Equivalent doses for anticancer agents used in pediatric oncology : a literature review and evaluation of a novel approach for conversion factors

Background Epidemiological research on late effects of therapy shows the necessity to aggregate chemotherapy agents to substance classes. This requires using conversion factors by substance classes. Aims The aim of this study was to identify previously used conversion factors from the literature, to present a novel approach for additional factors, and to compare these approaches. Methods and Results A literature review was performed, which identified two main principles of deriving conversion factors: effect-equivalence and equimolar. Thirty-five articles presenting effect equivalence-based factors in the widest sense were found in the literature. Ten articles presented the equimolar approach which can be applied to almost all chemotherapy substances. Based on a comprehensive list of treatment protocols used in German pediatric oncology, we derived alternative conversion factors from typical doses. We compared the conversion factors using Pearson correlation coefficients and linear regression. At least two types of conversion factor were available for each of the 49 substances included. The equivalent effect-based and the typical dose-based factors were highly correlated with a regression coefficient close to 1. The equimolar factors are independent. Conclusions For substances for which no conversion factor based on some type of effect equivalence has been published so far, a factor based on a typical doses-approach may be used in epidemiological late effects research. Doses aggregated based on the equimolar approach may not be compatible with doses aggregated based on equivalent effects

Chemotherapy-induced peripheral neuropathy: evidence from genome-wide association studies and replication within multiple myeloma patients

Background: Based on the possible shared mechanisms of chemotherapy-induced peripheral neuropathy (CIPN) for different drugs, we aimed to aggregate results of all previously published genome-wide association studies (GWAS) on CIPN, and to replicate them within a cohort of multiple myeloma (MM) patients. Methods: Following a systematic literature search, data for CIPN associated single nucleotide polymorphisms (SNPs) with P-values< 10− 5 were extracted; these associations were investigated within a cohort of 983 German MM patients treated with bortezomib, thalidomide or vincristine. Cases were subjects that developed CIPN grade 2–4 while controls developed no or sub-clinical CIPN. Logistic regression with additive model was used. Results: In total, 9 GWASs were identified from the literature on CIPN caused by different drugs (4 paclitaxel, 2 bortezomib, 1 vincristine, 1 docetaxel, and 1 oxaliplatin). Data were extracted for 526 SNPs in 109 loci. One hundred fourty-eight patients in our study population were CIPN cases (102/646 bortezomib, 17/63 thalidomide and 29/274 vincristine). In total, 13 SNPs in 9 loci were replicated in our population (p-value< 0.05). The four smallest P-values relevant to the nerve function were 0.0006 for rs8014839 (close to the FBXO33 gene), 0.004 for rs4618330 (close to the INTU gene), 0.006 for rs1903216 (close to the BCL6 gene) and 0.03 for rs4687753 (close to the IL17RB gene). Conclusions: Replicated SNPs provide clues of the molecular mechanism of CIPN and can be strong candidates for further research aiming to predict the risk of CIPN in clinical practice, particularly rs8014839, rs4618330, rs1903216, and rs4687753, which showed relevance to the function of nervous system

Acute exposure to nocturnal train noise induces endothelial dysfunction and pro-thromboinflammatory changes of the plasma proteome in healthy subjects

Nocturnal train noise exposure has been associated with hypertension and myocardial infarction. It remains unclear whether acute nighttime train exposure may induce subclinical atherosclerosis, such as endothelial dysfunction and other functional and/or biochemical changes. Thus, we aimed to expose healthy subjects to nocturnal train noise and to assess endothelial function, changes in plasma protein levels and clinical parameters. In a randomized crossover study, we exposed 70 healthy volunteers to either background or two different simulated train noise scenarios in their homes during three nights. After each night, participants visited the study center for measurement of vascular function and assessment of other biomedical and biochemical parameters. The three nighttime noise scenarios were exposure to either background noise (control), 30 or 60 train noise events (Noise30 or Noise60), with average sound pressure levels of 33, 52 and 54 dB(A), respectively. Flow-mediated dilation (FMD) of the brachial artery was 11.23 ± 4.68% for control, compared to 8.71 ± 3.83% for Noise30 and 8.47 ± 3.73% for Noise60 (p < 0.001 vs. control). Sleep quality was impaired after both Noise30 and Noise60 nights (p < 0.001 vs. control). Targeted proteomic analysis showed substantial changes of plasma proteins after the Noise60 night, mainly centered on redox, pro-thrombotic and proinflammatory pathways. Exposure to simulated nocturnal train noise impaired endothelial function. The proteomic changes point toward a proinflammatory and pro-thrombotic phenotype in response to nocturnal train noise and provide a molecular basis to explain the increased cardiovascular risk observed in epidemiological noise studies

The association of chronic anxiousness with cardiovascular disease and mortality in the community : results from the Gutenberg Health Study

In a large German community sample of adults, we investigated the association of chronic anxiousness with cardiovascular disease and mortality. Self-reported anxiousness from 11,643 German adults between 40 and 80 years of age from the Gutenberg Health Study (GHS) was analyzed over 5 years. Multivariable regression modeling assessed the relation between the variables, cardiovascular disease and mortality. Twelve percent of the participants reported consistently raised (chronic) anxiousness over at least 2.5 years. Anxiousness was more often reported by female, younger participants with a lower socioeconomic status, smokers and those with a family history of stroke and myocardial infarction. New onset of cardiovascular disease was linked to chronic anxiousness in men and new onset of anxiousness in women. However, chronic anxiousness did not predict all-cause mortality. Our results revealed that anxiousness is highly prevalent in German adults from middle to old age, affecting women in particular. In our study, we found sex-specific associations between new onset of cardiovascular disease and different forms of anxiousness in men and women. We suggest that even subclinical levels of anxiety need to be considered as cardiovascular risk factors. To elucidate potential harm of anxiousness for mental and physical health, we propose sex-specific analyses in further research studies, taking age and the course of anxiousness into account

Global reporting of pulmonary embolism-related deaths in the World Health Organization mortality database: Vital registration data from 123 countries

Introduction Pulmonary embolism (PE) has not been accounted for as a cause of death contributing to cause-specific mortality in global reports. Methods We analyzed global PE-related mortality by focusing on the latest year available for each member state in the World Health Organization (WHO) mortality database, which provides age-sex-specific aggregated mortality data transmitted by national authorities for each underlying cause of death. PE-related deaths were defined by International Classification of Diseases, Tenth Revision codes for acute PE or nonfatal manifestations of venous thromboembolism (VTE). The 2001 WHO standard population served for standardization. Results We obtained data from 123 countries covering a total population of 2 602 561 422. Overall, 50 (40.6%) were European, 39 (31.7%) American, 13 (10.6%) Eastern Mediterranean, 13 (10.6%) Western Pacific, 3 (2.4%) Southeast Asian, and 2 (1.6%) African. Of 116 countries classifiable according to population income, 57 (49.1%) were high income, 42 (36.2%) upper-middle income, 14 (12.1%) lower-middle income, and 3 (2.6%) low income. A total of 18 726 382 deaths were recorded, of which 86 930 (0.46%) were attributed to PE. PE-related mortality rate increased with age in most countries. The reporting of PE-related deaths was heterogeneous, with an age-standardized mortality rate ranging from 0 to 24 deaths per 100 000 population-years. Income status only partially explained this heterogeneity. Conclusions Reporting of PE-related mortality in official national vital registration was characterized by extreme heterogeneity across countries. These findings mandate enhanced efforts toward systematic and uniform coverage of PE-related mortality and provides a case for full recognition of PE and VTE as a primary cause of death

Aggiornamento sui dati relativi alla mortalità da embolia polmonare in Italia (2003-2015)

BACKGROUND Data regarding pulmonary embolism (PE)-related mortality in Italy are scarce. We assessed PE-related mortality and its time trend in Italy by using the World Health Organization (WHO) Mortality Database. METHODS The vital registration data of Italy from the WHO Mortality Database were analyzed for the period between 2003 and 2015, and compared with time trends in Southern Europe. Death was defined as PE-related when classified with specific codes for PE or limb vein thrombosis listed as the primary cause of death. This coding was based on the International Classification of Diseases, tenth revision. RESULTS Overall, 28 647 PE-related deaths (10 178 men and 18 469 women) were recorded between 2003 and 2015. The observed age-standardized annual PE-related mortality rates were 2.5 per 100 000 men and 2.8 per 100 000 women. Moreover, PE-related mortality increased with age with a seemingly exponential distribution. Joinpoint regression analysis demonstrated a statistically significant linear decrease in age-standardized PE-related mortality of -0.21 (95% confidence interval -0.27; -0.15) and -0.22 (95% confidence interval -0.28; -0.16) deaths per 100 000 population for men and women, respectively. CONCLUSIONS The Italian age-adjusted mortality rates appeared lower compared to overall Southern Europe, despite a similar decreasing trend over time

Prescription patterns of angiotensin-converting enzyme inhibitors for various indications : A UK population-based study

AIM: Angiotensin-converting enzyme inhibitors (ACEIs) are widely prescribed for several cardiovascular indications. This study investigated patterns of ACEI use for various indications. METHODS: A descriptive, retrospective population-based study was conducted using data from the UK Clinical Practice Research Datalink. Patients starting ACEIs (2007-2014) were selected and ACEI indications were retrieved from electronically recorded medical records. Stratified by indication, we distinguished between persistent and nonpersistent ACEI use, considering a 6-month interval between two prescription periods as a maximum for persistent use. Five-year persistence rates for various indications were calculated using the Kaplan-Meier method and compared in a log-rank test. Nonpersistent users were subdivided into three groups: (i) stop; (ii) restart; and (iii) switch to an angiotensin II-receptor blocker. Patients who received ACEIs for hypertension who switched to other classes of antihypertensive medications were further investigated. RESULTS: In total, 254 002 ACEI initiators were identified with hypertension (57.6%), myocardial infarction (MI; 4.2%), renal disease (RD; 3.7%), heart failure (HF; 1.5%), combinations of the above (17.2%) or none of the above (15.8%). Five-year persistence rates ranged from 43.2% (RD) to 68.2% (MI; P < 0.0001). RD and HF patients used ACEIs for the shortest time (average 23.6 and 25.0 months, respectively). For the nonpersistent group, the percentage of switchers to angiotensin II-receptor blockers ranged from 27.6% (RD) to 42.2% (MI) and the restarters ranged from 15.0% (HF) to 18.1% (group without indication). CONCLUSIONS: Depending on the indication, there are various rates of ACEI nonpersistence. Patients with RD are most likely to discontinue treatment

Prescription patterns of angiotensin-converting enzyme inhibitors for various indications: A UK population-based study

Aim: Angiotensin-converting enzyme inhibitors (ACEIs) are widely prescribed for several cardiovascular indications. This study investigated patterns of ACEI use for various indications. Methods: A descriptive, retrospective population-based study was conducted using data from the UK Clinical Practice Research Datalink. Patients starting ACEIs (2007–2014) were selected and ACEI indications were retrieved from electronically recorded medical records. Stratified by indication, we distinguished between persistent and nonpersistent ACEI use, considering a 6-month interval between two prescription periods as a maximum for persistent use. Five-year persistence rates for various indications were calculated using the Kaplan–Meier method and compared in a log-rank test. Nonpersistent users were subdivided into three groups: (i) stop; (ii) restart; and (iii) switch to an angiotensin II-receptor blocker. Patients who received ACEIs for hypertension who switched to other classes of antihypertensive medications were further investigated. Results: In total, 254 002 ACEI initiators were identified with hypertension (57.6%), myocardial infarction (MI; 4.2%), renal disease (RD; 3.7%), heart failure (HF; 1.5%), combinations of the above (17.2%) or none of the above (15.8%). Five-year persistence rates ranged from 43.2% (RD) to 68.2% (MI; P < 0.0001). RD and HF patients used ACEIs for the shortest time (average 23.6 and 25.0 months, respectively). For the nonpersistent group, the percentage of switchers to angiotensin II-receptor blockers ranged from 27.6% (RD) to 42.2% (MI) and the restarters ranged from 15.0% (HF) to 18.1% (group without indication). Conclusions: Depending on the indication, there are various rates of ACEI nonpersistence. Patients with RD are most likely to discontinue treatment