Publications by authors named "Catherine Rechnitzer"

52 Publications

9p21.3 microdeletion involving in a young patient with multiple primary cancers and review of the literature.

Cold Spring Harb Mol Case Stud 2022 Apr 14. Epub 2022 Apr 14.

Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark;

Germline pathogenic variants in predispose to various cancers, including melanoma, pancreatic cancer, and neural system tumors, while variants are associated with renal cell carcinoma. A few case reports have described heterozygous germline deletions spanning both and associated with a cancer predisposition syndrome (CPS) which constitutes a risk of cancer beyond those associated with haploinsufficiency of each gene individually, indicating an additive effect or a contiguous gene deletion syndrome. We report a young woman with a germline 9p21 microdeletion involving the genes, who developed six primary cancers since childhood, including a very rare extraskeletal osteosarcoma (eOS) at the age of 8. To our knowledge this is the first report of eOS in a patient with deletion.
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http://dx.doi.org/10.1101/mcs.a006164DOI Listing
April 2022

Effects of early maternal cancer and fertility treatment on the risk of adverse birth outcomes.

EClinicalMedicine 2022 Apr 4;46:101369. Epub 2022 Apr 4.

Childhood Cancer Research Group, Danish Cancer Society Research Center, Danish Cancer Society, Strandboulevarden 49, Copenhagen 2100, Denmark.

Background: Early maternal cancer and fertility treatment each increase the risk for adverse birth outcomes, but the joint effect of these outcomes has not yet been reported. Thus, the aim was to assess the individual and joint effect of maternal cancer and fertility treatment on the risk for adverse birth outcomes.

Methods: This population-based cohort study included 5487 live-born singletons identified in the Danish Medical Birth Register (1994-2016) of mothers with previous cancer (<40 years) recorded in the Danish Cancer Registry (1955-2014). We randomly selected 80,262 live-born singletons of mothers with no cancer <40 years matched to mothers with cancer by birth year and month. We calculated odds ratios (ORs) for preterm birth, low birth weight (LBW) (<2500 g) and small for gestational age (SGA), mean differences in birth weight in grams, and additional cases of preterm birth (gestational age<259 days) per 100,000 person-years. Multiplicative and additive interaction of maternal cancer and fertility treatment was compared with outcomes of children conceived naturally to mothers with no maternal cancer (reference group).

Findings: Among 84,332 live-born singletons, increased ORs for preterm birth were observed among children born to mothers with previous cancer (1·48, 95% confidence interval [CI] 1·33-1.65) or after fertility treatment (1·43, 95% 1·28-1-61), with 22 additional cases of preterm birth among both group of children (95% CI 15-29; 95% CI 14-30). In the joint analyses, the OR for SGA for children born after fertility treatment to mothers with previous cancer was similar to that of the reference group (OR 1·02, 95% CI 0·72-1·44, for interaction=0·52). Children with both exposures had increased ORs for LBW (1·86, 95% CI 1·17-2·96, for interaction=0·06) and preterm birth (2·31, 955 CI 1·66-3·20, for interaction = 0·56), with 61 additional cases of preterm birth (95% CI 27-95, for interaction=0.26) over that of children in the reference group. The mean birth weight was also lower in children born to mothers with both exposures (-140 g, 95% CI -215; -65) ( for interaction=0.06) but decreased to -22 g (95% CI -76; 31) after adjustment for GA.

Interpretation: Although we did not find any statistically significant additive interaction between maternal cancer and fertility treatment, children born after fertility treatment of mothers with previous cancer were at increased risk for adverse birth outcomes. Thus, pregnant women with both exposures need close follow-up during pregnancy.

Funding: The Danish Cancer Society and the Danish Childhood Cancer Foundation.
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http://dx.doi.org/10.1016/j.eclinm.2022.101369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8987408PMC
April 2022

Background sensitivity to chemotherapy-induced nausea and vomiting and response to antiemetics in paediatric patients: a genetic association study.

Pharmacogenet Genomics 2022 02;32(2):72-78

Department of Clinical Pharmacology, Bispebjerg and Frederiksberg University Hospital.

Chemotherapy-induced nausea and vomiting (CINV) remains a common adverse effect for children with cancer. In children, chemotherapy emetogenicity and patient factors such as susceptibility to motion sickness and age group determine a patient's risk of CINV. Besides known risk factors, genetic factors may play a role in interindividual variation in the occurrence of CINV. We investigated the influence of candidate gene polymorphisms on the efficacy of antiemetics and on the background sensitivity to CINV in children. This prospective study included 100 children with cancer (median age 6.4 years, range 0.8-17.9) who received moderately to highly emetogenic chemotherapy. Participants registered nausea and vomiting episodes in a mobile app. Genotypes were determined by whole-genome sequencing (n = 79) or Sanger sequencing (n = 21) for 71 genetic polymorphisms involved in motion sickness and antiemetic pathways. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate associations between acute CINV and genotypes adjusting for susceptibility to motion sickness and age group. Rs3782025 in the 5-hydroxytryptamine type 3 (5-HT3) receptor gene (HTR3B) [minor allele frequency (MAF): 0.48] affected response to 5-HT3 receptor antagonists; acute CINV occurred in 76% of patients with GA/AA genotypes and in 41% of patients with GG genotype (OR 5.59; 95% CI 1.74-17.9, dominant genetic model). Rs2975226 in the dopamine transporter gene (SLC6A3) (MAF: 0.54) was associated with acute CINV (OR 5.79; 95% CI 1.09-30.67, recessive genetic model). Polymorphisms in HTR3B and SLC6A3 may contribute to the variability in response to antiemetic prophylaxis for CINV in children.
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http://dx.doi.org/10.1097/FPC.0000000000000460DOI Listing
February 2022

Somatic Disease in Survivors of Childhood Malignant Bone Tumors in the Nordic Countries.

Cancers (Basel) 2021 Sep 7;13(18). Epub 2021 Sep 7.

Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.

Survivors of malignant bone tumors in childhood are at risk of long-term adverse health effects. We comprehensively reviewed cases of somatic diseases that required a hospital contact in survivors of osteosarcoma and Ewing sarcoma. In a population-based cohort study, 620 five-year survivors of osteosarcoma (n = 440) or Ewing sarcoma (n = 180), diagnosed before the age of 20 years in Denmark, Finland, Iceland, and Sweden during 1943-2008, were followed in the national hospital registers. Overall rates of hospital contacts for any somatic disease and for 12 main diagnostic groups and 120 specific disease categories were compared with those in a matched comparison cohort (n = 3049) randomly selected from the national population registers. The rate of hospital contact for any somatic disease was 80% higher in survivors of malignant bone tumors than in comparisons and remained elevated up to 30 years after diagnosis. The rate of hospital contacts was higher after Ewing sarcoma (rate ratio (RR) 2.24; 95% confidence interval (CI) 1.76-2.85) than after osteosarcoma (RR 1.67; 95% CI 1.41-1.98). Elevated rates were observed for 11 main diagnostic groups, including infections, second malignant neoplasms, and diseases of the skin, bones, and circulatory, digestive, endocrine, and urinary systems. Survivors of malignant bone tumors in childhood are at increased risk of somatic diseases many years after diagnosis. This comprehensive study contributes new insight into the risk of late effects in survivors of osteosarcoma and Ewing sarcoma, which is an essential basis for optimal patient counseling and follow-up care.
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http://dx.doi.org/10.3390/cancers13184505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467516PMC
September 2021

Clinical characteristics and outcomes of children with WAGR syndrome and Wilms tumor and/or nephroblastomatosis: The 30-year SIOP-RTSG experience.

Cancer 2021 02 4;127(4):628-638. Epub 2020 Nov 4.

Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.

Background: WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare contiguous gene deletion syndrome with a 45% to 60% risk of developing Wilms tumor (WT). Currently, surveillance and treatment recommendations are based on limited evidence.

Methods: Clinical characteristics, treatments, and outcomes were analyzed for patients with WAGR and WT/nephroblastomatosis who were identified through International Society of Pediatric Oncology Renal Tumor Study Group (SIOP-RTSG) registries and the SIOP-RTSG network (1989-2019). Events were defined as relapse, metachronous tumors, or death.

Results: Forty-three patients were identified. The median age at WT/nephroblastomatosis diagnosis was 22 months (range, 6-44 months). The overall stage was available for 40 patients, including 15 (37.5%) with bilateral disease and none with metastatic disease. Histology was available for 42 patients; 6 nephroblastomatosis without further WT and 36 WT, including 19 stromal WT (52.8%), 12 mixed WT (33.3%), 1 regressive WT (2.8%) and 2 other/indeterminable WT (5.6%). Blastemal type WT occurred in 2 patients (5.6%) after prolonged treatment for nephroblastomatosis; anaplasia was not reported. Nephrogenic rests were present in 78.9%. Among patients with WT, the 5-year event-free survival rate was 84.3% (95% confidence interval, 72.4%-98.1%), and the overall survival rate was 91.2% (95% confidence interval, 82.1%-100%). Events (n = 6) did not include relapse, but contralateral tumor development (n = 3) occurred up to 7 years after the initial diagnosis, and 3 deaths were related to hepatotoxicity (n = 2) and obstructive ileus (n = 1).

Conclusions: Patients with WAGR have a high rate of bilateral disease and no metastatic or anaplastic tumors. Although they can be treated according to existing WT protocols, intensive monitoring of toxicity and surveillance of the remaining kidney(s) are advised.

Lay Summary: WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare genetic condition with an increased risk of developing Wilms tumor. In this study, 43 patients with WAGR and Wilms tumor (or Wilms tumor precursor lesions/nephroblastomatosis) were identified through the international registry of the International Society of Pediatric Oncology Renal Tumor Study Group (SIOP-RTSG) and the SIOP-RTSG network. In many patients (37.5%), both kidneys were affected. Disease spread to other organs (metastases) did not occur. Overall, this study demonstrates that patients with WAGR syndrome and Wilms tumor can be treated according to existing protocols. However, intensive monitoring of treatment complications and surveillance of the remaining kidney(s) are advised.
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http://dx.doi.org/10.1002/cncr.33304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894534PMC
February 2021

Antidepressant Use in Siblings of Children With Cancer: A Danish Population-Based Cohort Study.

JNCI Cancer Spectr 2020 Oct 13;4(5):pkaa046. Epub 2020 Jun 13.

Danish Cancer Society Research Center, Survivorship, Copenhagen, Denmark.

Siblings of children with cancer experience severe stress early in life. Most studies of mental health problems in these siblings are limited by being small, cross-sectional, or self-reporting. In a population-based cohort study, we investigated the risk for antidepressant use by linking several nationwide, population-based registries comparing 6644 siblings of children diagnosed with cancer from 1991-2009 with 128 436 population-based sibling comparisons using the Cox proportional hazards model. Irrespective of cancer type, no increased risk of antidepressant use in siblings of children with cancer was found (hazard ratio = 1.00, 95% confidence interval = 0.91 to 1.11). However, data suggested that siblings being young at cancer diagnosis had an increased risk (2-sided = .01). Interaction analyses showed no modifying effect of parental socioeconomic position or antidepressant use. Findings from this study with a very low risk of bias are reassuring and important for families facing childhood cancer and for clinicians counseling these families.
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http://dx.doi.org/10.1093/jncics/pkaa046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583159PMC
October 2020

Association of candidate pharmacogenetic markers with platinum-induced ototoxicity: PanCareLIFE dataset.

Data Brief 2020 Oct 24;32:106227. Epub 2020 Aug 24.

Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.

Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase () is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The PanCareLIFE cross-sectional cohort study evaluated the genetic associations in a large pan-European population and assessed the diagnostic accuracy of the genetic markers. 1,112 pediatric cancer survivors who had provided biomaterial for genotyping were screened for participation in the pharmacogenetic association study. 900 participants qualified for inclusion. Based on the assessment of original audiograms, patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes ( and ) were genotyped. The genotype and phenotype data represent a resource for conducting meta-analyses to derive a more precise pooled estimate of the effects of genes on the risk of hearing loss due to platinum treatment.
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http://dx.doi.org/10.1016/j.dib.2020.106227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477761PMC
October 2020

Usefulness of current candidate genetic markers to identify childhood cancer patients at risk for platinum-induced ototoxicity: Results of the European PanCareLIFE cohort study.

Eur J Cancer 2020 10 6;138:212-224. Epub 2020 Sep 6.

Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; Paediatric Oncology, Dept. of Paediatrics, Inselspital, University of Bern, Switzerland.

Background: Irreversible sensorineural hearing loss is a common side effect of platinum treatment with the potential to significantly impair the neurocognitive, social and educational development of childhood cancer survivors. Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The aim of this cross-sectional cohort study was to confirm the genetic associations in a large pan-European population and to evaluate the diagnostic accuracy of the genetic markers.

Methods: Eligibility criteria required patients to be aged less than 19 years at the start of chemotherapy, which had to include cisplatin and/or carboplatin. Patients were assigned to three phenotype categories: no, minor and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1 and ACYP2) were investigated. Multinomial logistic regression was performed to model the relationship between genetic predictors and platinum ototoxicity, adjusting for clinical risk factors. Additionally, measures of the diagnostic accuracy of the genetic markers were determined.

Results: 900 patients were included in this study. In the multinomial logistic regression, significant unique contributions were found from SLC22A2 rs316019, the age at the start of platinum treatment, cranial radiation and the interaction term [platinum compound]∗[cumulative dose of cisplatin]. The predictive performance of the genetic markers was poor compared with the clinical risk factors.

Conclusions: PanCareLIFE is the largest study of cisplatin-induced ototoxicity to date and confirmed a role for the polyspecific organic cation transporter SLC22A2. However, the predictive value of the current genetic candidate markers for clinical use is negligible, which puts the value of clinical factors for risk assessment of cisplatin-induced ototoxicity back into the foreground.
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http://dx.doi.org/10.1016/j.ejca.2020.07.019DOI Listing
October 2020

Smartphone App to Self-Monitor Nausea During Pediatric Chemotherapy Treatment: User-Centered Design Process.

JMIR Mhealth Uhealth 2020 07 20;8(7):e18564. Epub 2020 Jul 20.

Department of Clinical Pharmacology, Bispebjerg and Frederiksberg University Hospital, Copenhagen, Denmark.

Background: Nausea and vomiting are common and distressing side effects for children receiving chemotherapy. Limited evidence is available to guide antiemetic recommendations; therefore, prospective and reliable evaluation of antiemetic efficacy is needed. Smartphone apps can be used to effortlessly and precisely collect patient-reported outcomes in real time.

Objective: Our objective was to develop a smartphone app to monitor nausea and vomiting episodes in pediatric cancer patients aged 0 to 18 years and to test its usability and adherence to its use.

Methods: We used a user-centered design process and the evolutionary prototype model to develop and evaluate the app. Multidisciplinary group discussions and several rounds of patient feedback and modification were conducted. We translated the validated Pediatric Nausea Assessment Tool to assess nausea severity in children aged 4 to 18 years. The child's own term for nausea was interactively incorporated in the nausea severity question, with response options expressed as 4 illustrative faces. Parent-reported outcomes were used for children aged 0 to 3 years. Reminders were sent using push notifications in order to ensure high response rates. Children aged 0 to 18 years who were undergoing chemotherapy were recruited from the Department of Pediatric Oncology at Copenhagen University Hospital Rigshospitalet to evaluate the app.

Results: The app's most important function was to record nausea severity in children. After assistance from a researcher, children aged 4 to 18 years were able to report their symptoms in the app, and parents were able to report symptoms for their children aged 0 to 3 years. Children (n=20, aged 2.0-17.5 years) and their parents evaluated the app prospectively during a collective total of 60 chemotherapy cycles. They expressed that the app was user-friendly, intuitive, and that the time spent on data entry was fair. The response rates were on average 92%, 93%, and 80% for the day before, the first day of, and the next 3 days after chemotherapy, respectively. Researchers and clinicians were able to obtain an overview of the patient's chemotherapy dates and responses through a secure and encrypted web-based administrative portal. Data could be downloaded for further analysis.

Conclusions: The user-friendly app could be used to facilitate future pediatric antiemetic trials and to refine antiemetic treatment during chemotherapy.
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http://dx.doi.org/10.2196/18564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400028PMC
July 2020

Risk of late health effects after soft-tissue sarcomas in childhood - a population-based cohort study within the Adult Life after Childhood Cancer in Scandinavia research programme.

Acta Oncol 2020 Oct 21;59(10):1246-1256. Epub 2020 Jul 21.

Unit of Statistics and Pharmaco-epidemiology, Danish Cancer Society Research Center, Copenhagen, Denmark.

Background: In the 1960s only 1/3 of children with soft-tissue sarcomas survived, however with improved treatments survival today has reached 70%. Given the previous poor survival and the rarity of soft-tissue sarcomas, the risk of somatic late effects in a large cohort of Nordic soft-tissue sarcoma survivors has not yet been assessed.

Methods: In this population-based cohort study we identified 985 five-year soft-tissue sarcoma survivors in Nordic nationwide cancer registries and late effects in national hospital registries covering the period 1964-2012. Information on tumour site and radiotherapy was available for Danish and Finnish survivors ( = 531). Using disease-specific rates of first-time hospital contacts for somatic diseases in survivors and in 4,830 matched comparisons we calculated relative rates (RR) and rate differences (RD).

Results: Survivors had a RR of 1.5 (95% CI 1.4-1.7) and an absolute RD of 23.5 (17.7-29.2) for a first hospital contact per 1,000 person-years. The highest risks in both relative and absolute terms were of endocrine disorders (RR = 2.5; RD = 7.6), and diseases of the nervous system (RR = 1.9; RD = 6.6), digestive organs (RR = 1.7; RD = 5.4) and urinary system (RR = 1.7; RD = 5.6). By tumour site, excess risk was lower after extremity tumours. Irradiated survivors had a 2.6 (1.2-5.9) times higher risk than non-irradiated.

Conclusions: Soft-tissue sarcoma survivors have an increased risk of somatic late effects in 5 out of 10 main diagnostic groups of diseases, and the risk remains increased up to 40 years after cancer diagnosis. Risks were slightly lower for those treated for tumours in the extremities, and radiotherapy increased the risk by more than two-fold.
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http://dx.doi.org/10.1080/0284186X.2020.1794031DOI Listing
October 2020

Pharmacogenetics of antiemetics for chemotherapy-induced nausea and vomiting: A systematic review and meta-analysis.

Crit Rev Oncol Hematol 2020 May 4;149:102939. Epub 2020 Apr 4.

Department of Paediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark. Electronic address:

A substantial proportion of cancer patients experience chemotherapy-induced nausea and vomiting (CINV) despite the use of antiemetic drugs. Prevalent genetic polymorphisms involved in antiemetic drug metabolism, drug transport and receptor pathways likely affect the effectiveness of antiemetics. Knowledge on which polymorphisms to integrate into individualised clinical care is needed. We did a systematic review evaluating the association between polymorphisms and effectiveness of antiemetics in cancer patients receiving moderately to highly emetogenic chemotherapy. Twenty studies n = 2331 evaluated eight polymorphisms in five candidate genes involved in 5-HT antagonist pathways. HTR3C C1214G increased the risk of acute chemotherapy-induced vomiting in the dominant model (odds ratio (OR) = 2.67, 95 % confidence interval (CI): 1.08-6.63). ABCB1 C3435T reduced the risk of acute CINV in the recessive model (OR = 0.60, 95 % CI: 0.44-0.81). Future studies should evaluate candidate genes that affect pharmacogenetics of other antiemetics beside 5-HT antagonists.
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http://dx.doi.org/10.1016/j.critrevonc.2020.102939DOI Listing
May 2020

Genetic variation of cisplatin-induced ototoxicity in non-cranial-irradiated pediatric patients using a candidate gene approach: The International PanCareLIFE Study.

Pharmacogenomics J 2020 04 31;20(2):294-305. Epub 2019 Oct 31.

Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Ototoxicity is a common side effect of platinum treatment and manifests as irreversible, high-frequency sensorineural hearing loss. Genetic association studies have suggested a role for SNPs in genes related to the disposition of cisplatin or deafness. In this study, 429 pediatric patients that were treated with cisplatin were genotyped for 10 candidate SNPs. Logistic regression analyses revealed that younger age at treatment (≤5 years vs >15 years: OR: 9.1; 95% CI: 3.8-21.5; P = 5.6 × 10) and higher cumulative dose of cisplatin (>450 vs ≤300 mg/m: OR: 2.4; 95% CI: 1.3-4.6; P = 0.007) confer a significant risk of ototoxicity. Of the SNPs investigated, none of them were significantly associated with an increase of ototoxicity. In the meta-analysis, ACYP2 rs1872328 (OR: 3.94; 95% CI: 1.04-14.03; P = 0.04) and SLC22A2 rs316019 (OR: 1.46; 95% CI: 1.07-2.00; P = 0.02) were associated with ototoxicity. In order to increase the understanding of the association between SNPs and ototoxicity, we propose a polygenic model, which takes into account multiple interacting genes of the cisplatin pathway that together confer an increased risk of ototoxicity.
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http://dx.doi.org/10.1038/s41397-019-0113-1DOI Listing
April 2020

Improved Survival of Children, Adolescents, and Young Adults With Head and Neck Soft Tissue Sarcomas in Denmark.

J Pediatr Hematol Oncol 2020 04;42(3):175-180

Departments of Otorhinolaryngology, Head and Neck Surgery and Audiology.

Aim: The aim of this study was to estimate nationally the survival of children, adolescents, and young adults with head and neck soft tissue sarcomas.

Materials And Methods: The authors included patients 0 to 21 years of age and diagnosed with rhabdomyosarcoma (RMS) or nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) located in the head and neck between 1980 and 2014. Survival probabilities were estimated using the Kaplan-Meier method. The authors estimated the effect of covariates with univariate and multivariate Cox regression analyses. The cumulative recurrence in RMS was estimated when considering death as a competing risk.

Results: We identified 72 patients (50% male individuals, whereas 72% had RMS). Elder patients (older than 15 y) did worse compared with younger patients (log-rank test P=0.001). Patients diagnosed from 1980 to 1999 did worse than patients diagnosed from 2000 to 2014 (log-rank test P=0.02). Similarly, younger (younger than 15 y) patients did significantly better when diagnosed from 2000 to 2014 with reference to those diagnosed from 1980 to 1999 (log-rank test P=0.026). The multivariate hazard ratio was 0.46 (95% confidence interval, 0.23-0.92) for patients diagnosed from 2000 to 2014 with reference to patients diagnosed from 1980 to 1999. The 1-year cumulative recurrence for RMS was 21.2% (95% confidence interval, 12.3%-35.0%).

Conclusion: Overall survival has improved throughout the study period, which is attributable to advancement in diagnostics, treatment, and the application of standardized guidelines from international protocols.
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http://dx.doi.org/10.1097/MPH.0000000000001615DOI Listing
April 2020

Neurologic disorders in long-term survivors of neuroblastoma - a population-based cohort study within the Adult Life after Childhood Cancer in Scandinavia (ALiCCS) research program.

Acta Oncol 2020 Feb 8;59(2):134-140. Epub 2019 Oct 8.

Danish Cancer Society Research Center, Childhood Cancer Research Group, Copenhagen, Denmark.

Neuroblastoma is the commonest extracranial solid tumor of childhood, yet rare, and with poor survival before 1990, especially for high-risk disease; thus, information on late effects is sparse. With great advances in cancer treatment, survival has reached 80% in the Nordic countries. The aim of the study was to investigate the risk of developing neurologic disorders after neuroblastoma. Through population-based cancer registries of four Nordic countries we identified 654 5-year survivors of neuroblastoma (diagnosed 1959-2008) and 133,668 matched population comparisons. We grouped neurologic diagnoses from national hospital registries into 11 main diagnostic categories and 56 disease-specific sub-categories and calculated relative risks (RRs), absolute excess risks (AERs), cumulative incidence and mean cumulative count (MCC). Information on cancer treatment was available for 49% of survivors. A hospital contact for a neurologic disorder was observed in 181 survivors 5 years or more from cancer diagnosis with 59 expected, yielding a RR of 3.1 (95% CI 2.7-3.6) and an AER of 16 per 1,000 person-years (95% CI 12-19). The most frequent disorders included epilepsy, paralytic syndromes, diseases of the eyes and ears and hearing loss. The cumulative incidence of any neurologic disorder was 31% in survivors 20 years after cancer diagnosis with a MCC of 0.5 unique diagnoses. All risks were highest in survivors of high-risk neuroblastoma. Neuroblastoma survivors represent a population with a high risk of developing neurologic disorders. Our results should contribute to improving health care planning and underscores the need for systematic follow-up care of this vulnerable group of survivors.
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http://dx.doi.org/10.1080/0284186X.2019.1672892DOI Listing
February 2020

Genetic Determinants of Ototoxicity During and After Childhood Cancer Treatment: Protocol for the PanCareLIFE Study.

JMIR Res Protoc 2019 Mar 19;8(3):e11868. Epub 2019 Mar 19.

Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands.

Background: Survival rates after childhood cancer now reach nearly 80% in developed countries. However, treatments that lead to survival and cure can cause serious adverse effects with lifelong negative impacts on survivor quality of life. Hearing impairment is a common adverse effect in children treated with cisplatin-based chemotherapy or cranial radiotherapy. Ototoxicity can extend from high-tone hearing impairment to involvement of speech frequencies. Hearing impairment can impede speech and language and neurocognitive development. Although treatment-related risk factors for hearing loss following childhood cancer treatment have been identified, the individual variability in toxicity of adverse effects after similar treatment between childhood cancer patients suggests a role for genetic susceptibility. Currently, 12 candidate gene approach studies have been performed to identify polymorphisms predisposing to platinum-induced ototoxicity in children being treated for cancer. However, results were inconsistent and most studies were underpowered and/or lacked replication.

Objective: We describe the design of the PanCareLIFE consortium's work packages that address the genetic susceptibility of platinum-induced ototoxicity.

Methods: As a part of the PanCareLIFE study within the framework of the PanCare consortium, we addressed genetic susceptibility of treatment-induced ototoxicity during and after childhood cancer treatment in a large European cohort by a candidate gene approach and a genome-wide association screening.

Results: This study included 1124 survivors treated with cisplatin, carboplatin, or cranial radiotherapy for childhood cancer, resulting in the largest clinical European cohort assembled for this late effect to date. Within this large cohort we defined a group of 598 cisplatin-treated childhood cancer patients not confounded by cranial radiotherapy. The PanCareLIFE initiative provided, for the first time, a unique opportunity to confirm already identified determinants for hearing impairment during childhood cancer using a candidate gene approach and set up the first international genome-wide association study of cisplatin-induced direct ototoxicity in childhood cancer patients to identify novel allelic variants. Results will be validated in an independent replication cohort. Patient recruitment started in January 2015 and final inclusion was October 2017. We are currently performing the analyses and the first results are expected by the end of 2019 or the beginning of 2020.

Conclusions: Genetic factors identified as part of this pan-European project, PanCareLIFE, may contribute to future risk prediction models that can be incorporated in future clinical trials of platinum-based therapies for cancer and may help with the development of prevention strategies.

International Registered Report Identifier (irrid): DERR1-10.2196/11868.
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http://dx.doi.org/10.2196/11868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444213PMC
March 2019

Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort.

Eur J Cancer 2019 03 25;109:36-50. Epub 2019 Jan 25.

CDC MRC Clinical Trials Unit at UCL, London, UK.

Background: High-grade osteosarcoma is a primary malignant bone tumour mainly affecting children and young adults. The European and American Osteosarcoma Study (EURAMOS)-1 is a collaboration of four study groups aiming to improve outcomes of this rare disease by facilitating randomised controlled trials.

Methods: Patients eligible for EURAMOS-1 were aged ≤40 years with M0 or M1 skeletal high-grade osteosarcoma in which case complete surgical resection at all sites was deemed to be possible. A three-drug combination with methotrexate, doxorubicin and cisplatin was defined as standard chemotherapy, and between April 2005 and June 2011, 2260 patients were registered. We report survival outcomes and prognostic factors in the full cohort of registered patients.

Results: For all registered patients at a median follow-up of 54 months (interquartile range: 38-73) from biopsy, 3-year and 5-year event-free survival were 59% (95% confidence interval [CI]: 57-61%) and 54% (95% CI: 52-56%), respectively. Multivariate analyses showed that the most adverse factors at diagnosis were pulmonary metastases (hazard ratio [HR] = 2.34, 95% CI: 1.95-2.81), non-pulmonary metastases (HR = 1.94, 95% CI: 1.38-2.73) or an axial skeleton tumour site (HR = 1.53, 95% CI: 1.10-2.13). The histological subtypes telangiectatic (HR = 0.52, 95% CI: 0.33-0.80) and unspecified conventional (HR = 0.67, 95% CI: 0.52-0.88) were associated with a favourable prognosis compared with chondroblastic subtype. The 3-year and 5-year overall survival from biopsy were 79% (95% CI: 77-81%) and 71% (95% CI: 68-73%), respectively. For patients with localised disease at presentation and in complete remission after surgery, having a poor histological response was associated with worse outcome after surgery (HR = 2.13, 95% CI: 1.76-2.58). In radically operated patients, there was no good evidence that axial tumour site was associated with worse outcome.

Conclusions: In conclusion, data from >2000 patients registered to EURAMOS-1 demonstrated survival rates in concordance with institution- or group-level osteosarcoma trials. Further efforts are required to drive improvements for patients who can be identified to be at higher risk of adverse outcome. This trial reaffirms known prognostic factors, and owing to the large numbers of patients registered, it sheds light on some additional factors to consider.
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http://dx.doi.org/10.1016/j.ejca.2018.11.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506906PMC
March 2019

[Insufficient evidence in prophylactic therapy of chemotherapy-induced nausea and vomiting in children and adolescents].

Ugeskr Laeger 2018 Aug;180(35)

Nausea and vomiting are burdensome side effects of chemotherapy. Vomiting is observed in up to 60% of treated children. An appropriate and effective antiemetic regimen has the potential to eradicate or reduce the symptoms. Differences in local guidelines characterise the antiemetic treatment across the four Danish paediatric oncology departments because the overall knowledge of the most effective antiemetics is incomplete. There is an unmet need for research, which can promote evidence-based guidelines. The impact of host genome polymorphisms should be included in the research.
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August 2018

Somatic late effects in 5-year survivors of neuroblastoma: a population-based cohort study within the Adult Life after Childhood Cancer in Scandinavia study.

Int J Cancer 2018 12 16;143(12):3083-3096. Epub 2018 Oct 16.

Danish Cancer Society, Danish Cancer Society Research Center, Copenhagen, Denmark.

Because of the rarity of neuroblastoma and poor survival until the 1990s, information on late effects in neuroblastoma survivors is sparse. We comprehensively reviewed the long-term risk for somatic disease in neuroblastoma survivors. We identified 721 5-year survivors of neuroblastoma in Nordic population-based cancer registries and identified late effects in national hospital registries covering the period 1977-2012. Detailed treatment information was available for 46% of the survivors. The disease-specific rates of hospitalization of survivors and of 152,231 randomly selected population comparisons were used to calculate standardized hospitalization rate ratios (SHRRs) and absolute excess risks (AERs). During 5,500 person-years of follow-up, 501 5-year survivors had a first hospital contact yielding a SHRR of 2.3 (95% CI 2.1-2.6) and a corresponding AER of 52 (95% CI 44-60) per 1,000 person-years. The highest relative risks were for diseases of blood and blood-forming organs (SHRR 3.8; 95% CI 2.7-5.4), endocrine diseases (3.6 [3.1-4.2]), circulatory system diseases (3.1 [2.5-3.8]), and diseases of the nervous system (3.0 [2.6-3.3]). Approximately 60% of the excess new hospitalizations of survivors were for diseases of the nervous system, urinary system, endocrine system, and bone and soft tissue. The relative risks and AERs were highest for the survivors most intensively treated. Survivors of neuroblastoma have a highly increased long-term risk for somatic late effects in all the main disease groups as compared to background levels. Our results are useful for counseling survivors and should contribute to improving health care planning in post-therapy clinics.
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http://dx.doi.org/10.1002/ijc.31631DOI Listing
December 2018

Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss.

N Engl J Med 2018 Jun;378(25):2376-2385

From Great Ormond Street Hospital, London (P.R.B., K.R., D.R.), Nottingham Clinical Trials Unit, Nottingham (M. Childs), Royal Hospital for Sick Children, Glasgow (M.R.), Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne (G.J.V.), and University of Birmingham, Birmingham (B.M.) - all in the United Kingdom; International Breast Cancer Study Group, Bern (R.M.), and Hôpital Universitaire de Genève, Geneva (M.A.) - both in Switzerland; University of Melbourne, Melbourne, VIC, Australia (M.J.S.); University of Otago, Christchurch (M.J.S.), and Starship Children's Hospital, Auckland (J.S.) - both in New Zealand; Centre Hospitalier Universitaire, Besançon (V.L.), and Institut de Cancerologie Gustave Roussy, Villejuif (L.B.) - both in France; University of Padua, Padua (P.D., G.P.), and Consorzio Interuniversitario (CINECA), Bologna (A.C.) - both in Italy; Hiroshima University, Hiroshima, Japan (E.H.); Cliniques Universitaires Saint Luc, Brussels (B.B.); University Hospital Reina Sofia, Cordoba, Spain (M.E.M.); Our Lady's Children's Hospital, Dublin (M. Capra); Stanford University Medical Center, Palo Alto, CA (A.A.R.); University Hospital Rigshospitalet, Copenhagen (C.R.); Medical University of Gdansk, Gdansk, Poland (P.C.); and Oregon Health and Science University, Portland (E.A.N.).

Background: Cisplatin chemotherapy and surgery are effective treatments for children with standard-risk hepatoblastoma but may cause considerable and irreversible hearing loss. This trial compared cisplatin with cisplatin plus delayed administration of sodium thiosulfate, aiming to reduce the incidence and severity of cisplatin-related ototoxic effects without jeopardizing overall and event-free survival.

Methods: We randomly assigned children older than 1 month and younger than 18 years of age who had standard-risk hepatoblastoma (≤3 involved liver sectors, no metastatic disease, and an alpha-fetoprotein level of >100 ng per milliliter) to receive cisplatin alone (at a dose of 80 mg per square meter of body-surface area, administered over a period of 6 hours) or cisplatin plus sodium thiosulfate (at a dose of 20 g per square meter, administered intravenously over a 15-minute period, 6 hours after the discontinuation of cisplatin) for four preoperative and two postoperative courses. The primary end point was the absolute hearing threshold, as measured by pure-tone audiometry, at a minimum age of 3.5 years. Hearing loss was assessed according to the Brock grade (on a scale from 0 to 4, with higher grades indicating greater hearing loss). The main secondary end points were overall survival and event-free survival at 3 years.

Results: A total of 109 children were randomly assigned to receive cisplatin plus sodium thiosulfate (57 children) or cisplatin alone (52) and could be evaluated. Sodium thiosulfate was associated with few high-grade toxic effects. The absolute hearing threshold was assessed in 101 children. Hearing loss of grade 1 or higher occurred in 18 of 55 children (33%) in the cisplatin-sodium thiosulfate group, as compared with 29 of 46 (63%) in the cisplatin-alone group, indicating a 48% lower incidence of hearing loss in the cisplatin-sodium thiosulfate group (relative risk, 0.52; 95% confidence interval [CI], 0.33 to 0.81; P=0.002). At a median of 52 months of follow-up, the 3-year rates of event-free survival were 82% (95% CI, 69 to 90) in the cisplatin-sodium thiosulfate group and 79% (95% CI, 65 to 88) in the cisplatin-alone group, and the 3-year rates of overall survival were 98% (95% CI, 88 to 100) and 92% (95% CI, 81 to 97), respectively.

Conclusions: The addition of sodium thiosulfate, administered 6 hours after cisplatin chemotherapy, resulted in a lower incidence of cisplatin-induced hearing loss among children with standard-risk hepatoblastoma, without jeopardizing overall or event-free survival. (Funded by Cancer Research UK and others; SIOPEL 6 ClinicalTrials.gov number, NCT00652132 ; EudraCT number, 2007-002402-21 .).
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http://dx.doi.org/10.1056/NEJMoa1801109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117111PMC
June 2018

Importance of Comprehensive Molecular Profiling for Clinical Outcome in Children With Recurrent Cancer.

Front Pediatr 2018 20;6:114. Epub 2018 Apr 20.

Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark.

Pediatric cancers are often difficult to classify and can be complex to treat. To ensure precise diagnostics and identify relevant treatment targets, we implemented comprehensive molecular profiling of consecutive pediatric patients with cancer relapse. We evaluated the clinical impact of extensive molecular profiling by assessing the frequency of identified biological onco-drivers, altered diagnosis, and/or identification of new relevant targeted therapies. Forty-six tumor samples (44 fresh-frozen; two formalin-fixed paraffin embedded), two bone marrow aspirates, three cerebrospinal fluid samples, and one archived DNA were obtained from 48 children (0-17 years; median 9.5) with relapsed or refractory cancer, where the disease was rapidly progressing in spite of their current treatment or they had exhausted all treatment options. The samples were analyzed by whole-exome sequencing (WES), RNA sequencing (RNAseq), transcriptome arrays, and SNP arrays. Final reports were available within 3-4 weeks after patient inclusion and included mutation status, a description of copy number alterations, differentially expressed genes, and gene fusions, as well as suggestions for targeted treatment. Of the 48 patients, 33 had actionable findings. The most efficient method for the identification of actionable findings was WES (39%), followed by SNP array (37%). Of note, gene fusions were identified by RNAseq in 21% of the samples. Eleven findings led to clinical intervention, i.e., oncogenetic counseling, targeted treatment, and treatment based on changed diagnosis. Four patients received compassionate use targeted therapy. Six patients experienced direct benefits in the form of stable disease or response. The application of comprehensive genetic diagnostics in children with recurrent cancers allowed for discovery and implementation of effective targeted therapies and hereby improvement of outcome in some patients.
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http://dx.doi.org/10.3389/fped.2018.00114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920151PMC
April 2018

Incidence of head and neck cancer in children: A Danish nationwide study from 1978 to 2014.

Pediatr Blood Cancer 2018 07 30;65(7):e27037. Epub 2018 Mar 30.

Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Background: Pediatric head and neck malignancies are rare and only a few descriptive epidemiological studies have been published. Using unique nationwide registries, we report age-specific incidence rates of head and neck cancer (HNC) among children during four decades.

Methods: Data were obtained from the Danish Cancer Registry. We included children aged 0-14 years diagnosed between January 1, 1978 and December 31, 2014 with extra-orbital, nonskin and nonbone HNC. Patients were divided into nine groups in regard to tumor location: oral cavity, oropharynx, nasopharynx, hypopharynx, thyroid, major salivary glands, larynx, and middle ear. Based on the World Health Organization standard population and Danish age-specific population counts, age-adjusted incidence rates (AAIR) and average annual percentage change (AAPC) were calculated and examined for trends.

Results: In total, 169 children (55.6% females) were registered with a malignant tumor in the head and neck region. The AAIR increased with an AAPC of 2.2% (95% CI, 0.8-3.7%). Females showed an AAIR of 0.54 per 100,000 person years compared to that of males, with 0.41 per 100,000 person years (P < 0.01). The AAIR was higher among children aged 10-14 years compared to 0-9-year-old children (P < 0.01). Based on morphology, a significant increase in AAIR was observed for sarcomas, with an increase of 0.16-0.27 per 100,000 person years (P < 0.05).

Conclusions: The incidence rate of pediatric HNC was higher among females and evidence of increasing rates was observed during 1978-2014, explained by an increase mainly in sarcomas.
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http://dx.doi.org/10.1002/pbc.27037DOI Listing
July 2018

Survival and prognostic factors at time of diagnosis in high-grade appendicular osteosarcoma: a 21 year single institution evaluation from east Denmark.

Acta Oncol 2018 Mar 25;57(3):420-425. Epub 2017 Jul 25.

a The Musculoskeletal Tumour Section, The Department of Orthopedics, Rigshospitalet , University of Copenhagen , Copenhagen , Denmark.

Background: Survival of patients with high-grade osteosarcoma (HOS), the most common primary bone cancer, has not improved significantly the last 30 years and the disease remains a major challenge. The purpose of this study is to evaluate survival in relation to prognostic factors at time of diagnosis among patients diagnosed with primary appendicular HOS in East Denmark between 1990 and 2010.

Material And Methods: 101 patients (median age = 20 years, female/male ratio = 56/45) diagnosed with primary appendicular high-grade osteosarcoma between 1990 and 2010 were included in this study. Initially, 156 patients diagnosed with osteosarcoma between 1990 and 2010 were identified through the population based Regional Database of Pathology, which covers a population of approximately 2.7 million (east Denmark). 55 patients were excluded due to (A) tumor was low grade (n = 22), (B) located in axial skeleton (n = 18), (C) incorrect diagnosis (n = 11) or (D) biopsy represented a tumor relapse from a former primary osteosarcoma (n = 4). Overall survival was evaluated using the Kaplan-Meier survival analysis and log-rank test. Prognostic factors were analyzed using uni- and multivariate cox-regression method with variables scored equally in the model. p Values <.05 were considered statistically significant.

Results: The probability of 5- and 10-year survival was 51% (95% CI: 41-61) and 46% (95% CI: 36-56), respectively. Metastatic stage at diagnosis and tumor size ≥10 cm measured radiologically at the largest diameter were independent prognostic factors for decreased survival with significant increased hazard-risks of 3.5 (95% CI: 1.9-6.5) and 1.97 (95% CI: 1.1-3.6), respectively.

Discussion: In this single institution evaluation of primary appendicular HOS we found 5-and 10-year survival rates consistent with international standards for this patient group. Distant metastases and tumor size ≥10 cm at the time of diagnosis were independent prognostic factors for decreased survival in our cohort. These results underline the importance of awareness and early referral from the primary sector.
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http://dx.doi.org/10.1080/0284186X.2017.1351620DOI Listing
March 2018

Epidemiological study of paediatric germ cell tumours revealed the incidence and distribution that was expected, but a low mortality rate.

Acta Paediatr 2017 May 22;106(5):779-785. Epub 2017 Feb 22.

Department of Paediatric and Adolescent Haematology and Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Aim: Germ cell tumours (GCTs) are a rare heterogeneous tumour group derived from primordial germ cells, which can be benign or malignant and occur in the gonads or extragonadally. This study mapped the paediatric GCTs in Denmark from 1984 to 2013 to study the incidence and outcome.

Methods: We identified paediatric GCTs from the Danish Childhood Cancer and National Pathology Registries and reviewed the case records for patient characteristics, tumour characteristics and clinical outcome.

Results: We identified 403 (71% female) paediatric GCTs and the crude incidence was 1.43 per 100 000. Of these, 79 (20%) were malignant, 39 (10%) were potentially malignant and 285 (70%) were benign. Extragonadal GCTs (39%) were mainly observed in early childhood and were predominately sacrococcygeal teratomas. Gonadal GCTs (61%) in late childhood were most frequently mature teratomas in the ovaries. Nearly all patients underwent surgery. Of the malignant tumours, 62% were treated with chemotherapy. Radiotherapy was only administered to intracranial GCTs. In the cohort, 12 patients died (3%).

Conclusion: Paediatric GCTs in Denmark were mainly benign and mortality was low, even for malignant tumours. We identified a peak of extragonadal GCTs in early childhood and a peak of gonadal GCTs in late childhood, which was comparable to previous reports.
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http://dx.doi.org/10.1111/apa.13767DOI Listing
May 2017

Danish Childhood Cancer Registry.

Clin Epidemiol 2016 25;8:461-464. Epub 2016 Oct 25.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.

Aim Of Database: The overall aim is to monitor the quality of childhood cancer care in Denmark; to register late effects of treatment; to analyze complications of permanent central venous catheters (CVCs); to study blood stream infections in children with cancer; and to study acute toxicity of high-dose methotrexate infusions in children with leukemia.

Study Population: All children below 15 years of age at diagnosis living in Denmark diagnosed after January 1, 1985 according to the International Classification of Diseases 10, including diagnoses DC00-DD48.

Main Variables: Cancer type, extent of disease, treatment, participation in international studies, recurrence of malignant disease, survival, yearly follow-up status, causes of death, and development of secondary malignancies. Type of CVC, causes for removal of the CVC, type of blood stream infection, pathogens isolated, antimicrobial sensitivity, and outcome of antimicrobial chemotherapy.

Descriptive Data: Since 1985, 4,944 children below 15 years of age have been registered in the database. There has been no significant change in the incidence of childhood cancer in Denmark since 1985. The 5-year survival has increased significantly since 1985 and is now 86%. The median number of days from diagnosis to initiation of therapy is 7 days and in 80% of the children less than 14 days. Clinical data of 95% of the patients are reported to open international studies.

Conclusion: The survival of Danish children with cancer since 2003 compares favorably with other international population-based studies. The annual reports support the collaboration within pediatric oncology in Denmark.
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http://dx.doi.org/10.2147/CLEP.S99508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5094529PMC
October 2016

Effect of first line cancer treatment on the ovarian reserve and follicular density in girls under the age of 18 years.

Fertil Steril 2016 Dec 4;106(7):1757-1762.e1. Epub 2016 Oct 4.

Laboratory of Reproductive Biology, Juliane Marie Centre for Women, Children and Reproduction, Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Objective: To study the impact of first-line antineoplastic treatment on ovarian reserve in young girls returning for ovarian tissue cryopreservation (OTC) in connection with a relapse.

Design: Retrospective case-control study.

Setting: University hospitals.

Patient(s): Sixty-three girls under the age of 18 years who underwent OTC before (group 1: 31 patients) and after (group 2: 32 patients) their initial cancer treatment.

Intervention(s): None.

Main Outcome Measure(s): Follicular densities (follicles/mm) measured from an ovarian cortical biopsy before OTC. The ovarian volume (mL) of entire ovaries excised for OTC was also monitored.

Result(s): There was no statistically significant difference in the mean age or follicular density between groups 1 and 2 (334 ± 476/mm vs. 327 ± 756/mm). In contrast, the ovarian volume and total number of ovarian cortex chips cryopreserved were statistically significantly lower in patients who received gonadotoxic treatment before OTC (mean ± standard deviation [SD]: ovarian volume, 5.3 ± 3.1 mL vs. 2.9 ± 2.1 mL, respectively; number of cortex chips: 21.3 ± 8.1 vs. 15.2 ± 7.1, respectively). The reduction in the estimated ovarian reserve ranged from 10% to 20% in children to around 30% in adolescent girls (>10 years).

Conclusion(s): Girls under the age of 10 tolerate a gonadotoxic insult better than adolescents, who may experience up to a 30% reduction in the ovarian reserve via first-line gonadotoxic treatment, which at present is considered to have little effect on the follicle pool. This information will improve counseling of young female cancer patients in deciding whether to undergo fertility preservation treatment.
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http://dx.doi.org/10.1016/j.fertnstert.2016.09.001DOI Listing
December 2016

Nonparameningeal head and neck rhabdomyosarcoma in children and adolescents: Lessons from the consecutive International Society of Pediatric Oncology Malignant Mesenchymal Tumor studies.

Head Neck 2017 01 26;39(1):24-31. Epub 2016 Jul 26.

School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.

Background: This article reports risk factors and long-term outcome in localized nonparameningeal head and neck rhabdomyosarcomas in children and adolescents from a combined dataset from 3 consecutive international trials.

Methods: Data from 140 children (9.3% of total) prospectively enrolled in the International Society of Pediatric Oncology Malignant Mesenchymal Tumor (SIOP-MMT)-84/89/95 studies were analyzed.

Results: Primary site was: superficial face in 46%; oral cavity (21%); neck (19%); and salivary glands (14%). Local control was achieved in 96%, but 49% relapsed (locoregionally 91%). At median follow-up of 10 years, 5-year overall survival (OS) was 74.7% (67.4% to 81.9%) and event-free survival 48.9% (40.6% to 57.2%), although this improved with successive studies. Radiotherapy (RT) as first-line treatment was independently prognostic for event-free survival (relative risk [RR] = 0.4 [range, 0.2-0.7]; p < .01) even if it did not impact OS (RR = 1 [range, 0.5-2]).

Conclusion: High rates of locoregional relapse were seen in head and neck rhabdomyosarcoma that should be prevented by more frequent use of RT in this primary. © 2016 Wiley Periodicals, Inc. Head Neck 39: 24-31, 2017.
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http://dx.doi.org/10.1002/hed.24547DOI Listing
January 2017

Expression pattern of clinically relevant markers in paediatric germ cell- and sex-cord stromal tumours is similar to adult testicular tumours.

Virchows Arch 2014 Nov 30;465(5):567-77. Epub 2014 Jul 30.

Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Paediatric germ cell tumours (GCTs) are rare and account for less than 3 % of childhood cancers. Like adult GCTs, they probably originate from primordial germ cells, but the pattern of histopathological types is different, and they occur predominantly in extragonadal sites along the body midline. Because they are rare, histology of paediatric GCTs is poorly documented, and it remains unclear to what extent they differ from adult GCTs. We have analysed 35 paediatric germ cell tumours and 5 gonadal sex-cord stromal tumours from prepubertal patients aged 0-15 years, to gain further knowledge, elaborate on clinical-pathological associations and better understand their developmental divergence. The tumours were screened for expression of stemness-related factors (OCT4, AP-2γ, SOX2), classical yolk sac tumours (YSTs; AFP, SALL4), GCTs (HCG, PLAP, PDPN/D2-40), as well as markers for sex-cord stromal tumour (PDPN, GATA4). All YSTs expressed AFP and SALL4, with GATA4 present in 13/14. The majority of teratomas expressed SOX2 and PDPN, whereas SALL4 was found in 8/13 immature teratomas. Adult seminoma markers AP-2γ, OCT4, SALL4 and PDPN were all expressed in dysgerminoma. We further report a previously unrecognised pathogenetic relationship between AFP and SALL4 in YST in that different populations of YST cells express either SALL4 or AFP, which suggests variable differentiation status. We also show that AP-2γ is expressed in the granulosa layer of ovarian follicles and weakly expressed in immature but not in mature granulosa cell tumours. Our findings indicate that the expression pattern of these antigens is similar between paediatric and adult GCTs, even though they develop along different developmental trajectories.
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http://dx.doi.org/10.1007/s00428-014-1635-1DOI Listing
November 2014

A novel DICER1 mutation identified in a female with ovarian Sertoli-Leydig cell tumor and multinodular goiter: a case report.

J Med Case Rep 2014 Apr 3;8:112. Epub 2014 Apr 3.

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Introduction: Germ-line mutations in the micro-ribonucleic acid processing gene DICER1 have been shown to predispose to a subset of benign tumors susceptible to malignant transformation, including ovarian Sertoli-Leydig cell tumor, nontoxic multinodular goiter, multilocular cystic nephroma and pleuropulmonary blastoma, which can occur in children and young adults. This may be due to reduced Dcr-1 homolog expression in carriers of germline mutations, which causes impairment of micro-ribonucleic acid processing and deregulates the growth and differentiation of target cells, leading to an increased risk of tumorigenesis. Many carriers of germ-line DICER1 mutations remain unaffected, but development of tumors within carriers is associated with varying prognoses.

Case Presentation: Despite the Dcr-1 homolog syndrome phenotype being incompletely defined, a DICER1 mutation was suspected when a girl (case 1 patient) of Danish ethnicity presented with both an ovarian Sertoli-Leydig cell tumor and a multinodular goiter at the age of 13 years. In addition, family history included a male sibling (case 2 patient) who also had a multinodular goiter and had undergone a hemithyroidectomy at the age of 14 years. Subsequent DICER1 screening of the girl identified two novel mutations in exon 21 - a nonsense (c.3647C>A, p.Ser1216*) and a missense (c.3649T>A, p.Tyr1217Asn) mutation. The siblings had inherited the mutations from their father and paternal grandfather, which both currently were asymptomatic, indicating reduced penetrance of the nonsense mutation. Analysis of the parents revealed that the mutations were present in cis, making the contribution of the missense mutation less significant.

Conclusion: We report a novel pathogenic DICER1 mutation (p.Ser1216*) in a Danish family associated with ovarian Sertoli-Leydig cell tumor and a multinodular goiter. A multinodular goiter was diagnosed in the siblings during childhood. Clinicians should be aware of a potential germ-line DICER1 mutation when evaluating multinodular goiter in young patients with or without a family history of thyroid diseases.
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http://dx.doi.org/10.1186/1752-1947-8-112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234993PMC
April 2014

Recent advances in understanding the etiology and pathogenesis of pediatric germ cell tumors.

J Pediatr Hematol Oncol 2014 May;36(4):263-70

*Department of Growth and Reproduction †Department of Pediatrics, University Hospital of Rigshospitalet, Copenhagen ‡Department of Pediatrics, University Hospital of Hilleroed, Hilleroed, Denmark.

Pediatric germ cell tumors (GCTs) are rare neoplasms arising predominantly in the gonads and sacrococcygeal, mediastinal, and intracranial localizations. In this article, we review current knowledge of pathogenesis of pediatric GCTs, which differs from adult/adolescent GCTs. One distinctive feature is the absence of a progenitor stage, such as carcinoma in situ or gonadoblastoma, which are seen in adult/adolescent GCTs, except spermatocytic seminoma. The primordial germ cell (PGC) is the suggested origin of all GCTs, with variations in histology reflecting differentiation stage. Expression of pluripotency transcription factors OCT-3/4, NANOG, and AP-2γ in germinomas/seminomas/dysgerminomas is consistent with retaining a germ cell phenotype. Teratomas, in contrast, develop through a pathway of aberrant somatic differentiation of immature germ cells, and the yolk sac tumors and choriocarcinomas result from abnormal extraembryonic differentiation. In pediatric GCTs, origin is suggested at an earlier developmental stage because of predisposing genetic factors, although responsible genes remain largely unknown. Some extragonadal GCTs have been linked to overexpression of the KIT/KITLG system, allowing for survival of aberrantly migrated ectopic PGCs. Infant gonadal/sacrococcygeal GCTs may be caused by apoptosis-related pathways, consistent with an association with polymorphisms in BAK1. Although recent advances have identified candidate pathways, further effort is needed to answer central questions of pathogenesis of these fascinating tumors.
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http://dx.doi.org/10.1097/MPH.0000000000000125DOI Listing
May 2014

Effectiveness of propanolol for treatment of infantile haemangioma.

Dan Med J 2014 Feb;61(2):A4776

Lybækgade 3, 4. tv., 2300 Copenhagen S, Denmark.

Introduction: Infantile haemangiomas (IH) are the most common benign tumours in children. They are characterised by rapid growth during the first year of life followed by spontaneous regression during childhood. Indications for treatment are functional impairment, bleeding/ulceration, rapid growth and severe aesthetic risk. Recently, systemic treatment with propranolol has become the first-line therapy. The objective of this study was to assess the efficacy of propranolol in the treatment of IH and to investigate whether treatment with a low dose of 1 mg/kg/day was sufficient.

Material And Methods: This study was retrospective and based on a review of children treated for IH with propranolol from the 2010-2012 period at Rigshospitalet.

Results: Overall, propranolol was effective in all but one child (97%). The majority of the children (84%) were treated with an initial dose of 1 mg/kg/day, which was considered sufficient in most cases (71%). Children who started treatment before five months of age had a significantly better response than children who started treatment at a later age. No relation was found between location of IH and the effect of treatment. There were only few and mild side effects.

Conclusion: Propranolol is effective in the treatment of IH and it has only few and mild side effects. In most cases, a low dose of 1 mg/kg/day was sufficient. Early initiation of treatment is recommended as the response to treatment was better in younger children and because early initiation helps prevent large residual changes.

Funding: not relevant.

Trial Registration: not relevant.
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February 2014
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