No circulating biomarker is available for endometrial carcinoma (EC). We aimed to identify DNA positions universally hypermethylated in EC, and to develop a digital droplet PCR (ddPCR) assay for ...detection of hypermethylated circulating tumor DNA (meth-ctDNA) in plasma from patients with EC.
DNA positions hypermethylated in EC, and without unspecific hypermethylation in tissue/cell types releasing circulating cell-free DNA in plasma, were identified in silico from TCGA/Gene Expression Omnibus (GEO) data. A methylation-specific ddPCR (meth-ddPCR) assay following bisulfite conversion of DNA extracted from plasma was optimized for detection of meth-ctDNA according to dMIQE guidelines. Performances were validated on a retrospective cohort (n = 78 tumors, n = 30 tumor-adjacent tissues), a prospective pilot cohort (n = 33 stage I-IV patients), and 55 patients/donors without cancer.
Hypermethylation of zinc finger and SCAN domain containing 12 (ZSCAN12) and/or oxytocin (OXT) classified EC samples from multiple noncancer samples with high diagnostic specificity/sensitivity >97%; area under the curve (AUC) = 0.99; TCGA/GEO tissues/blood samples. These results were confirmed in the independent retrospective cohort (AUC = 0.99). Meth-ddPCR showed a high analytical specificity (limit of blank = 2) and sensitivity (absolute lower threshold of detection = 50 pgmethDNA/mLplasma). In the pilot cohort, meth-ctDNA was detected in pretreatment plasma samples from 9/11 and 5/20 patients with advanced and non-advanced EC, respectively. 2 of 9 patients had ctDNA detected after macroscopic complete surgery and experienced progression within 6 months. No healthy donors had any copy of hypermethylated DNA detected in plasma.
Meth-ddPCR of ZSCAN12/OXT allows a highly specific and sensitive detection of ctDNA in plasma from patients with EC and appears promising for personalized approaches for these patients.
International Federation of Gynecology and Obstetrics (FIGO) staging classification for stage IV epithelial ovarian cancer (EOC) separates stages IVA (pleural effusion) and IVB (parenchymal and/or ...extra-abdominal lymph node metastases). We aimed to evaluate its prognostic impact and to compare survival according to the initial metastatic location. We conducted a multicenter study between 2000 and 2020, including patients with a FIGO stage IV EOC. Primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS) and recurrence rates. We included 307 patients: 98 (32%) had FIGO stage IVA and 209 (68%) had FIGO stage IVB. The median OS and PFS of stage IVA patients were significantly lower than those of stage IVB patients (31 versus 45 months (
= 0.02) and 18 versus 25 months (
= 0.01), respectively). Recurrence rate was higher in stage IVA than IVB patients (65% versus 47% (
= 0.004)). Initial pleural involvement was a poor prognostic factor with a median OS of 35 months versus 49 months for patients without initial pleural involvement (
= 0.024). Patients with FIGO stage IVA had a worse prognosis than patients with FIGO stage IVB EOC. Pleural involvement appears to be relevant for predicting survival. We suggest a modification of the current FIGO staging classification.
Despite recent advances in endometrial carcinoma (EC) molecular characterization, its prognostication remains challenging. We aimed to assess whether RNAseq could stratify EC patient prognosis beyond ...current classification systems.
A prognostic signature was identified using a LASSO-penalized Cox model trained on TCGA (N = 543 patients). A clinically applicable polyA-RNAseq-based work-flow was developed for validation of the signature in a cohort of stage I-IV patients treated in two Hospitals 2010–2017. Model performances were evaluated using time-dependent ROC curves (prediction of disease-specific-survival (DSS)). The additional value of the RNAseq signature was evaluated by multivariable Cox model, adjusted on high-risk prognostic group (2021 ESGO-ESTRO-ESP guidelines: non-endometrioid histology or stage III-IVA orTP53-mutated molecular subgroup).
Among 209 patients included in the external validation cohort, 61 (30%), 10 (5%), 52 (25%), and 82 (40%), had mismatch repair-deficient, POLE-mutated, TP53-mutated tumors, and tumors with no specific molecular profile, respectively. The 38-genes signature accurately predicted DSS (AUC = 0.80). Most disease-related deaths occurred in high-risk patients (5-years DSS = 78% (95% CI = 68%–89%) versus 99% 97%–100% in patients without high-risk). A composite classifier accounting for the TP53-mutated subgroup and the RNAseq signature identified three classes independently associated with DSS: RNAseq-good prognosis (reference, 5-years DSS = 99%), non-TP53 tumors but with RNAseq-poor prognosis (adjusted-hazard ratio (aHR) = 5.75, 95% CI1.14–29.0), and TP53-mutated subgroup (aHR = 5.64 1.12–28.3). The model accounting for the high-risk group and the composite classifier predicted DSS with AUC = 0.84, versus AUC = 0.76 without (p = 0.01).
RNA-seq profiling can provide an additional prognostic information to established classification systems, and warrants validation for potential RNAseq-based therapeutic strategies in EC.
•One out of 3 endometrial cancer (EC) are at high risk of relapse (2021 guidelines).•Histological and molecular features of this group are widely heterogeneous.•RNAseq prognostication is feasible & robust from routine practice FFPE EC samples.•Integrating RNAseq to current classification improves EC prognostic stratification.
Background: Despite recent advances in endometrial carcinoma (EC) molecular characterization, its prognostication remains challenging. We aimed to assess whether RNAseq could stratify EC patient ...prognosis beyond current classification systems.Methods: A prognostic signature was identified using a LASSO-penalized Cox model trained on TCGA (N = 543 patients). A clinically applicable polyA-RNAseq-based work-flow was developed for validation of the signature in a cohort of stage I-IV patients treated in two Hospitals 2010-2017. Model performances were evaluated using time-dependent ROC curves (prediction of disease-specific-survival (DSS)). The additional value of the RNAseq signature was evaluated by multivariable Cox model, adjusted on high-risk prognostic group (2021 ESGO-ESTRO-ESP guidelines: non-endometrioid histology or stage III-IVA orTP53-mutated molecular subgroup).Results: Among 209 patients included in the external validation cohort, 61 (30%), 10 (5%), 52 (25%), and 82 (40%), had mismatch repair-deficient, POLE-mutated, TP53-mutated tumors, and tumors with no specific molecular profile, respectively. The 38-genes signature accurately predicted DSS (AUC = 0.80). Most disease-related deaths occurred in high-risk patients (5-years DSS = 78% (95% CI = 68%-89%) versus 99% 97%-100% in patients without high-risk). A composite classifier accounting for the TP53-mutated subgroup and the RNAseq signature identified three classes independently associated with DSS: RNAseq-good prognosis (reference, 5-years DSS = 99%), non-TP53 tumors but with RNAseq-poor prognosis (adjusted-hazard ratio (aHR) = 5.75, 95% CI1.14-29.0), and TP53-mutated subgroup (aHR = 5.64 1.12-28.3). The model accounting for the high-risk group and the composite classifier predicted DSS with AUC = 0.84, versus AUC = 0.76 without (p = 0.01).Conclusion: RNA-seq profiling can provide an additional prognostic information to established classification systems, and warrants validation for potential RNAseq-based therapeutic strategies in EC.
Objective
To compare survival and morbidity rates between primary cytoreductive surgery (pCRS) and interval cytoreductive surgery (iCRS) for epithelial ovarian cancer (EOC), using a propensity score.
...Design
We conducted a propensity score‐matched cohort study, using data from the FRANCOGYN cohort.
Setting
Retrospective, multicentre study of data from patients followed in 15 French department specialized in the treatment of ovarian cancer.
Sample
Patients included were those with International Federation of Gynaecology and Obstetrics (FIGO) stage III or IV EOC, with peritoneal carcinomatosis, having undergone CRS.
Methods
The propensity score was designed using pre‐therapeutic variables associated with both treatment allocation and overall survival (OS).
Main Outcome Measures
The primary outcome was OS. Secondary outcomes included recurrence‐free survival (RFS), quality of CRS and other variables related to surgical morbidity.
Results
A total of 513 patients were included. Among these, 334 could be matched, forming 167 pairs. No difference in OS was found (hazard ratio, HR = 0.8, p = 0.32). There was also no difference in RFS (median = 26 months in both groups) nor in the rate of CRS leaving no macroscopic residual disease (pCRS 85%, iCRS 81.4%, p = 0.76). The rates of gastrointestinal tract resections, stoma, postoperative complications and hospital stay were significantly higher in the pCRS group.
Conclusions
Analysis of groups of patients made comparable by propensity score matching showed no difference in survival, but lower postoperative morbidity in patients treated with iCRS.
Inflammation, measured by abnormal blood C-reactive protein (CRP) level, has been described in schizophrenia (SZ), being inconsistently related to impaired cognitive functions. The aim of the present ...study is to investigate cognitive impairment associated with abnormal CRP levels in a large multi-centric sample of community-dwelling SZ patients, using a comprehensive neuropsychological battery.
Three hundred sixty-nine community-dwelling stable SZ subjects (76.2% men, mean age 32.7 y) were included and tested with a comprehensive battery of neuropsychological tests. Abnormal CRP level was defined as >3mg/L.
Multiple factor analysis revealed that abnormal CRP levels, found in 104 patients (28.2%), were associated with impaired General Intellectual Ability and Abstract Reasoning (aOR = 0.56, 95% CI 0.35-0.90, P = .014), independently of age, sex, education level, psychotic symptomatology, treatments, and addiction comorbidities. Abnormal CRP levels were also associated with the decline of all components of working memory (respectively effect size ES = 0.25, P = .033; ES = 0.27, P = .04; ES = 0.33, P = .006; and ES = 0.38, P = .004) and a wide range of other impaired cognitive functions, including memory (ES = 0.26, P = .026), learning abilities (ES = 0.28, P = .035), semantic memory (ES = 0.26, P = .026), mental flexibility (ES = 0.26, P = .044), visual attention (ES = 0.23, P = .004) and speed of processing (ES = 0.23, P = .043).
Our results suggest that abnormal CRP level is associated with cognitive impairment in SZ. Evaluating the effectiveness of neuroprotective anti-inflammatory strategies is needed in order to prevent cognitive impairment in SZ.
Existing staging models have not been fully validated. Thus, after classifying patients with schizophrenia according to the staging model proposed by McGorry et al. (2010), we explored the validity ...of this staging model and its stability after one-year of follow-up.
Using unsupervised machine-learning algorithm, we classified 770 outpatients into 5 clinical stages, the highest being the most severe. Analyses of (co)variance were performed to compare each stage in regard to socio-demographics factors, clinical characteristics, co-morbidities, ongoing treatment and neuropsychological profiles.
The precision of clinical staging can be improved by sub-dividing intermediate stages (II and III). Clinical validators of class IV include the presence of concomitant major depressive episode (42.6% in stage IV versus 3.4% in stage IIa), more severe cognitive profile, lower adherence to medication and prescription of >3 psychotropic medications. Follow-up at one-year showed good stability of each stage.
Clinical staging in schizophrenia could be improved by adding clinical elements such as mood symptoms and cognition to severity, relapses and global functioning. In terms of therapeutic strategies, attention needs to be paid on the factors associated with the more stages of schizophrenia such as treatment of comorbid depression, reduction of the number of concomitant psychotropic medications, improvement of treatment adherence, and prescription of cognitive remediation.
•Clinical staging for schizophrenia can be improved by adding assessment of mood symptoms and cognitive handicap•Early treatment of depression and cognitive remediation might reduce the number of patients in the most severe stages•This data suggests a reverse gear to clinical staging, traditionally thought as uniformly progressive.
The functional outcome in schizophrenia spectrum disorders is affected by multiple factors such as cognitive performance and clinical symptoms. Psychiatric disability may be another important ...determinant of functional outcome. The purpose of this study was to test whether schizophrenia symptoms and psychiatric disability mediated the association between cognition and functioning.
Between April 2013 and July 2017, we included 108 community-dwelling adults with stable schizophrenia spectrum disorder in a multicenter study. Psychiatric disability was assessed with the Evaluation of Cognitive Processes involved in Disability in Schizophrenia (ECPDS) scale by relatives of patients. ECPDS focused on the broad array of motivational, neurocognitive, sociocognitive, and metacognitive impairments that result in activity restrictions. We used a battery of tests to assess seven cognition domains (processing speed, attention/vigilance, working, verbal and visual memory, reasoning and problem solving, and executive functioning) and cross-sectional structural equation modeling (SEM) for the mediation analyses. We estimated the one-year temporal stability of ECPDS scores in 45 participants.
The model provided showed good fit and explained 43.9% of the variance in functioning. The effect of neurocognition on functioning was fully mediated by symptoms (proportion mediated: 36.5%) and psychiatric disability (proportion mediated: 31.3%). The ECPDS score had acceptable one-year temporal stability.
The ECPDS scale has satisfactory psychometric properties, and shows significant convergence with neurocognition and functioning, suggesting a role for this tool in the routine evaluation of cognitive remediation needs. Our model validates psychiatric disability as a crucial step from cognitive impairment to restricted participation in life situations.
This study aimed was to investigate the relationship between different types of childhood trauma and the level of insight (i.e., awareness of having a psychiatric disorder) in subjects suffering from ...schizophrenia, as well as the putative role of clinical mediators.
294 community-dwelling subjects with stable schizophrenia were included into FACE-SZ, a multicentre cross-sectional study. All patients were assessed by specialized multidisciplinary teams. The level of insight was assessed by the Scale to assess Unawareness of Mental Disorder (SUMD), and childhood trauma by the Childhood Trauma Questionnaire (CTQ).
Path analyses from the five CTQ subscales (physical abuse and neglect, emotional abuse and neglect, and sexual abuse) and the SUMD, with current symptomatology (i.e., positive, negative, global psychopathology and depression) as mediator, was performed.
Physical neglect (β = 0.14) and abuse (β = 0.13) were significantly associated with poor insight. Negative symptoms were a clinical mediator of the relationship between physical neglect and poor insight. Moreover, positive (β = 0.21) and negative (β = 0.30) symptoms were associated with poor insight, whereas depression (β = −0.14) was associated with higher levels of insight.
For the first time, this study shows a significant relationship between childhood trauma, specifically physical neglect and abuse, and poor insight. The level of insight was linked to different clinical dimensions. Among subjects with schizophrenia, these results provide support for a role of childhood trauma in poorer management outcomes, and the need to provide treatment, including psycho-education that better targets the consequences of childhood trauma.
Abstract The association between advanced paternal age (APA) and increased risk of schizophrenia (SZ) is well established. The objectives of the present study were to further determine if SZ ...participants with APA (APA+), versus those without (APA-), had: (i) different illness characteristics; (ii) different responses to antipsychotic medication; and (iii) different cognitive characteristics. Participants were a non-selected representative multicentric sample of stabilized community-dwelling people diagnosed with SZ included in the FACE-SZ cohort. 389 participants (73% males, mean aged 32.7 years, mean illness duration 10.8 years) formed the study sample, with each comprehensively evaluated, clinically and neuropsychologically, over 2 days. 118 participants (30.3%) were defined as APA+ according to their father's age at birth (≥35 years). APA+ was associated with a wide range of cognitive dysfunctions in univariate analyses. In multivariate analyses, the only significant difference was the age at onset, with a mean 1.6 year earlier in APA+, compared to APA- (20.7 vs. 22.3 years; p=0.02). This difference is independent of sociodemographic characteristics and I.Q. No association with clinical symptomatology and treatment response was found. The present study supports the neomutation hypothesis and confirms APA as a relevant clinical variable to discriminate potential schizophrenia subtypes. Potential underlying pathophysiological mechanisms are discussed.
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