To Örebro University

PURPOSE: Preoperative chemotherapy is underused in conjunction with radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) due to concerns for complications and delay of surgery. Prospective data on short-term complications from population-based settings with frequent use of preoperative chemotherapy and standardised reporting of complications is lacking.

METHODS: We identified 1,340 patients who underwent RC between 2011 and 2015 in Sweden due to MIBC according to the Swedish Cystectomy Register. These individuals were followed through linkages to several national registers. Propensity score adjusted logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for complications and death within 90 days of surgery, comparing patients receiving preoperative chemotherapy or not.

RESULTS: Minimum two cycles of preoperative chemotherapy were given to 519 (39%) of the patients, who on average tended to be younger, have higher education, better physical status, and more advanced bladder cancer than patients not receiving chemotherapy. After adjusting for these and other parameters, there was no association between treatment with preoperative chemotherapy and short-term complications (OR 1.06 95% CI 0.82-1.39) or mortality (OR 0.75 95% CI 0.36-1.55). We observed a risk reduction for gastrointestinal complications among patients who received preoperative chemotherapy compared with those who did not (OR 0.49 95% CI 0.30-0.81).

CONCLUSION: This nation-wide population-based observational study does not suggest that preoperative chemotherapy, in a setting with high utilisation of such treatment, is associated with an increased risk of short-term complications in MIBC patients treated with radical cystectomy.

OBJECTIVE: To evaluate whether pregnancy is associated with increased risk for small bowel obstruction after laparoscopic gastric bypass surgery.

BACKGROUND: Small bowel obstruction is a common and feared long-term complication to laparoscopic gastric bypass surgery that may be more common during pregnancy. It is unclear if the risk truly increases during pregnancy.

METHODS: Women, 18 to 55 years, operated with a primary laparoscopic gastric bypass procedure from 2010 until 2015 were identified through the Scandinavian Obesity Surgery Registry (n = 25,853). Through record-linkage to the Medical Birth Registry, the National Patient Registry, and review of hospital charts, information on pregnancy periods and outcome were obtained. The main outcome was operation due to small bowel obstruction after the laparoscopic gastric bypass procedure.

RESULTS: Pregnancy was associated with increased risk for small bowel obstruction following laparoscopic gastric bypass surgery (incidence rates 46.5, 95% CI 38.0-56.9/1000 person-years, vs 20.9 95% CI 19.9-22.0; adjusted-HR 1.72, 95% CI 1.39-2.12, P < 0.001). While no excess risk was observed during the first trimester, the second (adjusted-HR 1.67, 95% CI 1.17-2.39, P = 0.005) and third (adjusted-HR 2.69, 95% CI 2.02-3.59, P < 0.001) conferred increased risk. The incidence rate of small bowel obstruction during pregnancy was 42.9 (95% CI 32.4-57.0/1000 person-years) among women for whom the mesenteric defects had been closed during the primary procedure, and 53.2 (95% CI 38.9-72.8/1000 person-years) for women in whom they had been left open.

CONCLUSION: Pregnancy is associated with increased risk for small bowel obstruction after laparoscopic gastric bypass surgery during the second and third trimesters.

BACKGROUND: While compromised stress resilience constitutes a recognised risk factor for somatic and psychiatric disease development in general, the knowledge about how individual variation in vulnerability to stress may specifically influence the long-term risks of disadvantageous health behaviours is limited.

METHODS: In this Swedish cohort study, we aimed to investigate the association between stress resilience in late adolescence and adult use of addictive substances. We included 9381 men with information on psychological stress resilience measured during military conscription examinations, who later responded to an extensive health survey (mean age 34.0±7.2 years) including detailed information on substance use. We modelled continuous outcomes using linear regression, binary outcomes with logistic regression and other categorical outcomes with multinomial logistic regression.

RESULTS: We found that low stress resilience in adolescence conferred increased risks of all studied measures of addictive behaviour. After adjusting for childhood socioeconomic information, low stress resilience was associated with adult current regular smoking (relative risk ratio: 5.85, 95% CI 4.32 to 7.93), higher nicotine dependence scores (beta: 0.76, 95% CI 0.29 to 1.23), hazardous use of alcohol (>14 alcoholic drink-equivalents per week, OR: 1.72, 95% CI 1.37 to 2.16), DSM-IV criteria for alcohol dependence (OR: 1.74, 95% CI 1.35 to 2.25), and drug use (OR: 1.77, 95% CI 1.51 to 2.08). The results remained largely unchanged after further adjustments for adult educational attainment and occupation as well as for additional conscription covariates.

CONCLUSION: Low stress resilience in late adolescence appears to be associated with an increased risk of disadvantageous and addictive health behaviours in adulthood.

PURPOSE: Although childhood traumatic experiences are recognized as important determinants for adolescent psychiatric health in general, our objective was to explore the specific influence of childhood bereavement on the stress resilience development trajectory.

METHODS: In this national register-based cohort study, we identified 407,639 men born in Sweden between 1973 and 1983, who underwent compulsory military enlistment examinations in late adolescence, including measures of psychological stress resilience. We defined exposure as loss of a first-degree family member in childhood, and estimated relative risk ratios (RRRs) for reduced (moderate or low), compared with high, stress resilience with 95% confidence intervals (CIs) using multinomial logistic regression.

RESULTS: Loss of a parent or sibling in childhood conferred a 49% increased risk of subsequent low stress resilience (RRR, 1.49, 95% CI, 1.41-1.57) and an 8% increased risk of moderate stress resilience (RRR, 1.08, 95% CI, 1.03-1.13) in late adolescence. There was also a graded increase in risk with increasing age at loss; teenagers were at higher risk for low resilience (RRR, 1.64, 95% CI, 1.52-1.77) than children aged 7-12 (RRR, 1.47, 95% CI, 1.34-1.61) and ≤6 years (RRR, 1.16 95% CI, 1.02-1.32). The excess risk was observed for all causes of death, including suicide and unexpected deaths as well as deaths due to other illnesses. The associations remained after exclusion of parents with a history of hospitalization for psychiatric diagnoses.

CONCLUSIONS: The long-term consequences of childhood bereavement may include lower stress resilience in late adolescence.

Early life stress has a major influence on one’s health through the life course. During childhood, early experience may not only affect the normal brain development, but also influence the susceptibility to mental and physical disorders. A cancer diagnosis in a parent may cause substantial distress in the children, who may have to confront and adapt to short- and long-term changes in their lives and subsequently experience a higher risk of physical and psychosocial problems. Therefore, the first aim of this thesis was to examine whether parental cancer is associated with physical and mental health problems in the affected children using data from the Swedish national registers. Further, to explore the potential mechanism determining the impact of stress on children’ health, we focused on the brain development in childhood and investigated the association between stress biomarkers and brain morphology, using data from a Dutch population-based cohort.

In Study I, we assessed the association between parental cancer and risk of injury in a large representative sample of Swedish children. We found that parental cancer was associated with a higher risk of hospital contacts for injury, particularly during the first year after the cancer diagnosis and when the parent experienced a psychiatric illness after the cancer diagnosis. The risk increment reduced during the second and third years and became null afterwards.

Given the observed higher risk of adverse physical health in terms of injury, we further investigated the influence of parental cancer on adverse mental health in terms of psychiatric disorders among children. In Study II, we constructed a matched cohort, and separately examined the associations between parental cancer diagnosed during pregnancy or after birth and clinical diagnoses of psychiatric disorders or use of prescribed psychiatric medications. Paternal but not maternal cancer during pregnancy appeared to be associated with a higher risk of psychiatric disorders, primary among girls. Parental cancer after birth conferred a higher risk of clinical diagnoses of psychiatric disorders, particularly stress reaction and adjustment disorders. The affected children also experienced a higher risk of use of prescribed psychiatric medications, particularly anxiolytics. The latter associations were most pronounced for parental cancer with poor expected survival and for parental death after cancer diagnosis.

In Study III, we focused on other domains of mental and physical health affected by parental cancer. We examined the associations of parental cancer with intellectual performance, stress resilience, and physical fitness among boys that underwent the compulsory military conscription examination during early adulthood. We observed positive associations of parental cancer with low stress resilience and low physical fitness, with stronger associations noted for parental cancer with poor expected survival and for a loss of parent through death after cancer diagnosis. No overall association was observed between parental cancer and intellectual performance, but the parental cancer with poor expected survival or resulting in a death of the parent was associated with a higher risk of low intellectual performance.

Little is known about the relationship between the long-term hypothalamic-pituitary-adrenal (HPA) axis functioning and brain structure in children. Glucocorticoid in hair has emerged as an important biomarker of HPA activity. In this study, we investigated the associations of hair cortisol and cortisone concentrations with brain morphology in young children. We included 219 children aged 6-10 years from the Generation R Study in Rotterdam, the Netherlands. We examined cortisol and cortisone concentrations by hair analysis using liquid chromatography-tandem mass spectrometry, and assessed brain morphometric measures with structural magnetic resonance imaging. The relationships of hair cortisol and cortisone concentrations with brain volumetrics, cortical thickness, cortical surface area and gyrification were analyzed separately after adjustment for several potential confounding factors. We observed a positive association between cortisol concentrations and cortical surface area in the parietal lobe, positive associations of cortisone concentrations with thalamus volume, occipital lobe volume and cortical surface area in the parietal lobe, and a negative association between cortisone concentrations and cortical surface area in the temporal lobe in the regions of interest analyses. A negative association between cortisol or cortisone concentrations and hippocampal volume was observed in children with behavioral problems. The whole brain vertex-wise analyses did however not show any association between cortisol or cortisone concentration and brain morphometric measures after correction for multiple testing. Although some associations are noted in region of interest analyses, we do not observe clear association of hair cortisol or cortisone with brain morphometric measures in typically developing young children.