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Aim: Assess first-line sunitinib dosing for treatment of metastatic renal cell carcinoma in Swedish clinical practice (2006-2019). Materials & methods: Retrospective analysis of three sunitinib dosing regimens: 2-weeks on, 1-week off (2:1 Start); standard 4-weeks on, 2-weeks off (4:2) and 4:2 start with switch to 2:1 (2:1 Switch). Results: Time-to-treatment discontinuation (95% CI) differed significantly ( p  < 0.001): 6.2 (5.6-7.2), 13.9 (8.1-20.6) and 4.6 (4.3-5.6) months for 2:1 Start ( n  = 320), 2:1 Switch ( n  = 71) and 4:2 ( n  = 704), respectively. Overall survival (95% CI) differed significantly ( p  < 0.001): 21.8 (18.1-26.1), 32.2 (25.1-48.3) and 13.5 (12.3-15.8) months for 2:1 Start ( n  = 320), 2:1 Switch ( n  = 71) and 4:2 ( n  = 704), respectively. Conclusion: Alternative dosing does not compromise clinical efficacy and may provide advantages in terms of improved treatment outcomes. However, due to the changing treatment patterns during this long-term study, and the absence of patient risk category data, caution is required when interpreting the main outcomes.

Aim: To show clinical characteristics, treatments, and comorbidities in chronic cough in a nationwide cohort., Methods: Two cohorts were created. A national cohort with individuals from two population-based databases; the National Patient Register and Swedish Prescribed Drug Register. Secondly, a regional cohort including primary care data. Adults with at least one cough diagnosis (ICD-10 R05) and/or individuals with ≥2 dispensed prescriptions for relevant cough-medication within the inclusion period, 2016-2018, were identified. Individuals on medications which may instigate cough or suggest acute infection or diagnosed with conditions where cough is a cardinal symptom, were excluded. Those remaining were defined as having possible refractory or unexplained chronic cough (RCC/UCC)., Results: Altogether 62,963 individuals were identified with possible RCC/UCC, giving a national prevalence of about 1%. Mean age was 56 years and 60% were females. Many (44%) of the individuals with possible RCC/UCC visited cough relevant specialist clinics during the study period, but less than 20% received a cough diagnosis. A majority (63%) had evidence of RCC/UCC in the 10 years prior to inclusion in the study. In the regional cohort, including primary care data, the prevalence of RCC/UCC was doubled (2%). Cough medicines were mainly prescribed by primary care physicians (82%)., Conclusion: Most individuals with possible RCC/UCC sought medical care in primary care, and had a long history of cough, with various treatments tried, indicating a substantial burden of the condition. Referrals to specialist care were very rare. The results underline the need for a structured multidisciplinary approach and future therapeutic options., Competing Interests: Conflicts of interest: The authors report no conflicts of interest in this work, except that LW is employed by MSD (Sweden) AB, but with no stock ownership. ÖE has received honoraria from MSD and AstraZeneca for advisory work, unrelated to this manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Walz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Bladder cancer (BC) and Renal cell carcinoma (RCC) are the most common urogenital cancers among both sexes, with a yearly global incidence of around 500 000 each. Both BC and RCC have been linked to diabetes. Poor glycemic control (malglycemia) is a serious consequence of diabetes and a possible consequence of systemic treatments used in BC and RCC. The objective of this study was to investigate the prevalence of diabetes and use of hospital-based care for malglycemia in people with BC or RCC., Methods: This Swedish retrospective population-based register study used national health-data registers for longitudinal data on cancer incidence covering 15 years, use of hospital-based health care, and filled prescriptions of outpatient medications. Study endpoints included co-prevalence of diabetes in individuals with BC/RCC, healthcare resource utilization due to malglycemia, use of systemic corticosteroids, and changes in diabetes management for people with concomitant type 2 diabetes., Results: We identified 36,620 and 15,581 individuals diagnosed with BC and RCC, respectively, between 2006 and 2019. The proportion of individuals registered with diabetes was 24% in BC and 23% in RCC. An association between BC/RCC and poor glycemic control was found, although the number of malglycemic events in hospital-based care were few (65/59 per 1000 individuals with diabetes and BC/RCC respectively with at least one event). An earlier switch to insulin-based diabetes management was observed in BC/RCC compared to matched individuals with type 2 diabetes but no cancer. The results also indicated an association between steroid treatment and poor glycemic control, and that systemic corticosteroids were more common among people with BC/RCC compared to diabetes controls., Conclusion: The high prevalence of diabetes and increased use of systemic corticosteroid treatment observed in this large national study highlights the need for specific clinical management, risk-assessment, and monitoring of individuals with BC/RCC and diabetes., (© 2024. The Author(s).)

Aim: Assess the time-to-treatment discontinuation (TTD) and overall survival (OS) in a Swedish metastatic renal cell carcinoma (mRCC) nationwide cohort who received second-line axitinib. Methods: Retrospective analysis of 110 patients with mRCC treated with second-line axitinib in Sweden (2012-2019). Patients included in the study received axitinib after mainly first-line sunitinib or pazopanib. Results: The median (95% CI) TTD of patients who received second-line axitinib was 5.2 (3.7-6.1) months with 6 (5.5%) patients still receiving treatment at the time of analysis. Median (95% CI) OS was 12.2 (7.7-14.2) months. Conclusion: The results are consistent with previous findings in mRCC and add to the evidence demonstrating efficacy of second-line axitinib, after failure of a prior anti-angiogenic therapy in a real-world setting. Clinical Trial Registration: NCT04669366 (ClinicalTrials.gov).

Background: Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation., Objectives: The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population., Methods: We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure., Results: Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 × 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 × 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0.994), which was statistically different from the observational estimate (p = 1.6 × 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD., Conclusions: Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cystatin C is associated with both renal function and atherosclerotic cardiovascular disease (ASCVD). We have previously shown a genetic correlation between cystatin C and prevalent ASCVD. The objective of this article is to study whether variation in cystatin C or creatinine predicts incident ASCVD when controlled for genetic factors., Methods and Results: The predictive value of cystatin C and creatinine for incident ASCVD was studied in 11 402 Swedish twins, free of CVD at baseline, in an adjusted Cox-regression model during a median follow-up of 71 months. Twin pairs discordant for incident stroke, myocardial infarction and ASCVD during follow-up were identified and within-pair comparisons regarding cystatin C and creatinine levels were performed. We also investigated whether contact frequency and degree of shared environment influences were associated with similarity in cystatin C levels. In univariate analysis, cystatin C predicted incident ASCVD hazard ratio 1.57, 95% CI 1.47-1.67. When adjusted for traditional Framingham risk factors as covariates, cystatin C remained a predictor of incident stroke hazard ratio 1.45, 95% CI (1.25-1.70), ASCVD hazard ratio 1.26, 95% CI (1.13-1.41), and myocardial infarction hazard ratio 1.16, 95% CI (1.01-1.33). In twins discordant for incident stroke, cystatin C at baseline was higher in the twin who experienced a stroke compared to the healthy co-twin (1.11±0.3 mg/L versus 1.06±0.3 mg/L), whereas creatinine was lower in the twin who developed CVD compared to their healthy co-twins (76.1±16.9 μmol/L versus 79.4±20.3 μmol/L)., Conclusions: Variation in cystatin C relates to incident ASCVD and to stroke when adjusted for genetic confounding. In identical twins, cystatin C may be a sensitive marker of early hypertensive end-organ damage and small-vessel disease, whereas creatinine level may reflect nutritional status. The findings in disease-discordant monozygotic twins indicate that unique, possibly preventable, environmental factors are important., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

In order to further illuminate the potential role of dominant genetic variation in the "missing heritability" debate, we investigated the additive (narrow-sense heritability, h(2)) and dominant (δ(2)) genetic variance for 18 human complex traits. Within the same study base (10,682 Swedish twins), we calculated and compared the estimates from classic twin-based structural equation model with SNP-based genomic-relatedness-matrix restricted maximum likelihood [GREML(d)] method. Contributions of δ(2) were evident for 14 traits in twin models (average δ(2)twin = 0.25, range 0.14-0.49), two of which also displayed significant δ(2) in the GREMLd analyses (triglycerides δ(2)SNP = 0.28 and waist circumference δ(2)SNP = 0.19). On average, the proportion of h(2)SNP/h(2)twin was 70% for ADE-fitted traits (for which the best-fitting model included additive and dominant genetic and unique environmental components) and 31% for AE-fitted traits (for which the best-fitting model included additive genetic and unique environmental components). Independent evidence for contribution from shared environment, also in ADE-fitted traits, was obtained from self-reported within-pair contact frequency and age at separation. We conclude that despite the fact that additive genetics appear to constitute the bulk of genetic influences for most complex traits, dominant genetic variation might often be masked by shared environment in twin and family studies and might therefore have a more prominent role than what family-based estimates often suggest. The risk of erroneously attributing all inherited genetic influences (additive and dominant) to the h(2) in too-small twin studies might also lead to exaggerated "missing heritability" (the proportion of h(2) that remains unexplained by SNPs)., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Decreased renal function is an established risk factor for cardiovascular disease (CVD). Causal mechanisms between estimates of renal function and CVD are intricate and investigation of the relative importance of genetic and environmental factors for the variability of these phenotypes could provide new knowledge., Methods and Results: Cystatin C and creatinine levels in 12 313 twins were analyzed. Uni- and bivariate heritability for these traits and CVD was estimated through structured equation modelling and genome-wide complex trait analysis (GCTA) in order to independently confirm additive genetic effects. Twin model-estimated heritability of Cystatin C was 0.55 (95% confidence interval [CI], 0.49 to 0.60) in men, 0.63 (0.59 to 0.66) in women, and 0.60 (0.56 to 0.63) in both sexes combined. For creatinine, heritability estimates were in the same range. Heritability of CVD was 0.39 (0.02 to 0.67) in men and 0.20 (0.00 to 0.61) in women. The phenotypic correlation between Cystatin C and CVD correlation was 0.16 (0.12 to 0.20) in men and 0.17 (0.13 to 0.21) in women, whereas the genetic correlation in males was 0.41 (0.21 to 0.62) while it was non-significant in females. Trough GCTA, the heritability of Cystatin C and creatinine in both sexes combined was estimated to 0.40 (SE 0.07, P=8E(-9)) and 0.19 (SE 0.07, P=0.003), respectively., Conclusions: Twin model-based heritability of Cystatin C was higher compared to previous studies. Co-variation between Cystatin C and CVD in males was partly explained by additive genetic components, indicating that Cystatin C and CVD share genetic influences. The GCTA provided independent evidence for significant contribution of additive genetics to trait variance of Cystatin C., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Patients with peripheral arterial disease (PAD) are at high risk for cardiovascular (CV) events. We have previously shown that ambulatory pulse pressure (APP) predicts CV events in PAD patients. The biomarkers amino-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP), and cystatin C are related to a worse outcome in patients with CV disease, but their predictive values have not been studied in relation to APP., Methods: Blood samples and 24-hour measurements of ambulatory blood pressure were examined in 98 men referred for PAD evaluation during 1998-2001. Patients were followed for a median of 71 months. The outcome variable was CV events defined as either CV mortality or any hospitalization for myocardial infarction, stroke, or coronary revascularization. The predictive values of log(NT-proBNP), log(hs-CRP), and log(cystatin C) alone and together with APP were assessed by multivariable Cox regression. Area under the curve (AUC) and net reclassification improvement (NRI) were calculated compared with a model containing other significant risk factors., Results: During follow-up, 36 patients had at least 1 CV event. APP, log(NT-proBNP), and log(hs-CRP) all predicted CV events in univariable analysis, whereas log(cystatin C) did not. In multivariable analysis log(NT-proBNP) (hazard ratio (HR) = 1.62; 95% confidence interval (CI) = 1.05-2.51) and log(hs-CRP) (HR = 1.63; 95% CI = 1.19-2.24) predicted events independently of 24-hour PP. The combination of log(NT-proBNP), log(hs-CRP), and average day PP improved risk discrimination (AUC = 0.833 vs. 0.736; P < 0.05) and NRI (37%; P < 0.01) when added to other significant risk factors., Conclusions: NT-proBNP and hs-CRP predict CV events independently of APP and the combination of hs-CRP, NT-proBNP, and day PP improves risk discrimination in PAD patients.