Angela Punnett

Posttransplant Lymphoproliferative Diseases

The risk of developing cancer after solid organ transplantation (SOT) is about 5- to 10-fold greater than that of the general population. The cumulative risk of cancer rises to more than 50% at 20 years after transplant and increases with age, and so children receiving transplants are at high risk of developing a malignancy. Posttransplant lymphoproliferative disease (PTLD) is the most common cancer observed in children following SOT, accounting for half of all such malignancies. PTLD is a heterogeneous group of disorders with a wide spectrum of pathologic and clinical manifestations and is a major contributor to long-term morbidity and mortality in this population. Among children, most cases are associated with Epstein-Barr virus infection. This article reviews the pathology, immunobiology, epidemiology, and clinical aspects of PTLD, underscoring the need for ongoing systematic study of complex biologic and therapeutic questions.

Ototoxicity following pediatric hematopoietic stem cell transplantation: A prospective cohort study

Our objectives were to describe the frequency and determine risk factors for hearing deterioration following pediatric stem cell transplantation (SCT).

Risk factors for infection-related outcomes during induction therapy for childhood acute lymphoblastic leukemia.

Background: The primary objective was to describe microbiologically documented infections during induction therapy for acute lymphoblastic leukemia. The secondary objectives were to describe risk factors for microbiologically documented infections and for patients with a febrile episode, to identify risk factors for recurrence of fever or reinitiation of antibiotics. Methods: This study was a retrospective review of children from 1 to 18 years of age who received induction chemotherapy between March 1997 and September 2006. Microbiologically documented infections were examined through the induction period. Results: There were 425 children evaluated. The most common pre-existing risk factor for infection was Down syndrome in 11 children. Of the 425 children, 83 (19.5%) experienced at least one microbiologically documented infection. There were 85 infections consisting of 65 bacterial, 15 viral and 5 fungal infections. Variables significantly associated with a microbiologically documented infection were pre-existing risk factors (odds ratio [OR]: 3.63; P = 0.01) and neutropenia at initial infectious episode (OR: 1.86; P = 0.03). Factors associated with recurrence of fever and reinitiation of antibiotics after an initial infectious episode were receipt of a 4-drug induction, neutropenia at the initial infectious episode, initial fever documented in hospital, and lack of bone marrow recovery at the time of initial antibiotic cessation. Conclusions: About 20% of children with acute lymphoblastic leukemia have a microbiologically documented infection during induction. Those with pre-existing risk factors and neutropenia at the initial infectious episode were at higher risk of microbiologically documented infection. Continued efforts to refine risk groups may allow for risk-directed prophylactic or empiric strategies.

A cross Canada survey of sperm banking practices in pediatric oncology centers

Childhood cancer survivors have identified fertility preservation as a major concern. Sperm banking is an established fertility preservation option in pubertal males. We sought to describe current practices in Canadian pediatric oncology programs, and to identify perceived barriers to sperm banking for male adolescents.

Identification of educational and infrastructural barriers to prompt antibiotic delivery in febrile neutropenia: a quality improvement initiative.

Antibiotic administration within 60 minutes of presentation for medical care may be used as a treatment target for febrile neutropenia (FN); however, anecdotal evidence suggests this target is often missed. Few studies have examined the prevalence or causes of delay. We describe the median time to antibiotic administration at our institution, predictors of delay, and barriers to prompt administration to inform quality improvement strategies.

Patients with primary brain tumors as organ donors: case report and review of the literature.

Malignancy is considered a contra‐indication to organ donation, with a few possible exceptions. We present the case of a child with fatal intracranial hemorrhage from a primary brain tumor (PBT) whose organs were denied for transplant after recovery. We review the literature of organ donors with PBTs in the context of the current organ shortage and discuss the implications for the practicing oncologist. Transmission of donor brain tumor to organ recipients has been documented but the incidence appears to be very low. Risk factors for tumor transmission include underlying donor tumor histology, history of craniotomy and/or shunt placement, use of systemic chemotherapy and radiation therapy, and duration of disease prior to donation. Ongoing data collection by national registries will provide more information on the potential risk to organ recipients. It may be appropriate to expand the donor pool to include donors with PBTs in certain situations. The transplantation team ultimately decides upon the use of organs from specific donors. Many families will appreciate the opportunity to donate specific tissues even if solid organ transplantation is prohibited.

Achievement of target cyclosporine concentrations as a predictor of severe acute graft versus host disease in children undergoing hematopoietic stem cell transplantation and receiving cyclosporine and methotrexate prophylaxis.

This study evaluates our institutions target trough cyclosporine (CSA) concentrations as predictors of severe acute graft versus host disease (aGvHD) in children receiving either matched related or unrelated hematopoietic stem cell transplantation (HSCT). The outcomes of 87 consecutive children who underwent allogeneic HSCT and received CSA and methotrexate as prophylaxis against aGvHD between October 1, 1999 and September 30, 2002 were retrospectively evaluated. The proportion of time that each patient maintained a whole blood CSA concentration within or above the initial target range (105-155 ng/mL or 155-210 ng/mL) was calculated for each of the following time periods: in each week after HSCT from day 0 to +28; in the week preceding engraftment; and in the week preceding the onset of aGvHD. Patients were prospectively evaluated twice weekly for the presence and severity of aGvHD by senior attending physicians. The relationship between potential predictors and the development of severe aGvHD was examined using univariate logistic regression. The main variables of interest were the proportion of time that therapeutic or supratherapeutic CSA concentrations were maintained; median CSA concentrations; the number of methotrexate doses received; and the use of folinic acid rescue. Mean follow-up time was 3.0 ± 1.9 years among children who survived beyond day +100. Three variables were significantly associated with the development of severe aGvHD on univariate analysis: initial CSA target concentration [odds ratio (OR), 0.24; P = 0.03], proportion of time the target CSA concentration was achieved during the second week after transplant (OR, 0.16; P = 0.02), and proportion of time the target CSA concentration was achieved during the week before engraftment (OR, 0.22; P = 0.0489). Multivariable analysis demonstrated an inverse relationship between the median CSA concentration during the week before engraftment and the development of severe aGvHD (OR, 0.99; P = 0.045). These results suggest that achievement of our CSA target concentrations is important to aGvHD outcomes.

The prognostic impact of tumour-associated macrophages and Reed-Sternberg cells in paediatric Hodgkin lymphoma

BACKGROUND Tumour-associated macrophages (TAM) are associated with treatment failure in adults with Hodgkin lymphoma (HL). Equivalent data in paediatric HL are sparse. We aimed to determine the prognostic significance of TAM and Reed-Sternberg (RS) cells in paediatric HL. METHODS All children aged 0-18 with HL between 1980 and 2009 with available diagnostic biopsy material were identified. A treatment failure-enriched cohort was assembled. Demographic, disease and outcome data were abstracted. Tissue microarrays with duplicate cores were constructed from diagnostic biopsy material and stained with immunohistochemical markers for TAM (CD68, CD163) and RS (CD30). A high score was defined as >5% positive cells relative to overall cellularity in any core. The association of candidate variables with event-free survival (EFS) was determined using Cox proportional hazards. RESULTS The final study cohort comprised 96 patients with a median age of 14 years (interquartile range 11-15). Agreement on scores between cores from the same biopsy revealed weighted kappas of 0.60, 0.68 and 0.73 for CD30, CD68 and CD163 respectively, indicating moderate tumour heterogeneity. In univariate analysis, a high CD30 score was significantly associated with treatment failure (hazard ratio (HR) 2.27; 95th confidence interval 1.01-5.11; p<0.05). High CD68 and CD163 scores were not associated with EFS. CONCLUSIONS Unlike adult HL, a higher percentage of RS cells was associated with poor outcome, while a higher percentage of TAM was not. Adult HL findings may not extend to paediatric HL. Cooperative group trials of paediatric HL should prospectively determine the association of different components of the tumour microenvironment with outcome.

The value of 18F‐FDG PET in pediatric patients with post‐transplant lymphoproliferative disorder at initial diagnosis

PTLD is a serious complication of both solid organ and BMT. This study assessed whether 18F‐FDG PET, when added to CT scan, had additional value in the initial evaluation of PTLD in pediatric patients and whether PET/CT at baseline can reliably guide biopsy. This retrospective study evaluated 34 consecutive pediatric patients (14 female), aged 3.5–17.0 yr (mean age: 9.9 yr, s.d.: 4.9 yr), who had undergone 18F‐FDG PET/CT from May 2007 to December 2014 at initial diagnosis of PTLD following heart (n = 13), lung (n = 8), kidney (n = 4), liver (n = 3), liver and bowel (n = 3), and bone marrow (n = 3) transplantation. PTLD was diagnosed histopathologically in 33 patients and was based on clinical findings, elevated EBV, and imaging and follow‐up results in one patient. On lesion‐based analysis, 18F‐FDG PET showed more lesions than conventional CT scan (168 vs. 134), but CT revealed 22 lesions negative on PET. On per patient analysis, PET detected more lesions in 13 patients, CT identified more abnormalities in seven, and both showed the same number of lesions in 14. Adding 18F‐FDG PET to CT scans upstaged the disease in seven patients (20.5%). A combination of 18F‐FDG PET and CT was also useful in guiding biopsy, being positive in 36 of 39 samples (92.3%). These findings indicated that 18F‐FDG PET and CT are complementary at initial staging of pediatric PTLD and that 18F‐FDG PET/CT scanning can guide biopsies.

Staging Evaluation and Response Criteria Harmonization (SEARCH) for Childhood, Adolescent and Young Adult Hodgkin Lymphoma (CAYAHL): Methodology statement

International harmonization of staging evaluation and response criteria is needed for childhood, adolescence, and young adulthood Hodgkin lymphoma. Two Hodgkin lymphoma protocols from cooperative trials in Europe and North America were compared for areas in need of harmonization, and an evidence‐based approach is currently underway to harmonize staging and response evaluations with a goal to enhance comparisons, expedite identification of effective therapies, and aid in the approval process for new agents by regulatory agencies.