Time to diagnosis among young patients with cancer.

BACKGROUND: Sociodemographic and clinical factors associated with diagnostic delays in pediatric, adolescent, and young adult cancers are poorly understood. METHODS: Using the Optum Labs Data Warehouse's de-identified claims data for commercial health plan enrollees, we identified children (0-14 years) and adolescents/young adults (AYAs) (15-39 years) diagnosed with one of 10 common cancers from 2001 to 2017, who were continuously enrolled for 6 months preceding diagnosis. Time to diagnosis was calculated as days between first medical encounter with possible cancer symptoms and cancer diagnosis date. Median times from first symptom to diagnosis were compared using Wilcoxon rank sum test. Multivariable unconditional logistic regression identified sociodemographic factors associated with longer time (>3 months) to cancer diagnosis (from symptom onset). RESULTS: Of 47,296 patients, 87% presented prior to diagnosis with symptoms. Patients with central nervous system (CNS) tumors were most likely to present with symptoms (93%), whereas patients with cervical cancer were least likely (70%). Symptoms varied by malignancy. Of patients with symptoms, thyroid (105 days [range: 50-154]) and cervical (104 days [range: 41-151]) cancer had the longest median time to diagnosis. Females and patients at either end of the age spectrum were more likely to experience diagnosis delays of more than 3 months. CONCLUSION: In a commercially insured population, time to diagnosis varies by cancer type, age, and sex. Further work is needed to understand the patient, provider, and health system-level factors contributing to time from symptom onset to diagnosis, specifically in the very young children and the young adult patient population going forward.

Defining the cellular origin of seminoma by transcriptional and epigenetic mapping to the normal human germline.

Aberrant male germline development can lead to the formation of seminoma, a testicular germ cell tumor. Seminomas are biologically similar to primordial germ cells (PGCs) and many bear an isochromosome 12p [i(12p)] with two additional copies of the short arm of chromosome 12. By mapping seminoma transcriptomes and open chromatin landscape onto a normal human male germline trajectory, we find that seminoma resembles premigratory/migratory PGCs; however, it exhibits enhanced germline and pluripotency programs and upregulation of genes involved in apoptosis, angiogenesis, and MAPK/ERK pathways. Using pluripotent stem cell-derived PGCs from Pallister-Killian syndrome patients mosaic for i(12p), we model seminoma and identify gene dosage effects that may contribute to transformation. As murine seminoma models do not exist, our analyses provide critical insights into genetic, cellular, and signaling programs driving seminoma transformation, and the in vitro platform developed herein permits evaluation of additional signals required for seminoma tumorigenesis.

A 20-year overview of fertility preservation in boys: new insights gained through a comprehensive international survey.

STUDY QUESTION: Twenty years after the inception of the first fertility preservation programme for pre-pubertal boys, what are the current international practices with regard to cryopreservation of immature testicular tissue? SUMMARY ANSWER: Worldwide, testicular tissue has been cryopreserved from over 3000 boys under the age of 18 years for a variety of malignant and non-malignant indications; there is variability in practices related to eligibility, clinical assessment, storage, and funding. WHAT IS KNOWN ALREADY: For male patients receiving gonadotoxic treatment prior to puberty, testicular tissue cryopreservation may provide a method of fertility preservation. While this technique remains experimental, an increasing number of centres worldwide are cryopreserving immature testicular tissue and are approaching clinical application of methods to use this stored tissue to restore fertility. As such, standards for quality assurance and clinical care in preserving immature testicular tissue should be established. STUDY DESIGN SIZE DURATION: A detailed survey was sent to 17 centres within the recently established ORCHID-NET consortium, which offer testicular tissue cryopreservation to patients under the age of 18 years. The study encompassed 60 questions and remained open from 1 July to 1 November 2022. PARTICIPANTS/MATERIALS SETTING METHODS: Of the 17 invited centres, 16 completed the survey, with representation from Europe, Australia, and the USA. Collectively, these centres have cryopreserved testicular tissue from patients under the age of 18 years. Data are presented using descriptive analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Since the establishment of the first formal fertility preservation programme for pre-pubertal males in 2002, these 16 centres have cryopreserved tissue from 3118 patients under the age of 18 years, with both malignant (60.4%) and non-malignant (39.6%) diagnoses. All centres perform unilateral biopsies, while 6/16 sometimes perform bilateral biopsies. When cryopreserving tissue, 9/16 centres preserve fragments sized ≤5 mm3 with the remainder preserving fragments sized 6-20 mm3. Dimethylsulphoxide is commonly used as a cryoprotectant, with medium supplements varying across centres. There are variations in funding source, storage duration, and follow-up practice. Research, with consent, is conducted on stored tissue in 13/16 centres. LIMITATIONS REASONS FOR CAUTION: While this is a multi-national study, it will not encompass every centre worldwide that is cryopreserving testicular tissue from males under 18 years of age. As such, it is likely that the actual number of patients is even higher than we report. Whilst the study is likely to reflect global practice overall, it will not provide a complete picture of practices in every centre. WIDER IMPLICATIONS OF THE FINDINGS: Given the research advances, it is reasonable to suggest that cryopreserved immature testicular tissue will in the future be used clinically to restore fertility. The growing number of patients undergoing this procedure necessitates collaboration between centres to better harmonize clinical and research protocols evaluating tissue function and clinical outcomes in these patients. STUDY FUNDING/COMPETING INTERESTS: K.D. is supported by a CRUK grant (C157/A25193). R.T.M. is supported by an UK Research and Innovation (UKRI) Future Leaders Fellowship (MR/S017151/1). The MRC Centre for Reproductive Health at the University of Edinburgh is supported by MRC (MR/N022556/1). C.L.M. is funded by Kika86 and ZonMW TAS 116003002. A.M.M.v.P. is supported by ZonMW TAS 116003002. E.G. was supported by the Research Program of the Research Foundation-Flanders (G.0109.18N), Kom op tegen Kanker, the Strategic Research Program (VUB_SRP89), and the Scientific Fund Willy Gepts. J.-B.S. is supported by the Swedish Childhood Cancer Foundation (TJ2020-0026). The work of NORDFERTIL is supported by the Swedish Childhood Cancer Foundation (PR2019-0123; PR2022-0115), the Swedish Research Council (2018-03094; 2021-02107), and the Birgitta and Carl-Axel Rydbeck's Research Grant for Paediatric Research (2020-00348; 2021-00073; 2022-00317; 2023-00353). C.E is supported by the Health Department of the Basque Government (Grants 2019111068 and 2022111067) and Inocente Inocente Foundation (FII22/001). M.P.R. is funded by a Medical Research Council Centre for Reproductive Health Grant No: MR/N022556/1. A.F. and N.R. received support from a French national research grant PHRC No. 2008/071/HP obtained by the French Institute of Cancer and the French Healthcare Organization. K.E.O. is funded by the University of Pittsburgh Medical Center and the US National Institutes of Health HD100197. V.B-L is supported by the French National Institute of Cancer (Grant Seq21-026). Y.J. is supported by the Royal Children's Hospital Foundation and a Medical Research Future Fund MRFAR000308. E.G., N.N., S.S., C.L.M., A.M.M.v.P., C.E., R.T.M., K.D., M.P.R. are members of COST Action CA20119 (ANDRONET) supported by COST (European Cooperation in Science and Technology). The Danish Child Cancer Foundation is also thanked for financial support (C.Y.A.). The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Effects of Radiation Therapy on the Female Reproductive Tract in Childhood Cancer Survivors: A PENTEC Comprehensive Review.

PURPOSE: The PENTEC (Pediatric Normal Tissue Effects in the Clinic) task force aimed to quantify effects of radiation therapy (RT) dose to the female reproductive organs after treatment for childhood cancer. METHODS AND MATERIALS: Relevant studies published 1970 to 2017 were identified systematically through PubMed, Medline, and Cochrane databases with additional articles before 2021 identified by the group. Two large studies reported sufficient data to allow modeling of acute ovarian failure (AOF; loss of function ≤5 year from diagnosis) and premature ovarian insufficiency (POI; loss of function at attained age <40 years) based on maximum dose to least affected ovary. Although normal tissue complication probability modeling was not feasible for the uterus due to limited data, the relationship between ultrasound-measured uterine volume and estimated amount of RT was plotted. Limited data regarding vaginal toxicity were available. RESULTS: The risk of AOF increases with RT dose to least affected ovary, alkylating agent cumulative dose (cyclophosphamide equivalent dose [CED] in g/m2), age at RT, and stem cell transplantation: Two Gy to the least affected ovary resulted in AOF risk of 1% to 5% (CED = 0, risk increasing with age), 4% to 7% (CED = 10 g/m2, risk increasing with age), and 6% to 13% (CED = 30 g/m2, risk increasing with age). For patients aged 1 and 20 years at time of RT, AOF risk was ≥50% at doses of 24 Gy and 20 Gy with no alkylating chemotherapy, 22.5 Gy and 17 Gy with intermediate alkylator dose (10 g/m2), and 17 Gy and 13 Gy with high alkylator dose (30 g/m2). Risk of POI increases with survivor (attained) age (rather than age at time of RT), radiation dose to least affected ovary, and alkylator dose. Data review suggested that higher radiation doses to the uterus are associated with uterine toxicity, with uterine size considerably restricted after 12 Gy. Vaginal radiation in children is associated with high toxicity risk, although dose-volume data are not available for quantification. CONCLUSIONS: Risk of AOF increases with age at RT, CED exposure, and RT dose; risk of POI likewise increases with RT dose, CED exposure, and survivor age. Both AOF and POI are expected to affect fertility and estrogen production. Data suggest that RT uterine dose >12 Gy may be associated with uterine size restriction. Adult literature suggests that maintaining vaginal dose <5 Gy may limit toxicity. Treatment of life-threatening malignancy remains a priority over reproductive preservation; however, when possible, radiation and surgical techniques should be considered to minimize dose to least affected ovary, uterus, and vagina. Survivors should receive endocrine and gynecologic support; those desiring pregnancy should be counseled early to maximize reproductive options.

Thyroid Ultrasound Screening in Childhood Cancer Survivors following Radiotherapy.

INTRODUCTION: Childhood cancer survivors (CCS) are at risk for radiotherapy (RT) late effects, including second malignancies. Optimal screening for differentiated thyroid cancer (DTC) in CCS post-RT remains controversial. We assessed the outcome of thyroid ultrasound (US) surveillance in CCS exposed to RT. METHODS: 306 CCS were surveilled with thyroid US between 2002-2021. Surveillance was dependent on age at the time of primary diagnosis, interval from receipt of RT, and individual provider. Thyroid US, clinicopathologic features, and outcomes were described. Cutpoints of CCS RT age associated with varying risk of nodule presentation were explored. The selected cutpoints were used to define age categories, which were then used to compare thyroid nodule-related outcomes. Risk factors for thyroid nodule(s) were evaluated using multivariate logistic regression (odds ratio [OR] [95% confidence interval]). RESULTS: The most common CCS diagnoses were leukemia (32%), CNS tumor (26%), and neuroblastoma (18%). Patients received TBI (45%) and/or RT to craniospinal (44%), chest (11%), and neck regions (6%). About 49% (n = 150) of patients had thyroid nodule(s). Forty-four patients underwent surgery, and 28 had DTC: 19 with American Thyroid Association (ATA) low-risk classification, 2 with ATA intermediate-risk, and 7 with ATA high-risk disease. Age cutpoint analyses identified cutpoints 3 and 10; hence, ≤3, >3 to ≤10, and >10 years were used. Of the 9 patients with intermediate- or high-risk disease, 8 were ≤10 years and 1 was >10 years at the time of RT. Female sex (OR = 1.62 [1.13-2.12] p = 0.054) and greater interval between RT and first US (OR = 1.10 [1.04-1.16] p = 0.001) were independent risk factors for nodule presentation. CONCLUSIONS: Thyroid US surveillance may be beneficial for CCS exposed to RT at younger ages (≤10 years) for earlier detection of DTC, prior to developing advanced metastatic disease.

Altered Peripheral Blood Gene Expression in Childhood Cancer Survivors With Anthracycline-Induced Cardiomyopathy - A COG-ALTE03N1 Report.

Background Anthracycline-induced cardiomyopathy is a leading cause of premature death in childhood cancer survivors, presenting a need to understand the underlying pathogenesis. We sought to examine differential blood-based mRNA expression profiles in anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Methods and Results We designed a matched case-control study (Children's Oncology Group-ALTE03N1) with mRNA sequencing on total RNA from peripheral blood in 40 anthracycline-exposed survivors with cardiomyopathy (cases) and 64 matched survivors without (controls). DESeq2 identified differentially expressed genes. Ingenuity Pathway Analyses (IPA) and Gene Set Enrichment Analyses determined the potential roles of altered genes in biological pathways. Functional validation was performed by gene knockout in human-induced pluripotent stem cell-derived cardiomyocytes using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) technology. Median age at primary cancer diagnosis for cases and controls was 8.2 and 9.7 years, respectively. Thirty-six differentially expressed genes with fold change ≥±2 were identified; 35 were upregulated. IPA identified "hepatic fibrosis" and "iron homeostasis" pathways to be significantly modulated by differentially expressed genes, including toxicology functions of myocardial infarction, cardiac damage, and cardiac dilation. Leading edge analysis from Gene Set Enrichment Analyses identified lactate dehydrogenase A (LDHA) and cluster of differentiation 36 (CD36) genes to be significantly upregulated in cases. Interleukin 1 receptor type 1, 2 (IL1R1, IL1R2), and matrix metalloproteinase 8, 9 (MMP8, MMP9) appeared in multiple canonical pathways. LDHA-knockout human-induced pluripotent stem cell-derived cardiomyocytes showed increased sensitivity to doxorubicin. Conclusions We identified differential mRNA expression profiles in peripheral blood of anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Upregulation of LDHA and CD36 genes suggests metabolic perturbations in a failing heart. Dysregulation of proinflammatory cytokine receptors IL1R1 and IL1R2 and matrix metalloproteinases, MMP8 and MMP9 indicates structural remodeling that accompanies the clinical manifestation of symptomatic cardiotoxicity.

Co-Occurrence of Pallister-Killian Syndrome and Burkitt Lymphoma in a Patient with Near-Normal Neurocognitive Development.

Background: Pallister-Killian syndrome (PKS) is typically recognized by its features that include developmental delay, seizures, sparse temporal hair, and facial dysmorphisms. PKS is most frequently caused by mosaic supernumerary isochromosome 12p. Case Presentation: Here, we report a patient with PKS who was subsequently diagnosed with Burkitt lymphoma. Following the successful treatment of lymphoma, this patient demonstrated very mild intellectual disability despite the diagnosis of PKS, which is usually associated with severe developmental delay. Discussion: This is the first reported patient with PKS and a hematologic malignancy. Although there is no significant reported association of tetrasomy 12p with cancer, the co-occurrence of two rare findings in this patient suggests a potential relationship. The localization of AICDA, a gene for which overexpression has been implicated in promoting t(8;14) noted in our patient's lymphoma, raises a potential mechanism of pathogenesis. In addition, this case indicates that children with PKS can demonstrate near-normal cognitive development.

Identification of novel hypermethylated or hypomethylated CpG sites and genes associated with anthracycline-induced cardiomyopathy.

Anthracycline-induced cardiomyopathy is a leading cause of late morbidity in childhood cancer survivors. Aberrant DNA methylation plays a role in de novo cardiovascular disease. Epigenetic processes could play a role in anthracycline-induced cardiomyopathy but remain unstudied. We sought to examine if genome-wide differential methylation at 'CpG' sites in peripheral blood DNA is associated with anthracycline-induced cardiomyopathy. This report used participants from a matched case-control study; 52 non-Hispanic White, anthracycline-exposed childhood cancer survivors with cardiomyopathy were matched 1:1 with 52 survivors with no cardiomyopathy. Paired ChAMP (Chip Analysis Methylation Pipeline) with integrated reference-based deconvolution of adult peripheral blood DNA methylation was used to analyze data from Illumina HumanMethylation EPIC BeadChip arrays. An epigenome-wide association study (EWAS) was performed, and the model was adjusted for GrimAge, sex, interaction terms of age at enrollment, chest radiation, age at diagnosis squared, and cardiovascular risk factors (CVRFs: diabetes, hypertension, dyslipidemia). Prioritized genes were functionally validated by gene knockout in human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) using CRISPR/Cas9 technology. DNA-methylation EPIC array analyses identified 32 differentially methylated probes (DMP: 15 hyper-methylated and 17 hypo-methylated probes) that overlap with 23 genes and 9 intergenic regions. Three hundred and fifty-four differential methylated regions (DMRs) were also identified. Several of these genes are associated with cardiac dysfunction. Knockout of genes EXO6CB, FCHSD2, NIPAL2, and SYNPO2 in hiPSC-CMs increased sensitivity to doxorubicin. In addition, EWAS analysis identified hypo-methylation of probe 'cg15939386' in gene RORA to be significantly associated with anthracycline-induced cardiomyopathy. In this genome-wide DNA methylation profile study, we observed significant differences in DNA methylation at the CpG level between anthracycline-exposed childhood cancer survivors with and without cardiomyopathy, implicating differential DNA methylation of certain genes could play a role in pathogenesis of anthracycline-induced cardiomyopathy.

Haptoglobin Gene Expression and Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors: A COG-ALTE03N1 Report.

Background: Anthracycline-related cardiomyopathy is a leading cause of premature death in childhood cancer survivors. The high interindividual variability in risk suggests the need to understand the underlying pathogenesis. Objectives: The authors interrogated differentially expressed genes (DEGs) to identify genetic variants serving regulatory functions or genetic variants not easily identified when using genomewide array platforms. Using leads from DEGs, candidate copy number variants (CNVs) and single-nucleotide variants (SNVs) were genotyped. Methods: Messenger RNA sequencing was performed on total RNA from peripheral blood of 40 survivors with cardiomyopathy (cases) and 64 matched survivors without cardiomyopathy (control subjects). Conditional logistic regression analysis adjusting for sex, age at cancer diagnosis, anthracycline dose, and chest radiation was used to assess the associations between gene expression and cardiomyopathy and between CNVs and SNVs and cardiomyopathy. Results: Haptoglobin (HP) was identified as the top DEG. Participants with higher HP gene expression had 6-fold greater odds of developing cardiomyopathy (OR: 6.4; 95% CI: 1.4-28.6). The HP2-specific allele among the HP genotypes (HP1-1, HP1-2, and HP2-2) had higher transcript levels, as did the G allele among SNVs previously reported to be associated with HP gene expression (rs35283911 and rs2000999). The HP1-2 and HP2-2 genotypes combined with the G/G genotype for rs35283911 and/or rs2000999 placed the survivors at 4-fold greater risk (OR: 3.9; 95% CI: 1.0-14.5) for developing cardiomyopathy. Conclusions: These findings provide evidence of a novel association between HP2 allele and cardiomyopathy. HP binds to free hemoglobin to form an HP-hemoglobin complex, thereby preventing oxidative damage from free heme iron, thus providing biological plausibility to the mechanistic basis of the present observation.

Genome-Wide Association Study Identifies ROBO2 as a Novel Susceptibility Gene for Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors.

PURPOSE: Interindividual variability in the dose-dependent association between anthracyclines and cardiomyopathy suggests a modifying role of genetic susceptibility. Few previous studies have examined gene-anthracycline interactions. We addressed this gap using the Childhood Cancer Survivor Study (discovery) and the Children's Oncology Group (COG) study COG-ALTE03N1 (replication). METHODS: A genome-wide association study (Illumina HumanOmni5Exome Array) in 1,866 anthracycline-exposed Childhood Cancer Survivor Study participants (126 with heart failure) was used to identify single-nucleotide polymorphisms (SNPs) with either main or gene-environment interaction effect on anthracycline-related cardiomyopathy that surpassed a prespecified genome-wide threshold for statistical significance. We attempted replication in a matched case-control set of anthracycline-exposed childhood cancer survivors with (n = 105) and without (n = 160) cardiomyopathy from COG-ALTE03N1. RESULTS: Two SNPs (rs17736312 [ROBO2]) and rs113230990 (near a CCCTC-binding factor insulator [< 750 base pair]) passed the significance cutoff for gene-anthracycline dose interaction in discovery. SNP rs17736312 was successfully replicated. Compared with the GG/AG genotypes on rs17736312 and anthracyclines ≤ 250 mg/m2, the AA genotype and anthracyclines > 250 mg/m2 conferred a 2.2-fold (95% CI, 1.2 to 4.0) higher risk of heart failure in discovery and an 8.2-fold (95% CI, 2.0 to 34.4) higher risk in replication. ROBO2 encodes transmembrane Robo receptors that bind Slit ligands (SLIT). Slit-Robo signaling pathway promotes cardiac fibrosis by interfering with the transforming growth factor-ß1/small mothers against decapentaplegic (Smad) pathway, resulting in disordered remodeling of the extracellular matrix and potentiating heart failure. We found significant gene-level associations with heart failure: main effect (TGF-ß1, P = .007); gene*anthracycline interaction (ROBO2*anthracycline, P = .0003); and gene*gene*anthracycline interaction (SLIT2*TGF-ß1*anthracycline, P = .009). CONCLUSION: These findings suggest that high-dose anthracyclines combined with genetic variants involved in the profibrotic Slit-Robo signaling pathway promote cardiac fibrosis via the transforming growth factor-ß1/Smad pathway, providing credence to the biologic plausibility of the association between SNP rs17736312 (ROBO2) and anthracycline-related cardiomyopathy.

Long-Term Kidney and Cardiovascular Complications in Pediatric Cancer Survivors.

OBJECTIVE: The objective of this study was to describe the burden of adverse kidney and hypertension outcomes in patients evaluated by pediatric nephrology in a multidisciplinary survivorship clinic. STUDY DESIGN: Retrospective chart review of all patients followed up by nephrology in our multidisciplinary survivorship clinic from August 2013 to June 2021. Data included clinic blood pressure, longitudinal ambulatory blood pressure monitoring (ABPM), echocardiography, serum creatinine, and first-morning urine protein/creatinine ratios. For patients with multiple ABPMs, results of initial and most recent ABPMs were compared. RESULTS: Of 422 patients followed in the multidisciplinary cancer survivorship clinic, 130 were seen by nephrology. The median time after therapy completion to first nephrology visit was 8 years. The most common diagnoses were leukemia/myelodysplastic syndrome (27%), neuroblastoma (24%), and Wilms tumor (15%). At the last follow-up, 68% had impaired kidney function, 38% had a clinical diagnosis of hypertension, and 12% had proteinuria. There were 91 ABPMs performed in 55 (42%) patients. Patients with multiple ABPMs (n = 21) had statistically significant reductions in overall median blood pressure loads: systolic initial load 37% vs most recent 10% (P = .005) and diastolic load 36% vs 14% (P = .017). Patients with impaired kidney function were more likely to have received ifosfamide. Patients with hypertension were more likely to have received total body irradiation or allogeneic stem cell transplant. CONCLUSIONS: History of leukemia/myelodysplastic syndrome, neuroblastoma, and Wilms tumor was frequent among survivors seen by nephrology. There was significant improvement in cardiovascular measures with increased recognition of hypertension and subsequent treatment.

Sociodemographics, Health Competence, and Transition Readiness Among Adolescent/Young Adult Cancer Survivors.

OBJECTIVE: Fewer than one-third of childhood cancer survivors receive follow-up from an adult provider, and adolescent and young adults (AYAs) from structurally minoritized sociodemographic groups often face health disparities that can impact transition to adult-oriented care. The primary aim of this study was to determine the relation among sociodemographic factors, cumulative effects, and transition beliefs/expectations and goals, and the moderating role of health competence beliefs in AYA survivors of childhood cancer. METHODS: A total of 195 AYAs (aged 15-29) reported sociodemographic information, completed the Transition Readiness Inventory assessing positive beliefs/expectations and goals related to transition, and completed the Health Competence Beliefs Inventory assessing health perceptions, healthcare satisfaction, cognitive competence, and autonomy. A cumulative sociodemographic factor variable was computed to investigate the potential additive effects of multiple sociodemographic factors associated with disparities. T-tests, Pearson correlations, and multivariate linear regressions were used. RESULTS: Cumulative sociodemographic factors were not related to transition readiness, and insurance type was the only factor associated with health competence beliefs and transition readiness, such that AYAs with public insurance reported lower healthcare satisfaction, cognitive competence, and transition goals relative to those with private insurance. There were no interaction effects; however, health competence beliefs were significantly associated with transition beliefs/expectations and goals. CONCLUSION: Public insurance is a barrier to holding positive beliefs/expectations and goals about transition, yet other sociodemographic factors associated with risks for poor transfer were not related to transition readiness. Multi-level interventions to reduce disparities and improve transition readiness should target health competence beliefs and barriers created by insurance.

Expenditures in Young Adults with Hodgkin Lymphoma: NCI-Designated Comprehensive Cancer Centers versus Other Sites.

BACKGROUND: Outcomes among Hodgkin lymphoma (HL) patients diagnosed between 22 and 39 years are worse than among those diagnosed <21 years, and have not seen the same improvement over time. Treatment at an NCI-designated Comprehensive Cancer Center (CCC) mitigates outcome disparities, but may be associated with higher expenditures. METHODS: We examined cancer-related expenditures among 22- to 39-year-old HL patients diagnosed between 2001 and 2016 using deidentified administrative claims data (OptumLabs Data Warehouse; CCC: n = 1,154; non-CCC: n = 643). Adjusting for sociodemographics, clinical characteristics, and months enrolled, multivariable general linear models modeled average monthly health-plan paid (HPP) expenditures, and incidence rate ratios compared CCC/non-CCC monthly visit rates. RESULTS: In the year following diagnosis, CCC patients had higher HPP expenditures ($12,869 vs. $10,688, P = 0.001), driven by higher monthly rates of CCC nontreatment outpatient hospital visits (P = 0.001) and per-visit expenditures for outpatient hospital chemotherapy ($632 vs. $259); higher CCC inpatient expenditures ($1,813 vs. $1,091, P = 0.001) were driven by 3.1 times higher rates of chemotherapy admissions (P = 0.001). Out-of-pocket expenditures were comparable (P = 0.3). CONCLUSIONS: Young adults with HL at CCCs saw higher health-plan expenditures, but comparable out-of-pocket expenditures. Drivers of CCC expenditures included outpatient hospital utilization (monthly rates of non-therapy visits and per-visit expenditures for chemotherapy). IMPACT: Higher HPP expenditures at CCCs in the year following HL diagnosis likely reflect differences in facility structure and comprehensive care. For young adults, it is plausible to consider incentivizing CCC care to achieve superior outcomes while developing approaches to achieve long-term savings.

Late effects in survivors of high-risk neuroblastoma following stem cell transplant with and without total body irradiation.

BACKGROUND: Neuroblastoma is the most common extracranial solid tumor in children. Those with high-risk disease are treated with multimodal therapy, including high-dose chemotherapy, stem cell transplant, radiation, and immunotherapy that have led to multiple long-term complications in survivors. In the late 1990s, consolidation therapy involved myeloablative conditioning including total body irradiation (TBI) with autologous stem cell rescue. Recognizing the significant long-term toxicities of exposure to TBI, more contemporary treatment protocols have removed this from conditioning regimens. This study examines an expanded cohort of 48 high-risk neuroblastoma patients to identify differences in the late effect profiles for those treated with TBI and those treated without TBI. PROCEDURE: Data on the study cohort were collected from clinic charts, provider documentation in the electronic medical record of visits to survivorship clinic, including all subspecialists, and ancillary reports of laboratory and diagnostic tests done as part of risk-based screening at each visit. RESULTS: All 48 survivors of BMT for high-risk neuroblastoma had numerous late effects of therapy, with 73% having between five and 10 late effects. TBI impacted some late effects significantly, including growth hormone deficiency (GHD), bone outcomes, and cataracts. CONCLUSION: Although high-risk neuroblastoma survivors treated with TBI have significant late effects, those treated without TBI also continue to have significant morbidity related to high-dose chemotherapy and local radiation. A multidisciplinary care team assists in providing comprehensive care to those survivors who are at highest risk for significant late effects.

Fertility preservation for male patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Male patients with childhood, adolescent, and young adult cancer are at an increased risk for infertility if their treatment adversely affects reproductive organ function. Future fertility is a primary concern of patients and their families. Variations in clinical practice are barriers to the timely implementation of interventions that preserve fertility. As part of the PanCareLIFE Consortium, in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group, we reviewed the current literature and developed a clinical practice guideline for fertility preservation in male patients who are diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger, including guidance on risk assessment and available methods for fertility preservation. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the available evidence and to form the recommendations. Recognising the need for global consensus, this clinical practice guideline used existing evidence and international expertise to rigorously develop transparent recommendations that are easy to use to facilitate the care of male patients with childhood, adolescent, and young adult cancer who are at high risk of fertility impairment and to enhance their quality of life.

Communication and ethical considerations for fertility preservation for patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Patients with childhood, adolescent, and young adult cancer who will be treated with gonadotoxic therapies are at increased risk for infertility. Many patients and their families desire biological children but effective communication about treatment-related infertility risk and procedures for fertility preservation does not always happen. The PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group reviewed the literature and developed a clinical practice guideline that provides recommendations for ongoing communication methods for fertility preservation for patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger and their families. Moreover, the guideline panel formulated considerations of the ethical implications that are associated with these procedures. Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the evidence and recommendations. In this clinical practice guideline, existing evidence and international expertise are combined to develop transparent recommendations that are easy to use to facilitate ongoing communication between health-care providers and patients with childhood, adolescent, and young adult cancer who might be at high risk for fertility impairment and their families.

Expenditures among young adults with acute lymphoblastic leukemia by site of care.

BACKGROUND: Individuals diagnosed with acute lymphoblastic leukemia (ALL) between the ages of 22 and 39 years experience worse outcomes than those diagnosed when they are 21 years old or younger. Treatment at National Cancer Institute-designated Comprehensive Cancer Centers (CCC) mitigates these disparities but may be associated with higher expenditures. METHODS: Using deidentified administrative claims data (OptumLabs Data Warehouse), the cancer-related expenditures were examined among patients with ALL diagnosed between 2001 and 2014. Multivariable generalized linear model with log-link modeled average monthly health-plan-paid (HPP) expenditures and amount owed by the patient (out-of-pocket [OOP]). Cost ratios were used to calculate excess expenditures (CCC vs non-CCC). Incidence rate ratios (IRRs) compared CCC and non-CCC monthly visit rates. Models adjusted for sociodemographics, comorbidities, adverse events, and months enrolled. RESULTS: Clinical and sociodemographic characteristics were comparable between CCC (n = 160) and non-CCC (n = 139) patients. Higher monthly outpatient expenditures in CCC patients ($15,792 vs $6404; P < .001) were driven by outpatient hospital HPP expenditures. Monthly visit rates and per visit expenditures for nonchemotherapy visits (IRR = 1.6; P = .001; CCC = $8247, non-CCC = $1191) drove higher outpatient hospital expenditures among CCCs. Monthly OOP expenditures were higher at CCCs for outpatient care (P = .02). Inpatient HPP expenditures were significantly higher at CCCs ($25,918 vs $13,881; ꞵ = 0.9; P < .001) before accounting for adverse events but were no longer significant after adjusting for adverse events (ꞵ = 0.4; P = .1). Hospitalizations and length of stay were comparable. CONCLUSIONS: Young adults with ALL at CCCs have higher expenditures, likely reflecting differences in facility structure, billing practices, and comprehensive patient care. It would be reasonable to consider CCCs comparable to the oncology care model and incentivize the framework to achieve superior outcomes and long-term cost savings. LAY SUMMARY: Health care expenditures in young adults (aged 22-39 years) with acute lymphoblastic leukemia (ALL) are higher among patients at National Cancer Institute-designated Comprehensive Cancer Centers (CCC) than those at non-CCCs. The CCC/non-CCC differences are significant among outpatient expenditures, which are driven by higher rates of outpatient hospital visits and outpatient hospital expenditures per visit at CCCs. Higher expenditures and visit rates of outpatient hospital visits among CCCs may also reflect how facility structure and billing patterns influence spending or comprehensive care. Young adults at CCCs face higher inpatient HPP expenditures; these are driven by serious adverse events.

A predictive model for chemotherapy-related diminished ovarian reserve in reproductive-age women.

OBJECTIVE: To develop and internally validate a clinical predictive tool to assess the likelihood that a young cancer patient will experience diminished ovarian reserve (DOR) after chemotherapy. DESIGN: Prospective cohort study. SETTING: University hospitals. PATIENT(S): Postpubertal adolescent and young adult women with a new diagnosis of cancer requiring chemotherapy. INTERVENTION: None. MAIN OUTCOME MEASURE(S): Diminished ovarian reserve after completion of and recovery from chemotherapy, defined as serum antimüllerian hormone (AMH) <1 ng/mL at 8-24 months after completion of chemotherapy. RESULT(S): A multivariable logistic regression model which includes age, cancer type, exposure to an alkylating agent, and baseline AMH value accurately predicts the diagnosis of DOR after chemotherapy with an area under the receiver operating characteristic curve of 0.89. CONCLUSION(S): Pretreatment information on age, cancer type, use of an alkylating agent, and baseline AMH levels make up a clinically useful predictive tool to identify which women are most at risk for DOR caused by chemotherapy.

Acceptability and feasibility of survivorship care plans and an accompanying mobile health intervention for adolescent and young adult survivors of childhood cancer.

BACKGROUND: Self-management interventions for adolescent and young adult (AYA) survivors of childhood cancer are needed. The present study reports on the acceptability and feasibility of delivering survivorship care plans (SCPs) and an accompanying app to AYA. PROCEDURE: AYA (n = 224) ages 15-29 who completed treatment for cancer were randomized and received a digital SCP only or an SCP plus a mobile app intended to enhance self-management. For 16 weeks, the app delivered one to two daily messages complementing information in their SCP and tailored based on age, treatment, and health goal. Data are presented on feasibility, self-reported acceptability (including satisfaction and perceived benefits) and its relationship to app engagement (for those in app group), and feedback from qualitative interviews conducted with 10 AYA. RESULTS: The SCP and app proved feasible as evidenced by high recruitment and retention, access to technology, time analysis, moderate app engagement, and minimal technical issues. However, 12% reported never reading the SCP and 8% never used the app. The app and SCP were acceptable to AYA, and SCP acceptability ratings did not differ between groups. For those with the app, acceptability was positively related to message engagement. AYA recommended enhanced individualization and design features of the SCP and app. CONCLUSIONS: Results support the use of tailored SCPs and mobile health interventions for most AYA, as well as the need for further refinement and research. Delivery of SCPs and digital interventions are acceptable and feasible to AYA survivors, and may help promote health-related knowledge and survivorship self-management.

A View from the past into our collective future: the oncofertility consortium vision statement.

PURPOSE: Today, male and female adult and pediatric cancer patients, individuals transitioning between gender identities, and other individuals facing health extending but fertility limiting treatments can look forward to a fertile future. This is, in part, due to the work of members associated with the Oncofertility Consortium. METHODS: The Oncofertility Consortium is an international, interdisciplinary initiative originally designed to explore the urgent unmet need associated with the reproductive future of cancer survivors. As the strategies for fertility management were invented, developed or applied, the individuals for who the program offered hope, similarly expanded. As a community of practice, Consortium participants share information in an open and rapid manner to addresses the complex health care and quality-of-life issues of cancer, transgender and other patients. To ensure that the organization remains contemporary to the needs of the community, the field designed a fully inclusive mechanism for strategic planning and here present the findings of this process. RESULTS: This interprofessional network of medical specialists, scientists, and scholars in the law, medical ethics, religious studies and other disciplines associated with human interventions, explore the relationships between health, disease, survivorship, treatment, gender and reproductive longevity. CONCLUSION: The goals are to continually integrate the best science in the service of the needs of patients and build a community of care that is ready for the challenges of the field in the future.