Constitutional Factors and Irradiation as Risk Factors for Thymoma: A European Case-Control Study.

Little is known about the aetiology of thymoma. This study aims to identify medical risk factors for thymoma as a systematic approach to new hypotheses on the aetiology of this disease. A European multi-centre case-control study was conducted from 1995 to 1997, including incident cases aged 35-69 years with thymoma. Altogether, we accepted 85 cases and 3350 controls, of which we interviewed 77 cases and 2071 population controls about constitutional factors, medical examinations, and former diseases. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated. Medical examinations with X-ray or radiotherapy performed >20 times at least one year before the thymoma diagnosis indicated a possible risk factor for thymoma (OR 1.58, 95% CI 0.93-2.69). Having the first radiotherapy treatment at least one year before the thymoma diagnosis yielded an OR for thymoma of 2.39; 95% CI (0.96-5.99), and if it was at least five years before, the OR for thymoma was 2.81; 95% CI (1.03-7.72). Having a red/auburn hair colour was associated with thymoma, (OR 3.6, 95% CI 1.4-9.5) whereas having pigmented skin was slightly associated with thymoma (OR 1.8, 95% CI 0.8-3.8). Over twenty instances of X-ray examinations or radiotherapy were identified as potential risk factors for thymoma, along with certain constitutional factors. The observed correlations between benign tumours and thymoma could stem from an inherent predisposition to tumour development or result from detection bias. Given that this is the initial analytical study examining medical risk factors for thymoma, all of the results should be approached with caution, acknowledging the possibility that some findings might be incidental.

Transcriptomic profiles of myxofibrosarcoma and undifferentiated pleomorphic sarcoma correlate with clinical and genomic features.

Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) are two common and aggressive subtypes of soft tissue sarcoma. The aim of this study was to assess potential transcriptomic differences between MFS and UPS tumours and to evaluate the extent to which differences in gene expression profiles were associated with genomic and clinical features. The study included 162 patients with tumours diagnosed as MFS (N = 62) or UPS (N = 100). The patients had been diagnosed and treated at two Swedish sarcoma centres during a 30-year period. For gene expression profiling and gene fusion detection all tumours were analysed using RNA-sequencing and could be compared with data on clinical outcome (N = 155), global copy number profiles (N = 145), and gene mutations (N = 128). Gene expression profiling revealed three transcriptomic clusters (TCs) without any clear separation of MFS and UPS. One TC was associated with longer metastasis-free survival. These tumours had lower tumour mutation burden (TMB), were enriched for a copy number signature representative of focal LOH and chromosomal instability on a diploid background, and were relatively immune-depleted. MFS and UPS showed extensive genomic overlap, with whole genome doubling occurring more frequently among the latter. The results support the idea that MFS and UPS tumours have largely overlapping genomic and transcriptomic features, with UPS tumours showing more aggressive behaviour and more complex genomes. Independently of the tumour type, clinically relevant subgroups were revealed by gene expression analysis, and the finding of multiple genomic subgroups strongly suggest the existence of subgroups of relevance to treatment stratification. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset.

Co-observation of a gene variant with a pathogenic variant in another gene that explains the disease presentation has been designated as evidence against pathogenicity for commonly used variant classification guidelines. Multiple variant curation expert panels have specified, from consensus opinion, that this evidence type is not applicable for the classification of breast cancer predisposition gene variants. Statistical analysis of sequence data for 55,815 individuals diagnosed with breast cancer from the BRIDGES sequencing project was undertaken to formally assess the utility of co-observation data for germline variant classification. Our analysis included expected loss-of-function variants in 11 breast cancer predisposition genes and pathogenic missense variants in BRCA1, BRCA2, and TP53. We assessed whether co-observation of pathogenic variants in two different genes occurred more or less often than expected under the assumption of independence. Co-observation of pathogenic variants in each of BRCA1, BRCA2, and PALB2 with the remaining genes was less frequent than expected. This evidence for depletion remained after adjustment for age at diagnosis, study design (familial versus population-based), and country. Co-observation of a variant of uncertain significance in BRCA1, BRCA2, or PALB2 with a pathogenic variant in another breast cancer gene equated to supporting evidence against pathogenicity following criterion strength assignment based on the likelihood ratio and showed utility in reclassification of missense BRCA1 and BRCA2 variants identified in BRIDGES. Our approach has applicability for assessing the value of co-observation as a predictor of variant pathogenicity in other clinical contexts, including for gene-specific guidelines developed by ClinGen Variant Curation Expert Panels.

Antidepressant drug use after intensive care: a nationwide cohort study.

Modern intensive care has improved survival rates, but emerging evidence suggests a high prevalence of post-intensive care unit (ICU) health problems, including post-traumatic stress disorder, depression and anxiety. These symptoms may have a detrimental effect on quality of life and increase mortality. The primary objective of this study is to examine the extent of initiation of antidepressant medication among ICU survivors and identify the factors associated with its usage. The secondary objective is to investigate whether the use of these medications is linked to an increased mortality. The nationwide study cohort included 125,130 ICU survivors admitted between 2010 and 2017. Within the first 3 months after ICU discharge, 7% of patients initiated antidepressant medication, by 1 year 15.5% had started medication. We found no tendency to a decrease during the 2-year follow-up period. Factors associated with antidepressant use included middle age, female sex, psychiatric and somatic comorbid conditions, substance dependence, higher illness severity, and longer ICU stay. Antidepressant users had a higher mortality rate, and deaths due to external causes and suicide were more frequent in this group. This study emphasizes the importance of detecting and addressing depression in ICU survivors to improve their quality of life and reduce mortality rates.

Onset of Prolonged High-Potency Benzodiazepine Use Among ICU Survivors: A Nationwide Cohort Study.

OBJECTIVES: Exposure to critical illness and intensive care may lead to long-term psychologic and physical impairments. To what extent ICU survivors become prolonged users of benzodiazepines after exposure to critical care is not fully explored. This study aimed to describe the extent of onset of prolonged high-potency benzodiazepine use among ICU survivors not using these drugs before admission, identify factors associated with this use, and analyze whether such usage is associated with increased mortality. DESIGN: Retrospective cohort study. SETTING: Sweden, including all registered ICU admissions between 2010 and 2017. PATIENTS: ICU patients surviving for at least 3 months, not using high-potency benzodiazepine before admission, were eligible for inclusion. INTERVENTIONS: Admission to intensive care. MEASUREMENTS AND MAIN RESULTS: A total of 237,904 patients were screened and 137,647 were included. Of these 5338 (3.9%) became prolonged users of high-potency benzodiazepines after ICU discharge. A peak in high-potency benzodiazepine prescriptions was observed during the first 3 months, followed by sustained usage throughout the follow-up period of 18 months. Prolonged usage was associated with older age, female sex, and a history of both somatic and psychiatric comorbidities, including substance abuse. Additionally, a longer ICU stay, a high estimated mortality rate, and prior consumption of low-potency benzodiazepines were associated with prolonged use. The risk of death between 6 and 18 months post-ICU admission was significantly higher among high-potency benzodiazepine users, with an adjusted hazard ratio of 1.8 (95% CI, 1.7-2.0; p < 0.001). No differences were noted in causes of death between users and nonusers. Conclusions: Despite the lack of evidence supporting long-term treatment, prolonged usage of high-potency benzodiazepines 18 months following ICU care was notable and associated with an increased risk of death. Considering the substantial number of ICU admissions, prevention of benzodiazepine misuse may improve long-term outcomes following critical care.

Chemical-Saving Potential for Membrane Bioreactor (MBR) Processes Based on Long-Term Pilot Trials.

Membrane bioreactors (MBRs) have gained attraction in municipal wastewater treatment because of their capacity to meet strict water quality standards and support water reuse. Despite this, their operational sustainability is often compromised by high resource consumption, especially regarding the use of chemicals for membrane cleaning. This study explores innovative membrane-cleaning strategies to enhance the sustainability of MBR processes. Through long-term pilot trials at Stockholm's largest wastewater treatment plant, this study showed that alternative cleaning strategies can reduce chemical use by up to 75% without sacrificing treatment performance. The results further suggest that these alternative strategies could result in cost reductions of up to 70% and a reduction in environmental impacts by as much as 95% for certain indicators. Given that MBRs play a crucial role in addressing increasing treatment demands and advancing circular water management, the outcomes of this study are beneficial for the broader adoption of MBR processes. These results also have implications for existing installations, offering a pathway to more sustainable wastewater treatment. Moreover, the presented cleaning strategies provide significant opportunities for lowering operational costs and reducing the environmental footprint of new and existing MBR installations.

Survival of patients with ruptured gastrointestinal stromal tumour treated with adjuvant imatinib in a randomised trial.

BACKGROUND: Patients with ruptured gastrointestinal stromal tumour (GIST) have poor prognosis. Little information is available about how adjuvant imatinib influences survival. METHODS: We explored recurrence-free survival (RFS) and overall survival (OS) of patients with ruptured GIST who participated in a randomised trial (SSG XVIII/AIO), where 400 patients with high-risk GIST were allocated to adjuvant imatinib for either 1 year or 3 years after surgery. Of the 358 patients with confirmed localised GIST, 73 (20%) had rupture reported. The ruptures were classified retrospectively using the Oslo criteria. RESULTS: Most ruptures were major, four reported ruptures were reclassified unruptured. The 69 patients with rupture had inferior RFS and OS compared with 289 patients with unruptured GIST (10-year RFS 21% vs. 55%, OS 59% vs. 78%, respectively). Three-year adjuvant imatinib did not significantly improve RFS or OS of the patients with rupture compared with 1-year treatment, but in the largest mutational subset with KIT exon 11 deletion/indel mutation OS was higher in the 3-year group than in the 1-year group (10-year OS 94% vs. 54%). CONCLUSIONS: About one-fifth of ruptured GISTs treated with adjuvant imatinib did not recur during the first decade of follow-up. Relatively high OS rates were achieved despite rupture. CLINICAL TRIAL REGISTRATION: NCT00116935.

Smoking is associated with higher risk of contracting bacterial infection and pneumonia, intensive care unit admission and death.

BACKGROUND: Smoking has been associated with a higher risk of contracting pneumonia, but contradictory results have shown that smoking may or may not decrease the risk of dying in pneumonia. The aim of this study is to investigate how smoking is associated with contracting any infection and pneumonia and death. METHOD AND FINDINGS: Participants were drawn from the population-based Cohort of Swedish Men and the Swedish Mammography Cohort, which are representative of the Swedish population. Participants have answered detailed lifestyle questionnaires and have been followed in national registers, such as the Patient Register, Cause of Death register and Swedish Intensive Care Registry. The risks of contracting infection and pneumonia or dying in infection and pneumonia were assessed using Cox regression. Of 62,902 cohort participants, 25,297 contracted an infection of which 4,505 died; and 10,471 contracted pneumonia of which 2,851 died. Compared to never smokers, former smokers at baseline had hazard ratio (HR) 1.08 (95% confidence interval (CI) 1.05-1.12) of contracting and HR 1.19 (95% CI 1.11-1.28) of dying in infection and HR 1.17 (95% CI 1.12-1.23) of contracting and HR 1.16 (95% CI 1.06-1.27) of dying in pneumonia during follow-up. Compared to never smokers, current smokers at baseline had HR 1.17 (95% CI 1.13-1.21) of contracting infection and HR 1.64 (95% CI 1.52-1.77) dying in infection; HR 1.42 (95% CI 1.35-1.49) of contracting pneumonia and HR 1.70 (95% CI 1.55-1.87) of dying in pneumonia during follow-up. The risk of contracting and dying in infection and pneumonia increased in a dose-response manner with number of pack years smoked and decreased with years since smoking cessation. CONCLUSION: Smoking is associated with contracting and dying in any infection and pneumonia and the risk increases with pack years smoked, highlighting the importance of both primary prevention and smoking cessation.

Association of area- and volumetric-mammographic density and breast cancer risk in women of Asian descent: a case control study.

BACKGROUND: Mammographic density (MD) has been shown to be a strong and independent risk factor for breast cancer in women of European and Asian descent. However, the majority of Asian studies to date have used BI-RADS as the scoring method and none have evaluated area and volumetric densities in the same cohort of women. This study aims to compare the association of MD measured by two automated methods with the risk of breast cancer in Asian women, and to investigate if the association is different for premenopausal and postmenopausal women. METHODS: In this case-control study of 531 cases and 2297 controls, we evaluated the association of area-based MD measures and volumetric-based MD measures with breast cancer risk in Asian women using conditional logistic regression analysis, adjusting for relevant confounders. The corresponding association by menopausal status were assessed using unconditional logistic regression. RESULTS: We found that both area and volume-based MD measures were associated with breast cancer risk. Strongest associations were observed for percent densities (OR (95% CI) was 2.06 (1.42-2.99) for percent dense area and 2.21 (1.44-3.39) for percent dense volume, comparing women in highest density quartile with those in the lowest quartile). The corresponding associations were significant in postmenopausal but not premenopausal women (premenopausal versus postmenopausal were 1.59 (0.95-2.67) and 1.89 (1.22-2.96) for percent dense area and 1.24 (0.70-2.22) and 1.96 (1.19-3.27) for percent dense volume). However, the odds ratios were not statistically different by menopausal status [p difference = 0.782 for percent dense area and 0.486 for percent dense volume]. CONCLUSIONS: This study confirms the associations of mammographic density measured by both area and volumetric methods and breast cancer risk in Asian women. Stronger associations were observed for percent dense area and percent dense volume, and strongest effects were seen in postmenopausal individuals.

Physical activity is associated with a lower risk of contracting and dying in infection and sepsis: a Swedish population-based cohort study.

BACKGROUND: Sepsis is a condition where the immune response to infection becomes dysregulated and life-threatening. It is not known whether lifestyle factors influence the risk of sepsis. The aim of the present study is to investigate the association between physical activity and the risk of acquiring and dying in infection or sepsis. METHODS: The population-based Swedish Mammography Cohort and Cohort of Swedish Men sent participants lifestyle questionnaires in 1997 and have subsequently followed participants in national Swedish registers, including the National Patient Register, the Swedish Intensive Care Registry and the Cause of Death Register. The risk of contracting infection and sepsis, the risk of intensive care unit admission and the risk of death were estimated using multivariable Cox regression. RESULTS: Among 64,850 cohort participants, 26,124 individuals suffered at least one episode of infection or sepsis and 4708 individuals died of infection or sepsis during the study period. In adjusted analyses, compared to exercising less than one hour per week, stated exercise one hour per week was associated with lower risk of contracting infection or sepsis, hazard ratio (HR) 0.93 (95% confidence interval (CI) 0.90-0.97), and lower risk of dying in infection or sepsis, HR 0.87 (95% CI 0.80-0.96). Further exercise was associated with even lower risk, and similar patterns were observed for walking. The population-attributable risks of contracting and dying in infection or sepsis for not exercising were 2.6% and 4.5%, respectively. CONCLUSIONS: Exercise and walking demonstrate inverse dose-response associations with both the risk of contracting and dying in infection and sepsis, presenting possible preventative interventions for this critical condition.

Uromodulin in sepsis and severe pneumonia: a two-sample Mendelian randomization study.

The outcome for patients with sepsis-associated acute kidney injury in the intensive care unit (ICU) remains poor. Low serum uromodulin (sUMOD) protein levels have been proposed as a causal mediator of this effect. We investigated the effect of different levels of sUMOD on the risk of sepsis and severe pneumonia and outcomes in these conditions. A two-sample Mendelian randomization (MR) study was performed. Single-nucleotide polymorphisms (SNPs) associated with increased levels of sUMOD were identified and used as instrumental variables for association with outcomes. Data from different cohorts were combined based on disease severity and meta-analyzed. Five SNPs associated with increased sUMOD levels were identified and tested in six datasets from two biobanks. There was no protective effect of increased levels of sUMOD on the risk of sepsis [two cohorts, odds ratio (OR) 0.99 (95% confidence interval 0.95-1.03), P = 0.698, and OR 0.95 (0.91-1.00), P = 0.060, respectively], risk of sepsis requiring ICU admission [OR 1.04 (0.93-1.16), P = 0.467], ICU mortality in sepsis [OR 1.00 (0.74-1.37), P = 0.987], risk of pneumonia requiring ICU admission [OR 1.05 (0.98-1.14), P = 0.181], or ICU mortality in pneumonia [OR 1.17 (0.98-1.39), P = 0.079]. Meta-analysis of hospital-admitted and ICU-admitted patients separately yielded similar results [OR 0.98 (0.95-1.01), P = 0.23, and OR 1.05 (0.99-1.12), P = 0.86, respectively]. Among patients with sepsis and severe pneumonia, there was no protective effect of different levels of sUMOD. Results were consistent regardless of geographic origins and not modified by disease severity. NEW & NOTEWORTHY The presence of acute kidney injury in severe infections increases the likelihood of poor outcome severalfold. A decrease in serum uromodulin (sUMOD), synthetized in the kidney, has been proposed as a mediator of this effect. Using the Mendelian randomization technique, we tested the hypothesis that increased sUMOD is protective in severe infections. Analyses, however, showed no evidence of a protective effect of higher levels of sUMOD in sepsis or severe pneumonia.

Cancer risks among first-degree relatives of women with a genetic predisposition to breast cancer.

BACKGROUND: Associations between germline alterations in women and cancer risks among their relatives are largely unknown. METHODS: We identified women from 2 Swedish cohorts Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) and prevalent KARMA (pKARMA), including 28 362 women with genotyping data and 13 226 with sequencing data. Using Swedish Multi-Generation Register, we linked these women to 133 389 first-degree relatives. Associations between protein-truncating variants in 8 risk genes and breast cancer polygenic risk score in index women and cancer risks among their relatives were modeled via Cox regression. RESULTS: Female relatives of index women who were protein-truncating variant carriers in any of the 8 risk genes had an increased breast cancer risk compared with those of noncarriers (hazard ratio [HR] = 1.85, 95% confidence interval [CI] = 1.52 to 2.27), with the strongest association found for protein-truncating variants in BRCA1 and 2. These relatives had a statistically higher risk of early onset than late-onset breast cancer (P = .001). Elevated breast cancer risk was also observed in female relatives of index women with higher polygenic risk score (HR per SD = 1.28, 95% CI = 1.23 to 1.32). The estimated lifetime risk was 22.3% for female relatives of protein-truncating variant carriers and 14.4% for those related to women in the top polygenic risk score quartile. Moreover, relatives of index women with protein-truncating variant presence (HR = 1.30, 95% CI = 1.06 to 1.59) or higher polygenic risk score (HR per SD = 1.04, 95% CI = 1.01 to 1.07) were also at higher risk of nonbreast hereditary breast and ovary cancer syndrome-related cancers. CONCLUSIONS: Protein-truncating variants of risk genes and higher polygenic risk score in index women are associated with an increased risk of breast and other hereditary breast and ovary syndrome-related cancers among relatives.

Differences in polygenic score distributions in European ancestry populations: implications for breast cancer risk prediction.

The 313-variant polygenic risk score (PRS313) provides a promising tool for breast cancer risk prediction. However, evaluation of the PRS313 across different European populations which could influence risk estimation has not been performed. Here, we explored the distribution of PRS313 across European populations using genotype data from 94,072 females without breast cancer, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 225,105 female participants from the UK Biobank. The mean PRS313 differed markedly across European countries, being highest in south-eastern Europe and lowest in north-western Europe. Using the overall European PRS313 distribution to categorise individuals leads to overestimation and underestimation of risk in some individuals from south-eastern and north-western countries, respectively. Adjustment for principal components explained most of the observed heterogeneity in mean PRS. Country-specific PRS distributions may be used to calibrate risk categories in individuals from different countries.

European validation of an image-derived AI-based short-term risk model for individualized breast cancer screening-a nested case-control study.

Background: Image-derived artificial intelligence (AI)-based risk models for breast cancer have shown high discriminatory performances compared with clinical risk models based on family history and lifestyle factors. However, little is known about their generalizability across European screening settings. We therefore investigated the discriminatory performances of an AI-based risk model in European screening settings. Methods: Using four European screening populations in three countries (Italy, Spain, Germany) screened between 2009 and 2020 for women aged 45-69, we performed a nested case-control study to assess the predictive performance of an AI-based risk model. In total, 739 women with incident breast cancers were included together with 7812 controls matched on year of study-entry. Mammographic features (density, microcalcifications, masses, left-right breast asymmetries of these features) were extracted using AI from negative digital mammograms at study-entry. Two-year absolute risks of breast cancer were predicted and assessed after two years of follow-up. Adjusted risk stratification performance metrics were reported per clinical guidelines. Findings: The overall adjusted Area Under the receiver operating characteristic Curve (aAUC) of the AI risk model was 0.72 (95% CI 0.70-0.75) for breast cancers developed in four screening populations. In the 6.2% [529/8551] of women at high risk using the National Institute of Health and Care Excellence (NICE) guidelines thresholds, cancers were more likely diagnosed after 2 years follow-up, risk-ratio (RR) 6.7 (95% CI 5.6-8.0), compared with the 69% [5907/8551] of women classified at general risk by the model. Similar risk-ratios were observed across levels of mammographic density. Interpretation: The AI risk model showed generalizable discriminatory performances across European populations and, predicted ∼30% of clinically relevant stage 2 and higher breast cancers in ∼6% of high-risk women who were sent home with a negative mammogram. Similar results were seen in women with fatty and dense breasts. Funding: Swedish Research Council.

Investigation of Genetic Alterations Associated With Interval Breast Cancer.

Importance: Breast cancers (BCs) diagnosed between 2 screening examinations are called interval cancers (ICs), and they have worse clinicopathological characteristics and poorer prognosis than screen-detected cancers (SDCs). However, the association of rare germline genetic variants with IC have not been studied. Objective: To evaluate whether rare germline deleterious protein-truncating variants (PTVs) can be applied to discriminate between IC and SDC while considering mammographic density. Design, Setting, and Participants: This population-based genetic association study was based on women aged 40 to 76 years who were attending mammographic screening in Sweden. All women with a diagnosis of BC between January 2001 and January 2016 were included, together with age-matched controls. Patients with BC were followed up for survival until 2021. Statistical analysis was performed from September 2021 to December 2022. Exposure: Germline PTVs in 34 BC susceptibility genes as analyzed by targeted sequencing. Main Outcomes and Measures: Odds ratios (ORs) were used to compare IC with SDC using logistic regression. Hazard ratios were used to investigate BC-specific survival using Cox regression. Results: All 4121 patients with BC (IC, n = 1229; SDC, n = 2892) were female, with a mean (SD) age of 55.5 (7.1) years. There were 5631 age-matched controls. The PTVs of the ATM, BRCA1, BRCA2, CHEK2, and PALB2 genes were more common in patients with IC compared with SDC (OR, 1.48; 95% CI, 1.06-2.05). This association was primarily influenced by BRCA1/2 and PALB2 variants. A family history of BC together with PTVs of any of these genes synergistically increased the probability of receiving a diagnosis of IC rather than SDC (OR, 3.95; 95% CI, 1.97-7.92). Furthermore, 10-year BC-specific survival revealed that if a patient received a diagnosis of an IC, carriers of PTVs in any of these 5 genes had significantly worse survival compared with patients not carrying any of them (hazard ratio, 2.04; 95% CI, 1.06-3.92). All of these associations were further pronounced in a subset of patients with IC who had a low mammographic density at prior screening examination. Conclusions and Relevance: The results of this study may be helpful in future optimizations of screening programs that aim to lower mortality as well as the clinical treatment of patients with BC.

Breast Cancer Incidence After a False-Positive Mammography Result.

Importance: False-positive mammography results are common. However, long-term outcomes after a false-positive result remain unclear. Objectives: To examine long-term outcomes after a false-positive mammography result and to investigate whether the association of a false-positive mammography result with cancer differs by baseline characteristics, tumor characteristics, and time since the false-positive result. Design, Setting, and Participants: This population-based, matched cohort study was conducted in Sweden from January 1, 1991, to March 31, 2020. It included 45 213 women who received a first false-positive mammography result between 1991 and 2017 and 452 130 controls matched on age, calendar year of mammography, and screening history (no previous false-positive result). The study also included 1113 women with a false-positive result and 11 130 matched controls with information on mammographic breast density from the Karolinska Mammography Project for Risk Prediction of Breast Cancer study. Statistical analysis was performed from April 2022 to February 2023. Exposure: A false-positive mammography result. Main Outcomes and Measures: Breast cancer incidence and mortality. Results: The study cohort included 497 343 women (median age, 52 years [IQR, 42-59 years]). The 20-year cumulative incidence of breast cancer was 11.3% (95% CI, 10.7%-11.9%) among women with a false-positive result vs 7.3% (95% CI, 7.2%-7.5%) among those without, with an adjusted hazard ratio (HR) of 1.61 (95% CI, 1.54-1.68). The corresponding HRs were higher among women aged 60 to 75 years at the examination (HR, 2.02; 95% CI, 1.80-2.26) and those with lower mammographic breast density (HR, 4.65; 95% CI, 2.61-8.29). In addition, breast cancer risk was higher for women who underwent a biopsy at the recall (HR, 1.77; 95% CI, 1.63-1.92) than for those without a biopsy (HR, 1.51; 95% CI, 1.43-1.60). Cancers after a false-positive result were more likely to be detected on the ipsilateral side of the false-positive result (HR, 1.92; 95% CI, 1.81-2.04) and were more common during the first 4 years of follow-up (HR, 2.57; 95% CI, 2.33-2.85 during the first 2 years; HR, 1.93; 95% CI, 1.76-2.12 at >2 to 4 years). No statistical difference was found for different tumor characteristics (except for larger tumor size). Furthermore, associated with the increased risk of breast cancer, women with a false-positive result had an 84% higher rate of breast cancer death than those without (HR, 1.84; 95% CI, 1.57-2.15). Conclusions and Relevance: This study suggests that the risk of developing breast cancer after a false-positive mammography result differs by individual characteristics and follow-up. These findings can be used to develop individualized risk-based breast cancer screening after a false-positive result.

The impact of circulating protein levels identified by affinity proteomics on short-term, overall breast cancer risk.

OBJECTIVE: Current breast cancer risk prediction scores and algorithms can potentially be further improved by including molecular markers. To this end, we studied the association of circulating plasma proteins using Proximity Extension Assay (PEA) with incident breast cancer risk. SUBJECTS: In this study, we included 1577 women participating in the prospective KARMA mammographic screening cohort. RESULTS: In a targeted panel of 164 proteins, we found 8 candidates nominally significantly associated with short-term breast cancer risk (P < 0.05). Similarly, in an exploratory panel consisting of 2204 proteins, 115 were found nominally significantly associated (P < 0.05). However, none of the identified protein levels remained significant after adjustment for multiple testing. This lack of statistically significant findings was not due to limited power, but attributable to the small effect sizes observed even for nominally significant proteins. Similarly, adding plasma protein levels to established risk factors did not improve breast cancer risk prediction accuracy. CONCLUSIONS: Our results indicate that the levels of the studied plasma proteins captured by the PEA method are unlikely to offer additional benefits for risk prediction of short-term overall breast cancer risk but could provide interesting insights into the biological basis of breast cancer in the future.

Polymorphisms in genes of melatonin biosynthesis and signaling support the light-at-night hypothesis for breast cancer.

Light-at-night triggers the decline of pineal gland melatonin biosynthesis and secretion and is an IARC-classified probable breast-cancer risk factor. We applied a large-scale molecular epidemiology approach to shed light on the putative role of melatonin in breast cancer. We investigated associations between breast-cancer risk and polymorphisms at genes of melatonin biosynthesis/signaling using a study population of 44,405 women from the Breast Cancer Association Consortium (22,992 cases, 21,413 population-based controls). Genotype data of 97 candidate single nucleotide polymorphisms (SNPs) at 18 defined gene regions were investigated for breast-cancer risk effects. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CI) by logistic regression for the main-effect analysis as well as stratified analyses by estrogen- and progesterone-receptor (ER, PR) status. SNP-SNP interactions were analyzed via a two-step procedure based on logic regression. The Bayesian false-discovery probability (BFDP) was used for all analyses to account for multiple testing. Noteworthy associations (BFDP < 0.8) included 10 linked SNPs in tryptophan hydroxylase 2 (TPH2) (e.g. rs1386492: OR = 1.07, 95% CI 1.02-1.12), and a SNP in the mitogen-activated protein kinase 8 (MAPK8) (rs10857561: OR = 1.11, 95% CI 1.04-1.18). The SNP-SNP interaction analysis revealed noteworthy interaction terms with TPH2- and MAPK-related SNPs (e.g. rs1386483R ∧ rs1473473D ∧ rs3729931D: OR = 1.20, 95% CI 1.09-1.32). In line with the light-at-night hypothesis that links shift work with elevated breast-cancer risks our results point to SNPs in TPH2 and MAPK-genes that may impact the intricate network of circadian regulation.

Outcome of rare primary malignant bone sarcoma treated with multimodal therapy: Results from the EUROpean Bone Over 40 Sarcoma Study (EURO-B.O.S.S.).

BACKGROUND: Rare primary malignant bone sarcomas (RPMBS) account for 5%-10% of primary high-grade bone tumors and represent a major treatment challenge. The outcome of patients with RPMBS enrolled in the EUROpean Bone Over 40 Sarcoma Study (EURO-B.O.S.S) is presented. METHODS: Inclusion criteria were as follows: age from 41 to 65 years and a diagnosis of high-grade spindle cell, pleomorphic, or vascular RPMBS. The chemotherapy regimen included doxorubicin 60 mg/m2 , ifosfamide 9 g/m2 , and cisplatin 90 mg/m2 ; postoperative methotrexate 8 g/m2 was added in case of a poor histologic response. Version 2.0 of the Common Terminology Criteria for Adverse Events, Kaplan-Meier curves, log-rank tests, and univariate Cox regression models were used. RESULTS: In total, 113 patients were evaluable for analysis. The median patient age was 52 years (range, 40-66 years), and 67 patients were men. Eighty-eight tumors were categorized as undifferentiated pleomorphic sarcomas (UPS), 20 were categorized as leiomyosarcomas, three were categorized as fibrosarcomas, and two were categorized as angiosarcomas. Eighty-three of 113 tumors were located in the extremities. Ninety-five of 113 patients presented with no evidence of metastases. After a median follow-up of 6.8 years (interquartile range [IQR], 3.5-9.8 years), the 5-year overall survival rate for patients with localized disease was 68.4% (IQR, 56.9%-77.5%), and it was 71.7% (IQR, 58.1%-81.6%) for patients with UPS and 54.9% (IQR, 29.5%-74.5%) for patients with leiomyosarcoma. Grade III-IV hematologic toxicity was reported in 81% patients; 23% had grade II-III neurotoxicity, and 37.5% had grade I-II nephrotoxicity. Five-year overall survival was significantly better for patients with localized disease, for patients who obtained surgical complete remission, and when the primary tumor was located in the extremities. CONCLUSIONS: The survival of patients who had RPMBS in the current series was similar to that of age-matched patients who had high-grade osteosarcoma treated according to the same protocol. An osteosarcoma-like chemotherapy may be proposed in patients who have RPMBS.