Body constitution, statin use, and tumor characteristics. Implications for prognosis.

Breast cancer is an important cause of disease-burden and death in women. To prevent over- and undertreatment of breast cancer patients, new prognostic and predictive factors are needed. We aimed to study associations between prognosis and body constitution, genetic factors, and tumor-specific protein levels related to metabolic pathways, and to examine the prognostic impact of statin use and body size changes in breast cancer patients. In paper I, we studied the prognostic impact of tumor-specific HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway and the target of statin treatment, in breast cancer. Moderate/strong HMGCR levels were associated with older age and favorable tumor characteristics but not with breast cancer-free interval. In paper II, we studied the interplay between tumor-specific HMGCR levels, preoperative statin use, and the multi-drug resistance gene (MDR1/ABCB1) in breast cancer. Significant interactions were found between ABCB1 C3435T genotype and statin use on clinical outcomes. Preoperative statin use was not associated with prognosis. In paper III, we studied cytoplasmic and nuclear levels of the master regulator aryl hydrocarbon receptor (AhR) and their associations with intratumoral aromastase, patients’ characteristics, clinicopathological factors, and prognosis in adjuvant-treated breast cancer patients. High cytoplasmic levels of AhR conferred good prognosis, particularly if tamoxifen was used as the only endocrine therapy. Intratumoral aromatase had little prognostic impact. In paper IV, we studied the prognostic impact of body size changes during the first postoperative year. Landmark survival analyses revealed that weight gain conferred poor prognosis in patients <50 years while weight loss was associated with poor prognosis in patients ≥70 years. Changes between WHR categories were associated with differential recurrence risk depending on tumor ER status.In conclusion, our results suggest that patient factors could, when taken into account, yield additional prognostic information when combined with clinically established tumor characteristics for personalized breast cancer treatment

Tumor-specific expression of HMG-CoA reductase in a population-based cohort of breast cancer patients

The mevalonate pathway synthetizes cholesterol, steroid hormones, and non-steriod isoprenoids necessary for cell survival. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) is the rate-limiting enzyme of the mevalonate pathway and the target for statin treatment. HMGCR expression in breast tumors has recently been proposed to hold prognostic and treatment-predictive information. This study aimed to investigate whether HMGCR expression in breast cancer patients was associated with patient and tumor characteristics and disease-free survival (DFS)

Developing and testing inter‐rater reliability of a data collection tool for patient health records on end‐of‐life care of neurological patients in an acute hospital ward

From Wiley via Jisc Publications RouterHistory: received 2021-07-14, rev-recd 2022-11-21, accepted 2023-04-16, epub 2023-05-04Article version: VoRPublication status: PublishedFunder: Landspitali, The National University Hospital of IcelandFunder: The Icelandic Nurses AssociationFunder: The University of IcelandHaraldsdottir, Erna - ORCID: 0000-0003-4891-0743 https://orcid.org/0000-0003-4891-0743Research Funding: Landspitali, The National University Hospital of Iceland The Icelandic Nurses Association The University of IcelandAim: Develop and test a data collection tool—Neurological End‐Of‐Life Care Assessment Tool (NEOLCAT)—for extracting data from patient health records (PHRs) on end‐of‐life care of neurological patients in an acute hospital ward. Design: Instrument development and inter‐rater reliability (IRR) assessment. Method: NEOLCAT was constructed from patient care items obtained from clinical guidelines and literature on end‐of‐life care. Expert clinicians reviewed the items. Using percentage agreement and Fleiss' kappa we calculated IRR on 32 nominal items, out of 76 items. Results: IRR of NEOLCAT showed 89% (range 83%–95%) overall categorical percentage agreement. The Fleiss' kappa categorical coefficient was 0.84 (range 0.71–0.91). There was fair or moderate agreement on six items, and moderate or almost perfect agreement on 26 items. Conclusion: The NEOLCAT shows promising psychometric properties for studying clinical components of care of neurological patients at the end‐of‐life on an acute hospital ward but could be further developed in future studies.aheadofprintaheadofprin

Transition to end-of-life care in patients with neurological diseases in an acute hospital ward

From Springer Nature via Jisc Publications RouterHistory: received 2024-04-22, registration 2024-07-16, accepted 2024-07-16, epub 2024-07-22, online 2024-07-22, collection 2024-12-01Acknowledgements: We thank the data abstractors Andrea Jona Eggertsdottir, Berglind Osk Olafsdottir, Mona Sif Hadaya and Kristin Asgeirsdottir for their invaluable contribution to this study.Publication status: PublishedFunder: The Icelandic Nurses´ Association; Grant(s): 71545Funder: The University of Iceland Research Fund of Ingibjorg R. MagnusdottirFunder: Landspitali, The National University Hospital of IcelandErna Haraldsdottir - ORCID: 0000-0003-4891-0743 https://orcid.org/0000-0003-4891-0743Background: Transitioning to end-of-life care and thereby changing the focus of treatment directives from life-sustaining treatment to comfort care is important for neurological patients in advanced stages. Late transition to end-of-life care for neurological patients has been described previously. Objective: To investigate whether previous treatment directives, primary medical diagnoses, and demographic factors predict the transition to end-of-life care and time to eventual death in patients with neurological diseases in an acute hospital setting. Method: All consecutive health records of patients diagnosed with stroke, amyotrophic lateral sclerosis (ALS), and Parkinson’s disease or other extrapyramidal diseases (PDoed), who died in an acute neurological ward between January 2011 and August 2020 were retrieved retrospectively. Descriptive statistics and multivariate Cox regression were used to examine the timing of treatment directives and death in relation to medical diagnosis, age, gender, and marital status. Results: A total of 271 records were involved in the analysis. Patients in all diagnostic categories had a treatment directive for end-of-life care, with patients with haemorrhagic stroke having the highest (92%) and patients with PDoed the lowest (73%) proportion. Cox regression identified that the likelihood of end-of-life care decision-making was related to advancing age (HR = 1.02, 95% CI: 1.007–1.039, P = 0.005), ischaemic stroke (HR = 1.64, 95% CI: 1.034–2.618, P = 0.036) and haemorrhagic stroke (HR = 2.04, 95% CI: 1.219–3.423, P = 0.007) diagnoses. End-of-life care decision occurred from four to twenty-two days after hospital admission. The time from end-of-life care decision to death was a median of two days. Treatment directives, demographic factors, and diagnostic categories did not increase the likelihood of death following an end-of-life care decision. Conclusions: Results show not only that neurological patients transit late to end-of-life care but that the timeframe of the decision differs between patients with acute neurological diseases and those with progressive neurological diseases, highlighting the particular significance of the short timeframe of patients with the progressive neurological diseases ALS and PDoed. Different trajectories of patients with neurological diseases at end-of-life should be further explored and clinical guidelines expanded to embrace the high diversity in neurological patients.pubpu

Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.publishedVersio

Interactions between ABCB1genotype and preoperative statin use impact clinical outcomes among breast cancer patients

Multiple clinical trials investigate statins' effects in breast cancer. The ABCB1 genotype appears to influence statin response and toxicity in the cardiovascular setting. This exploratory study aimed to investigate the interplay between preoperative statin use, ABCB1 genotype, and tumor-specific expression of the statin target 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in breast cancer. Preoperative statin use, ABCB1 C3435T genotype, and HMGCR expression in relation to outcome were analyzed in 985 primary breast cancer patients from a population-based prospective cohort in Sweden from 2002 to 2012. Preoperative statin use (n = 80) was not associated with ABCB1 C3435T genotype (n = 576), HMGCR expression (n = 848), or clinical outcomes. ABCB1 C3435T TT-carriers had lower risk of breast cancer events than any C-carriers (adjusted hazard ratio (HRadj) 0.74; 95%CI 0.49, 1.12), but only in non-statin users (Pinteractio n = 0.042). Statin users with TT genotype had higher risk of distant metastasis (HRadj 4.37; 95%CI 1.20, 15.91; Pinteraction = 0.009) and shorter overall survival than other patients (HRadj 3.77; 95%CI 1.37, 10.39; Pinteractio n = 0.019). In conclusion, there were nominally significant interactions between ABCB1 genotype and preoperative statin use on clinical outcomes, while preoperative statin use was not associated with outcomes. Since this is an exploratory study of the impact of the ABCB1 genotype in relation to statin use and clinical outcomes in the breast cancer setting, the results should be interpreted with caution and warrant replication in an independent cohort, preferably in a randomized setting. Since statin use is common in breast cancer patients, it would be of interest to further elucidate the clinical impact of the ABCB1 genotype in breast cancer

Prognostic Impact of Menopausal Hormone Therapy in Breast Cancer Differs According to Tumor Characteristics and Treatment

This study investigated how a history of menopausal hormone therapy (MHT) impacts clinical outcomes overall and in different subgroups of breast cancer patients. The study included 814 primary breast cancer patients aged ≥50 years in Sweden (2002–2012) with follow-up until 2016. Associations between patient- and tumor characteristics, recurrences, and overall survival were analyzed in relation to MHT. After a median follow-up of 7 years, 119 recurrences, and 111 deaths occurred. Ever MHT (n = 433, 53.2%) was associated with a lower BMI, frequency of alcohol abstinence, and histological grade, higher frequency of oral contraceptive use, and lobular cancer. Overall, MHT was not associated with prognosis, but there were significant effect modifications by estrogen receptor (ER) status, node status, main histological type, and aromatase inhibitor (AI) treatment on recurrence-risk (all Pinteractions≤ 0.017). MHT conferred an increased recurrence-risk in patients with ER- tumors, adjusted Hazard Ratio (HRadj) 3.99 (95% Confidence Interval (CI) 1.40–11.33), in node-negative patients HRadj 1.88 (95% CI 1.11–3.17), and in non-AI-treated patients HRadj 1.81 (95% CI 1.01–3.24), but decreased recurrence-risk in AI-treated patients HRadj 0.46 (95% CI 0.25–0.84) and in patients with lobular cancer HRadj 0.15 (95% CI 0.04–0.64). MHT was associated with lower risk of death in node-positive patients HRadj of 0.48 (95% CI 0.27–0.86) and in AI-treated patients HRadj of 0.41 (95% CI 0.22–0.77), but not in other patients (both Pinteractions≤ 0.027). A history of MHT may have prognostic value for certain subgroups of breast cancer patients such as AI-treated or node-negative patients

Effects of an intervention program for reducing severe perineal trauma during the second stage of labor.

To access publisher's full text version of this article click on the hyperlink belowBACKGROUND: Obstetric anal sphincter injuries lead frequently to short- and long-term consequences for the mother, including perineal pain, genital prolapse, and sexual problems. The aim of the study was to evaluate whether the implementation of an intervention program in the second stage of labor involving altered perineal support techniques reduced severe perineal trauma. METHODS: All women reaching the second stage of labor and giving birth vaginally to singleton babies at Landspítali University Hospital (comprising 76% of births in Iceland in 2013) were enrolled in a cohort study. Data were recorded retrospectively for 2008-2010 and prospectively in 2012-2014, for a total of 16 336 births. During 2011, an intervention program was implemented, involving all midwives and obstetricians working in the labor wards. Two professionals assessed and agreed on classification of every perineal tear. RESULTS: The prevalence of obstetric anal sphincter injuries decreased from 5.9% to 3.7% after the implementation (P < 0.001). Third-degree tears decreased by 40%, and fourth-degree tears decreased by 56% (P < 0.001). The prevalence of first-degree tears increased from 25.8% to 33.1%, whereas second-degree tears decreased from 44.7% to 36.6% between the before and after study periods. Severe perineal trauma was linked to birthweight, and this did not change despite the new intervention. CONCLUSIONS: Active intervention to reduce perineal trauma was associated with an overall significant decrease in obstetric anal sphincter injuries. Good perineal visualization, manual perineal support, and controlled delivery of the fetal head were essential components for reducing perineal trauma.Icelandic Ministry of Welfare Landspitali University Hospital Research Fund, Reykjavik, Icelan

Caveolin-1 genotypes as predictor for locoregional recurrence and contralateral disease in breast cancer

Purpose: Caveolin-1 (CAV1) has been implicated in breast cancer oncogenesis and metastasis and may be a potential prognosticator, especially for non-distant events. CAV1 functions as a master regulator of membrane transport and cell signaling. Several CAV1 SNPs have been linked to multiple cancers, but the prognostic impact of CAV1 SNPs in breast cancer remains unclear. Here, we investigated CAV1 polymorphisms in relation to clinical outcomes in breast cancer. Methods: A cohort of 1017 breast cancer patients (inclusion 2002–2012, Sweden) were genotyped using Oncoarray by Ilumina. Patients were followed for up to 15 years. Five out of six CAV1 SNPs (rs10256914, rs959173, rs3807989, rs3815412, and rs8713) passed quality control and were used for haplotype construction. CAV1 genotypes and haplotypes in relation to clinical outcomes were assessed with Cox regression and adjusted for potential confounders (age, tumor characteristics, and adjuvant treatments). Results: Only one SNP was associated with lymph node status, no other SNPs or haplotypes were associated with tumor characteristics. The CAV1 rs3815412 CC genotype (5.8% of patients) was associated with increased risk of contralateral breast cancer, adjusted hazard ratio (HRadj) 4.26 (95% CI 1.86–9.73). Moreover, the TTACA haplotype (13% of patients) conferred an increased risk for locoregional recurrence HRadj 2.24 (95% CI 1.24–4.04). No other genotypes or haplotypes were associated with clinical outcome. Conclusion: CAV1 polymorphisms were associated with increased risk for locoregional recurrence and contralateral breast cancer. These findings may identify patients that could derive benefit from more tailored treatment to prevent non-distant events, if confirmed

Increasing preoperative body size in breast cancer patients between 2002 and 2016 : implications for prognosis

Overweight and obesity are increasing worldwide, but the extent in breast cancer patients is unknown. The two aims were to study secular trends in preoperative body mass index (BMI), waist circumference, and breast volume and their impacts on clinical outcome. BMI, waist circumference, and breast volume were measured preoperatively in 24–99-year-old primary breast cancer patients (n = 640) in Sweden 2002–2016. The measurements were analyzed alone and combined in relation to recurrence and overall survival (OS). BMI, waist circumference, and breast volume increased 2002–2016 (ptrends < 0.0001). Of these, a breast volume ≥ 850 mL was associated with the strongest recurrence-risk (adjusted hazard ratio [adjHR] 1.67; 95% CI 1.17–2.39), especially combined with waist circumference ≥ 80 cm (adjHR 2.07; 95% CI 1.25–3.44), while BMI ≥ 25 kg/m2 or large waist circumference conferred almost a twofold risk for death (both Log-Rank p ≤ 0.0001). Chemotherapy seemed to counteract the negative impact of a high BMI or large waist circumference on OS. Large breast volume was the strongest predictor for recurrence in all treatment groups. In conclusion, preoperative BMI, waist circumference, and breast volume increased between 2002 and 2016. Larger body size negatively impacted breast cancer-free interval and OS. If confirmed, body measurements may help select patients requiring more individualized treatment