Purpose: Buprenorphine transdermal system is increasingly prescribed in people with advanced dementia, but no clinical trial has investigated the safety and factors associated with discontinuation due to adverse events in this population. Patients and methods: One hundred sixty-two people with advanced dementia and significant depression from 47 nursing homes were included and randomized to active analgesic treatment (acetaminophen/buprenorphine) or identical placebo for 13 weeks. In this secondary analysis, the main outcomes were time to and reasons for discontinuation of buprenorphine due to adverse events. Change in daytime activity as measured by actigraphy was a secondary outcome. Results: Of the 44 patients who received active buprenorphine 5 μg/hour, 52.3% (n=23) discontinued treatment due to adverse events compared to 13.3% (6 of 45) in the placebo group (p<0.001). Psychiatric and neurological adverse events were the most frequently reported causes of discontinuation (69.6%, n=16). Concomitant use of antidepressants significantly increased the risk of discontinuation (HR 23.2, 95% CI: 2.95–182, p=0.003). Adjusted for age, sex, cognitive function, pain and depression at baseline, active buprenorphine was associated with 24.0 times increased risk of discontinuation (Cox model, 95% CI: 2.45–235, p=0.006). Daytime activity dropped significantly during the second day of active treatment (-21.4%, p=0.005) and decreased by 12.9% during the first week (p=0.053). Conclusion: Active buprenorphine had significantly higher risk of discontinuation compared with placebo in people with advanced dementia and depression, mainly due to psychiatric and neurological adverse events. Daytime activity dropped significantly during the first week of treatment. Concomitant use of antidepressants further reduced the tolerability of buprenorphine.

Objective To examine associations between birth defects and cancer from birth into adulthood. Design Population based nested case-control study. Setting Nationwide health registries in Denmark, Finland, Norway, and Sweden. Participants 62 295 cancer cases (0-46 years) and 724 542 frequency matched controls (matched on country and birth year), born between 1967 and 2014. Main outcome measures Relative risk of cancer in relation to major birth defects, estimated as odds ratios with 99% confidence intervals from logistic regression models. Results Altogether, 3.5% (2160/62 295) of cases and 2.2% (15 826/724 542) of controls were born with major birth defects. The odds ratio of cancer for people with major birth defects compared with those without was 1.74 (99% confidence interval 1.63 to 1.84). For individuals with non-chromosomal birth defects, the odds ratio of cancer was 1.54 (1.44 to 1.64); for those with chromosomal anomalies, the odds ratio was 5.53 (4.67 to 6.54). Many structural birth defects were associated with later cancer in the same organ system or anatomical location, such as defects of the eye, nervous system, and urinary organs. The odds ratio of cancer increased with number of defects and decreased with age, for both non-chromosomal and chromosomal anomalies. The odds ratio of cancer in people with any non-chromosomal birth defect was lower in adults (≥20 years: 1.21, 1.09 to 1.33) than in adolescents (15-19 years: 1.58, 1.31 to 1.90) and children (0-14 years: 2.03, 1.85 to 2.23). The relative overall cancer risk among adults with chromosomal anomalies was markedly reduced from 11.3 (9.35 to 13.8) in children to 1.50 (1.01 to 2.24). Among adults, skeletal dysplasia (odds ratio 3.54, 1.54 to 8.15), nervous system defects (1.76, 1.16 to 2.65), chromosomal anomalies (1.50, 1.01 to 2.24), genital organs defects (1.43, 1.14 to 1.78), and congenital heart defects (1.28, 1.02 to 1.59) were associated with overall cancer risk. Conclusions The increased risk of cancer in individuals with birth defects persisted into adulthood, both for non-chromosomal and chromosomal anomalies. Further studies on the molecular mechanisms involved are warranted.

Background: Accurate information on childhood cancer survival is essential for improving health systems. Survival is believed to be low in low-resource countries, but population-based survival estimates are scant. We aim to provide reliable and comparable survival estimates in these settings. Methods: We included 16 821 patients from 47 population-based cancer registries in 23 countries in Africa, Latin America and the Caribbean, and Asia. We used the Cancer Survival in Countries in Transition project data (children aged younger than 15 years, diagnosed 2008-2012, followed until 2014) and data from Rwanda (2013-2017, followed until 2022). We estimated 1-year, 3-year, and 5-year observed survival using the Kaplan–Meier method, by diagnostic group, country, region, Human Development Index, income, and sex. Results: Survival was higher in registries included from the Caribbean (namely, Puerto Rico [United States], Martinique [France]) and Central America (Costa Rica), Asia, and the Middle East and North Africa compared with those included from South America and sub-Saharan Africa. Survival correlated with the Human Development Index. For leukemia, 3-year survival varied from 30.4% (95% confidence interval [CI] = 12.4% to 50.6%) in Kenya to 89.5% (95% CI = 83.8% to 93.2%) in Puerto Rico; for central nervous system tumors from 32.0% (95% CI = 13.9% to 51.8%) in Algeria to 79.3% (95% CI = 69.1% to 86.5%) in Puerto Rico. The findings should be interpreted with care, as registry coverage varies and may not reflect national and regional survival. Conclusion: The variability of the population-based survival estimates across predominantly low- and middle-income countries highlights gaps in cancer registration, access to care, and quality of care. This study provides benchmark data for the World Health Organization Global Initiative for Childhood Cancer generated by population-based cancer registries, which should be supported in all countries.

Childhood cancer is more common among children with birth defects, suggesting a common aetiology. Whether this association differs by sex is unclear. We performed a population-based nested case-control study using nationwide health registries in four Nordic countries. We included 21 898 cancer cases (0–19 years) and 218 980 matched population controls, born 1967–2014. Associations between childhood cancer and major birth defects were calculated as odds ratios (ORs) with 95% confidence intervals (CIs) using logistic regression models. Effect modification was evaluated using a counterfactual framework to estimate confidence intervals and P-values for the natural indirect effects. Birth defects were present for 5.1% (1117/21 898) of childhood cancer cases and 2.2% (4873/218 980) of controls; OR of cancer was higher for chromosomal (OR = 10, 95% CI = 8.6–12) than for non-chromosomal defects (OR = 1.9, 95% CI = 1.8–2.1), strongest between genetic syndromes/microdeletion and renal tumours, Down syndrome and leukaemia, and nervous system defects and central nervous system tumours. The association between birth defects and cancer was stronger among females (OR = 2.8, 95% CI = 2.6–3.1) than males (OR = 2.1, 95% CI = 1.9–2.2, P_interaction <0.001). Male sex was an independent risk factor for childhood cancer, but very little of the overall association between sex and childhood cancer was mediated through birth defects (4.8%, P_NIE <0.001), although more at younger ages (10% below years and 28% below 1 year). The birth defect–cancer associations were generally stronger among females than males. Birth defects did not act as a strong mediator for the modest differences in childhood cancer risk by sex, suggesting that other biological pathways are involved.

Individuals with major birth defects are at increased risk of developing cancer, indicating a common aetiology. However, whether the siblings of individuals with birth defects are also at an increased risk of cancer is unclear. We used nationwide health registries in four Nordic countries and conducted a nested case-control study. We included 40 538 cancer cases (aged 0–46 years) and 481 945 population controls (matched by birth year and country), born between 1967 and 2014. The relative risk of cancer among individuals whose siblings had birth defects was computed with odds ratios (OR) and 95% confidence intervals (CIs), using logistic regression models. In the total study population (aged 0–46 years), we observed no overall difference in cancer risk between individuals whose siblings had birth defects and those who had unaffected siblings (OR 1.02; 95% CI 0.97–1.08); however, the risk of lymphoid and haematopoietic malignancies was elevated (1.16; 1.05–1.28). The overall risk of childhood cancer (0–19 years) was increased for siblings of individuals who had birth defects (1.09; 1.00–1.19), which was mainly driven by lymphoma (1.35; 1.09–1.66), neuroblastoma (1.51; 1.11–2.05) and renal carcinoma (5.03; 1.73–14.6). The risk of cancer also increased with the number of siblings with birth defects (P_trend = 0.008). Overall risk of cancer among individuals (aged 0–46 years) whose siblings had birth defects was not elevated, but the risk of childhood cancer (ages 0–19 years) was increased. Our novel findings are consistent with the common aetiologies of birth defects and cancer, such as shared genetic predisposition and environmental factors.