Erratum to: PD-1, PD-L1, PD-L2 expression in the chordoma microenvironment

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The association between attention-deficit/hyperactivity (ADHD) symptoms and self-employment

Abstract

Attention-deficit/hyperactivity (ADHD) symptoms have been associated with the decision to become self-employed. Although these symptoms are generally regarded as disadvantageous, there may also be a bright side. To our knowledge, however, there has been no systematic, epidemiological evidence to support this claim. This paper examines the association between ADHD symptoms and self-employment in a population-based sample from the STAGE cohort of the Swedish Twin Registry (N = 7208). For replication, we used a sample of Dutch students who participated in the Global University Entrepreneurial Spirit Students' Survey (N = 13,112). In the Swedish sample, we found a positive association with self-employment for both general ADHD symptoms [odds ratio (OR) 1.13; 95 % confidence intervals (CI) 1.04–1.23] and hyperactivity symptoms [OR 1.19; 95 % CI 1.08–1.32], whereas no association was found for attention-deficit symptoms [OR 0.99; 95 % CI 0.89–1.10]. The positive association between hyperactivity and self-employment was replicated in the Dutch student sample [OR 1.09; 95 % CI 1.03–1.15]. Our results show that certain aspects of ADHD, in particular hyperactivity, can have a bright side, as they are positively associated with self-employment.

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Disability and all-cause mortality in the older population: evidence from the English Longitudinal Study of Ageing

Abstract

Despite the vast body of literature studying disability and mortality, evidence to support their association is scarce. This work investigates the role of disability in explaining all‐cause mortality among individuals aged 50+ who participated in the English Longitudinal Study of Aging. The aim is to explain the gender paradox in health and mortality by analysing whether the association of disability with mortality differs between women and men. Disability was conceived following the International Classification of Functioning, Disability and Health (ICF), proposed by the WHO, that conceptualizes disability as a combination of three components: impairment, activity limitation and participation restriction. Latent variable models were used to identify domain-specific factors and general disability. The association of the latter with mortality up to 10 years after enrolment was estimated using discrete-time survival analysis. Our work confirms the validity of the ICF framework and finds that disability is strongly associated with mortality, with a time-varying effect among men, and a smaller constant effect for women. Adjusting for demographic, socioeconomic and behavioural factors attenuated the association for both sexes, but overall the effects remained high and significant. These findings confirm the existence of gender paradox by showing that, when affected by disability, women survive longer than men, although if men survive the first years they appear to become more resilient to disability. Sensitivity analyses suggested that the gender paradox cannot be solely explained by gender-specific health conditions: there must be other mechanisms acting within the pathway between disability and mortality that need to be explored.

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Suicide in married couples in Sweden: Is the risk greater in same-sex couples?

Abstract

Minority sexual orientation is a predictor of suicide ideation and attempts, though its association with suicide mortality is less clear. We capitalize on Sweden's extensively linked databases, to investigate whether, among married individuals, same-sex marriage is associated with suicide. Using a population-based register design, we analyzed suicide risk among same-sex married women and men (n = 6456), as compared to different-sex married women and men (n = 1181723) in Sweden. We selected all newly partnered or married individuals in the intervening time between 1/1/1996 and 12/31/2009 and followed them with regard to suicide until 12/31/2011. Multivariate Poisson regression was used to calculate adjusted incidence risk ratios (IRR) with 95 % confidence intervals (CI). The risk of suicide was higher among same-sex married individuals as compared to different-sex married individuals (IRR 2.7, 95 % CI 1.5–4.8), after adjustment for time at risk and socioeconomic confounding. Sex-stratified analyses showed a tentatively elevated risk for same-sex married women (IRR 2.5, 95 % CI 0.8–7.7) as compared to different-sex married women. Among same-sex married men the suicide risk was nearly three-fold greater as compared to different-sex married (IRR 2.895 % CI 1.5–5.5). This holds true also after adjustment for HIV status. Even in a country with a comparatively tolerant climate regarding homosexuality such as Sweden, same-sex married individuals evidence a higher risk for suicide than other married individuals.

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How much do tumor stage and treatment explain socioeconomic inequalities in breast cancer survival? Applying causal mediation analysis to population-based data

Abstract

Substantial socioeconomic inequalities in breast cancer survival persist in England, possibly due to more advanced cancer at diagnosis and differential access to treatment. We aim to disentangle the contributions of differential stage at diagnosis and differential treatment to the socioeconomic inequalities in cancer survival. Information on 36,793 women diagnosed with breast cancer during 2000–2007 was routinely collected by an English population-based cancer registry. Deprivation was determined for each patient according to her area of residence at the time of diagnosis. A parametric implementation of the mediation formula using Monte Carlo simulation was used to estimate the proportion of the effect of deprivation on survival mediated by stage and by treatment. One-third (35 % [23–48 %]) of the higher mortality experienced by most deprived patients at 6 months after diagnosis, and one tenth (14 % [−3 to 31 %]) at 5 years, was mediated by adverse stage distribution. We initially found no evidence of mediation via differential surgical treatment. However, sensitivity analyses testing some of our study limitations showed in particular that up to thirty per cent of the higher mortality in most deprived patients could be mediated by differential surgical treatment. This study illustrates the importance of using causal inference methods with routine medical data and the need for testing key assumptions through sensitivity analyses. Our results suggest that, although effort for earlier diagnosis is important, this would reduce the cancer survival inequalities only by a third. Because of data limitations, role of differential surgical treatment may have been under-estimated.

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Phase I safety and pharmacokinetic dose-escalation study of pilaralisib polymorph E, a phosphoinositide 3-kinase inhibitor in tablet formulation, in patients with solid tumors or lymphoma

Abstract

Purpose

Pilaralisib (SAR245408), a pan-class I PI3K inhibitor, has been investigated in Phase I/II trials in several solid tumors and lymphomas in capsule and tablet formulations of polymorph A (capsule-A and tablet-A). This Phase I study was conducted to determine the recommended Phase II dose (RP2D) of a more thermodynamically stable form of pilaralisib (polymorph E), in tablet formulation (tablet-E), in patients with advanced solid tumors or relapsed/refractory lymphoma.

Methods

A modified '3 + 3' dose-escalation design was employed. Patients received pilaralisib once daily (QD; starting dose 400 mg) for two 28-day cycles. Primary endpoints were safety and pharmacokinetics (PK). Exploratory endpoints were pharmacodynamics and efficacy.

Results

Eighteen patients were enrolled: Six patients received pilaralisib 400 mg QD and 12 patients received pilaralisib 600 mg QD. Two patients in the 600 mg QD cohort had dose-limiting toxicities (DLTs) (one patient with Grade 3 maculopapular rash and one patient with Grade 3 generalized rash and Grade 4 lipase increased). The most frequently occurring treatment-related, treatment-emergent adverse events were decreased appetite (22 %), dry skin (22 %), nausea (22 %) and vomiting (22 %). In PK analyses, individual exposures observed with 600 mg tablet-E were within the range of data at steady state from previous studies of 400 mg tablet-A and 600 mg capsule-A. Five patients (28 %) had stable disease as best response.

Conclusions

With pilaralisib tablet-E, the RP2D was 600 mg QD, drug exposure was similar to the 400 mg tablet-A and 600 mg capsule-A formulations, and safety was consistent with the known safety profile of pilaralisib.

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Everolimus pharmacokinetics and its exposure–toxicity relationship in patients with thyroid cancer

Abstract

Background

Everolimus is a mTOR inhibitor used for the treatment of different solid malignancies. Many patients treated with the registered fixed 10 mg dose once daily are in need of dose interruptions, reductions or treatment discontinuation due to severe adverse events. This study determined the correlation between systemic everolimus exposure and toxicity. Additionally, the effect of different covariates on everolimus pharmacokinetics (PK) was explored.

Methods

Forty-two patients with advanced thyroid carcinoma were treated with 10 mg everolimus once daily. Serial pharmacokinetic sampling was performed on days 1 and 15. Subsequently, a population PK model was developed using NONMEM to estimate individual PK values used for analysis of an exposure–toxicity relationship. Furthermore, this model was used to investigate the influence of patient characteristics and genetic polymorphisms in genes coding for enzymes relevant in everolimus PK.

Results

Patients who required a dose reduction (n = 18) due to toxicity at any time during treatment had significant higher everolimus exposures [mean AUC_0–24 (SD) 600 (274) vs. 395 (129) µg h/L, P = 0.008] than patients without a dose reduction (n = 22). A significant association between everolimus exposure and stomatitis was found in the four-level ordered logistic regression analysis (P = 0.047). The presence of at least one TTT haplotype in the ABCB1 gene was associated with a 21 % decrease in everolimus exposure.

Conclusion

The current study showed that dose reductions and everolimus-induced stomatitis were strongly associated with systemic everolimus drug exposure in patients with cancer. Our findings confirm observations from another study in patients with cancer and show us that everolimus is a good candidate for individualized dosing in patients with cancer.

ClinicalTrial.gov number

NCT01118065.

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