The metabolic syndrome in cancer survivors.

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.

Use of Benzodiazepines and Z-Drugs in Nursing Home Residents with Dementia: Prevalence and Appropriateness.

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.

Contrasting the Genetic Background of Type 1 Diabetes and Celiac Disease Autoimmunity.

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.

Vascular damage in testicular cancer patients: a study on endothelial activation by bleomycin and cisplatin in vitro.

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.

Association of PAI-1 gene polymorphism with survival and chemotherapy-related vascular toxicity in testicular cancer.

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.

Variation in bleomycin hydrolase gene is associated with reduced survival after chemotherapy for testicular germ cell cancer.

PURPOSE: Response to chemotherapy may be determined by gene polymorphisms involved in metabolism of cytotoxic drugs. A plausible candidate is the gene for bleomycin hydrolase (BLMH), an enzyme that inactivates bleomycin, an essential component of chemotherapy regimens for disseminated testicular germ-cell cancer (TC). We investigated whether the single nucleotide polymorphism (SNP) A1450G of the BLMH gene (rs1050565) is associated with survival. PATIENTS AND METHODS: Data were collected on survival and BLMH genotype of 304 patients with TC treated with bleomycin-containing chemotherapy at the University Medical Center Groningen, the Netherlands, between 1977 and 2003. Survival according to genotype was analyzed using Kaplan-Meier curves with log-rank testing and Cox regression analysis with adjustment for confounders. RESULTS: BLMH gene SNP A1450G has a significant effect on TC-related survival (log-rank P = .001). The homozygous variant (G/G) genotype (n = 31) is associated with decreased TC related survival compared with the heterozygous variant (A/G; n = 133) and the wild-type (A/A; n = 140). With Cox regression the G/G genotype proves to be an unfavorable prognostic factor, in addition to the commonly used International Germ Cell Consensus Classification prognosis group, with a hazard ratio of 4.97 (95% CI, 2.17 to 11.39) for TC-related death. Furthermore, the G/G genotype shows a higher prevalence of early relapses. CONCLUSION: The homozygous variant G/G of BLMH gene SNP A1450G is associated with reduced survival and higher prevalence of early relapses in TC patients treated with bleomycin-containing chemotherapy. This association is hypothesis generating and may eventually be of value for risk classification and selection for alternative treatment strategies in patients with disseminated TC.

Clinical evaluation of M30 and M65 ELISA cell death assays as circulating biomarkers in a drug-sensitive tumor, testicular cancer.

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.