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Background and Objective: Thioguanine (TG), azathioprine (AZA), and mercaptopurine (MP) are thiopurine prodrugs commonly used to treat diseases, such as leukemia and inflammatory bowel disease (IBD). 6-thioguanine nucleotides (6-TGNs) have been commonly used for monitoring treatment. High levels of 6-TGNs in red blood cells (RBCs) have been associated with leukopenia, the cutoff levels that predict this side effect remain uncertain. Thiopurines are metabolized and incorporated into leukocyte DNA. Measuring levels of DNA-incorporated thioguanine (DNA-TG) may be a more suitable method for predicting clinical response and toxicities such as leukopenia. Unfortunately, most methodologies to assay 6-TGNs are unable to identify the impact of NUDT15 variants, effecting mostly ethnic populations (e.g., Chinese, Indian, Malay, Japanese, and Hispanics). DNA-TG tackles this problem by directly measuring thioguanine in the DNA, which can be influenced by both TPMT and NUDT15 variants. While RBC 6-TGN concentrations have traditionally been used to optimize thiopurine therapy due to their ease and affordability of measurement, recent developments in liquid chromatography–tandem mass spectrometry (LC–MS/MS) techniques have made measuring DNA-TG concentrations in lymphocytes accurate, reproducible, and affordable. The objective of this systematic review was to assess the current evidence of DNA-TG levels as marker for thiopurine therapy, especially with regards to NUDT15 variants. Methods: A systematic review and meta-analysis were performed on the current evidence for DNA-TG as a marker for monitoring thiopurine therapy, including methods for measurement and the illustrative relationship between DNA-TG and various gene variants (such as TPMT, NUDT15, ITPA, NT5C2, and MRP4). PubMed and Embase were systematically searched up to April 2024 for published studies, using the keyword "DNA-TG" with MeSH terms and synonyms. The electronic search strategy was augmented by a manual examination of references cited in articles, recent reviews, editorials, and meta-analyses. A meta-analysis was performed using R studio 4.1.3. to investigate the difference between the coefficients (Fisher's z-transformed correlation coefficient) of DNA-TG and 6-TGNs levels. A meta-analysis was performed using RevMan version 5.4 to investigate the difference in DNA-TG levels between patients with or without leukopenia using randomized effect size model. The risk of bias was assessed using the Newcastle–Ottowa quality assessment scale. Results: In this systematic review, 21 studies were included that measured DNA-TG levels in white blood cells for either patients with ALL (n = 16) or IBD (n = 5). In our meta-analysis, the overall mean difference between patients with leukopenia (ALL + IBD) versus no leukopenia was 134.15 fmol TG/µg DNA [95% confidence interval (CI) (83.78–184.35), P < 0.00001; heterogeneity chi squared of 5.62, I2 of 47%]. There was a significant difference in DNA-TG levels for patients with IBD with and without leukopenia [161.76 fmol TG/µg DNA; 95% CI (126.23–197.29), P < 0.00001; heterogeneity chi squared of 0.20, I2 of 0%]. No significant difference was found in DNA-TG level between patients with ALL with or without leukopenia (57.71 fmol TG/µg DNA [95% CI (− 22.93 to 138.35), P < 0.80]). DNA-TG monitoring was found to be a promising method for predicting relapse rates in patients with ALL, and DNA-TG levels are likely a better predictor for leukopenia in patients with IBD than RBC 6-TGNs levels. DNA-TG levels have been shown to correlate with various gene variants (TPMT, NUDT15, ITPA, and MRP4) in various studies, points to its potential as a more informative marker for guiding thiopurine therapy across diverse genetic backgrounds. Conclusions: This systematic review strongly supports the further investigation of DNA-TG as a marker for monitoring thiopurine therapy. Its correlation with treatment outcomes, such as relapse-free survival in ALL and the risk of leukopenia in IBD, underscores its role in enhancing personalized treatment approaches. DNA-TG effectively identifies NUDT15 variants and predicts late leukopenia in patients with IBD, regardless of their NUDT15 variant status. The recommended threshold for late leukopenia prediction in patients with IBD with DNA-TG is suggested to be between 320 and 340 fmol/µg DNA. More clinical research on DNA-TG implementation is mandatory to improve patient care and to improve inclusivity in thiopurine treatment. [ABSTRACT FROM AUTHOR]

Introduction: Despite treatment with antiemetic medications, nausea remains uncontrolled for many children receiving chemotherapy. One reason is that risk factors for nausea in children remain poorly explored. The purpose of this study was to identify risk factors for chemotherapy-induced nausea (CIN) in children. Methods: Prospective, observational study including 101 children (median age 6.4 years, range 0.8–17.9) with cancer receiving moderately or highly emetogenic chemotherapy. Primary endpoints were complete control of acute and delayed CIN, defined as no nausea in the acute phase 0–24 h after chemotherapy and in the delayed phase starting after the acute phase and ending 5 days later. Multivariable analyses included age, sex, cancer type, susceptibility to motion sickness, chemotherapy duration, numbers of antiemetics, co-administration with opioids or tricyclic antidepressants, and previously uncontrolled nausea or vomiting. Results: Acute CIN was associated with susceptibility to motion sickness (odds ratio [OR] 5.73, 95% confidence interval [CI] 1.36–33.7) and older age (OR 4.19, 95% CI 1.30–14.7), comparing age group 8–18 years with 0–3 years. Delayed CIN was associated with uncontrolled acute nausea or vomiting (OR 10.3, 95% CI 2.65–50.9), highly emetogenic chemotherapy (OR 8.26, 95% CI 1.17–76.8), and having a hematologic cancer type (OR 7.81, 95% CI 1.05–79.2). Conclusions: Susceptibility to motion sickness and age can influence the risk of acute CIN. More research is needed on how best to integrate risk information in preventive antiemetic strategies. Sufficient acute nausea and vomiting control are crucial to prevent delayed CIN. [ABSTRACT FROM AUTHOR]

Study Question: Is the rate of fatherhood among men diagnosed with cancer in childhood and early adulthood different from men without cancer, and, if so, have the differences changed over time?Summary Answer: Men diagnosed with cancer have had significantly reduced rates of fatherhood compared with undiagnosed men; however, the rates of fatherhood among the cancer survivors have increased markedly over time.What Is Known Already: The number of children and young adolescents who survive cancer has steadily increased over recent decades, with a current 5-year survival rate of approximately 80%. Consequently, life circumstances after cancer have gained increasing importance, including the desire among survivors to have children and a family. ARTs to aid reproduction among cancer survivors have been developed, and fertility preservation is increasingly a topic being discussed before undergoing cancer treatment. But the potential for fertility preservation differs dependent on age at diagnosis and type of cancer. Earlier studies have shown a decreased fertility rate among survivors of child and adolescent cancer compared to those diagnosed in early adulthood.Study Design, Size, Duration: This study is a national, register-based cohort study. Men diagnosed with cancer in childhood and early adulthood (<30 years of age) were registered in the Danish Cancer Register in 1978-2016 (n = 9353). According to the time of diagnosis, each cancer-diagnosed man was randomly matched with 150 undiagnosed men from the background population within the same birth year. The men were followed until having their first child, death, migration or the end of the study (31 December 2017) in medical registers and socio-demographic population registers.Participants/materials, Setting, Methods: Fatherhood among the boys and young men diagnosed with cancer were compared with the age-matched comparison group in all statistical analyses. Cancer diagnoses were categorised as central nervous system (CNS) cancers, haematological cancers or solid cancers. Analyses were stratified by age at diagnosis (0-9, 10-19, 20-29 years) and time of diagnosis (1978-1989, 1990-1999, 2000-2009, 2010-2016). Death was incorporated as a competing risk in all analyses.Main Results and the Role Of Chance: The study population consisted of 9353 boys and young men diagnosed with cancer between 1978 and 2016 and 1 386 493 men in the age-matched comparison group. Those surviving CNS cancer as young men had the lowest hazard ratio (HR) of fatherhood compared with the age-matched comparison group (HR 0.67, 95% CI 0.57-0.79), followed by survivors of haematological cancers (HR 0.90, 95% CI 0.81-1.01), while the highest chance of fatherhood was among survivors of solid cancers (HR 1.16, 95% CI 1.12-1.20) with a slightly increased HR compared with undiagnosed males. The HR of becoming a father increased over time. From the first decade to the last decade 30 years later, the HR of becoming a father increased for solid tumours (HR 0.78, 95% CI 0.73-0.83 to HR 1.08, 95% CI 0.95-1.22), haematological cancers (HR 0.64, 95% CI 0.53-0.79 to HR 0.97, 95% CI 0.73-1.30) and CNS cancers (HR 0.44, 95% CI 0.34-0.57 to HR 0.98, 95% CI 0.49-1.95) compared to the age-matched comparison group. Also, when compared with the age-matched comparison group, men diagnosed with cancer when aged 20-29 years were more likely became fathers over the time of the study (HR 0.80, 95% CI 0.74-0.86 to HR 1.08, 95% CI 0.96-1.22).Limitations, Reasons For Caution: The study was based on register data, and information was not available about the men's fertility potential, whether they had a desire to have children and whether it was possible for them to find a partner. Information about fertility preservation, e.g. sperm freezing, could also have provided additional insights. Furthermore, information about diagnosis and ART treatment would have been beneficial.Wider Implications Of the Findings: Information and education of male patients diagnosed with cancer about fertility preservation options and their chances to create their own family is crucial. Reassuringly, time trends showed more men with a previous cancer diagnosis becoming fathers in recent years than in earlier years, reflecting that survival and fertility preservation have improved over time.Study Funding/competing Interest(s): R.S. received a PhD grant from the Rosa Ebba Hansen Foundation and from the Health Foundation (J.nr. 15-B-0095). The funding for the establishment of the DANAC II Cohort was obtained from the Rosa Ebba Hansen Foundation. The authors have no conflicts of interest to declare.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Background: Infectious diseases and social contacts in early life have been proposed to modulate brain tumour risk during late childhood and adolescence.Methods: CEFALO is an interview-based case-control study in Denmark, Norway, Sweden and Switzerland, including children and adolescents aged 7-19 years with primary intracranial brain tumours diagnosed between 2004 and 2008 and matched population controls.Results: The study included 352 cases (participation rate: 83%) and 646 controls (71%). There was no association with various measures of social contacts: daycare attendance, number of childhours at daycare, attending baby groups, birth order or living with other children. Cases of glioma and embryonal tumours had more frequent sick days with infections in the first 6 years of life compared with controls. In 7-19 year olds with 4+ monthly sick day, the respective odds ratios were 2.93 (95% confidence interval: 1.57-5.50) and 4.21 (95% confidence interval: 1.24-14.30).Interpretation: There was little support for the hypothesis that social contacts influence childhood and adolescent brain tumour risk. The association between reported sick days due to infections and risk of glioma and embryonal tumour may reflect involvement of immune functions, recall bias or inverse causality and deserve further attention. [ABSTRACT FROM AUTHOR]

Childhood acute lymphoblastic leukaemia is treated with long-term intensive chemotherapy. During the latter part of the treatment, the maintenance therapy, the patients receive oral doses of two cytostatics. The doses are tailored to blood counts measured on a weekly basis, and the treatment is therefore highly dynamic. In 1992-1996, the Nordic Society of Paediatric Haematology and Oncology (NOPHO) conducted a randomised study (NOPHO-ALL-92) to investigate the effect of a new and more sophisticated dynamic treatment strategy. Unexpectedly, the new strategy worsened the outcome for the girls, whereas there were no treatment differences for the boys. There are as yet no general guidelines for optimising the treatment. On basis of the data from this study, our goal is to formulate an alternative dosing strategy. We use recently developed methods proposed by van der Laan et al. [1] to obtain statistical models that may be used in the guidance of how the physicians should assign the doses to the patients to obtain the target of the treatment. We present a possible strategy and discuss the reliability of this strategy. The implementation is complicated, and we touch upon the limitations of the methods in relation to the formulation of alternative dosing strategies for the maintenance therapy. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: An infective, mostly viral basis has been found in different human cancers. To test the hypothesis of a possible infectious aetiology for central nervous system (CNS) tumours in children, we investigated the associations with proxy measures of exposure to infectious disease.Methods: In a large case-control study nested in the populations of Denmark, Norway, Sweden, and Finland of 4.4 million children, we studied the association of birth order and seasonal variation of birth with subsequent risk for CNS tumours. We identified 3983 children from the national cancer registries, and information on exposure was obtained from the high-quality national administrative health registries. We investigated the association between childcare attendance during the first 2 years of life and the risk for CNS tumours in a subset of Danish children with CNS tumours, using information from the Danish Childcare database.Results: We observed no association between birth order and risk of CNS tumours overall (odds ratio (OR) for second born or later born vs first born, 1.03; 95% confidence interval (CI), 0.96-1.10) or by histological subgroup, and children with CNS tumours did not show a seasonal variation of birth that was distinct from that of the background population. Childcare attendance compared with homecare showed a slightly increased OR (1.29; 95% CI, 0.90-1.86) for CNS tumours, with the highest risk observed in children attending a crèche. The strongest association was observed for embryonal CNS tumours. We found no effect of age at enrolment or duration of enrolment in childcare.Conclusion: These results do not support the hypothesis that the burden of exposure to infectious disease in early childhood has an important role in the aetiology of paediatric CNS tumours. [ABSTRACT FROM AUTHOR]