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Introduction: Despite the effect on blood lipid levels, the clinical benefits of intensive versus standard pharmacological lipid-lowering therapy remain unclear. Previous reviews have presented relative effects on the risk of clinical outcomes, but not the absolute risk reductions (ARRs) and the time gained to a clinical outcome, also called outcome postponement (OP). The aim of this study was to estimate the effect of intensive versus standard lipid-lowering therapy in terms of ARR and OP of major adverse cardiovascular events (MACE), myocardial infarction (MI), stroke, and all-cause mortality., Methods: We searched PubMed, Embase, and prior reviews to identify trials comparing intensive versus standard lipid-lowering therapy for the risk of cardiovascular disease. We extracted the number of patients with MACE, MI, stroke, and all-cause mortality. Risk of bias was assessed according to the five domains of the Cochrane Risk of Bias Tool 2.0. We calculated ARRs and OPs to assess the clinical benefits of intensive versus standard therapy for each outcome. We conducted meta-analyses standardizing the results to 2 and 5 years of follow-up., Results: We identified 11 double-blind, randomized, controlled trials (n = 101,357). The follow-up period ranged from 1.5 to 7.0 years, with an average follow-up duration of 3.7 years. Risk of bias was generally high. During an estimated 2 years of intensive versus standard lipid-lowering therapy, 1.1% (95% confidence interval [CI] 0.7-1.5) fewer patients had MACE and the OP of MACE was 4.1 days (95% CI 2.6-5.6). The effects were 0.7% (95% CI 0.4-0.8) and 2.5 days (95% CI 1.6-3.3) for MI, 0.2% (95% CI 0.1-0.3) and 0.9 days (95% CI 0.5-1.2) for stroke, and 0.2% (95% CI - 0.1 to 0.4) and 0.6 days (95% CI - 0.4 to 1.5) for all-cause death. During on average 5 years of intensive versus standard lipid-lowering therapy, 2.4% (95% CI 1.5-3.3) fewer patients had MACE and the time gained to MACE was 23.5 days (95% CI 14.9-32.0). The effects were 1.5% (95% CI 1.0-2.1) and 14.6 days (95% CI 9.3-20.0) for MI, 0.6% (95% CI 0.4-0.8) and 5.3 days (95% CI 3.3-7.4) for stroke, and 0.4% (95% CI -0.2 to 0.1) and 3.6 days (95% CI - 2.1 to 9.2) for all-cause death., Conclusion: Intensive lipid-lowering therapy during 2 or 5 years did not lead to fewer deaths or lifetime gained, and the effects on MI and stroke were negligible. The largest effect was that MACE did not occur in two of 100 patients and was postponed 3-4 weeks after 5 years of intensive treatment. Given the small effect, patients should receive this information as part of shared decision making., (© 2024. The Author(s).)

Background: Guidelines worldwide recommend restricted prescription of benzodiazepine receptor agonists (BZRAs), i.e., benzodiazepines and Z-drugs, for the treatment of dementia-associated behavioral and psychological symptoms and insomnia., Objective: To assess the prevalence and appropriateness of BZRA use among nursing home residents with dementia., Methods: This is a post-hoc analysis of BZRA prescriptions from two intervention studies on psychotropic drug use, conducted from 2016 to 2018. It includes 1,111 residents of dementia special care units from 24 Dutch long-term care organizations. We assessed the prevalence of use of continuous and as-needed BZRA prescriptions and their association with registered symptoms. Continuous BZRA prescriptions were evaluated for appropriateness, i.e., whether indication, dosage, duration, and evaluation accorded with guidelines for the treatment of challenging behavior in dementia and sleep disorders., Results: The prevalence of BZRA use is 39.2% (95% CI: 36.3%-42.0%): continuous 22.9%; only as-needed 16.3%. Combinations of preferred BZRAs and appropriate indications occur in 19.0% of continuous anxiolytic prescriptions and 44.8% of hypnotic prescriptions. Frequently registered inappropriate indications are aggression/agitation for anxiolytics (continuous: 75.7%; as-needed: 75.2%) and nighttime agitation for hypnotics (continuous: 40.3%; as-needed: 26.7%). None of the continuous prescriptions with appropriate indications were appropriate for all other items. For most of the prescriptions, duration and time to evaluation exceeded 4 weeks., Conclusion: BZRA use in nursing home residents with dementia is highly frequent. A large proportion of prescriptions do not follow the guidelines with regard to indication, exceed the recommended duration and are not evaluated in a timely manner. The discrepancy between evidence-based guidelines and daily practice calls for an exploration of factors maintaining inappropriate use., Competing Interests: The authors have no conflict of interest to report., (© 2021 – The authors. Published by IOS Press.)

Type 1 diabetes (T1D) and celiac disease (CeD) cluster in families and can occur in the same individual. Genetic loci have been associated with susceptibility to both diseases. Our aim was to explore the genetic differences between individuals developing both these diseases (double autoimmunity) versus those with only one. We hypothesized that double autoimmunity individuals carry more of the genetic risk markers that are shared between the two diseases independently. SNPs were genotyped in loci associated with T1D (n=42) and CeD (n=28) in 543 subjects who developed double autoimmunity, 2,472 subjects with T1D only, and 2,223 CeD-only subjects. For identification of loci that were specifically associated with individuals developing double autoimmunity, two association analyses were conducted: double autoimmunity versus T1D and double autoimmunity versus CeD. HLA risk haplotypes were compared between the two groups. The CTLA4 and IL2RA loci were more strongly associated with double autoimmunity than with either T1D or CeD alone. HLA analyses indicated that the T1D high-risk genotype, DQ2.5/DQ8, provided the highest risk for developing double autoimmunity (odds ratio 5.22, P=2.25×10(-29)). We identified a strong HLA risk genotype (DQ2.5/DQ8) predisposing to double autoimmunity, suggesting a dominant role for HLA. Non-HLA loci, CTLA4 and IL2RA, may also confer risk to double autoimmunity. Thus, CeD patients who carry the DQ2.5/DQ8 genotype may benefit from periodic screening of autoantibodies related to T1D., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Background: The metabolic syndrome (MS) might increase the risk of cardiovascular disease in testicular cancer (TC) survivors. We investigated its prevalence, development, vascular implications, and the role of gonadal function., Methods: TC survivors treated with chemotherapy and follow-up ≥3 years (N = 370, study I) were retrospectively evaluated for the development of cardiovascular risk factors. A subgroup followed 3-20 years (N = 173, study II) was compared with controls (N = 1085) for MS prevalence and evaluated for vascular function., Results: In TC survivors (study I), 24% developed overweight, 24% hypercholesterolemia, and 30% hypertension, after median follow-up of 1.7, 0.9, and 5.1 years, respectively. At the median follow-up of 5 years (study II), 25% of survivors have the MS {odds ratio (OR) 2.2, [95% confidence interval (CI) 1.5-3.3] compared with controls}. Survivors with MS have features of inflammation and prothrombotic state, increased carotid artery intima-media thickness. Survivors with testosterone levels <15 nmol/l (22%) have an increased risk of the MS (OR 4.1, 95% CI 1.8-9.3)., Conclusions: The current data suggest that the MS occurs at earlier age in TC survivors treated with chemotherapy compared with controls and is accompanied by early signs of atherosclerosis. As low testosterone may have a causal role, it is a target for interventions.

Background: High Plasminogen-Activator Inhibitor 1 (PAI-1) expression by tumors has been associated with poor prognosis in several cancer types, and high systemic PAI-1 levels with increased thrombosis risk. The authors investigated whether the germline 4G/5G deletion/insertion polymorphism in the PAI-1 promoter (rs1799889), which may influence PAI-1 expression, is associated with survival and chemotherapy-related vascular toxicity in testicular cancer (TC)., Methods: Data were collected on PAI-1 4G/5G polymorphism, survival, venous thromboembolism (VTE), and coronary heart disease (CHD) for 324 non-seminomatous TC patients treated with platinum-based chemotherapy. Genotypes were compared regarding survival and disease outcome. VTE and CHD incidence were compared with adjustment for cardiovascular risk factors and prothrombotic gene polymorphisms of coagulation factors II/prothrombin (G20210A) and V (G1691A)., Results: The 4G/4G variant of PAI-1 4G/5G polymorphism shows a higher prevalence of International Germ Cell Cancer Classification (IGCCC) poor prognosis compared with 4G/5G and 5G/5G (24% vs 8% and 15%; chi-square P = .003). In addition, the 4G/4G variant shows reduced TC-related survival with a hazard ratio of 2.69 (95% CI, 1.26-5.73; P = .010) for TC-related death (adjusted for IGCCC). This is related to an increased risk for refractory disease and early relapses (odds ratio, 3.35; 95% CI, 1.48-7.59; P = .004). PAI-1 4G/5G polymorphism is not associated with VTE and CHD risk., Conclusions: The 4G/4G variant of PAI-1 4G/5G polymorphism may be an unfavorable prognostic as well as predictive factor for response to chemotherapy in TC patients. If confirmed, it may contribute to the identification of patients with increased risk for refractory disease., (Copyright © 2010 American Cancer Society.)

The metabolic syndrome, as a cluster of cardiovascular risk factors, may represent an important connection between cancer treatment and its common late effect of cardiovascular disease. Insight into the aetiology of the metabolic syndrome after cancer treatment might help to identify and treat cancer survivors with increased cardiovascular risk. In this review, we summarise current knowledge on the prevalence and pathophysiology of the metabolic syndrome in cancer survivors, and discuss current intervention strategies with an emphasis on new developments., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: Patients with elevated human chorionic gonadotrophin (HCG) can have hyperthyroidism. We assessed the prevalence of hyperthyroidism in patients presenting with disseminated non-seminomatous germ-cell tumors (NSGCT)., Patients and Methods: In all patients with metastatic NSGCT who started chemotherapy at our center from April 2001 to April 2007, thyroid function was analyzed. The association between thyroid function and HCG level was examined and the frequency of hyperthyroidism in patients with low (<5000 IU/l), intermediate (> or = 5000 but <50 000 IU/l) and high (> or = 50 000 IU/l) serum HCG was assessed., Results: For 144 of 148 eligible patients, thyroid function tests were available. Five patients with hyperthyroidism (3.5%) were identified, who all had high-serum HCG (mean 1 325 147 IU/l). Fifty percent of the patients with high HCG levels had hyperthyroidism versus 0% of the patients with HCG <50 000 IU/l (P < 0.001). Free thyroxin levels normalized within 26 days after starting chemotherapy in all patients., Conclusions: Hyperthyroidism frequently accompanies NSGCT with highly elevated HCG. Since its symptoms overlap with those of extensive metastatic disease, it may not be recognized. Thyroid function should be assessed in patients with high HCG levels and symptomatic hyperthyroidism should be treated temporarily with beta-blockade or antithyroidal medication.

Following treatment with bleomycin- and cisplatin-containing chemotherapy, testicular cancer patients frequently develop vascular complications, which may result from damage to endothelial cells. Understanding bleomycin- and cisplatin-induced endothelial alterations may help to develop strategies to prevent or reduce vascular toxicity. The effects of bleomycin and cisplatin on proliferation and apoptosis of the human dermal microvascular endothelial cell line HMEC-1 were determined. In addition, modulation of drug-induced cytotoxicity by the free radical scavenger amifostine, the low molecular weight heparin dalteparin, the iron-chelator dexrazoxane, the HMG-CoA reductase inhibitor rosuvastatin and the PPAR agonist troglitazone was tested. Furthermore, the effects of bleomycin and cisplatin on endothelial activation measured by the expression of the intercellular adhesion molecule-1 (ICAM-1) and on two main proteins involved in fibrinolysis, tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI-1), were measured. Decreased endothelial cell survival induced by bleomycin and cisplatin coincided with the induction of apoptosis. Only troglitazone was able to protect the endothelial cells from both bleomycin- and cisplatin-induced cytotoxicity. At high concentrations, amifostine and dexrazoxane also protected HMEC-1 from drug-induced cytotoxicity. However, due to the required high (toxic) concentrations of both modulators no absolute cell survival benefit could be achieved. Both bleomycin and cisplatin induced up-regulation of ICAM-1, tPA and PAI-1. Summarizing, bleomycin and cisplatin induce alterations in the function of endothelial cells regarding proliferation, inflammation and fibrinolysis in vitro. Strategies aimed at these functions should be developed in order to ameliorate or prevent cytostatic agent-induced vascular damage.

Long-term cardiovascular morbidity is increasingly observed in chemotherapy-treated testicular cancer survivors, but little is known of early sub-clinical changes in cardiac function. We prospectively evaluated cardiac function in testicular cancer patients by echocardiography. Systolic (Wall Motion Score Index) and diastolic (E/A-ratio and Tissue Velocity Imaging (TVI)) parameters, and serum levels of N-Terminal pro-Brain Natriuretic Peptide (NT-proBNP) were assessed before the start of chemotherapy and 1 year later. Echocardiography data were compared with an age-matched group of healthy controls. Forty-two patients treated with bleomycin, etoposide and cisplatin were evaluated (median age 27 years, range 18-50). Systolic function and E/A-ratio did not change, whereas the median TVI decreased (12.0 vs 10.0 cms(-1); P=0.002). Median levels of NT-proBNP increased (5 vs 18 pmoll(-1), P=0.034). Compared with controls, TVI before the start of chemotherapy was not significantly different. In conclusion, we found that at a median of 10 months after cisplatin-based treatment for testicular cancer, TVI decreased significantly, indicating a deterioration of diastolic cardiac function. Serum levels of NT-proBNP increased. The prognostic significance of these changes for future cardiovascular morbidity is not clear.

Circulating full-length and caspase-cleaved cytokeratin 18 (CK18) are considered biomarkers of chemotherapy-induced cell death measured using a combination of the M30 and M65 ELISAs. M30 measures caspase-cleaved CK18 produced during apoptosis and M65 measures the levels of both caspase-cleaved and intact CK18, the latter of which is released from cells undergoing necrosis. Previous studies have highlighted their potential as prognostic, predictive, and pharmacological tools in the treatment of cancer. Disseminated testicular germ cell cancer (TC) is a paradigm for a chemosensitive solid malignancy of epithelial origin and has a cure rate of 80% to 90%. We conducted M30/M65 analyses on 34 patients with TC before and during treatment with bleomycin, etoposide, and cisplatin and showed that prechemotherapy serum levels of M65 and M30 antigens are correlated with established TC tumor markers lactate dehydrogenase, alpha-fetoprotein, and beta-human chorionic gonadotropin, probably reflecting tumor load. Cumulative percentage change of M65 and M30 from baseline to end of study was highest in poor prognosis patients (P < .05). Moreover, area under the curve profiles of M65 and M30 during chemotherapy mirrored dynamic profiles for lactate dehydrogenase, alpha-fetoprotein, and beta-human chorionic gonadotropin. Consequently, M65 and M30 levels appear to reflect chemotherapy-induced changes that correlate with changes in markers routinely used in the clinic for management of patients with TC. This is the first clinical study where M65 and M30 antigen levels correlate with established prognostic markers and provides impetus for their exploration in other epithelial cancers where there is a pressing need for informative circulating biomarkers.