Universal genetic testing for women with newly diagnosed breast cancer in the context of multidisciplinary team care.

OBJECTIVE: To determine the feasibility of universal genetic testing of women with newly diagnosed breast cancer, to estimate the incidence of pathogenic gene variants and their impact on patient management, and to evaluate patient and clinician acceptance of universal testing. DESIGN, SETTING, PARTICIPANTS: Prospective study of women with invasive or high grade in situ breast cancer and unknown germline status discussed at the Parkville Breast Service (Melbourne) multidisciplinary team meeting. Women were recruited to the pilot (12 June 2020 - 22 March 2021) and expansion phases (17 October 2021 - 8 November 2022) of the Mutational Assessment of newly diagnosed breast cancer using Germline and tumour genomICs (MAGIC) study. MAIN OUTCOME MEASURES: Germline testing by DNA sequencing, filtered for nineteen hereditary breast and ovarian cancer genes that could be classified as actionable; only pathogenic variants were reported. Surveys before and after genetic testing assessed pilot phase participants' perceptions of genetic testing, and psychological distress and cancer-specific worry. A separate survey assessed clinicians' views on universal testing. RESULTS: Pathogenic germline variants were identified in 31 of 474 expanded study phase participants (6.5%), including 28 of 429 women with invasive breast cancer (6.5%). Eighteen of the 31 did not meet current genetic testing eligibility guidelines (probability of a germline pathogenic variant ≥ 10%, based on CanRisk, or Manchester score ≥ 15). Clinical management was changed for 24 of 31 women after identification of a pathogenic variant. Including 68 further women who underwent genetic testing outside the study, 44 of 542 women carried pathogenic variants (8.1%). Acceptance of universal testing was high among both patients (90 of 103, 87%) and clinicians; no decision regret or adverse impact on psychological distress or cancer-specific worry were reported. CONCLUSION: Universal genetic testing following the diagnosis of breast cancer detects clinically significant germline pathogenic variants that might otherwise be missed because of testing guidelines. Routine testing and reporting of pathogenic variants is feasible and acceptable for both patients and clinicians.

Tumor-Infiltrating Neutrophils after Neoadjuvant Therapy are Associated with Poor Prognosis in Esophageal Cancer.

BACKGROUND: In esophageal cancer (EC), there is a paucity of knowledge regarding the interplay between the tumor immune microenvironment and response to neoadjuvant treatment and, therefore, which factors may influence outcomes. Thus, our goal was to investigate the changes in the immune microenvironment with neoadjuvant treatment in EC by assessing the expression of immune related genes and their association with prognosis. METHODS: We examined the transcriptome of paired pre- and post-neoadjuvant treated EC specimens. Based on these findings, we validated the presence of tumor-infiltrating neutrophils using CD15+ immunohistochemistry in a discovery cohort of patients with residual pathologic disease. We developed a nomogram as a predictor of progression-free survival (PFS) incorporating the variables CD15+ cell count, tumor regression grade, and tumor grade. RESULTS: After neoadjuvant treatment, there was an increase in genes related to myeloid cell differentiation and a poor prognosis associated with high neutrophil (CD15+) counts. Our nomogram incorporating CD15+ cell count was predictive of PFS with a C-index of 0.80 (95% confidence interval [CI] 0.68-0.9) and a concordance probability estimate (CPE) of 0.77 (95% CI 0.69-0.86), which indicates high prognostic ability. The C-index and CPE of the validation cohort were 0.81 (95% CI 0.69-0.91) and 0.78 (95% CI 0.7-0.86), respectively. CONCLUSIONS: Our nomogram incorporating CD15+ cell count can potentially be used to identify patients at high risk of recurrent disease and thus stratify patients who will benefit most from adjuvant treatment.

Molecular characterization of low-grade serous ovarian carcinoma identifies genomic aberrations according to hormone receptor expression.

Hormone receptor expression is a characteristic of low-grade serous ovarian carcinoma (LGSOC). Studies investigating estrogen receptor (ER) and progesterone receptor (PR) expression levels suggest its prognostic and predictive significance, although their associations with key molecular aberrations are not well understood. As such, we sought to describe the specific genomic profiles associated with different ER/PR expression patterns and survival outcomes in a cohort of patients with advanced disease. The study comprised fifty-five advanced-staged (III/IV) LGSOCs from the Canadian Ovarian Experimental Unified Resource (COEUR) for which targeted mutation sequencing, copy-number aberration, clinical and follow-up data were available. ER, PR, and p16 expression were assessed by immunohistochemistry. Tumors were divided into low and high ER/PR expression groups based on Allred scoring. Copy number analysis revealed that PR-low tumors (Allred score <2) had a higher fraction of the genome altered by copy number changes compared to PR-high tumors (p = 0.001), with cancer genes affected within specific loci linked to altered peptidyl-tyrosine kinase, MAP-kinase, and PI3-kinase signaling. Cox regression analysis showed that ER-high (p = 0.02), PR-high (p = 0.03), stage III disease (p = 0.02), low residual disease burden (p = 0.01) and normal p16 expression (p<0.001) were all significantly associated with improved overall survival. This study provides evidence that genomic aberrations are linked to ER/PR expression in primary LGSOC.

Effectiveness of the conservation areas on the Mornington Peninsula for the common resident shorebird species using citizen science data.

Conservation areas are critical for biodiversity conservation, but few citizen science studies have evaluated their efficiency. In the absence of thorough survey data, this study assessed which species benefit most from conservation areas using citizen science bird counts extracted from the Atlas of Living Australia. This was accomplished by fitting temporal models using citizen science data taken from ALA for the years 2010-2019 using the INLA approach. The trends for six resident shorebird species were compared to those for the Australian Pied Oystercatcher, with the Black-fronted Dotterel, Red-capped Dotterel, and Red-kneed Dotterel exhibiting significantly steeper increasing trends. For the Black-fronted Dotterel, Masked Lapwing, and Red-kneed Dotterel, steeper rising trends were recorded in conservation areas than in other locations. The Dotterel species' conservation status is extremely favourable. This study demonstrates that, with some limits, statistical models can be used to track the persistence of resident shorebirds and to investigate the factors affecting these data.

Risk factors associated with suicide in adolescents and young adults (AYA) with cancer.

BACKGROUND: Higher rates of death by suicide are recognized both in individuals of any age with cancer and, separately, among adolescents and young adults (AYA) without cancer. Given this intersection, identifying risk factors associated with suicidal risk among AYA with cancer is critical. OBJECTIVE: To identify characteristics associated with suicide among AYA with cancer. METHODS: A retrospective analysis of AYA (aged 15-39) during 1975-2016 from the Surveillance, Epidemiology, and End Results database was conducted. Clinical and demographic factors associated with death by suicide among the AYA cancer population were compared to (i) US population normative data (standardized mortality ratios [SMRs]) and (ii) other AYA individuals with cancer (odds ratios). RESULTS: In total, 922 suicides were found in 500,366 AYA with cancer (0.18%), observed for 3,198,261 person-years. The SMR for AYA with cancer was 34.1 (95% confidence interval [CI]: 31.4-36.9). Suicide risk was particularly high in females (SMR = 43.4, 95% CI: 37.2-50.4), unmarried persons (SMR = 50.6, 95% CI: 44.7-57.1), those with metastatic disease (SMR = 45.2, 95% CI: 33.1-60.3), or certain histological subtypes (leukemia, central nervous system, and soft tissue sarcoma). Risk generally reduced over time, however remained elevated ≥5 years following a cancer diagnosis (SMR > 5 years = 28.1, 95% CI: 25.4-31.0). When comparing those who died from suicide and those who did not, the following factors demonstrated significant associations: sex (males > females), race (White ethnicity > Black/other ethnicity), relationship status (never married > other), and disease stage (distant > localized). CONCLUSIONS: Death due to suicide/non-accidental injury is high compared to normative data, requiring increased awareness among health-care providers, suicide risk monitoring in AYA, and appropriately tailored psychosocial interventions.

Loss of SMAD4 Is Sufficient to Promote Tumorigenesis in a Model of Dysplastic Barrett's Esophagus.

BACKGROUND & AIMS: Esophageal adenocarcinoma (EAC) develops from its precursor Barrett's esophagus through intermediate stages of low- and high-grade dysplasia. However, knowledge of genetic drivers and molecular mechanisms implicated in disease progression is limited. Herein, we investigated the effect of Mothers against decapentaplegic homolog 4 (SMAD4) loss on transforming growth factor ß (TGF-ß) signaling functionality and in vivo tumorigenicity in high-grade dysplastic Barrett's cells. METHODS: An in vivo xenograft model was used to test tumorigenicity of SMAD4 knockdown or knockout in CP-B high-grade dysplastic Barrett's cells. RT2 polymerase chain reaction arrays were used to analyze TGF-ß signaling functionality, and low-coverage whole-genome sequencing was performed to detect copy number alterations upon SMAD4 loss. RESULTS: We found that SMAD4 knockout significantly alters the TGF-ß pathway target gene expression profile. SMAD4 knockout positively regulates potential oncogenes such as CRYAB, ACTA2, and CDC6, whereas the CDKN2A/B tumor-suppressor locus was regulated negatively. We verified that SMAD4 in combination with CDC6-CDKN2A/B or CRYAB genetic alterations in patient tumors have significant predictive value for poor prognosis. Importantly, we investigated the effect of SMAD4 inactivation in Barrett's tumorigenesis. We found that genetic knockdown or knockout of SMAD4 was sufficient to promote tumorigenesis in dysplastic Barrett's esophagus cells in vivo. Progression to invasive EAC was accompanied by distinctive and consistent copy number alterations in SMAD4 knockdown or knockout xenografts. CONCLUSIONS: Altogether, up-regulation of oncogenes, down-regulation of tumor-suppressor genes, and chromosomal instability within the tumors after SMAD4 loss implicates SMAD4 as a protector of genome integrity in EAC development and progression. Foremost, SMAD4 loss promotes tumorigenesis from dysplastic Barrett's toward EAC.

Treatment and outcomes of metastatic colorectal cancer patients in public and private hospitals: results from the South Australian Metastatic Colorectal Cancer Registry.

BACKGROUND: Studies have reported significant differences in baseline characteristics and outcomes of metastatic colorectal cancer (mCRC) patients when managed in private versus public hospitals. AIMS: To compare disease, treatment and survival outcomes of patients with mCRC in public versus private hospitals in South Australia (SA). METHODS: Analysis of prospectively collected data from the SA mCRC Registry. Patterns of care and outcome data according to location of care and socioeconomic status based on Index of Relative Socio-Economic Advantage and Disadvantage were analysed. RESULTS: A total of 3470 patients' data was analysed during February 2006-January 2015. The majority (70%) of patients received treatment in public hospitals. Patients in the upper 50% for Index of Relative Socio-Economic Advantage and Disadvantage score were more likely to receive treatment at a private hospital (41.2% vs 21.56%) compared to <50%. Public patients had higher burden of disease (10.49% vs 7.41%, P = 0.005). Public patients received less treatment compared to the private patients (odds ratio = 0.48 (0.38-0.61), P = 0.01) and rates of surgical resections were lower in public patients. After adjusting for the covariates, public patients survive 1.33 months (P = 0.025) shorter than private patients with follow-up time of 5 years. Patients receiving metastasectomy and more than three lines of treatment were shown to have the greatest survival benefit. CONCLUSION: Public patients have a higher burden of disease and in comparison are less likely to receive systemic therapy and have lower survival than patients treated in private hospitals.

Detecting possible persons of interest in a physical activity program using step entries: Including a web-based application for outlier detection and decision-making.

According to recent statistics from the World Health Organization, 23% of people aged 18 years and over are not sufficiently physically active. Strangely, this is at a time when, due to the improvement in sensor technology, physical activity programs that track physical activity have become popular. However, some participants who enroll in these programs cheat by manipulating the data they enter. This can be discouraging for other participants, also invalidating the overall accuracy of program outcomes. Therefore, detecting these participants and discarding their manipulated entries is important in order to maintain the quality of the program. Currently, most of these physical activity programs use manual processes to detect and reject fraudulent step entries by reviewing the participant's demographic profiles along with their longitudinal step count performance data. In this study, a process, including two parallel models for detecting person of interest characteristics and abnormal step count entries, is developed. The first model uses the penalized logistic regression with Synthetic Minority Over-sampling Technique subsampling to address the imbalance in the proportion of genuine and persons of interest. Having a highly imbalanced distribution between genuine and person of interest profiles makes this task more challenging. The second model uses a variety of outlier detection methods to detect and reject abnormal step entries based on previously entered data. This process will be more efficient and productive compared to the current manual system and will support better decision-making in the future. The proposed system can be applied for other fraud detection applications after suitable adjustments.

Insulin resistance in prostate cancer patients and predisposing them to acute ischemic heart disease.

Lack of insulin or insulin resistance (IR) plays a central role in diabetes mellitus and makes diabetics prone to acute ischemic heart disease (AIHD). It has likewise been found that many cancer patients, including prostate cancer patients die of AIHD. Previously it has been delineated from our laboratory that dermcidin could induce anomalous platelet aggregation in AIHD and also impaired nitric oxide and insulin activity and furthermore dermcidin was also found in a few types of cancer patients. To determine the role of this protein in prostatic malignancy, a retrospective case-control study was conducted and blood was collected from prostate cancer patients and healthy normal volunteers. So, we measured the level of dermcidin protein and analyzed the IR by Homeostasis Model Assessment (HOMA) score calculation. Nitric oxide was measured by methemoglobin method. HDL, glycated hemoglobin (HbA1c), BMI, hs-cTroponin-T were measured for the validation of the patients' status in the presence of Dermcidin isoform-2 (DCN-2). Multiple logistic regression model adjusted for age and BMI identified that the HOMA score was significantly elevated in prostate cancer patients (OR = 7.19, P<0.001). Prostate cancer patients are associated with lower level of NO and higher level of both proteins dermcidin (OR = 1.12, P<0.001) and hs-TroponinT (OR = 1.76, P<0.001). From the results, it can be interpreted that IR plays a key role in the pathophysiology of prostate cancer where dermcidin was the cause of IR through NO inhibition leading to AIHD was also explained by high-sensitive fifth generation cTroponin-T (hs-cTroponinT) and HbA1c level which are associated with endothelial dysfunction.

Predictors of Success of Workplace Physical Activity Interventions: A Systematic Review.

BACKGROUND: Despite holding great potential for addressing concerns regarding public health, recent systematic reviews have found effect sizes for interventions targeting physical activity to be small. Before interventions can be improved, the factors influencing outcomes must be identified. This systematic review aimed to identify predictors of success, measured in terms of engagement (eg, involvement duration) and health behavior change (eg, increased step counts), of workplace interventions targeting physical activity. METHODS: A structured search of 3 databases (PubMed, PsycINFO, and Web of Science) was conducted to identify articles published between January 2000 and April 2017. For inclusion, articles needed to test a workplace intervention targeting physical activity and perform a quantitative analysis, identifying predictors of engagement or health behavior change. RESULTS: Twenty-two studies were identified for review (median quality score = 70%). Demographic variables (eg, gender, age) were inconsistent predictors of success. However, employees in better health and physically active at baseline were found to have a greater likelihood of success. CONCLUSIONS: It appears that achieving successful results among employees at high risk of poor health outcomes remains a significant challenge for interventions. It is hoped that program developers can use this information to create effective interventions particularly for more sedentary employees.

Statistical methods to model and evaluate physical activity programs, using step counts: A systematic review.

BACKGROUND: Physical activity reduces the risk of noncommunicable diseases and is therefore an essential component of a healthy lifestyle. Regular engagement in physical activity can produce immediate and long term health benefits. However, physical activity levels are not as high as might be expected. For example, according to the global World Health Organization (WHO) 2017 statistics, more than 80% of the world's adolescents are insufficiently physically active. In response to this problem, physical activity programs have become popular, with step counts commonly used to measure program performance. Analysing step count data and the statistical modeling of this data is therefore important for evaluating individual and program performance. This study reviews the statistical methods that are used to model and evaluate physical activity programs, using step counts. METHODS: Adhering to PRISMA guidelines, this review systematically searched for relevant journal articles which were published between January 2000 and August 2017 in any of three databases (PubMed, PsycINFO and Web of Science). Only the journal articles which used a statistical model in analysing step counts for a healthy sample of participants, enrolled in an intervention involving physical exercise or a physical activity program, were included in this study. In these programs the activities considered were natural elements of everyday life rather than special activity interventions. RESULTS: This systematic review was able to identify 78 unique articles describing statistical models for analysing step counts obtained through physical activity programs. General linear models and generalized linear models were the most popular methods used followed by multilevel models, while structural equation modeling was only used for measuring the personal and psychological factors related to step counts. Surprisingly no use was made of time series analysis for analysing step count data. The review also suggested several strategies for the personalisation of physical activity programs. CONCLUSIONS: Overall, it appears that the physical activity levels of people involved in such programs vary across individuals depending on psychosocial, demographic, weather and climatic factors. Statistical models can provide a better understanding of the impact of these factors, allowing for the provision of more personalised physical activity programs, which are expected to produce better immediate and long-term outcomes for participants. It is hoped that this review will identify the statistical methods which are most suitable for this purpose.

Promoting Psychological Well-Being at Work by Reducing Stress and Improving Sleep: Mixed-Methods Analysis.

BACKGROUND: Workplace programs designed to improve the health and psychological well-being of employees are becoming increasingly popular. However, there are mixed reports regarding the effectiveness of such programs and little analysis of what helps people to engage with such programs. OBJECTIVE: This evaluation of a particularly broad, team-based, digital health and well-being program uses mixed methods to identify the elements of the program that reduce work stress and promote psychological well-being, sleep quality, and productivity of employees. METHODS: Participation in the Virgin Pulse Global Challenge program during May to September 2016 was studied. Self-reported stress, sleep quality, productivity, and psychological well-being data were collected both pre- and postprogram. Participant experience data were collected through a third final survey. However, the response rates for the last 2 surveys were only 48% and 10%, respectively. A random forest was used to estimate the probability of the completion of the last 2 surveys based on the preprogram assessment data and the demographic data for the entire sample (N=178,350). The inverse of these estimated probabilities were used as weights in hierarchical linear models in an attempt to address any estimation bias caused by the low response rates. These linear models described changes in psychological well-being, stress, sleep, and productivity over the duration of the program in relation to gender and age, engagement with each of the modules, each of the program features, and participant descriptions of the Virgin Pulse Global Challenge. A 0.1% significance level was used due to the large sample size for the final survey (N=18,653). RESULTS: The final analysis suggested that the program is more beneficial for older people, with 2.9% greater psychological well-being improvements observed on average in the case of women than men (P<.001). With one exception, all the program modules contributed significantly to the outcome measures with the following average improvements observed: psychological well-being, 4.1%-6.0%; quality of sleep, 3.2%-6.9%; work-related stress, 1.7%-6.8%; and productivity, 1.9%-4.2%. However, only 4 of the program features were found to have significant associations with the outcome measures with the following average improvements observed: psychological well-being, 3.7%-5.6%; quality of sleep, 3.4%-6.5%; work-related stress, 4.1%-6.4%; and productivity, 1.6%-3.2%. Finally, descriptions of the Virgin Pulse Global Challenge produced 5 text topics that were related to the outcome measures. Healthy lifestyle descriptions showed a positive association with outcomes, whereas physical activity and step count tracking descriptions showed a negative association with outcomes. CONCLUSIONS: The complementary use of qualitative and quantitative survey data in a mixed-methods analysis provided rich information that will inform the development of this and other programs designed to improve employee health. However, the low response rates and the lack of a control group are limitations, despite the attempts to address these problems in the analysis.