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Background: Breast cancer is a well-recognised late adverse effect in female childhood cancer survivors (CCSs), especially after chest radiotherapy; information on subsequent male breast cancer (SMBC) is limited. We summarised the existing evidence on SMBC after childhood cancer in a systematic review and investigated the risk of SMBC among males in a Pan-European cohort., Methods: We searched Medline/PubMed for cohort studies and case reports/series that assessed SMBC after childhood cancer (≤21 years). Furthermore, we analysed data on SMBC in the PanCareSurFup cohort, reporting standardised incidence ratios (SIRs), absolute excess risks (AERs), and 5- and 10-year survival rates., Results: The systematic review included 38 of 7080 potentially eligible articles. Cohort-specific SMBC frequencies were 0-0.40% (31 studies). SMBC occurred after a follow-up ranging from 24.0 to 42.0 years. Nine case reports/series described 11 SMBC cases, occurring 11.0-42.5 years after primary childhood cancer. In the PanCareSurFup cohort (16 SMBC/37,738 males; 0.04%), we observed a 22.3-fold increased risk of SMBC relative to the general male population (95% CI 12.7-36.2; absolute excess risk/100,000 person-years: 2.3, 95% CI 1.3-3.7). The five- and ten-year survival rates after SMBC diagnosis were 60.3% (95% CI 35.6%-85.0%) and 43.0% (95% CI 16.1%-69.9%), respectively. Clear evidence of risk factors did not emerge from these comprehensive efforts., Conclusions: Compared to the general population, male CCSs have an elevated risk of developing subsequent breast cancer, although the absolute risk is low. Health care providers should be aware of this rare yet serious late effect; male CCSs with symptoms potentially related to SMBC warrant careful examination., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: During the past 4 decades, there has been a growing focus on preserving the fertility of patients with childhood cancer; however, no large studies have been conducted of live births across treatment decades during this period. Therefore, the authors estimated the potential birth deficit in female childhood cancer survivors and the probability of live births., Methods: In total, 8886 women were identified in the 5 Nordic cancer registries in whom a childhood cancer had been diagnosed during 1954 through 2006. A population comparison cohort of 62,903 women was randomly selected from the central population registries matched by age and country. All women were followed for live births recorded in medical birth registries. The cumulative probability and the risk ratio (RR) with 95% confidence intervals (CIs) of a live birth were calculated by maternal age across treatment decades., Results: The probability of a live birth increased with treatment decade, and, at age 30 years, the rate for survivors most recently diagnosed was close to the rate among the general population (1954-1969: RR, 0.65 [95% CI, 0.54-0.78]; 1970s: RR, 0.67 [95% CI, 0.60-0.74]; 1980s: RR, 0.69 [95% CI, 0.64-0.74]; 1990s: RR, 0.91 [95% CI, 0.87-0.95]; 2000s: RR, 0.94 [95% CI, 0.91-0.97])., Conclusions: Female childhood cancer survivors had a lower probability of a live birth than women in the general population, although, in survivors diagnosed after 1989, the probability was close to that of the general population. Because the pattern of live births differs by cancer type, continuous efforts must be made to preserve fertility, counsel survivors, and refer them rapidly to fertility treatment if necessary., Lay Summary: The purpose of this study was to compare the probability of giving birth to a liveborn child in female survivors of childhood cancer with that of women in the general population. Survivors of childhood cancer had a lower probability of live births than women in the general population, although survivors diagnosed after 1989 had a probability close to that of the general population. Continuing focus on how to preserve the potential for fertility among female patients with childhood cancer during treatment is important to increase their chances of having a child., (© 2021 American Cancer Society.)

Background: Hyperthyroidism is a rare disorder which may negatively affect health and quality of life. Its occurrence in childhood cancer survivors has not previously been investigated in detail., Material and Methods: In the hospital registers of the five Nordic countries, 32,944 childhood cancer survivors and 212,675 population comparisons were followed for the diagnosis of hyperthyroidism. Hospitalisation rates, standardised hospitalisation rate ratios and absolute excess risks were calculated with 95% confidence intervals (CI)., Results: Hyperthyroidism was diagnosed in 131 childhood cancer survivors, yielding an overall relative risk of 1.6 (95% CI: 1.3-1.9) compared with population comparisons. The risk was greatest 1-5 years after the diagnosis of cancer and in survivors of thyroid cancers, neuroblastomas, acute lymphoblastic leukaemia and Hodgkin lymphoma. Sixty-seven percent of survivors with hyperthyroidism had tumours located in the head, neck or upper body and half of survivors with hyperthyroidism were irradiated with 77% of them in the head and neck area., Conclusion: Childhood cancer survivors are at an increased risk of hyperthyroidism, potentially resulting in non-endocrine morbidity.

Background: Childhood cancer survivors have an increased risk of cardiovascular disease (CVD) and diabetes mellitus. Because diabetes is a potentially modifiable risk factor for CVD in the general population, it is important to understand how diabetes affects the risk of CVD among childhood cancer survivors., Methods: This study examined the risk of CVD among survivors with diabetes and 142,742 population comparison subjects. From the national cancer registries of the 5 Nordic countries, 29,324 one-year survivors of cancer diagnosed before the age of 20 years between 1968 and 2008 were identified. Study subjects were linked to the national hospital registers. The cumulative incidence of CVD was determined with competing risk methods. A Cox proportional hazards model was used to estimate the effects of diabetes and cancer on the hazard of CVD. The interaction between diabetes and cancer was analyzed., Results: Diabetes was diagnosed in 324 of the 29,324 one-year survivors, and CVD was diagnosed in 2108. The hazard of diabetes was 1.7 times higher among survivors than comparison subjects (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.5-1.9), whereas the HR of CVD was 3.6 (95% CI, 3.3-3.8) 1 to 15 years after the cancer diagnosis and 1.9 (95% CI, 1.8-2.0) after more than 15 years. Individuals with diabetes had a 2.4 times higher hazard of CVD (95% CI, 2.1-2.8) among both survivors and comparison subjects in comparison with individuals without diabetes., Conclusions: Childhood cancer survivors with diabetes have a markedly increased risk of CVD in comparison with survivors without diabetes. However, diabetes does not increase the risk of CVD more in survivors than the general population., (© 2018 American Cancer Society.)

Background: Second malignant neoplasms and cardiotoxicity are among the most serious and frequent adverse health outcomes experienced by childhood and adolescent cancer survivors (CCSs) and contribute significantly to their increased risk of premature mortality. Owing to differences in health-care systems, language and culture across the continent, Europe has had limited success in establishing multi-country collaborations needed to assemble the numbers of survivors required to clarify the health issues arising after successful cancer treatment. PanCareSurFup (PCSF) is the first pan-European project to evaluate some of the serious long-term health risks faced by survivors. This article sets out the overall rationale, methods and preliminary results of PCSF., Methods: The PCSF consortium pooled data from 13 cancer registries and hospitals in 12 European countries to evaluate subsequent primary malignancies, cardiac disease and late mortality in survivors diagnosed between ages 0 and 20 years. In addition, PCSF integrated radiation dosimetry to sites of second malignancies and to the heart, developed evidence-based guidelines for long-term care and for transition services, and disseminated results to survivors and the public., Results: We identified 115,596 individuals diagnosed with cancer, of whom 83,333 were 5-year survivors and diagnosed from 1940 to 2011. This single data set forms the basis for cohort analyses of subsequent malignancies, cardiac disease and late mortality and case-control studies of subsequent malignancies and cardiac disease in 5-year survivors., Conclusions: PCSF delivered specific estimates of risk and comprehensive guidelines to help survivors and care-givers. The expected benefit is to provide every European CCS with improved access to care and better long-term health., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

This corrects the article DOI: 10.1038/bjc.2017.85.

Childhood cancer survivors face risks from a variety of late effects, including cardiac events, second cancers, and late mortality. The aim of the pan-European PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies (PanCareSurFup) Consortium was to collect data on incidence and risk factors for these late effects among childhood cancer survivors in Europe. This paper describes the methodology of the data collection for the overall PanCareSurFup cohort and the outcome-related cohorts. In PanCareSurFup 13 data providers from 12 countries delivered data to the data centre in Mainz. Data providers used a single variable list that covered all three outcomes. After validity and plausibility checks data was provided to the outcome-specific working groups. In total, we collected data on 115,596 patients diagnosed with cancer from 1940 to 2011, of whom 83,333 had survived 5 years or more. Due to the eligibility criteria and other requirements different numbers of survivors were eligible for the analysis of each of the outcomes. Thus, 1014 patients with at least one cardiac event were identified from a cohort of 39,152 5-year survivors; for second cancers 3995 survivors developed at least one second cancer from a cohort of 71,494 individuals, and from the late mortality cohort of 79,441 who had survived at least 5 years, 9247 died subsequently. Through the close cooperation of many European countries and the establishment of one central data collection and harmonising centre, the project succeeded in generating the largest cohort of children with cancer to date.

Information on late onset liver complications after childhood cancer is scarce. To ensure an appropriate follow-up of childhood cancer survivors and reducing late liver complications, the need for comprehensive and accurate information is presented. We evaluate the risk of liver diseases in a large childhood cancer survivor cohort. We included all 1-year survivors of childhood cancer treated in the five Nordic countries. A Cox proportional hazards model was used to estimate hospitalisation rate (hazard) ratios (HRs) for each liver outcome according to type of cancer. We used the risk among survivors of central nervous system tumour as internal reference. With a median follow-up time of 10 years, 659 (2%) survivors had been hospitalised at least once for a liver disease. The risk for hospitalisation for any liver disease was high after hepatic tumour (HR = 6.9) and leukaemia (HR = 1.7). The Danish sub-cohort of leukaemia treated with haematopoietic stem cell transplantation had a substantially higher risk for hospitalisation for all liver diseases combined (HR = 3.8). Viral hepatitis accounted for 286 of 659 hospitalisations corresponding to 43% of all survivors hospitalised for liver disease. The 20-year cumulative risk of viral hepatitis was 1.8% for survivors diagnosed with cancer before 1990 but only 0.3% for those diagnosed after 1990. The risk of liver disease was low but significantly increased among survivors of hepatic tumours and leukaemia. Further studies with focus on the different treatment modalities are needed to further strengthen the prevention of treatment-induced late liver complications., (© 2017 UICC.)

Background: Survivors of childhood cancer are at increased risk for a wide range of late effects. However, no large population-based studies have included the whole range of somatic diagnoses including subgroup diagnoses and all main types of childhood cancers. Therefore, we aimed to provide the most detailed overview of the long-term risk of hospitalisation in survivors of childhood cancer., Methods and Findings: From the national cancer registers of Denmark, Finland, Iceland, and Sweden, we identified 21,297 5-year survivors of childhood cancer diagnosed with cancer before the age of 20 years in the periods 1943-2008 in Denmark, 1971-2008 in Finland, 1955-2008 in Iceland, and 1958-2008 in Sweden. We randomly selected 152,231 population comparison individuals matched by age, sex, year, and country (or municipality in Sweden) from the national population registers. Using a cohort design, study participants were followed in the national hospital registers in Denmark, 1977-2010; Finland, 1975-2012; Iceland, 1999-2008; and Sweden, 1968-2009. Disease-specific hospitalisation rates in survivors and comparison individuals were used to calculate survivors' standardised hospitalisation rate ratios (RRs), absolute excess risks (AERs), and standardised bed day ratios (SBDRs) based on length of stay in hospital. We adjusted for sex, age, and year by indirect standardisation. During 336,554 person-years of follow-up (mean: 16 years; range: 0-42 years), childhood cancer survivors experienced 21,325 first hospitalisations for diseases in one or more of 120 disease categories (cancer recurrence not included), when 10,999 were expected, yielding an overall RR of 1.94 (95% confidence interval [95% CI] 1.91-1.97). The AER was 3,068 (2,980-3,156) per 100,000 person-years, meaning that for each additional year of follow-up, an average of 3 of 100 survivors were hospitalised for a new excess disease beyond the background rates. Approximately 50% of the excess hospitalisations were for diseases of the nervous system (19.1% of all excess hospitalisations), endocrine system (11.1%), digestive organs (10.5%), and respiratory system (10.0%). Survivors of all types of childhood cancer were at increased, persistent risk for subsequent hospitalisation, the highest risks being those of survivors of neuroblastoma (RR: 2.6 [2.4-2.8]; n = 876), hepatic tumours (RR: 2.5 [2.0-3.1]; n = 92), central nervous system tumours (RR: 2.4 [2.3-2.5]; n = 6,175), and Hodgkin lymphoma (RR: 2.4 [2.3-2.5]; n = 2,027). Survivors spent on average five times as many days in hospital as comparison individuals (SBDR: 4.96 [4.94-4.98]; n = 422,218). The analyses of bed days in hospital included new primary cancers and recurrences. Of the total 422,218 days survivors spent in hospital, 47% (197,596 bed days) were for new primary cancers and recurrences. Our study is likely to underestimate the absolute overall disease burden experienced by survivors, as less severe late effects are missed if they are treated sufficiently in the outpatient setting or in the primary health care system., Conclusions: Childhood cancer survivors were at increased long-term risk for diseases requiring inpatient treatment even decades after their initial cancer. Health care providers who do not work in the area of late effects, especially those in primary health care, should be aware of this highly challenged group of patients in order to avoid or postpone hospitalisations by prevention, early detection, and appropriate treatments.

Suicide risk in adult cancer patients is found to be elevated, but limited information exists regarding risks of suicide and non-suicidal violent deaths when diagnosed with cancer in young age. We investigate suicide and violent deaths in a national cohort including individuals diagnosed with cancer before age 25. Through the linkage of different national registries (Cancer Registry of Norway, Norwegian Causes of Death Registry and the National Registry) a cohort of all live births in Norway during 1965-1985 was defined and followed up through 2008. Individuals diagnosed with cancer before age 25 and the cancer-free references were compared using an extended Cox proportional hazard regression model. The cohort comprised 1,218,013 individuals, including 5,440 diagnosed with cancer before age 25. We identified 24 suicides and 14 non-suicidal violent deaths in the cancer group. The hazard ratio (HR) of suicide in the cancer group was 2.5 (95% confidence interval (CI) 1.7-3.8), and was increased both when diagnosed with cancer in childhood (0-14 years of age); HR = 2.3 (95% CI: 1.2-4.6), and during adolescence/young adulthood (15-24 years); HR = 2.6 (95% CI: 1.5-4.2). Survivors of bone/soft tissue sarcomas, CNS tumors and testicular cancer were at particular risk. The risk of non-suicidal violent death was not increased in the cancer survivors (HR = 1.0; 95% CI: 0.6-1.7). Although based on small numbers and the absolute risk of suicide being low, these are novel findings with important implications for establishing adequate follow-up including suicide prevention strategies for young cancer survivors., (© 2016 UICC.)

Background: The impact of cancer on socioeconomic outcomes is attracting attention as the number of survivors of cancer in young age continues to rise. This study examines economic independence in a national cohort of survivors of cancer at a young age in Norway., Methods: Through the linkage of several national registries, the study cohort comprised 1,212,013 individuals born in Norway during 1965 through 1985, of which 5440 had received a cancer diagnosis before age 25 years. Follow-up was through 2007, and the main outcomes were receipt of governmental financial assistance, employment, income, and occupation. Analytic methods included Cox proportional hazard regression, log-binomial regression, and quantile regression models., Results: Individuals in the cancer survivor group had an increased probability of receiving governmental financial assistance (men: hazard ratio [HR], 1.4; 95% confidence interval [CI], 1.3-1.5; women: HR, 1.5; 95% CI, 1.3-1.6) and of not being employed (men: HR, 1.4; 95% CI, 1.2-1.7; women: HR, 1.4; 95% CI, 1.2-1.6) compared with those in the noncancer group. Income discrepancies were particularly pronounced for survivors of central nervous system tumors. There was no difference in representation in higher skilled occupations., Conclusions: Survivors of cancer at a young age in Norway had an increased risk of being economically dependent and unemployed. This was evident in several tumor groups and was most pronounced in female survivors. There were only small differences in income or representation in higher skilled occupations for most employed survivors compared with the noncancer group. The current results are important for understanding the impact of a cancer diagnosis at a young age on subsequent job market outcomes. Cancer 2016;122:3873-3882. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society., (© 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Survival after childhood cancer diagnosis has remarkably improved, but emerging evidence suggests that cancer-directed therapy may have adverse gastrointestinal late effects. We aimed to comprehensively assess the frequency of gastrointestinal and liver late effects among childhood cancer survivors and compare this frequency with the general population. Our population-based cohort study included all 1-year survivors of childhood and adolescent cancer in Denmark, Finland, Iceland, Norway and Sweden diagnosed from the 1940s and 1950s. Our outcomes of interest were hospitalization rates for gastrointestinal and liver diseases, which were ascertained from national patient registries. We calculated standardized hospitalization rate ratios (RRs) and absolute excess rates comparing hospitalizations of any gastrointestinal or liver disease and for specific disease entities between survivors and the general population. The study included 31,132 survivors and 207,041 comparison subjects. The median follow-up in the hospital registries were 10 years (range: 0-42) with 23% of the survivors being followed at least to the age of 40 years. Overall, survivors had a 60% relative excess of gastrointestinal or liver diseases [RR: 1.6, 95% confidence interval (CI): 1.6-1.7], which corresponds to an absolute excess of 360 (95% CI: 330-390) hospitalizations per 100,000 person-years. Survivors of hepatic tumors, neuroblastoma and leukemia had the highest excess of gastrointestinal and liver diseases. In addition, we observed a relative excess of several specific diseases such as esophageal stricture (RR: 13; 95% CI: 9.2-20) and liver cirrhosis (RR: 2.9; 95% CI: 2.0-4.1). Our findings provide useful information about the breadth and magnitude of late complications among childhood cancer survivors and can be used for generating hypotheses about potential exposures related to these gastrointestinal and liver late effects., (© 2016 UICC.)

Background: Childhood cancer has been associated with long-term risk of urinary tract diseases, but risk patterns remain to be comprehensively investigated. We analysed the lifetime risk of urinary tract diseases in survivors of childhood cancer in the Nordic countries., Methods: We identified 32,519 one-year survivors of childhood cancer diagnosed since the 1940s and 1950s in the five Nordic cancer registries and selected 211,156 population comparisons of a corresponding age, sex, and country of residence from the national population registries. To obtain information on all first-time hospitalizations for a urinary tract disease, we linked all study subjects to the national hospital registry of each country. Relative risks (RRs) and absolute excess risks (AERs) and associated 95% confidence intervals (CIs) for urinary tract diseases among cancer survivors were calculated with the appropriate morbidity rates among comparisons as reference., Results: We observed 1645 childhood cancer survivors ever hospitalized for urinary tract disease yielding an RR of 2.5 (95% CI 2.4-2.7) and an AER of 229 (95% CI 210-248) per 100,000 person-years. The cumulative risk at age 60 was 22% in cancer survivors and 10% in comparisons. Infections of the urinary system and chronic kidney disease showed the highest excess risks, whereas survivors of neuroblastoma, hepatic and renal tumours experienced the highest RRs., Conclusion: Survivors of childhood cancer had an excess risk of urinary tract diseases and for most diseases the risk remained elevated throughout life. The highest risks occurred following therapy of childhood abdominal tumours., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: The number of young cancer survivors has increased over the past few decades due to improvement in treatment regimens, and understanding of long-term effects among the survivors has become even more important. Educational achievements and choice of educational fields were explored here., Methods: Five-year cancer survivors born in Norway during 1965-1985 (diagnosed <19 years) were included in our analysis by linking Norwegian population-based registries. Cox regression was applied to study the educational attainment among survivors of central nervous system (CNS) tumours, those assumed to have received CNS-directed therapy, and other cancer survivors relative to the cancer-free population. Logistic regression was used to compare the choice of educational fields between the cancer survivors at undergraduate and graduate level and the cancer-free population., Results: Overall, a lower proportion of the cancer survivors completed intermediate (67 vs. 70 %), undergraduate (31 vs. 35 %) and graduate education (7 vs. 9 %) compared with the cancer-free population. Deficits in completion of an educational level were mainly observed among survivors of CNS-tumours and those assumed to have received CNS-directed therapy. Choices of educational fields among cancer survivors were in general similar with the cancer-free population at both undergraduate and graduate levels., Conclusion: Survivors of CNS-tumours and those assumed to have received CNS-directed therapy were at increased risk for educational impairments compared with the cancer-free population. Choices of educational fields were in general similar., Implications for Cancer Survivors: Careful follow-up of the survivors of CNS-tumours and those assumed to have received CNS-directed therapy is important at each level of education.

The lifetime risk for cardiovascular disease in a large cohort of childhood cancer survivors has not been fully assessed. In a retrospective population-based cohort study predicated on comprehensive national health registers, we identified a cohort of 32,308 one-year survivors of cancer diagnosed before the age of 20 in the five Nordic countries between the start of cancer registration in the 1940s and 1950s to 2008; 211,489 population comparison subjects were selected from national population registers. Study subjects were linked to national hospital registers, and the observed numbers of first hospital admission for cardiovascular disease among survivors were compared with the expected numbers derived from the population comparison cohort. Cardiovascular disease was diagnosed in 2,632 childhood cancer survivors (8.1%), yielding a standardized hospitalization rate ratio (RR) of 2.1 (95% CI 2.0-2.2) and an overall absolute excess risk (AER) of 324 per 100,000 person-years. At the end of follow-up 12% of the survivors were ≥ 50 years of age and 4.5% ≥ 60 years of age. Risk estimates were significantly increased throughout life, with an AER of ∼500-600 per 100,000 person-years at age ≥ 40. The highest relative risks were seen for heart failure (RR, 5.2; 95% CI 4.5-5.9), valvular dysfunction (4.6; 3.8-5.5) and cerebrovascular diseases (3.7; 3.4-4.1). Survivors of hepatic tumor, Hodgkin lymphoma and leukemia had the highest overall risks for cardiovascular disease, although each main type of childhood cancer had increased risk with different risk profiles. Nordic childhood cancer survivors are at markedly increased risk for cardiovascular disorders throughout life. These findings indicate the need for preventive interventions and continuous follow-up for this rapidly growing population., (© 2015 UICC.)

With the advent of multimodality therapy, the overall five-year survival rate from childhood cancer has improved considerably now exceeding 80% in developed European countries. This growing cohort of survivors, with many years of life ahead of them, has raised the necessity for knowledge concerning the risks of adverse long-term sequelae of the life-saving treatments in order to provide optimal screening and care and to identify and provide adequate interventions. Childhood cancer survivor cohorts in Europe. Considerable advantages exist to study late effects in individuals treated for childhood cancer in a European context, including the complementary advantages of large population-based cancer registries and the unrivalled opportunities to study lifetime risks, together with rich and detailed hospital-based cohorts which fill many of the gaps left by the large-scale population-based studies, such as sparse treatment information. Several large national cohorts have been established within Europe to study late effects in individuals treated for childhood cancer including the Nordic Adult Life after Childhood Cancer in Scandinavia study (ALiCCS), the British Childhood Cancer Survivor Study (BCCSS), the Dutch Childhood Oncology Group (DCOG) LATER study, and the Swiss Childhood Cancer Survivor Study (SCCSS). Furthermore, there are other large cohorts, which may eventually become national in scope including the French Childhood Cancer Survivor Study (FCCSS), the French Childhood Cancer Survivor Study for Leukaemia (LEA), and the Italian Study on off-therapy Childhood Cancer Survivors (OTR). In recent years significant steps have been taken to extend these national studies into a larger pan-European context through the establishment of two large consortia - PanCareSurFup and PanCareLIFE. The purpose of this paper is to present an overview of the current large, national and pan-European studies of late effects after childhood cancer. This overview will highlight the strong cooperation across Europe, in particular the EU-funded collaborative research projects PanCareSurFup and PanCareLIFE. Overall goal. The overall goal of these large cohort studies is to provide every European childhood cancer survivor with better care and better long-term health so that they reach their full potential, and to the degree possible, enjoy the same quality of life and opportunities as their peers.

Background: The pattern of endocrine disorders in long-term survivors of childhood cancer has not been investigated comprehensively. Here, we aimed to assess the lifetime risk of these disorders in Nordic survivors of childhood cancer., Methods: From the national cancer registries of Denmark, Finland, Iceland, Norway, and Sweden, we identified 31,723 1-year survivors of childhood cancer, notified since the start of registration in the 1940s and 1950s. From the national population registries, we randomly selected a comparison cohort of people matched by age, sex, and country. Study participants were linked to the national hospital registries, and observed numbers of first-time hospital contacts for endocrine disorders in survivors of childhood cancer were compared with the expected numbers derived from the population comparison cohort. We calculated the absolute excess risks attributable to status as a childhood cancer survivor and standardised hospitalisation rate ratios (SHRRs)., Findings: Of the childhood cancer survivors, 3292 had contact with a hospital for an endocrine disorder, yielding a SHRR of 4·8 (95% CI 4·6-5·0); the highest risks were in survivors of leukaemia (SHRR 7·3 [95% CI 6·7-7·9]), CNS tumours (6·6 [6·2-7·0]), and Hodgkin's lymphoma (6·2 [5·6-7·0]). The absolute excess risk for endocrine disorders was roughly 1000 per 100,000 person-years before 20 years of age, and 400 per 100,000 person-years during the remaining lifetime. For children with cancer diagnosed at 5-9 years of age, the cumulative risk for endocrine disorders was highest, and reached 43% at the age of 60 years. Diagnoses of pituitary hypofunction (SHRR 88·0), hypothyroidism (9·9), and testicular and ovarian dysfunction (42·5 and 4·7, respectively) together constituted 61% (655 of 1078) of all excess disease-induced and treatment-induced endocrine disorders in survivors of childhood cancer., Interpretation: A cumulative risk for endocrine disorders at 60 years of age of above 40% in survivors of childhood cancer emphasises the importance of minimisation of damaging treatment, intensification of secondary prevention, and targeting of survivor follow-up throughout life. Since most long-term childhood cancer survivors are not followed in a specialised late-effect clinic, they are a growing challenge for the primary care physician and medical specialists working outside the late-effect area., Funding: The Danish Council for Strategic Research., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Aim: An increased risk for diabetes mellitus (DM) adds significantly to the burden of late complications in childhood cancer survivors. Complications of DM may be prevented by using appropriate screening. It is, therefore, important to better characterise the reported increased risk for DM in a large population-based setting., Materials and Methods: From the national cancer registries of the five Nordic countries, a cohort of 32,903 1-year survivors of cancer diagnosed before the age of 20 between start of cancer registration in the 1940s and 1950s through 2008 was identified; 212,393 comparison subjects of the same age, gender and country were selected from national population registers. Study subjects were linked to the national hospital registers. Absolute excess risks (AERs) and standardised hospitalisation rate ratios (SHRRs) were calculated., Results: DM was diagnosed in 496 childhood cancer survivors, yielding an overall SHRR of 1.6 (95% confidence interval (CI), 1.5-1.8) and an AER of 43 per 100,000 person-years, increasing from approximately 20 extra cases of DM in ages 0-19 to more than 100 extra cases per 100,000 person-years in ages > or =50. The relative risks for DM were significantly increased after Wilms' tumour (SHRR, 2.9), leukaemia (2.0), CNS neoplasms (1.8), germ-cell neoplasms (1.7), malignant bone tumours (1.7) and Hodgkin's lymphoma (1.6). The risk for DM type 2 was slightly higher than that for type 1., Conclusion: Childhood cancer survivors are at increased risk for DM, with absolute risks increasing throughout life. These findings underscore the need for preventive interventions and prolonged follow-up of childhood cancer survivors., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: As the number of cancer survivors increases, their health and welfare have come into focus. Thus, long-term medical consequences of cancer at a young age (<25 years), obtained from social security benefit records, were studied., Methods: Standardised incidence ratios (SIRs) of long-term medical consequences for 5-year cancer survivors, born during 1965-1985, were explored by linking population-based registries in Norway., Results: Among the 5-year cancer survivors (4031 individuals), 29.7% received social security benefits. The survivors had an overall 4.4 times (95% confidence interval (95% CI): 4.1-4.6) higher risk of social security benefit uptake than the cancer-free population. Survivors of malignancies of bone and connective tissues (SIR: 10.8; 95% CI: 9.1-12.9), CNS tumours (SIR: 7.7; 95% CI: 6.9-8.6) and malignancies of the haematopoietic system (SIR: 6.1; 95% CI: 5.3-7.0) had the highest risks of social security benefits uptake. The most notified causes of social security benefit uptake were diseases of the nervous system, and injury and poisoning., Conclusion: The uptake of social security benefits among 5-year cancer survivors increased substantially and it may represent a solid outcome measure for the burden of the most severe late effects, especially in countries with comparable social welfare systems.

Purpose: Cancer is one of the most common causes of death among young individuals. The purpose of this study was to explore the risk of early death (the first five years after diagnosis) among children (0-14 years), adolescents (15-19 years), and young adults (20-24 years) with cancer in Norway, born during 1965-1985., Methods: The overall and cancer-specific early deaths were explored by linking population-based national registers (including the Cancer Registry of Norway and the Cause of Death Registry) that include the entire population of Norway (approximately 1.3 million individuals). Hazard and sub-hazard ratios were estimated using Cox regression analyses and competing risk models., Results: A total of 5,828 individuals were diagnosed with cancer (56.3 % males). During follow-up, 1,415 individuals died from cancer (60.2 % males) within five years after diagnosis. The hazard ratio (HR) of overall death of the cancer patients relative to the general population decreased from 1965 (from HR, 385.8 (95 % confidence interval (CI): 335.3, 443.4) in 1965-74 to HR, 19.7 (CI: 9.3, 41.5) in 2005-09). Over all, there were fewer cancer-related deaths among female compared with male patients (sub-hazard ratio (SHR), 0.83 (CI: 0.74, 0.92)). Except for all hematopoietic malignancies, adolescents and young adult patients had lower risk of cancer death than children., Conclusion: The difference in risk of cancer and overall deaths between the cancer patients and the general population has been substantially reduced since 1965.

Clinical management of warfarin therapy is complex, and dosing algorithms do not include genetic factors or interactions with other drugs for warfarin dose determinations. We evaluated the interaction of warfarin and CYP2C9 polymorphisms and concomitant corticosteroids in 29 children with cancer. Children with heterozygous polymorphisms of CYP2C9 achieved target INR sooner and more frequently had INR above the target level, compared to children without mutations. Children on concomitant steroids had significantly lower warfarin requirements. Thus, awareness of CYP2C9 genotype and steroid-induced responsiveness to warfarin may be important when administrating oral anticoagulation in children., ((c) 2007 Wiley-Liss, Inc.)

New biomedical knowledge may improve the diagnostic procedures and treatment provided by the Health Services, but at additional cost. In a social democratic health care system, the hospital budgets have no room for expensive, new procedures or treatments, unless these are funded through extra allocation from the central authorities. High dose therapy with autologous stem cell support in malignant disorders is an example of a new and promising, but rather expensive treatment, but its role in cancer therapy has yet to be established. The indications for testing high dose therapy with autologous stem cell support in various malignancies are discussed, with emphasis on the principles for deciding which categories of disease should have priority. The authors suggest some malignant disorders for which high dose therapy with stem cell support should be explored versus conventional treatment in randomised prospective trials.

Eluates of 13 malignant tumours were prepared at 56 degrees C using the continuous flow technique. By using immunodiffusion techniques, 50--80 per cent of the IgG detected was found to be of the IgG1 subclass. The ratio of Ig/kappa to Ig/lambda was similar in eluates and in the corresponding extracts, and this ratio was similar to that obtained using pooled human serum. This indicates a normal distribution of IgG subclasses in the eluates. Besides whole IgG, the eluates and corresponding extracts contained fragments of IgG. This was revealed by using sodium dodecyl sulphate electrophoresis (SDS-PAGE). However, since parts of the IgG associated with human malignant tumours can be non-specifically bound, and since fragments of IgG was found in extracts and eluates of normal tissues, although to a lesser degree than in those of malignant tissue, no conclusive evidence was obtained that the malignant tissue could degrade Ig. SDS-PAGE of extracts and eluates of malignant tissues showed 2--3 constant bands not detected in isolated IgG or in extracts and eluates of most of the normal tissues. These bands were not identified.

Eluates of 13 malignant and 17 normal tissues were prepared at 56 degrees C using the continuous flow technique. Albumin was detected in all the eluates. IgG, IgA, C3 or haptoglobin were detected in most of the malignant and some of the normal tissues. Carcinoembryonic antigen, beta 2-microglobulin, alpha 1-antitrypsin or alpha 1-antichymotrypsin were detected in some of the eluates of the malignant tissues only. IgM, IgD, C1q, C4, Cl-INH, alpha 1-macroglobulin, beta 2-lipoprotein, fibrinogen and alpha 1-foetoprotein were not detected in any of the eluates. The ratio of the concentration of albumin to the concentration of IgG was similar in extracts and eluates of all the normal tissue and in 3 of the malignant tissues indicating non-specific binding of IgG.

Eluates of different were prepared at 56 degrees C using a continuous flow technique. More IgG and other serum proteins were found in liver from patients with non-malignant diseases than in liver tissue from healthy control individuals. Cancer-free liver tissue from patients with carcinomas was similar to that of patients with non-malignant diseases, but liver metastases contained twice the amount of IgG. No differences were found between non-perfused carcinomas of the kidney and cancer-free renal tissue, whereas more IgG was present in perfused carcinomas of the kidney than in cancer-free renal tissue. Most eluates of the malignant tissues and of the cancer-free renal tissue showed a reduced ratio of albumin IgG compared to that of serum or extracts, indicating a binding of IgG to antigens and/or receptors.

Heat eluates of homogenized human malignant and normal tissues were prepared using the continuous flow elution technique. IgG antibodies to rabbit erythrocytes served as marker antibodies for non-specifically bound IgG. Eluates of all of the 13 malignant tumours tested contained IgG. Most were eluted at 56C, but considerable amounts also at 37C and 45C. Marker antibodies were present in eluates of 4 of the tumours, indicating that at least parts of the IgG associated with malignant human tumours are non-specifically bound. Eight tumours contained too little IgG to detect marker antibodies, and one contained high amounts of IgG without marker antibodies. Eluates of normal organs contained either no or only small amounts of IgG, although apparently normal kidneys from older individuals contained some more IgG. Marker antibodies were detected in some of the eluates indicating non-specific binding.

Similar amounts of non-specifically bound IgG were found in the eluates of the same tissues both after the Fc gamma receptor activity (FcRA) had been abolished by disrupting the tissue and when FcRA was intact. This indicates that the non-specifically bound IgG is either not attached to the FcR, or that only the free FcR were abolished. No FcRA was detected in the supernatant of the tissue from which the FcRA was abolished, thus indicating that the FcRA was destroyed.

Thirteen solid tumours were tested for Fc gamma receptors (FcR) using tissue sections and sheep erythrocytes sensitized with rabbit antibodies as indicator cells. No alteration was found in FcR activity (FcRA) between untreated tissue and tissue homogenized for 2 min or less. More extensive homogenization abolished the FcRA. Tissues homogenized for 1 min were washed at 4C and eluted at 37, 45 and 56C. The FcRA was not altered after elution at 37 and 45C. However, elution at 56C abolished the activity indicating that the FcR were either eluted or destroyed. Tumours which showed a diffuse pattern of FcRA and no non-specifically bound IgG displayed an inverse relationship between the FcRA and the eluted IgG. Such relationship was not found with tumours containing non-specifically bound IgG.

Mixed haemagglutination with tissue sections was used to study the tissue reactivity of IgG eluted from human carcinomas. IgG eluted from 21 of 29 tumours, bound to the autologous tissue. The binding was mediated through the Fab-portion, and the bound IgG had an intact Fc-portion. Most eluted IgG bound to the autologous tissue, but binding was also seen to other carcinomas of the same type as well as to other types. In addition, the IgG bound to several cancer-free tissues. Accordingly, the eluates of the 21 tumours contained IgG with a broad tissue reactivity. The eluates of a) the remaining 8 tumours, b)normal tissue, and c) liver tissue from patients with non-malignant diseases, contained IgG which did not bind to any tissue. The IgG associated with these tissues was probably non-specifically bound or bound to receptors in vivo.

Agglutinins to rabbit erythrocytes in extracts from human malignant tissues were identified as the naturally occurring IgG antibodies in human serum to rabbit erythrocytes. This was revealed by agglutination, absorption, antiglobulin and inhibition tests, immunization of rabbits and immunochemical analyses. The agglutinins can therefore be used as convenient markers for both extracellular immunoglobulin and unspecifically bound immunoglobulin in tumour tissues. Apparently the extracts also contained small amounts of IgA antibodies to rabbit erythrocytes.