St. Jude Children's Research Hospital Research Articles

Efficacy of Interventions to Build Transition Readiness for Youth with Sickle Cell Disease: A 13-Year Evaluation of a Healthcare Transition Program

Background Progress in pediatric care has improved survival into adulthood for children with sickle cell disease (SCD); however, mortality and acute care utilization rise among emerging adults. With unmet needs to improve health outcomes in young adults, SCD effective transition programs that transfer care from pediatric to adult providers are needed. Since 2007, the St. Jude Children's Research Hospital (SJCRH) SCD Transition to Adult care Program has served patients between 12-25 years of age by providing transition readiness-building activities, including in-person and online SCD education, experiential learning, academic planning, and introduction to adult providers at age 17 years. We tested the efficacy of individual components of the SJCRH Transition Program in ensuring optimal post-pediatric transition outcomes. Methods We retrospectively reviewed all patients with SCD treated at SJCRH who would have reached age 18 years between 2007 and 2020. Of the 722 patients, 142 (19.7%) died, relocated, or were lost to follow up before age 18 years and were excluded from the analysis. The association between pediatric transition intervention components and the following transition outcomes: 1) adult care transfer completion <6 months from completing pediatric care, 2) frequency of adult outpatient visits, 3) adult acute care utilization [emergency room (ER) and hospitalizations], and 4) quality of life (QoL) PedsQL™ SCDModule scores at ages 18 or 24 years was investigated using Wilcoxon rank sum, Fisher's exact, Spearman correlation (with spearman correlation coefficient ρ), or Kruskal Wallis tests. Analyses were adjusted for multiple comparisons to control for false discovery rate and q-value was calculated. Results Of the 580 pediatric patients who received transition services to age 18, 476 (82.1%) completed adult transfer of care. There was no difference in completion of a first adult visit relative to SCD genotype or sex, but longer exposure duration to any SCD-modifying therapy was associated with higher rate of adult care transfer completion (Table 1). Patients who successfully transferred to adult care had significantly higher participation in all components of the transition program and higher transition readiness scores (Table 1). Frequency of pediatric outpatient visits was not associated with completion of a first adult visit. However, patients with a transfer gap <6 months had higher frequency of pediatric visits than those with ≥6 months gap (median 77 vs 27 visits/patient, respectively, q<0.00001). Patients with HbSS/SB0-thalassemia attended more adult outpatient visits compared to those with HbSC/SB+thalassemia genotypes (median 62 vs 27 total visits/patient, q<0.0001). Longer exposure to any SCD-modifying therapy (ρ=0.44, q<0.00001), higher frequency of pediatric outpatient visits (ρ=0.61, q <0.00001), and adult provider introduction at 17 years (q=0.025) were associated with greater attendance to adult outpatient visits. Longer exposure to SCD-modifying therapies (ρ=0.26, q<0.0001) was associated with higher adult acute care utilization, while no association was observed with SCD genotype and adult acute care utilization. Higher frequency of academic planning (ρ=-0.23, q=0.0002) and disease education sessions (ρ=-0.28, q<0.0001, Fig 1) were negatively correlated with adult acute care utilization. QoL was lower among females than males (median q=0.002), but no differences were observed relative to SCD genotypes or duration of exposure to SCD therapies. The frequency of SCD education (ρ=0.19, q=0.008) and training on personal health history reporting (ρ=0.22, q=0.004) were positively correlated with QoL. More self-reported internalizing problems due to anxiety and depression (BASC-ESI scores) did not predict adult transfer completion but were associated with lower QoL in young adulthood (ρ=-0.32, q=0.008). Conclusion The transition program at SJRCH was effective in placing 82% of patients in adult care. Demographic factors (sex, SCD genotype) were not always predictive of transition outcomes. However, our results suggest transition interventions designed to increase transition readiness may promote improved transition outcomes. Future analyses will focus on building multivariable models to determine the optimal combination of transition interventions to improve transition outcomes in SCD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long term survival outcome of childhood acute lymphoblastic leukemia treated with modified TXIIIB protocol at South Egypt Cancer Institute

Background: The survival of children with acute lymphoblastic leukemia (ALL) has greatly improved in recent decades. Aim: We aimed at evaluating the outcome of children with ALL and their prognostic factors. Materials & Methods: A prospective study included 200 newly diagnosed pediatric ALL patients from 2009 to 2017. All patients were treated according to the modified total therapy study XIIIB for higher risk ALL adopted from St. Jude Children's Research hospital (SJCRH), USA. Results: Favorable age (< 10 y) and total leucocytic count (TLC) (≥ 50x109/L) occurred in 75% and 69%, respectively. B-precursor ALL represented 82.5%. Central nervous system (CNS) involvement occurred in 4.5%. High-risk patients represented 47%. Complete remission was achieved in 92.5% and was significantly affected by the early morphologic response of BM d15, while it wasn’t related to the phenotype. Eight- year overall survival, disease-free survival, and event-free survival were 77 ± 3%, 70 ± 4%, and 66 ± 3%, respectively. Adverse events included induction deaths (4.5 %(, refractory leukemia (3%), relapse (23.2%), secondary AML (0.5%), and deaths in remission (3.5%). By multivariate analysis, unfavorable age group ≥ 10 years, hyperleukocytosis, and patients with slow early response were the only ones associated with unfavorable impact on the outcome. There was statistical significant difference between standard and high risk for B-precursor ALL but not for T- precursor ALL. Conclusion: We concluded that treating children with ALL through modified TXIIIB protocol improved the survival at our institute than previous and the early response to treatment has a strong implication on the outcome.

Abstract 1: Novel pediatric AML patient risk stratification by inferred protein activity through integrative network analysis and machine learning

Abstract Despite recent advances, overall survival for children with acute myeloid leukemia (AML) remains relatively low at 70 to 80%. Further refinement of risk stratification is paramount to guiding optimal therapy selection and improving outcomes. In this study, we leverage machine learning and network-based systems biology approaches that infer tumor protein activity and define key disease drivers - master regulator (MR) proteins - in pediatric AML to further refine existing patient risk stratification and identify potential therapeutic targets. Using the ARACNe and VIPER algorithms1, we reverse-engineered an AML gene regulatory network and inferred protein activity from enrichment of the proteins' transcriptional targets in gene expression signatures from a novel 1080-patient cohort treated on COG AAML1031. We integrated ensemble clustering with feed-forward feature selection on VIPER-inferred protein activity to identify groups of patients with unique protein activity signatures and correlated them to survival by Cox proportional-hazards regression analysis. We identified features predictive of each group by Monte Carlo cross-validation and binary classification. We found that the activity of 2-4 MR proteins was sufficient to predict patient stratification for each group with areas under the receiver-operator characteristic curve above 0.9. We validated our findings in three external test datasets: St-Jude Children's Research Hospital (n=249), TARGET (n=682) and Erasmus MC Sophia's Children's Hospital (n=237). We identified 10 groups with significant survival differences (P &amp;lt; 0.0001, overall survival range 42-85%). This includes a new high-risk group that is not associated with any known cytogenomic features, but shows high activity of NOTCH signaling pathway regulators HES1 and HEY2. Other groups show aberrant activity for known transcription regulators; for example RUNX1, KDM5B and POU4F1. In conclusion, we propose novel patient risk stratification based on VIPER-inferred MR protein activity in pediatric AML. We define 10 groups with differential survival, including refinement of a classically-characterized intermediate-risk cytogenomically normal group as high-risk. We classify patients into therapeutically-relevant risk groups that can guide treatment decision-making. We define the MR proteins driving these groups to offer mechanistic insights into AML tumorigenesis as well as suggest potential molecular targets for therapies. Reference: 1. Califano A, Alvarez M, The recurrent architecture of tumour initiation, progression and drug sensitivity, Nat Rev Cancer (2017), 17(2): 116-130 Citation Format: Alexandre P. Alloy, Jovana Pavisic, Rhonda E. Ries, Tanja Gruber, C Michel Zwaan, Monique L. den Boer, James R. Downing, Adolfo Ferrando, Soheil Meshinchi, Andrea Califano. Novel pediatric AML patient risk stratification by inferred protein activity through integrative network analysis and machine learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1.

The changing burden of long-term health outcomes in survivors of childhood acute lymphoblastic leukaemia: a retrospective analysis of the St Jude Lifetime Cohort Study

Treatment for childhood acute lymphoblastic leukemia has evolved over the past five decades, with moderation of traditional chemotherapy and radiotherapy and the introduction of targeted immune-based and cellular-based therapies. The affect of these changes on late health outcomes has not been assessed. Using data from the The St Jude Lifetime (SJLIFE) Cohort, we aimed to characterise the magnitude of morbidity and patterns of late health outcomes among survivors of childhood acute lymphoblastic leukaemia treated over time. The St Jude Lifetime (SJLIFE) Cohort is a retrospective cohort study with prospective follow-up and ongoing data accrual designed to facilitate longitudinal, clinically-based assessment of health outcomes among survivors of paediatric malignancies. 980 survivors included in this analysis were diagnosed with paediatric acute lymphoblastic leukaemia at St Jude Children's Research Hospital (SJCRH) between Aug 28, 1963, and July 19, 2003, were aged 18 years old and older at enrolment, had a minimum follow-up of 10 years after diagnosis, and completed an initial on-campus SJLIFE assessment as of data cutoff (June 30, 2015). 272 community control participants, matched to survivors on 5-year age blocks in each sex, were recruited for comparison. Cumulative chemotherapy and radiation dose exposures and major medical events during and after therapy were retrieved from the medical records of the survivors. History or physical examination, laboratory analysis, physical fitness, and neurocognitive testing were done. Health conditions were graded according to a modified version of the Common Terminology Criteria for Adverse Events. Neurocognitive domains of attention (Trial Making Test Part A and Conner's Continuous Performance Test-II) and executive function (Trail Making Test Part B, Controlled Oral Word Association Test, and Wechsler Adult Intelligence Scale-III Digit Span Test Backward) were measured and age-adjusted Z scores were calculated. Mean cumulative count was used to calculate the age-standardised cumulative burden of health conditions over time. This cohort study is registered at ClinicalTrials.gov, number NCT00760656. 980 survivors of acute lymphoblastic leukaemia (50% women, median age at diagnosis 5 years [IQR 3·1-9·1 years], and median time from diagnosis of 30·0 years [22·7-36·3]) had a median age of 35·8 years (29·4-42·9) at assessment compared with 35·1 years (28·7-42·6) for 272 controls. Survivors had significantly more growth hormone deficiency, hypogonadism, and neuropathy than controls. By age 30 years, survivors of acute lymphoblastic leukaemia had, on average, 5·4 (95% CI 5·1-5·8) grade 1-4 health conditions, including 3·2 (2·9-3·4) grade 2-4 health conditions, compared with 2·0 (CI 1·7-2·2) grade 1-4 and 1·2 (1·03-1·4) grade 2-4 health conditions among controls. The cumulative burden of grade 2-4 health conditions involved multiple organ systems for survivors treated on protocols between 1962-91, but after elimination of cranial radiotherapy for children with acute lymphoblastic leukaemia, conditions now predominately include musculoskeletal and endocrine disorders for survivors on protocols between 1991-2007. Although changes in paediatric acute lymphoblastic leukaemia treatment protocols have improved overall survival, the burden of late morbidity remains high for these patients. We show that the pattern of late toxic effects has markedly changed over time, with survivors having a reduction in health conditions that are immediately life-threatening, however, maintaining health status and quality of life for survivors of paediatric acute lymphoblastic leukaemia requires continued medical surveillance, counselling, and lifestyle modifications. US National Cancer Institute and the American Lebanese Syrian Associated Charities.

Screening for Early Childhood Intervention in Oncology

Infants and toddlers (birth to 3 years of age) diagnosed with cancer are at a critical phase of development and are at greater risk for developmental delays due to this early adversity. Because of this risk, St. Jude Children's Research Hospital (SJCRH) developed an Early Childhood Clinic (ECC). Psychologists screen children using the Battelle Developmental Inventory, Second Edition (BDI-2). If physical and occupational therapy services are needed on the basis of the results of the BDI-2, the physical therapists and occupational therapists administer the Peabody Developmental Motor Scales, Second Edition (PDMS-2). If scores from the PDMS-2 display a delay in gross and/or fine motor skills, physical therapy and/or occupational therapy are initiated. At SJCRH, the psychologists in the ECC have screened 107 patients. Eighty-eight of the 107 patients (82%) were referred to physical therapy. Because 82% of patients who received a developmental screen are then referred to physical therapy, it appears beneficial to screen children younger than 3 years who have been diagnosed with a malignancy. The ECC at SJCRH is a program dedicated to improving quality of life for children and their families through hospital-based early intervention for chronically ill children. The ECC developed at SJCRH may be a model of care for pediatric oncology settings to encourage the development of age-appropriate motor skills while providing families with resources in home communities to further this development.

Genome-Wide Study Links PNPLA3 Variant With Elevated Hepatic Transaminase After Acute Lymphoblastic Leukemia Therapy.

Remission induction therapy for acute lymphoblastic leukemia (ALL) includes medications that may cause hepatotoxicity, including asparaginase. We used a genome-wide association study to identify loci associated with elevated alanine transaminase (ALT) levels after induction therapy in children with ALL enrolled on St. Jude Children's Research Hospital (SJCRH) protocols. Germline DNA was genotyped using arrays and exome sequencing. Adjusting for age, body mass index, ancestry, asparaginase preparation, and dosage, the PNPLA3 rs738409 (C>G) I148M variant, previously associated with fatty liver disease risk, had the strongest genetic association with ALT (P = 2.5 × 10-8 ). The PNPLA3 rs738409 variant explained 3.8% of the variability in ALT, and partly explained race-related differences in ALT. The PNPLA3 rs738409 association was replicated in an independent cohort of 2,285 patients treated on Children's Oncology Group protocol AALL0232 (P = 0.024). This is an example of a pharmacogenetic variant overlapping with a disease risk variant.

Addressing regional disparities in pediatric oncology: Results of a collaborative initiative across the Mexican-North American border.

Cancer is emerging as a major cause of childhood mortality in low- and middle-income countries. In Mexico, cancer is the number one cause of death in children aged 5-14. Until recently, many children with cancer from Baja California, Mexico, went untreated. We reasoned that an initiative inspired by the St. Jude Children's Research Hospital (SJCRH) "twinning" model could successfully be applied to the San Diego-Tijuana border region. In 2008, a twinning project was initiated by Rady Children's Hospital, SJCRH, and the General Hospital Tijuana (GHT). Our aim was to establish a pediatric oncology unit in a culturally sensitive manner, adapted to the local healthcare system. An initial assessment revealed that despite existence of basic hospital infrastructure at the GHT, the essential elements of a pediatric cancer unit were lacking, including dedicated space, trained staff, and uniform treatment. A 5-year action plan was designed to offer training, support the staff financially, and improve the infrastructure. After 7 years, accomplishments include the opening of a new inpatient unit with updated technology, fully trained staff, and a dedicated, interdisciplinary team. Over 700 children have benefited from accurate diagnosis and treatment. Initiatives that implement long-term partnerships between institutions along the Mexican-North American border can be highly effective in establishing successful pediatric cancer control programs. The geographic proximity facilitated accelerated training and close monitoring of project development. Similar initiatives across other disciplines may benefit additional patients and synergize with pediatric oncology programs to reduce health disparities in underserved areas.

High Incidence of Induction Failure and Poor Outcome in Patients with Gamma Delta T Cell Acute Lymphoblastic Leukemia

The two lineages of T cells, αβ and γδ, diverge early in development and recognize ligands differently. γδ T cells are not restricted by the major histocompatibility complex (MHC)and can recognize peptides, non-peptides as well as small molecules. The effector functions of αβ and γδ T cells are also biologically distinct. Mature T cell lymphomas derived from the γδ lineage are often aggressive with poor prognosis. For T cell acute lymphoblastic leukemia (T-ALL), it is customary to view the TCR expression on lymphoblasts as an indicator for the maturational state, although identification of the heterodimer can distinguish two distinct T cells. The αβ and γδ T cells are derived from different lineages with distinct developmental stages and biological characteristics. Here we evaluated the clinical presentation and outcomes of patients with γδ T-ALL who were treated on protocol to determine the impact of lineage specification on T-ALL prognosis.From January 2004 to July 2014, 100 consecutive patients with newly diagnosed T- ALL were enrolled onto the Total Therapy XV or XVI study at St. Jude Children's Research Hospital (SJCRH). Of the 100 patients, 93 had diagnostic samples screened and confirmed for γδ TCR and were evaluable for follow up. Patients received risk-adaptive treatment consisted of remission induction, consolidation and continuation as previously described.Of the 93 patients, 12 (13%) had γδ T-ALL. With the exception of higher percentage of γδT-ALL patients classified to have high risk disease based on high MRD levels (≥1%) at the end of remission induction (25% vs. 11%; P =0.04), there was no significant differences between the two groups in regards to age, gender, race, presenting leukocyte count, presence of a mediastinal mass and CNS involvement at diagnosis. Patients with γδ T-ALL had a significantly higher risk for induction failure with MRD ≥ 1% at day 15 (67% vs. 33%; P =0.006) and day 42 (25% vs. 11%; P =0.04). High portion of patients with γδ T-ALL (40%) were referred for an allogeneic hematopoietic stem cell transplantation. The overall survival was significantly lower for patients with γδ T-ALL compared to non-γδT-ALL at 5 years (63 ± 20% vs. 91 ± 4%) and 10 years (63 ± 38% vs. 88 ± 31%) (P =0.01). The event free survival was lower and relapse rate was higher for the γδ T-ALL patients compared to the non- γδ T-ALL patients, although not significant.Majority of patients with γδ T-ALL had complex cytogenetic abnormalities (91%) and one patient had normal karyotype. Interestingly, hyperdiploidy (47-53) was common, but only one patient had high hyperdiploidy with a DNA index of 1.17. Immunophenotype showed variable expression of CD34, CD1a, CD2 and CD7. The pairing of the Vγ and Vδ chains expressed by the lymphoblast was identified using high throughput single cell PCR on the expressed cDNA. Out of 12 patients, 9 patients had appropriate consents, samples and successful amplification The TCR was predominately Vδ1 (67%) and the CDRγ region was highly conserved (~88%) between patients. Despite the broad diversity of the rearranged TRG region, the CDR3γ region was highly conserved. The CDR3γ region contained an average of 14.2±2.2 amino acids and each patient had an average of 3.3 ± 2.6 unique amino acids. An average of 11 ± 0.5 amino acids (88%) were conserved amongst the T-ALL patients. All the patients used the terminal TRGC2, suggesting a bias towards a non-disulfide linked TCR. Majority (>75%) of γδ T cell in normal peripheral blood is Vγ9Vδ2, and none of the patients expressed Vδ2. The dominant Vδ1 has been shown to be resistant to activation induced cellular death (AICD) and can persist for many years. This may correlate to the recent association of SET-NUP214, a fusion gene involving 9q34 that is specific for the γδ lineage and confers chemotherapy resistance. Further studies evaluating the genetic alternations will shed insight into to potential mechanisms. In summary, expression of the γδ TCR on T-ALL lymphoblasts identified a subset of patients with high risk for induction failure and poor outcome. DisclosuresEvans:Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping.

Genome-Wide Association Study Identifies PNPLA3 I148M Variant Associated with Elevated Transaminase Levels after Induction Therapy in Pediatric ALL Patients

Current regimens for remission induction therapy of pediatric acute lymphoblastic leukemia (ALL) include multiple potentially hepatotoxic drugs, including asparaginase. The objective of our genome-wide association study (GWAS) was to identify genetic loci associated with elevated alanine transaminase (ALT) levels immediately after remission induction in children with ALL. The patients included were enrolled on St. Jude Children's Research Hospital (SJCRH) protocols Total XV (n = 373) or Total XVI (n = 342); germline DNA was genotyped using the Affymetrix 500K, Affymetrix 6.0, or the Illumina Exome Beadchip arrays. In multivariate analysis, risk factors associated with higher ALT included older age, higher body mass index, European (versus African) ancestry, treatment with PEGylated E. coli asparaginase (versus native E. coli asparaginase), and receiving additional doses of asparaginase during induction due to high level of minimal residual disease at day 15-19 of induction. GWAS identified an association between I148M PNPLA3 rs738409 (C>G) variant and post-induction ALT (Figure 1A; P = 7.9x10-9; median ALT of 34, 45, and 58 IU/L in CC, GC and GG genotypes, respectively), and the effect of the PNPLA3 variant was consistent for both protocols, both ALL risk groups, and among patients of European, African, and Hispanic ancestry. The PNPLA3 variant has previously been linked to elevated ALT and to the development of steatosis in adults;[PMID: 22001757; 18820647] in mice, this same variant led to a loss of catalytic function and to an increase of PNPLA3 accumulation in hepatic lipid droplets and to the development of steatosis.[PMID: 24917523] Within patients of African ancestry, we identified a variant near PIGV rs12748152 (C>T) associated with lower ALT levels at P = 1.7x10-8; median ALT of 28 and 6 IU/L in CC and TC genotypes, respectively (Figure 1B), consistent with lower ALT values observed in patients of African ancestry. The PIGV variant explained 7% of the variation in ALT for patients of African ancestry. The results of our study suggest that post-remission induction ALT levels may be related to treatment-related variables, such as increased asparaginase exposure, and to host genetic factors, at least some of which contribute to hepatic dysfunction in settings outside of ALL therapy. [Display omitted] DisclosuresEvans:Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping.

Genome-wide analysis links NFATC2 with asparaginase hypersensitivity

AbstractAsparaginase is used to treat acute lymphoblastic leukemia (ALL); however, hypersensitivity reactions can lead to suboptimal asparaginase exposure. Our objective was to use a genome-wide approach to identify loci associated with asparaginase hypersensitivity in children with ALL enrolled on St. Jude Children's Research Hospital (SJCRH) protocols Total XIIIA (n = 154), Total XV (n = 498), and Total XVI (n = 271), or Children's Oncology Group protocols POG 9906 (n = 222) and AALL0232 (n = 2163). Germline DNA was genotyped using the Affymetrix 500K, Affymetrix 6.0, or the Illumina Exome BeadChip array. In multivariate logistic regression, the intronic rs6021191 variant in nuclear factor of activated T cells 2 (NFATC2) had the strongest association with hypersensitivity (P = 4.1 × 10−8; odds ratio [OR] = 3.11). RNA-seq data available from 65 SJCRH ALL tumor samples and 52 Yoruba HapMap samples showed that samples carrying the rs6021191 variant had higher NFATC2 expression compared with noncarriers (P = 1.1 × 10−3 and 0.03, respectively). The top ranked nonsynonymous polymorphism was rs17885382 in HLA-DRB1 (P = 3.2 × 10−6; OR = 1.63), which is in near complete linkage disequilibrium with the HLA-DRB1*07:01 allele we previously observed in a candidate gene study. The strongest risk factors for asparaginase allergy are variants within genes regulating the immune response.

Pubertal development and primary ovarian insufficiency in female survivors of embryonal brain tumors following risk-adapted craniospinal irradiation and adjuvant chemotherapy.

Female survivors of central nervous system (CNS) tumors are at an increased risk for gonadal damage and variations in the timing of puberty following radiotherapy and alkylating agent-based chemotherapy. Clinical and laboratory data were obtained from 30 evaluable female patients with newly diagnosed embryonal CNS tumors treated on a prospective protocol (SJMB 96) at St. Jude Children's Research Hospital (SJCRH). Pubertal development was evaluated by Tanner staging. Primary ovarian insufficiency (POI) was determined by Tanner staging and FSH level. Females with Tanner stage I-II and FSH > 15 mIU/ml, or Tanner stage III-V, FSH > 25 mIU/ml and FSH greater than LH were defined to have ovarian insufficiency. Recovery of ovarian function was defined as normalization of FSH without therapeutic intervention. Median length of follow-up post completion of therapy was 7.2 years (4.0-10.8 years). The cumulative incidence of pubertal onset was 75.6% by the age of 13. Precocious puberty was observed in 11.1% and delayed puberty in 11.8%. The cumulative incidence of POI was 82.8%, though recovery was observed in 38.5%. Treatment for primary CNS embryonal tumors may cause variations in the timing of pubertal development, impacting physical and psychosocial development. Female survivors are at risk for POI, a subset of whom will recover function over time. Further refinement of therapies is needed in order to reduce late ovarian insufficiency. Pediatr Blood Cancer 2015;62:329-334. © 2014 Wiley Periodicals, Inc.

Histopathologic Diagnosis of Pediatric Neoplasms: A Review of International Consultations

Correct histopathologic diagnosis is fundamental to defining proper treatment and improving outcomes in children with malignancies. The Department of Pathology at St. Jude Children's Research Hospital (SJCRH) has collaborated with SJCRH International Outreach Program partner sites to improve the accuracy of histopathologic diagnoses in countries with limited resources. Pathologists at SJCRH provide review and evaluation of cases that are considered difficult or complex. To determine the quality of pathology diagnosis and to identify areas for improvement in our international partner sites, we retrospectively analyzed all the international cases that were submitted for review. A comparison of our data with selected reports of surgical pathology error rates published in the medical literature was performed. From January 2009 through December 2011, SJCRH received 763 cases submitted by international pathologists from 37 countries for histopathologic review and evaluation. Of 763 cases reviewed, 705 (92.4%) met the criteria for inclusion in this study. Rates of concordance between the submitted diagnoses and SJCRH reviewed diagnoses were analyzed. Overall concordance, minor disagreement, and major disagreement rates between submitted diagnoses and SJCRH reviewed diagnoses were 430 (61.0%), 98 (13.9%), and 177 (25.1%) of the cases, respectively. Major disagreement rates ranged from 13.7% to 37.1% among studied countries. The major disagreement rate between referring international sites and SJCRH was substantially higher than the major disagreement rate among US institutions. Lack of the availability of immunohistochemistry and the training of pathologists in the diagnosis of pediatric neoplasms may have contributed to the discrepancies.

Abstract 2544: Potential gene variants associated with obesity following cranial radiation treatment for childhood cancer in a genome-wide association study.

Abstract Survivors of childhood cancer who were exposed to cranial radiation during curative treatment are at high risk for obesity. Obesity is problematic in this population because it may add to the survivors’ already elevated risk for chronic diseases, including those with significant potential for premature mortality, like heart disease and some types of secondary cancers. Previous studies have suggested that genetic differences in response to anticancer therapies can influence the development of long-term adverse health effects in cancer survivors. Therefore, the aim of this study was to identify single nucleotide polymorphisms (SNPs) associated with obesity among survivors of childhood cancer using a genome-wide association study analysis. Participants included 1468 (714 male) adults previously treated for childhood cancer at St. Jude Children's Research Hospital (SJCRH) who survived ≥10 years from diagnosis. All participants underwent clinical evaluation at SJCRH and provided a DNA sample. Genotyping was conducted using the Affymetrix Genome-Wide Human SNP 6.0 Array. Imputation of SNPs not included on the array was performed using MACH (Version 1.0.18.c) and data from the 1000 Genomes Project was used as a reference panel. Obesity was defined as a body mass index (BMI) ≥30kg/m2. The cohort was stratified into two groups for analyses: survivors treated with cranial radiation (N=597) and survivors treated without cranial radiation (N=871). Logistic regression models, implemented in PLINK (Version 1.07) and mach2dat (Version v120), were used to identify potential SNPs associated with the obesity outcome. Over half (51%) of survivors treated with cranial radiation had a BMI≥30kg/m2 compared with 39% of survivors who did not receive cranial radiation. Among survivors previously treated with cranial radiation, multiple SNPs within the glycine receptor α 3 gene (GLRA3) were found to be associated with obesity (p&amp;lt;5 x 10−8). The strongest association with obesity was observed for SNP rs12641804 (p=3.9 x 10−10). In contrast, we did not observe an association between SNPs located within GLRA3 and obesity among survivors who did not receive cranial radiation, nor did any other SNP reach genome-wide significance (p&amp;lt;5 x 10−8) in this model. GLRA3 codes for a membrane-bound receptor protein involved in signaling by the neurotransmitter glycine. Our data suggest a possible role for glycine receptors in the pathogenesis of obesity among survivors of childhood cancer following cranial irradiation. Validation of our findings in an independent cohort is required. Citation Format: Carmen L. Wilson, Wei Liu, Geoffrey Neale, Deokumar Srivastava, James G. Gurney, Guolian Kang, Perdeep Mehta, Rohit Ojha, Melissa M. Hudson, Leslie L. Robison, Kirsten K. Ness. Potential gene variants associated with obesity following cranial radiation treatment for childhood cancer in a genome-wide association study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2544. doi:10.1158/1538-7445.AM2013-2544

Abstract B54: Addressing cancer disparities in the border region: A novel model of twinning in pediatric oncology.

Abstract Background: Health institutions located along the borders of countries with profound economic disparities often face difficulties in providing care for children with complex diseases such as cancer. Until recently, many children with cancer from Baja California went untreated. We postulated that the St. Jude Children's Research Hospital (SJCRH) twinning model used to improve pediatric cancer care in low income countries could successfully be applied in this particular setting to reduce disparities in care. The impact of twinning programs has already been proven. Twinning is defined as a form of cooperation between centers in developed countries and low-income countries, whereby knowledge and organizational skills are shared and pediatric oncology units are established in a culturally sensitive manner and adapted to local health care systems. SJCRH has established several successful twinning programs worldwide. Objectives: In 2008, Rady Children's Hospital San Diego (RCHSD) partnered with SJCRH and Hospital General-Tijuana (HGT), the largest hospital in northwestern Mexico, to initiate a twinning project aiming to establish a fully functional pediatric oncology unit and to improve care for children with cancer in the border region. Methods: A modified SJCRH assessment tool was developed and revealed that, although the basic hospital infrastructure and services, were available (e.g.: anatomic pathology, laboratory and blood bank) the essential elements of a pediatric cancer unit, such as dedicated space, trained pediatric oncologists and nurses and uniform treatment were lacking. In addition, chemotherapy medications were available but not prepared according to proper procedure; medical records were incomplete; patients had no access to intensive therapy; and supportive care programs were lacking. A 5-year strategic plan was designed to provide salary supplementation for health care professionals, intensive education and training, and infrastructure improvement. A bicultural, Spanish-speaking pediatric oncologist from RCHSD was appointed to supervise the project and visited the partner site weekly to monitor progress closely. Results: After four years, accomplishments include: the opening of a new isolated inpatient unit with updated technology, the training of nurses and staff, and the establishment of a dedicated inter-disciplinary team led by two local pediatric oncologists. Over 160 patients have benefited from accurate diagnosis and treatment, access to supportive care, infection control, specialized nurses, dedicated pediatricians, and psychosocial and nutritional programs. In December 2008, the pediatric oncology service at HGT received the Mexican Accreditation ensuring full coverage by a Federal insurance program for the underprivileged and contributing to local sustainability. Conclusion: Border towns have a particularly high need for the development of programs to address health disparities. Initiatives in the border region constitute a unique model of twinning, since the proximity permits close follow-up and leads to establishment of reducing disparities programs in record time, benefiting hundreds of children. Ongoing initiatives include, continued education and training for the staff and the community, a shelter for patients and expansion of education and subsidies for families. Citation Format: Paula Aristizabal, Raul C. Ribeiro, William D. Roberts. Addressing cancer disparities in the border region: A novel model of twinning in pediatric oncology. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B54.

Assessment of potential bias from non-participation in a dynamic clinical cohort of long-term childhood cancer survivors: results from the St. Jude Lifetime Cohort Study.

To evaluate long-term health outcomes among childhood cancer survivors, St. Jude Children's Research Hospital (SJCRH) has established the St. Jude Lifetime Cohort Study (SJLIFE), comprised of adult survivors who undergo risk-directed clinical assessments. As in any human research study, SJLIFE participants are volunteers who may not represent the source population from which they were recruited. A lack of proportional representation could result in biased estimates of exposure-outcome associations. We compared available demographic, disease, and neighborhood level characteristics between participants and the source population to assess the potential for selection bias. Potentially eligible patients for SJLIFE were enumerated as of October 31, 2011. Data from electronic medical records were combined with geocoded census data to develop an analytic data set of 3,108 patients (the evaluable source population) of whom 1,766 (57%) underwent clinical assessment (participants). The ratio of relative frequencies (RRFs) for characteristics was compared between participants and the source population, where RRF = 1.0 indicates equal frequency of the characteristic. Participants and the source population had similar frequencies for most characteristics. Characteristics with modest relative differences (RRFs between 0.86 and 1.11) included sex, distance from SJCRH, primary diagnosis, median household income, median home value, and urbanicity. Our results indicate a lack of substantive differences in the relative frequencies of demographic, disease, or neighborhood characteristics between participants and the source population in SJLIFE, thus alleviating serious concerns about selective non-participation in this cohort. Bias in specific exposure-outcome relations is still possible and will be considered in individual analyses.

Analysis of Prognostic Factors in Extraosseous Ewing Sarcoma Family of Tumors: Review of St. Jude Children’s Research Hospital Experience

Advances in the treatment of Ewing sarcoma family of tumors (ESFT) are the result of improvements in systemic and local therapies. Clinical data of extraosseous ESFT are scarce. A retrospective analysis of all patients with extraosseous ESFT treated at St. Jude Children's Research Hospital (SJCRH) from June 1982 to August 2009. Forty-six patients with extraosseous ESFT were identified. The mean age at diagnosis was 13.8years. The majority of patients were male and white. The most common site of primary tumor was the trunk. Twelve patients had subcutaneous tumors. The median tumor size was 8cm. Six patients (13%) had metastatic disease at diagnosis. A total of 59% of patients were alive at the time of analysis, with a median follow-up from diagnosis of 15.3years. Fifteen-year estimates of survival and event-free survival (EFS) for all patients were 53.3±9.4 and 50±9.1%, respectively. Fifteen-year estimates of survival and EFS with localized disease were 61.4±9.8 and 57.6±9.7%, respectively. Stage and subcutaneous ESFT were significant predictors of outcome. There was no significant difference in patient's demographics and tumor characteristics between patients with skeletal ESFT and extraosseous Ewing sarcoma. The outcome for patients with localized extraosseous Ewing sarcoma was similar to that reported for all localized ESFT patients treated at SJCRH. The outcome for localized patients treated with extraosseous ESFT was similar to that reported for all ESFT patients treated on protocols at SJCRH. Patients with subcutaneous ESFT had a favorable prognosis when compared to their counterparts.

Diagnostic value of routine chest radiography in febrile, neutropenic children for early detection of pneumonia and mould infections

Despite recent studies failing to demonstrate the value of routine chest radiography (CXR) in the initial evaluation of the febrile neutropenic patient with cancer, this screening test is advocated by some experts. We evaluated the benefits of CXR for early diagnosis of pulmonary infection at St. Jude Children's Research Hospital (SJCRH) with emphasis on early recognition of mould infections. We reviewed the courses of 200 consecutive febrile neutropenic pediatric patients to determine if routine CXR at initial evaluation was useful in the identification of clinically occult pneumonia. We also reviewed all cases of proven or probable mould infections from the opening of SJCRH in 1962 until 1998 when routine CXR was no longer practiced in our institution to identify cases that were first recognized by routine CXR. Of 200 febrile neutropenic patients, pulmonary abnormalities consistent with pneumonia were detected by routine CXR in only five patients without pulmonary signs or symptoms. In only one case was a change in management considered. Of the 70 patients with pulmonary mould infection identified from 1962 to 1998, routine CXR was performed in 45 patients at the onset of a febrile, neutropenic episode in which a mould infection was diagnosed. Routine CXR was pivotal in the recognition of the mould infection in only two cases over this 36-year period. CXR is warranted in the evaluation of the newly febrile neutropenic pediatric oncology patient only when respiratory signs or symptoms are present.

Efficacy of intravascular catheter lock solutions containing preservatives in the prevention of microbial colonization

There is little published evidence regarding whether heparin lock solutions containing preservatives prevent catheter-related infections. However, adverse effects from preservative-containing flushes have been documented in neonates, leading many hospitals to avoid their use altogether. Infection control records from 1982 to 2008 at St. Jude Children's Research Hospital (SJCRH) were reviewed regarding the incidence of catheter-related infections and the use of preservative-containing intravenous locks. In addition, the antimicrobial activities of heparin lock solution containing the preservatives parabens (0.165%) or benzyl alcohol (0.9%), and 70% ethanol were examined against Staphylococcus epidermidis, Staphylococcus aureus, Escherichia coli, Bacillus cereus, Pseudomonas aeruginosa and Candida albicans, and compared with preservative-free saline with and without heparin. Growth was assessed after exposure to test solutions for 0, 2, 4 and 24h at 35 °C. The activities of preservatives were assessed against both planktonic (free-floating) and sessile (biofilm-embedded) micro-organisms using the MBEC Assay. Infection control records revealed two periods of increased catheter-related infections, corresponding with two intervals when preservative-free heparin was used at SJCRH. Heparin solution containing preservatives demonstrated significant antimicrobial activity against both planktonic and sessile forms of all six microbial species. Ethanol demonstrated the greatest antimicrobial activity, especially following short incubation periods. Heparin lock solutions containing the preservatives parabens or benzyl alcohol, and 70% ethanol demonstrated significant antimicrobial activity against both planktonic and sessile micro-organisms commonly responsible for catheter-related infections. These findings, together with the authors' historical infection control experience, support the use of preservatives in intravenous lock solutions to reduce catheter related infections in patients beyond the neonatal period.

Severe H1N1‐associated acute respiratory failure in immunocompromised children

Severe pandemic influenza A (H1N1) infection can lead to acute respiratory failure (ARF) with associated high mortality. Children with malignancy may be at higher risk of H1N1-associated ARF because of underlying primary disease or immunosuppression associated with chemotherapy. We describe the clinical course and outcome of critically ill pediatric oncology/hematology patients with H1N1-associated ARF. Five patients were admitted to the St. Jude Children's Research Hospital (SJCRH) ICU with H1N1 infection during the 2009-2010 influenza season. Underlying diagnoses included 2 patients with acute lymphoblastic leukemia and one each with neuroblastoma, brainstem glioma, and hemolytic anemia secondary to pyruvate kinase deficiency. All patients were mechanically ventilated secondary to ARF following unsuccessful trials of non-invasive ventilatory support. The majority of patients (4/5) required inotropic support, and none required dialysis. Further measures to support their ARF included high frequency oscillatory ventilation in 2 patients, nitric oxide in 3 patients, and surfactant in 1 patient. Three patients had bronchopleural air leak. All patients received oseltamivir; however, 2 were switched to intravenous zanamivir once resistance to oseltamivir was documented. Mean duration of mechanical ventilation was 24 ± 6.8 days and mean duration of ICU admission was 37 ± 12 days. All patients survived to hospital discharge. Our series suggests an overall favorable outcome in immunocompromised children with H1N1-related ARF. Our experience underscores the value of aggressive support during H1N1-related ARF, and early detection and management of oseltamivir-resistant H1N1 infection in this high-risk population.

Prospective medical assessment of adults surviving childhood cancer: study design, cohort characteristics, and feasibility of the St. Jude Lifetime Cohort study.

To facilitate prospective medical assessment of adults surviving pediatric malignancies and advance knowledge about long-term childhood cancer survivor health, St. Jude Children's Research Hospital (SJCRH) is establishing a lifetime cohort of survivors. Eligibility criteria for inclusion in the St. Jude Lifetime Cohort (SJLIFE) study include: (1) diagnosis of childhood malignancy treated at SJCRH; (2) survival ≥ 10 years from diagnosis; and (3) current age ≥ 18 years. Three levels of participation are offered: (1) comprehensive evaluation on SJCRH campus; (2) limited home evaluation; or (3) completion of health surveys only. A systematic recruitment structure based upon blocks of 50 patients initially focused on leukemia and lymphoma survivors and patients eligible for pilot studies. As of January 1, 2010, 1,625 (42%) of 3,900 eligible ≥ 10-year survivors have been contacted. Among the first 1,000 potentially eligible survivors selected for recruitment, 971 were subsequently confirmed to fulfill eligibility criteria. To date, 898/971 (92.5%) have been successfully contacted of whom 825 (91.8%) have agreed to participate. Among participants, 88.6% agreed to comprehensive medical evaluation, 0.4% limited local evaluation, and 11.0% survey only. Anticipated minimum overall participation rate for medical evaluation is 75.3% (731/971). Comparison of those contacted who agreed versus declined to participate revealed a greater proportion of males who declined participation (P = 0.001). Early results of the SJLIFE study support its feasibility to recruit aging childhood cancer survivors to research investigations evaluating late health outcomes by medical assessments.