam Study with complete data on CRP and 1.5 T brain magnetic resonance imaging scans. Aβ levels were measured in a subsample (n=736). Markers of cerebral small vessel disease included lacunes, white matter hyperintensities, microbleeds, and enlarged perivascular spaces. Neurodegeneration was assessed by smaller volumes of gray matter, white matter, and hippocampus. Plasma levels of Aβ1–38, Aβ1–40, and Aβ1–42 were assessed using ELISA. Results— Higher CRP levels were associated with larger white matter hyperintensities volume (β=0.07; 95% CI, 0.00–0.13), increasing lacunar (rate ratios, 1.61; 95% CI, 1.19–2.19), enlarged perivascular spaces (rate ratios, 1.01; 95% CI, 1.00–1.03), and deep/infratentorial microbleeds (rate ratios, 1.30; 95% CI, 1.00–1.69) counts. People with high CRP levels had small gray matter volume. We also found significant interaction between CRP and Aβ such that among persons in higher tertiles of Aβ1–42, a strong association was observed between CRP and lacunar ( P interaction, 0.004), enlarged perivascular spaces ( P interaction, 0.002), and microbleed counts ( P interaction, P interaction, 0.004). Conclusions— Higher CRP levels were associated with subclinical markers of cerebral small vessel disease and neurodegeneration. This effect was augmented by an interaction between CRP and Aβ levels. Future longitudinal studies focusing on joint effects of CRP and Aβ on progression of magnetic resonance imaging markers and cognitive decline are warranted.

Parkinson's disease biomarkers are needed to increase diagnostic accuracy, to objectively monitor disease progression and to assess therapeutic efficacy as well as target engagement when evaluating novel drug and therapeutic strategies. This article summarizes perianalytical considerations for biomarker studies (based on immunoassays) in Parkinson's disease, with emphasis on quantifying total α-synuclein protein in biological fluids. Current knowledge and pitfalls are discussed, and selected perianalytical variables are presented systematically, including different temperature of sample collection and types of collection tubes, gradient sampling, the addition of detergent, aliquot volume, the freezing time, and the different thawing methods. We also discuss analytical confounders. We identify gaps in the knowledge and delineate specific areas that require further investigation, such as the need to identify posttranslational modifications of α-synuclein and antibody-independent reference methods for quantification, as well as the analysis of potential confounders, such as comorbidities, medication, and phenotypes of Parkinson's disease in larger cohorts. This review could be used as a guideline for future Parkinson's disease biomarker studies and will require regular updating as more information arises in this growing field, including new technical developments as they become available. In addition to reviewing best practices, we also identify the current technical limitations and gaps in the knowledge that should be addressed to enable accurate and quantitative assessment of α-synuclein levels in the clinical setting. © 2017 International Parkinson and Movement Disorder Society.

Introduction The exceedingly high rate of failed trials in Alzheimer's disease (AD) calls for immediate attention to improve efficiencies and learning from past, ongoing, and future trials. Accurate, highly rigorous standardized data are at the core of meaningful scientific research. Data standards allow for proper integration of clinical data sets and represent the essential foundation for regulatory endorsement of drug development tools. Such tools increase the potential for success and accuracy of trial results. Methods The development of the Clinical Data Interchange Standards Consortium (CDISC) AD therapeutic area data standard was a comprehensive collaborative effort by CDISC and Coalition Against Major Diseases, a consortium of the Critical Path Institute. Clinical concepts for AD and mild cognitive impairment were defined and a data standards user guide was created from various sources of input, including data dictionaries used in AD clinical trials and observational studies. Results A comprehensive collection of AD-specific clinical data standards consisting of clinical outcome measures, leading candidate genes, and cerebrospinal fluid and imaging biomarkers was developed. The AD version 2.0 (V2.0) Therapeutic Area User Guide was developed by diverse experts working with data scientists across multiple consortia through a comprehensive review and revision process. The AD CDISC standard is a publicly available resource to facilitate widespread use and implementation. Discussion The AD CDISC V2.0 data standard serves as a platform to catalyze reproducible research, data integration, and efficiencies in clinical trials. It allows for the mapping and integration of available data and provides a foundation for future studies, data sharing, and long-term registries in AD. The availability of consensus data standards for AD has the potential to facilitate clinical trial initiation and increase sharing and aggregation of data across observational studies and among clinical trials, thereby improving our understanding of disease progression and treatment.

Germline pathogenic alterations in the breast cancer susceptibility genes 1 (BRCA1) and 2 (BRCA2) are the most prevalent causes of hereditary breast and ovarian cancer. The increasing trend in proportion of cancer patients undergoing genetic testing, followed by predictive testing in families of new index patients, results in a significant increase of healthy germline BRCA1/2 mutation carriers who are at increased risk for breast, ovarian, and other BRCA-related cancers. This review aims to give an overview of available screening guidelines for female and male carriers of pathogenic or likely pathogenic germline BRCA1/2 variants per cancer type, incorporating malignancies that are more or less recently well correlated with BRCA1/2. We selected guidelines from national/international organizations and/or professional associations that were published or updated between January 1, 2015, and February 1, 2020. In total, 12 guidelines were included. This review reveals several significant discordances between the different guidelines. Optimal surveillance strategies depend on accurate age-specific cancer risk estimates, which are not reliably available for all BRCA-related cancers. Up-to-date national or international consensus guidelines are of utmost importance to harmonize counseling and proposed surveillance strategies for BRCA1/2 carriers.

Introduction/Background Poor survival of high-grade serous pelvic cancer (HGSC) is caused by a lack of effective screening measures. Uterine and tubal lavage (UtL) is the sampling technique for HGSC detection with the highest sensitivity ever reported. We combined UtL with the highest accuracy sequencing technology for TP53 mutations, Duplex Sequencing (DS) in order to develop a test potentially feasible for HGSC screening. Methodology In study I, the clinical feasibility of UtL using a new catheter was examined in 93 patients undergoing surgery for suspected HGSC. In study II, pain at UtL under local anesthesia was evaluated in 22 healthy women. In Study III, uterine lavages from 10 HGSC patients and 11 controls were subjected to DS to identify TP53 mutations. Results In study I, UtL was performed successfully in 92 (98.9%) of 93 cases by 16 gynecologists. In 84.8% of patients no cervical dilatation was required. For benign conditions, the need for dilatation was associated with menopause status (OR, 4.929; 95% CI, 1.439–16.884; P=0.016). In study II, pain during UtL was rated with a median VAS score of 1.6. During 4 weeks after UtL, no serious complications occurred. UtL took 6.5 minutes on average. The amount of extracted DNA was above the lower limit for sensitive, deep-sequencing mutation analysis in all cases. In study III, in 80% of all HGSC tumor-derived TP53 mutations in UtL samples were detected by DS. However, we detected low frequency TP53 mutations in nearly all samples tested. Mutations increased with age and shared the selection traits of clonal TP53 mutations commonly found in human tumors. However, tumor-derived TP53 mutations were present at frequencies at least 10-fold higher than background mutations. Conclusion The UtL concept fulfils all prerequisites to be used in a potential screening setting. Interpretation of DS results needs to consider TP53 biologic background mutations. Disclosure Philipp Harter COI: Honoraria: Astra Zeneca, Roche, Sotio, Tesaro, Stryker, ASCO, Zai Lab, MSD; Advisory Board: Astra Zeneca, Roche, Tesaro, Lilly, Clovis, Immunogen, MSD/Merck; Research funding (Inst): Astra Zeneca, Roche, GSK, Boehringer Ingelheim, Medac, DFG, European Union, DKH, Tesaro, Genmab Rosana Risques COI: RAR shares equity in NanoString Technologies Inc. and is the principal investigator on an NIH SBIR subcontract research agreement with TwinStrand Biosciences Inc. Florian Heitz COI: Honoraria: AstraZeneca, Roche, Tesaro, Clovis; Advisory Board: Astra Zeneca, Roche, Tesaro, Clovis Christoph Grimm COI: Consultant: AstraZeneca, Celgene, MSD, PharmaMar, Roche, Tesaro, Vifor Pharma Speaker: Amgen, AstraZeneca, MSD, PharmaMar, Roche, Tesaro Direct research funding: Meda Pharma, Roche Diagnostics Ignace Vergote COI: CONSULTING = ADVISORY BOARD: Advaxis, Inc., Eisai Inc., MSD Belgium, Roche NV, Genmab, F. Hoffmann-La Roche Ltd, Pharmamar, Millennium Pharmaceuticals, Clovis Oncology Inc., AstraZeneca NV, Tesaro, Oncoinvent AS, Immunogen Inc, Sotio CONTRACTED RESEARCH (via KULeuven): Oncoinvent AS, Genmab GRANT = CORPORATE SPONSORED RESEARCH: Amgen, Roche, Stichting tegen Kanker Accomodations, travel Fabian Trillsch COI:Consultant: AstraZeneca, Roche, Tesaro Speaker/Travel Expenses: AstraZeneca, Medac, PharmaMar, Roche, Tesaro Paul Speisr: Share Holder OVARTEC GmbH.

Introduction/Background Patients with relapsed ovarian cancer receive multiple lines of chemotherapy, each negatively affecting their health-related quality of life (HRQOL). The CLIO trial randomized patients with platinum-resistant relapsed ovarian cancer (PROC) to treatment with olaparib versus standard chemotherapy (paclitaxel weekly, or pegylated liposomal doxorubicin, or gemcitabine or topotecan). Olaparib showed a favorable response rate compared with chemotherapy (Vanderstichele A et al., ASCO 2019). We aimed to assess HRQOL and quality-adjusted survival measures including Q-TWIST (quality-adjusted time without symptoms and toxicities of treatment) and QAPFS (quality-adjusted progression free survival). Methodology EORTC questionnaires QLQ-C30 and QLQ-OV28 were administered at baseline and every three months until end of treatment. Scoring of HRQOL focused on abdominal/gastrointestinal symptoms. Overall survival was partitioned into three health states to calculate Q-TWIST: time with grade ≥2 nausea, vomiting and fatigue (toxicity), time without toxicities (twist) and relapse. Each health state was adjusted by a utility weight derived from the QLQ-C30 global health status. QAPFS calculation was based on Q-TWIST, but excluded relapse status. Results In CLIO, we randomized 100 PROC patients 2:1 towards olaparib (n=67) and chemotherapy (n=33). Baseline compliance rate of questionnaires was 83% (88% olaparib vs. 73% chemotherapy). There was no significant difference in abdominal/gastrointestinal symptoms between both arms (p=0.4). In the olaparib-arm, significant differences were observed between responders and non-responders (p=0.001). Adverse events (AEs) of grade ≥3 occurred in 60% and 52% of patients in the olaparib and chemotherapy arm respectively (p=0.521). The difference in Q-TWIST was 35.6 days (95%CI: -121.5–27.8) in favour of chemotherapy. The difference in QAPFS was 23.8 days (95% CI: -42.2–63.5) in favour of olaparib. Conclusion In PROC patients, olaparib monotherapy showed similar HRQOL compared to standard chemotherapy. There were no significant differences in abdominal/gastrointestinal symptoms, Q-TWIST and QAPFS between the two treatment arms. Disclosure The presenting author, T. Callewaert, has no conflict of interest.

Introduction/Background Detecting tumor-specific genetic alterations in cell-free DNA (cfDNA) obtained from cancer patients allows for a quantification of the tumoral fraction, i.e. the circulating tumor DNA (ctDNA). Previous studies in metastatic cancer patients showed that early changes of this fraction during therapy are indicative of therapeutic response. We tested this hypothesis on cfDNA samples collected in the GANNET53 clinical trial (FP7, funded by the European Commission, grant no 602602). Methodology Patients with high-grade serous/endometrioid and/or undifferentiated PROC were recruited for treatment with weekly paclitaxel with or without Hsp90-inhibitor ganetespib. Archival biopsy samples were used for tumor TP53 genotyping. CfDNA was prospectively collected prior to treatment at baseline (cycle 1 day 1, C1D1), 24 hours later (cycle 1 day 2, C1D2) and after 4 and 8 weeks, at day 1 of cycle 2 (C2D1) and 3 (C3D1) respectively. Targeted TP53 resequencing was performed on cfDNA and allelic frequencies of the known TP53 variant (TP53 VAF) were quantified and correlated with clinical outcome. Results For 125 of the 133 randomized patients, at least 1 C1D1 cfDNA sample was available. For 119 tumor samples, TP53 genotyping was successful and identified deleterious TP53 mutations in 106 patients (89.1%). The median ctDNA level was 1.82% (IQR:0.17–8.34%) at C1D1 which decreased significantly after 4–8 weeks of therapy. Overall, ctDNA was detectable in 64.6% (64/99) of baseline samples. Baseline CA125 did not differ between cases with and without detectable ctDNA at C1D1. Detection of ctDNA at C1D1 (HR 2.3; 95%CI:1.4–3.9), C1D2 (HR 2.2; 95%CI:1.3–3.9) and C2D1 (HR 2.8; 95%CI:1.6–4.9) predicted a worse overall survival. A subgroup of patients for whom TP53 ctDNA was undetectable at C2D1 or C3D1 (14/64) had a high overall response rate of 64.2%. Conclusion Quantification of TP53 mutations in cfDNA of PROC patients has prognostic value at baseline. Favorable early changes during treatment may predict therapeutic response. Disclosure The presenting author, A.Vanderstichele, has no conflict of interest.

To explore the impact of breast cancer subtype on metastatic behavior and long-term outcome defined as breast cancer specific survival (BCSS). Retrospective single centre cross-sectional study of 5972 patients with newly diagnosed, unilateral first diagnosis of breast cancer, diagnosed 2000–2010. Patients had either early breast cancer (EBC) treated primarily by surgery (SURG n = 5072), neoadjuvant systemic therapy (NEO n = 592), or upfront metastatic disease (META n = 308). Surrogate breast cancer subtypes were defined according to classical pathological criteria. Analysis was performed using Kaplan–Meier method and logistic/Cox regression. After median follow-up time of 103.6 months (IQR 73.4–139.2 months), 817 patients with EBC at diagnosis (14.4%) developed distant metastases of which 621 (12.2%) SURG and 196 (33.1%) NEO. Metastasis rate after EBC was: LuminalA 8.1%, LuminalB1(HER2−) 20.4%, LuminalB2(HER2+) without (neo)adjuvant trastuzumab 21.7%, LuminalB2(HER2+) with trastuzumab 9.0%, HER2Positive(ER−) without trastuzumab 30.0%, HER2Positive(ER−) with trastuzumab 19.9% and TripleNegative 25.3%. There were major differences in site of first metastases according to subtype. For single site first metastases, median BCSS assessed from time of metastases was worst for brain localization (13.9 months) and best for bone (48.4 months). Multiple sites of first metastases had worse BCSS from date of metastases than single site first metastases (median BCSS for 1 site 40.0, 2 sites 27.1, ≥ 3 sites 20.5 months). Median BCSS from date of metastases is longer in upfront metastases compared to secondary metastases after EBC (43.4 vs. 27.9 months). Tumor subtype influences the metastatic behavior and survival after development of distant metastases.

Background: Aberrant amyloid-β (Aβ) deposition in the brain occurs two decades prior to the manifestation of Alzheimer’s disease (AD) clinical symptoms and therefore brain Aβ load measured using PET serves as a gold standard biomarker for the early diagnosis of AD. However, the uneconomical nature of PET makes blood markers, that reflect brain Aβ deposition, attractive candidates for investigation as surrogate markers. Objective:Investigation of plasma Aβ as a surrogate marker for brain Aβ deposition in cognitively normal elderly individuals. Methods: Plasma Aβ40 and Aβ42 concentrations were measured using the ultrasensitive Single Molecule Array (Simoa) assay in 95 cognitively normal elderly individuals, who have all undergone PET to assess brain Aβ deposition. Based on the standard uptake value ratios (SUVR) obtained from PET imaging, using the tracer 18F-Florbetaben, plasma Aβ was compared between 32 participants assessed to have low brain Aβ load (Aβ–, SUVR

BackgroundCoffee consumption has been shown to be associated with various health outcomes in observational studies. However, evidence for its association with epithelial ovarian cancer (EOC) is inconsistent and it is unclear whether these associations are causal.MethodsWe used single nucleotide polymorphisms associated with (i) coffee and (ii) caffeine consumption to perform Mendelian randomization (MR) on EOC risk. We conducted a two-sample MR using genetic data on 44 062 individuals of European ancestry from the Ovarian Cancer Association Consortium (OCAC), and combined instrumental variable estimates using a Wald-type ratio estimator.ResultsFor all EOC cases, the causal odds ratio (COR) for genetically predicted consumption of one additional cup of coffee per day was 0.92 [95% confidence interval (CI): 0.79, 1.06]. The COR was 0.90 (95% CI: 0.73, 1.10) for high-grade serous EOC. The COR for genetically predicted consumption of an additional 80 mg caffeine was 1.01 (95% CI: 0.92, 1.11) for all EOC cases and 0.90 (95% CI: 0.73, 1.10) for high-grade serous cases.ConclusionsWe found no evidence indicative of a strong association between EOC risk and genetically predicted coffee or caffeine levels. However, our estimates were not statistically inconsistent with earlier observational studies and we were unable to rule out small protective associations.

An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom-designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high-grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 1.2 × 10-6 , BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6-3.4, P = 1.6 × 10-5 , BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 2.3 × 10-5 , BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC. ispartof: CANCER MEDICINE vol:8 issue:5 pages:2503-2513 ispartof: location:United States status: published

This work contributes to the harmonisation of the quantitative methodologies of data science, computer science and statistics with the qualitative methodology of the law. It gives a layered answer to the research question whether the outcome of a machine learning algorithm with case law as an input can have normative value. The thesis argues first that the outcome of a machine learning algorithm with case law as an input is not ‘law’ as we know it today. Neither is it a fact in a court case, nor a secondary source of law. The thesis claims furthermore that for methodological reasons, such an outcome is to be considered as a ‘sui generis’ concept, a concept of its own kind, with which courts can, and even should, engage in adjudication. In addition, it is argued that modelling with machine learning can have an implicit normativity through the definition of the purpose of the algorithm, its design and the choices that are made by the software engineers. In the first part, the work introduces several building blocks that inform the following parts. The second part is a critical analysis of 9 experiments with mainly supervised machine learning algorithms, with case law as an input. The final part discusses the use of the outcome of such algorithms in court cases.

Background Approximately 40% of oestrogen receptor positive (ER+) metastatic breast cancer harbour PIK3CA hotspot mutations, leading to an over-activated PI3K pathway. The PI3Kα-selective inhibitor, alpelisib, is FDA approved and currently available in early access program for patients with ER+ HER2-negative metastatic disease, if an activating PIK3CA mutation is confirmed. Mutational analysis on liquid biopsies may increase the number of eligible patients given the challenges of tissue procurement in metastatic setting. We optimized and validated ddPCR assays for PIK3CA hotspot mutations in cell-free DNA (cfDNA) of metastatic breast cancer patients. Patients and Methods We prospectively collected two blood samples (cfDNA Collection tubes, Roche Diagnostics) of 20 metastatic breast cancer patients at progression (N=12) or during therapy (N=8). PIK3CA mutation status was previously demonstrated by Next Generation Sequencing (NGS) performed in 4 patients on primary tumor tissue and in 16 patients on metastatic tumor tissue; 8 patients tested positive and 12 negative. Tumors were ER+ HER2-negative, triple-negative and HER2-positive in 14, 5 and one patients, respectively. After plasma-isolation, cfDNA was manually extracted with Cobas® cfDNA Sample Preparation Kit (2mL plasma) and semi-automatically with Maxwell® RSC ccfDNA Plasma Kit (2mL and 4mL plasma). Inter-run variability, intra-run variability, precision and robustness of the assays, and concordance between NGS and ddPCR for the detection of PIK3CA hotspot mutations on tumor tissue and in plasma, respectively, were assessed. Results All 20 samples were successfully processed with ddPCR. The highest cfDNA yield was obtained by Maxwell 4mL extraction method (median: 0.483 ng/µL; range: 0.140 - 10.500 ng/µL). The per-mutation sensitivity and specificity was 87.5% and 95.8%, respectively. Two samples showed discordant results between PIK3CA mutations detected by NGS on tumor tissue and by ddPCR in plasma. One sample tested positive for p.(H1047R) on tumor tissue, and for p.(E542K), p.(E545K) and p.(H1047R) in cfDNA. The other switched between p.(E545K) mutation on tumor tissue and p.(E542K) in cfDNA. Tumor tissue of samples for which the results of the NGS test were discordant with the ddPCR test on plasma, was tested again using ddPCR on the tissue. This still showed discordances in PIK3CA mutations which can be explained by tumor heterogeneity and the lower detection limit of ddPCR versus NGS. Conclusion Detection of PIK3CA hotspot mutations with ddPCR in cfDNA is feasible. We observed good concordance between NGS and ddPCR for the detection of PIK3CA hotspot mutations on tumor tissue and in plasma, respectively. In 10% of cases, discordant PIK3CA mutation status in tissue versus plasma was detected. Further investigation of different metastatic lesions in these cases is ongoing. Citation Format: Laurence Slembrouck, Demi Renders, Sara Vander Borght, Patrick Neven, Giuseppe Floris, Lien Spans, Hans Wildiers, Kevin Punie, Ann Smeets, Ines Nevelsteen, Ignace Vergote, Adriaan Vanderstichele, Isabelle Vanden Bempt. Optimization and validation of PIK3CA mutation detection with droplet digital PCR in liquid biopsies of patients with metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-28.