Pre-treatment risk assessment of women with endometrial cancer: differences in outcomes of molecular and clinical classifications in the Slovenian patient cohort

Background The aim of this study was to evaluate changes in prognostic risk profiles of women with endometrial cancer by comparing the clinical risk assessment with the integrated molecular risk assessment profiling. Patients and methods This prospective study recruited patients with biopsy proven endometrial cancer treated at the University Medical Centre Maribor between January 2020 to February 2021. Patient clinical data was assessed and categorized according to the currently valid European Society of Gynaecological Oncology, European SocieTy for Radiotherapy and Oncology, and European Society of Pathology (ESGO/ESTRO/ESP) guidelines on endometrial cancer. Molecular tumour characterization included determination of exonuclease domain of DNA polymerase-epsilon (POLE) mutational status by Sanger sequencing and imunohistochemical specimen evaluation on the presence of mismatch repair deficiencies (MMRd) and p53 abnormalities (p53abn). Results Fourty-five women were included in the study. Twenty-two tumours were of non-specific mutational profile (NSMP) (56.4%), 13 were classified as MMRd (33.3%), 3 were classified as p53abn (7.7%) and 1 was classified as POLE mutated (2.6%). Six tumours (15.4%) had multiple molecular classifiers, these were studied separately and were not included in the risk assessment. The clinical risk-assessment classified 21 women (53.8%) as low-risk, 5 women (12.8%) as intermediate risk, 2 women as high-intermediate risk (5.1%), 10 women (25.6%) as high risk and 1 patient as advanced metastatic (2.6%). The integrated molecular classification changed risk for 4 women (10.3%). Conclusions Integrated molecular risk improves personalized risk assessment in endometrial cancer and could potentially improve therapeutic precision. Further molecular stratification with biomarkers is especially needed in the NSMP group to improve personalized risk-assessment.

A Smart Approach for Food Contaminants Risk Management, Complementary to Diet Nutritional Balance

Food is usually the major source of human exposure to environmental contaminants like heavy metals and synthetic compounds. This study proposes a quick and simple approach to combine the estimate of the intake of certain pollutants with the diet, in combination with different nutritional plans (Mediterranean diet, weight loss and for athletes). The estimation of the intake of three heavy metals and two perfluoroalkyl substances was carried out by entering the type and quantity of the foods provided by each of the three selected dietary plans in the UltraBio® app. Recurring elements are high levels of Cd and Pb and very low levels of PFASs, for all the plans considered. The Mediterranean diet scheme was the one with the lowest intake of all contaminants, which, in any case, remains within the safety limits by a large margin. The high protein diet leads to exceeding the limits for two metals and critical values for the third. The advantages of this approach are mainly represented by the possibility of having a personalized risk assessment of the intake of important food contaminants for the prevention of exposures that, over time, could put health at risk.

Personalized Risk Assessment for Prevention and Early Detection of Breast Cancer: Integration and Implementation (PERSPECTIVE I&I)

Early detection of breast cancer through screening reduces breast cancer mortality. The benefits of screening must also be considered within the context of potential harms (e.g., false positives, overdiagnosis). Furthermore, while breast cancer risk is highly variable within the population, most screening programs use age to determine eligibility. A risk-based approach is expected to improve the benefit-harm ratio of breast cancer screening programs. The PERSPECTIVE I&I (Personalized Risk Assessment for Prevention and Early Detection of Breast Cancer: Integration and Implementation) project seeks to improve personalized risk assessment to allow for a cost-effective, population-based approach to risk-based screening and determine best practices for implementation in Canada. This commentary describes the four inter-related activities that comprise the PERSPECTIVE I&I project. 1: Identification and validation of novel moderate to high-risk susceptibility genes. 2: Improvement, validation, and adaptation of a risk prediction web-tool for the Canadian context. 3: Development and piloting of a socio-ethical framework to support implementation of risk-based breast cancer screening. 4: Economic analysis to optimize the implementation of risk-based screening. Risk-based screening and prevention is expected to benefit all women, empowering them to work with their healthcare provider to make informed decisions about screening and prevention.

Refining the risk for fragile X–associated primary ovarian insufficiency (FXPOI) by FMR1 CGG repeat size

Purpose Approximately 20–30% of women with an FMR1 premutation experience fragile X–associated primary ovarian insufficiency (FXPOI); however, current risk estimates based on repeat size only identify women with the midrange of repeats to be at the highest risk. Methods To better understand the risk by repeat size, we collected self-reported reproductive histories on 1,668 women and divided them into high-resolution repeat size bins of ~5 CGG repeats to determine a more accurate risk for FXPOI in relation to CGG repeat length. Results As previously reported, women with 70–100 CGG repeats were at the highest risk for FXPOI using various statistical models to compare average age at menopause and risk of FXPOI, with women with 85–89 repeats being at the highest risk. Importantly, women with <65 repeats or >120 repeats did not have a significantly increased risk for FXPOI compared to women with <45 repeats. Conclusion Using a large cross-section study on 1,668 women, we have provided more personalized risk assessment for FXPOI using high-resolution repeat size bins. Understanding the variability in risk has important implications for family planning and overall health among women with a premutation.

Discovering Genotype Variants in an Infant with VACTERL through Clinical Exome Sequencing: A Support for Personalized Risk Assessment and Disease Prevention

Congenital anomalies may have an increased risk of noncommunicable diseases (NCDs) We performed a clinical exome analysis in an infant affected by “Vertebral, Anorectal, Cardiac, Tracheoesophageal, Genitourinary, and Limb” (VACTERL) malformation association to identify potential biomarkers that may be helpful for preventing malignancy risk or other chronic processes. Among the variants, six variants that may be linked with VACTERL were identified in the exome analysis. The variants c.501G>C on OLR1 and c.-8C>G on PSMA6 were previously associated with myocardial infarction. The variants c.1936A>G on AKAP10 and c.575A>G on PON1 are linked to defects in cardiac conduction and artery disease, respectively. Alterations in metabolism were also suggested by the variants c.860G>A on EPHX2 and c.214C>A on GHRL. In addition, three variants associated with colon cancer were discovered. Specifically, the reported variants were c.723G>A on CCND1 and c.91T>A on AURKA proto-oncogenes as well as c.827A>C in the tumor suppressor PTPRJ. A further inspection identified 15 rare variants carried by cancer genes. Specifically, these mutations are located on five tumor suppressors (SDHA, RB1CC1, PTCH1, DMBT1, BCR) and eight proto-oncogenes (MERTK, CSF1R, MYB, ROS1, PCM1, FGFR2, MYH11, BRCC3) and have an allele frequency lower than 0.01 in the Genome Aggregation Database (GnomAD). We observed that the cardiac and metabolic phenotypic traits are linked with the genotype of the patient. In addition, the risk of developing neoplasia cannot be excluded a priori. Long-term surgical issues of patients with VATER syndrome could benefit from the clinical exome sequencing of a personalized risk assessment for the appearance of further disease in pubertal timing and adult age.

Trends of incidence and prognosis of upper tract urothelial carcinoma

The purpose of this study was to investigate trends in the incidence of upper tract urothelial carcinoma (UTUC) in patients and to establish a reliable and practical nomogram based on significant clinical factors to predict the overall survival (OS) and cancer-specific survival (CSS) of UTUC patients. The Surveillance, Epidemiology, and End Results (SEER) database was used to extract data on UTUC patients between 1988 and 2015. Incidence was calculated using Joinpoint regression software, and trends were quantified by annual percentage change (APC). A nomogram was constructed using R software to predict the OS and CSS probabilities for individual patients. From 1988 to 2015, the incidence of UTUC showed a downward trend (1988: 1.57/100,000 to 2015: 1.51/100,000; APC=-0.1). After stratification according to sex, age and primary site, we found that the incidences of UTUC in males, patients 70+ years old and the renal pelvis were higher than those in females, patients <70 years old and ureter cancer patients. In the training cohort, the nomogram established based on multivariate Cox regression results showed better OS and CSS accuracy (OS: C-index=0.701, AUC=0.736; CSS: C-index=0.729, and AUC=0.688) than SEER stage. In addition, the calibration curves showed good consistency between the predicted and actual 3-, 5- and 10-year OS and CSS rates of the nomogram. In the past 30 years, the incidence of UTUC has shown a general downward trend, and the prognostic nomogram we established can provide a personalized risk assessment for the survival of UTUC patients.

Comparative Analysis of Risk Stratification Scores in Atrial Fibrillation

Background: Atrial Fibrillation (AF) has become a major global health concern and is associated with increased risk of poor outcomes. Identifying risk factors in patients with AF can be challenging, given the high burden of comorbidities in these patients. Risk stratification schemes appear to facilitate accurate prediction of outcomes and assist therapeutic management decisions. Objective: To summarize current evidence on risk stratification scores for patients with AF. Results: Traditional risk models rely heavily on demographics and comorbidities, while newer tools have been gradually focusing on novel biomarkers and diagnostic imaging to facilitate more personalized risk assessment. Several studies have been conducted to compare existing risk schemes and identify specific patient populations in which the prognostic ability of each scheme excels. However, current guidelines do not appear to encourage implementation of risk models in clinical practice, as they have not incorporated new ones in their recommendations for management of patients with AF since almost a decade. Conclusion: Further work is warranted to analyze new reliable risk stratification schemes and optimally implement them into routine clinical life.