BackgroundPatients with stage IV favorable histology Wilms tumor (FHWT) with extrapulmonary metas... more BackgroundPatients with stage IV favorable histology Wilms tumor (FHWT) with extrapulmonary metastases (EPM) constitute a small subset of patients with FHWT. Because of their rarity and heterogeneity, optimal FHWT treatment is not well understood. Children’s Oncology Group protocol AREN0533 assigned patients with FHWT and EPM to intensified chemotherapy, regimen M, after initial DD‐4A chemotherapy. To improve understanding of prognostic factors and best therapies, experiences of patients with EPM on AREN0533, as well as on protocols AREN03B2 and NWTS‐5, were reviewed.MethodsCombined outcomes for patients with EPM from NWTS‐5, AREN0533, and AREN03B2 were determined. Those treated on AREN0533 were compared with those treated on NWTS‐5. Prognostic factors were explored in the pooled cohort.ResultsForty‐seven patients with FHWT with EPM enrolled on AREN0533, 37 enrolled on NWTS‐5, and 64 were followed only on AREN03B2. The pooled cohort of all 148 patients demonstrated a 4‐year event‐fr...
Journal of Pediatric Hematology Oncology, Sep 1, 2004
Objective: To evaluate the ability of published dosage guidelines for enoxaparin to achieve thera... more Objective: To evaluate the ability of published dosage guidelines for enoxaparin to achieve therapeutic anticoagulation and to determine whether the routine monitoring of anti-Xa levels is still necessary at a tertiary care pediatric institution. Methods: Consecutive charts and laboratory records were reviewed for all patients receiving treatment doses of enoxaparin for thrombosis in the authors' institution over a 4-year period (1998-2002). Results: Sixty-six percent (25/38) of the anti-Xa levels were within the recommended therapeutic range (0.5-1.0 [± 10%] U/mL) after two doses. The success rates of achieving therapeutic levels were 1/6, 2/3, 6/9, 10/11, and 6/9, for patients 2 months or younger, more than 2 months to 1 year, more than 1 year to 6 years, more than 6 years to 12 years, and more than 12 years of age, respectively. Patients with cardiac or renal disease were more likely to achieve high anti-Xa levels. Thirty-seven percent of patients reported adverse effects. The most common effects were injection site-related bruising and minor bleeding. One patient experienced a major bleed that was not lifethreatening. Conclusions: Most patients achieved therapeutic anticoagulation when dosed according to the published guidelines. Children with cardiac conditions or renal insufficiency or those younger than 2 months were more likely to require dosage adjustments to achieve the therapeutic range. Routine monitoring of anti-Xa levels is still necessary in these patient populations, particularly when the early establishment of therapeutic anticoagulation may be critical. Enoxaparin appears to be well tolerated in the authors' patient population.
To the Editor: Rare cases of ocular findings have been reported with hemophagocytic lymphohistioc... more To the Editor: Rare cases of ocular findings have been reported with hemophagocytic lymphohistiocytosis (HLH) [1–4]. We report a 7-year-old patient with Epstein-Barr virus (EBV)-associated HLH with subhyaloid hemorrhages requiring bilateral vitrectomies. HLH is a rare and sometimes life-threatening disorder in which macrophages are activated due to uncontrolled T-lymphocyte activation and pro-inflammatory signaling [1,5]. This activation may be due to infectious or other stimuli, or as a result of an inherited T-cell or natural killer cell defect (e.g. perforin deficiency), and may result in diffuse inflammation [6]. The classic syndrome of HLH includes fevers, hepatosplenomegaly and bicytopenia or pancytopenia. Only a few cases of retinal findings associated with HLH have been reported [1–4], including two patients with retinal hemorrhages [2,4]. A previously well patient presented with a 2-month history of fevers, rash, arthralgias and anorexia. She was pancytopenic with marked hepatosplenomegaly. A bone marrow aspirate and biopsy showed extensive hemophagocytosis. Biochemical studies were supportive of the diagnosis of HLH: lactate dehydrogenase >20,000 U/L; triglyceride level 8.48 mmol/L; peak ferritin level 119,000 mg/L; fibrinogen level 3.06 g/L. She had no cerebral involvement. Active infection with EBV was documented by blood polymerase chain reaction (pcr) testing. Therapy was initiated as per the Histiocyte Society HLH-2004 protocol. No specific anti-EBV therapy was given after consultation with our Infectious Disease service. Genetic studies for familial HLH were negative. However, it is recognized that many cases of familial HLH are precipitated by infectious agents such as EBV [7]. At presentation, multiple subhyaloid hemorrhages were discovered with macular involvement. The optic discs were normal, with no vasculitis seen. Decreased visual acuity was documented bilaterally. Despite a response to treatment, continued ophthalmologic follow-up confirmed that the multiple subhyaloid hemorrhages were not clearing and were impairing her vision to 20/400 OD and 20/200 OS (Supplemental Fig. 1). Two months after diagnosis the child underwent vitrectomy, membrane peeling and hyaloid stripping of the right eye with air fluid exchange and endolaser application. Three weeks later the left eye required vitrectomy, air fluid exchange, membrane peeling and endolaser application. The patient’s vision improved to 20/20 in the right eye and 20/25þ in the left eye, uncorrected. Increased pressure in the right eye required prostaglandin analogue topical therapy, possibly due to subtenons steroids injected during a previous procedure. Unfortunately she relapsed with EBV reactivation while on continuation therapy. This unusual reactivation may have been due to immunosuppressive therapy. As previously noted, no anti-EBV therapy had been given initially. Re-induction chemotherapy was given as per HLH-2004 in addition to ganciclovir and rituximab, and she subsequently underwent an unrelated donor 5/6 antigen match cord blood stem cell transplant. Full donor engraftment was achieved, but the patient developed multi-organ failure due to transplant-related toxicity. She died on day þ56, autopsy was declined. Reports of ocular findings in HLH are rare [1–4]. However, we suggest careful ophthalmologic examination in all patients with HLH as eye findings may warrant close monitoring and intervention to preserve vision.
10009 Background: In National Wilms Tumor Study-5, tumor-specific combined loss of heterozygosity... more 10009 Background: In National Wilms Tumor Study-5, tumor-specific combined loss of heterozygosity (LOH) of chromosomes 1p and 16q was associated with adverse outcome in patients with favorable histology Wilms Tumor (FHWT): stage I/II patients treated with Regimen EE4A (vincristine (VCR)/dactinomycin (DACT)) had 4-year EFS of 91.2% without LOH and 74.9% with LOH; stage III/IV patients treated with Regimen DD4A (VCR/ DACT/doxorubicin(DOX)) and radiotherapy (RT) had 4-year EFS of 83% without LOH and 65.9% with LOH. The AREN0533/AREN0532 studies assessed whether augmenting therapy would improve EFS for FHWT with combined 1p/16q LOH. Stage I/II patients were treated with the addition of DOX (Regimen DD4A) but no RT. Stage III/IV patients were treated with Regimen M (VCR/DACT/DOX alternating with cyclophosphamide/etoposide) and RT. Methods: Patients were enrolled through the AREN03B2 Biology and Classification study between10/2006 and 7/2013. All patients underwent central review of pathology, surgical reports ...
Wilms tumor is the fourth most common malignancy of childhood; its pathogenesis, however, remains... more Wilms tumor is the fourth most common malignancy of childhood; its pathogenesis, however, remains largely unknown. With advancements in cytogenetic techniques, such as array comparative genomic hybridization (aCGH), there is new hope for uncovering small chromosomal microdeletions or microduplications that may contribute to our understanding of Wilms tumor. We performed aCGH on 10 samples of Wilms tumor with normal conventional cytogenetic and chromosomal CGH findings. Array CGH revealed abnormalities in 3 of the 10 samples, including microdeletions (2q37.1, 7q31 approximately q32, and 11q22.3), microduplication (18q21.1), and gains and losses of larger chromosomal areas (1q and 7q gain and loss of 7p, 11q, 14q, and 16q). Fluorescence in situ hybridization (FISH) analysis confirmed the abnormalities and revealed the majority of them existed only in a proportion cells (> or =30% of cells). We also performed aCGH on three samples of Wilms tumor with previously identified translocations between chromosomes 1 and 16, to determine the breakpoints. The breakpoints were seen in the pericentromeric regions of both chromosomes. Array CGH is useful for identifying submicroscopic changes in Wilms tumor and is more sensitive for detecting clonal abnormalities than conventional methods.
Testicular cancer, specifically germ cell tumors, are the most common malignancy in young men and... more Testicular cancer, specifically germ cell tumors, are the most common malignancy in young men and are curable in up to 95 % of cases, but the incidence is on the rise. The key event in the transformation to malignancy is hypothesized to occur in early adulthood, and the carcinogenic pathway for germ cell tumors is thought to begin in fetal life due to maternal or environmental estrogen exposure. Intratubular Germ Cell Neoplasia (ITGCN), previously known as Carcinoma in Situ (CIS) of the testis, is a premalignant condition that can progress to testicular cancer and is associated with testicular germ cell tumors. ITGCN is rarely reported in prepubertal children, and it would be helpful to know the prognostic implications of this finding. We present a case report of a 4-month-old male with undifferentiated ITGCN, and a co-morbid mature teratoma, one of only a few cases currently published. This patient had a normal 46, XY karyotype and all normal laboratory result except for a slightly elevated AFP, which is considered a normal finding for his age. Our report contributes to the growing body of evidence of ITGCN in the pediatric population and how little is known about this diagnosis. We will also briefly review management options for these patients and how we will be following this patient.
The metabolic control of phenylalanine levels is a challenge during illness. We present the metab... more The metabolic control of phenylalanine levels is a challenge during illness. We present the metabolic management of a 6 year old boy with classical PKU who was diagnosed with stage III intraabdominal Burkit's lymphoma and underwent surgical resection and chemotherapy. The metabolic control during chemotherapy was achieved by the use of parenteral custom made amino acid solution and pro-active adjustment of intake. From the 94 obtained plasma phenylalanine (Phe) levels, 18.4% were above our clinic's recommended upper limit (360 μmol/L, 6 mg/dL) while 52.7% of Phe levels were below the recommended lower limit (120 μmol/L, 2 mg/dL). Phe levels above recommended range were associated with low caloric/protein intake, while levels below recommended range reflected the difficulty in achieving the full prescribed Phe intake. We recommend early institution of custom made amino acid solution with maximum amino acid content and caloric intake to provide optimal phenylalanine control. Administration of phenylalanine via regular intravenous amino acid solution may assist in avoiding low Phe levels when prescribed intake is compromised due to vomiting and other disease related illnesses. Use of custom made, phenylalanine free amino acid solution proved beneficial in the management of blood phenylalanine levels in a PKU patient during chemotherapy for Burkitt lymphoma.
BACKGROUND: It is questionable whether enrollment on clinical trials offers any survival advantag... more BACKGROUND: It is questionable whether enrollment on clinical trials offers any survival advantage at the population level over standard-of-care treatment. The objectives of this study were to describe the impact of trial enrollment on event-free survival and overall survival in pediatric acute myeloid leukemia (AML) using the Cancer in Young People in Canada (CYP-C) database. METHODS: Children were included if they had had AML newly diagnosed between ages birth and 14 years from 2001 to 2012. CYP-C is a national pediatric cancer population-based database that includes all cases of pediatric cancer diagnosed and treated at 1 of the 17 tertiary pediatric oncology centers in Canada. Univariate and Cox proportional hazards models were used to evaluate the impact of initial trial enrollment on survival. RESULTS: In total, 397 eligible children with AML were included in the analysis, of whom 94 (23.7%) were enrolled on a clinical trial at initial diagnosis. The most common reason for non-enrollment was that no trial was available. The eventfree survival rate at 5 years was 57.8% ± 5.2% for those enrolled versus 54.8% ± 2.9% for those not enrolled (P = .75). The overall survival rate at 5 years was 70.1% ± 4.9% for those enrolled versus 66.3% ± 2.8% for those not enrolled (P = .58). Enrollment on a trial was not associated with improved event-free or overall survival in multiple regression analyses. CONCLUSIONS: Enrollment on a clinical trial was not associated with improved survival for children with AML in a population-based cohort. Rationale for trial enrollment should not include the likelihood of benefit compared with non-enrollment.
The assessment of quality of life (QOL) is key within pediatric oncology and requires a clearly d... more The assessment of quality of life (QOL) is key within pediatric oncology and requires a clearly defined construct of QOL. The purpose of our study was: (1) to conduct a qualitative study to inform the theoretical underpinnings of QOL and (2) to determine the appropriateness of patient-reported outcome (PRO) instruments to assess and evaluate QOL in pediatric cancer patients and survivors. The study used an interpretative description approach. Children diagnosed with childhood cancer, aged 8-18 years, were recruited from four Canadian hospitals. Semi-structured interviews were completed, transcribed verbatim and coded through methods of constant comparison. In-depth analysis facilitated a comparison between emerging themes and the content of commonly used PRO instruments. Thirty-seven children (19 females; 51 %) participated. The mean age was 13 years, and 19 (51 %) participants were post-treatment. Participant experiences reflected notions of positive and negative duality, including: maintaining physical functioning but longing for the ability to participate in activities; experiencing a new level of intimacy with family and friends amidst isolation; and developing positivity amidst anger, sadness and lingering worry. Analysis showed that existing PRO instruments are missing concerns specific to this population and contain content not reflective of the QOL experiences of childhood cancer patients and survivors. Our research highlights important problems with content validity of existing PRO scales, indicating that the tools we have to date have limited utility in research and clinical practice. The development of a new PRO instrument should be considered to ensure that content validity is achieved.
The primary objective was to describe predictors of physical, emotional and social quality of lif... more The primary objective was to describe predictors of physical, emotional and social quality of life (QoL) in children receiving active treatment for cancer. This Canadian multi-institutional cross-sectional study included children with cancer receiving any type of active treatment. The primary caregiver provided information on child physical, emotional and social QoL according to the PedsQL 4.0 Generic Core scales. Between November 2004 and February 2007, 376 families provided the data. In multiple regression, children with acute lymphoblastic leukemia had better physical health (OR: 0.37, 95% CI 0.23, 0.60; Po0.0001) while intensive chemotherapy treatment (OR: 2.34, 95% CI: 1.42, 3.85; P ¼ 0.0008) and having a sibling with a chronic condition (OR: 2.53, 95% CI: 1.54, 4.15; P ¼ 0.0002) were associated with poor physical QoL. Better emotional health was associated with good prognosis, less intensive chemotherapy treatment and greater household savings, whereas female children and those with a sibling with a chronic condition had poor social QoL. Physical, emotional and social QoL are influenced by demographic, diagnostic and treatment variables. Sibling and household characteristics are associated with QoL. This information will help to identify children at higher risk of poor QoL during treatment for cancer.
Background: Central venous lines (CVLs) are frequently associated with deep venous thrombosis (DV... more Background: Central venous lines (CVLs) are frequently associated with deep venous thrombosis (DVT) in children; however, little is known about the epidemiologic characteristics or outcome of CVL-related DVT. Methods: The Canadian Childhood ...
Etoposide‐based treatment is the standard of care for adult HLH in many centers, yet there remain... more Etoposide‐based treatment is the standard of care for adult HLH in many centers, yet there remains a paucity of data regarding treatment outcomes. We conducted a retrospective study of 23 adults treated with etoposide‐based therapy compared to 10 pediatric HLH cases at a single center. At diagnosis, the median serum ferritin was 20,071 µg/L and 937 µg/L in adults and children, respectively; median sIL‐2r was 14,524 U/mL and 4,478 U/mL. Biochemical response to treatment was high, with 21/23 adults achieving >75% reduction in serum ferritin, but one year survival was only 7/21 compared to 7/10 in pediatric cases.
Background In order to evaluate the family-centeredness of paediatric oncology services, a psycho... more Background In order to evaluate the family-centeredness of paediatric oncology services, a psychometrically sound measure of family-centred services is needed. We performed a comprehensive evaluation of the psychometric properties of the 20-item Measure of Processes of Care (MPOC-20) in parents of children undergoing treatment for cancer at five paediatric oncology centres in Canada. Methods The sample included 411 parents (80% response rate). Exploratory factor analysis was used to determine the best way to group the items into scales. Psychometric tests were used to examine data quality, targeting, internal consistency reliability, within-scale construct validity and known-groups validity. Results Exploratory factor analysis identified two factors: a summary measure of family-centred services and a scale measuring activities that meet parents' general informational needs. Scores spanned the entire scale range, floor and ceiling effects were low, and the sample distribution was not unduly skewed. Scales showed acceptable internal consistency reliability (Cronbach's alphas Ն0.93). Known-group hypotheses supported the scales' ability to differentiate between groups hypothesized to differ. Moderate effect sizes were found when MPOC-20 scale scores for parents and for children with good quality of life were compared with those with poor quality of life. Conclusions The MPOC-20 is the only evaluated instrument currently available to measure family-centred services in paediatric oncology. Paediatric cancer programmes can now use this tool to determine parental perception of the extent to which services are family-centred.
Journal of Pediatric Oncology Nursing, Mar 1, 2012
Research to understand the sources of stress and job satisfaction in pediatric oncology staff is ... more Research to understand the sources of stress and job satisfaction in pediatric oncology staff is limited. The aim of the authors’ qualitative study was to describe the key work-related demands and rewards in relation to working closely with parents from the perspective of health care providers (HCPs). Semistructured interviews were conducted with 13 doctors, 9 nurses, 5 social workers, and 6 child life specialists. Line-by-line, focused, and theoretical coding was used to establish categories and themes. Constant comparisons were used to examine the relationships within and across codes and categories. Interviewing continued until no new themes emerged. HCPs found it rewarding when they established close or long-term relationships with parents and to helped families through the entire cancer journey, including palliative care. HCPs found it challenging to work with complex families; with parents who are demanding, rude, or angry; with parents who have differing views about the treatments and palliative care; and with having to relay bad news to parents. Future research could explore the relationship between the factors that the authors have identified and burnout syndrome.
The National Wilms Tumor Study (NWTS) treatment of favorable histology Wilms tumor with lung meta... more The National Wilms Tumor Study (NWTS) treatment of favorable histology Wilms tumor with lung metastases was vincristine/dactinomycin/doxorubicin (DD4A) and lung radiation therapy (RT). The AREN0533 study applied a new risk stratification and treatment strategy to improve event-free survival (EFS) while reducing exposure to lung RT. Methods Patients with favorable histology Wilms tumor and isolated lung metastases showing complete lung nodule response (CR) after 6 weeks of DD4A continued receiving chemotherapy without lung RT. Patients with incomplete response (IR) or loss of heterozygosity at chromosomes 1p/16q received lung RT and four cycles of cyclophosphamide/etoposide in addition to DD4A drugs (Regimen M). AREN0533 was designed to preserve a 4-year EFS of 85% for lung nodule CR and improve 4-year EFS from 75% to 85% for lung nodule IR. Results Among 292 assessable patients, 133 had CR and 159 had IR. For patients with CR, 4-year EFS and overall survival (OS) estimates were 79.5% (95% CI, 71.2% to 87.8%) and 96.1% (95% CI, 92.1% to 100%), respectively. Expected versus observed event rates were 15% and 20.2% (P = .052), respectively. For patients with IR, 4-year EFS and OS estimates were 88.5% (95% CI, 81.8% to 95.3%) and 95.4% (95% CI, 90.9% to 99.8%), respectively. Expected versus observed event rates were 25% and 12.2% (P , .001), respectively. Overall, 4-year EFS and OS were 85.4% (95% CI, 80.5% to 90.2%) and 95.6% (95% CI, 92.8% to 98.4%) compared with 72.5% (95% CI, 66.9% to 78.1%; P , .001) and 84.0% (95% CI, 79.4% to 88.6%; P , .001), respectively, in the predecessor NWTS-5 study. Conclusion Excellent OS was achieved after omission of primary lung RT in patients with lung nodule CR, although there were more events than expected. EFS was significantly improved, with excellent OS, in patients with lung nodule IR using four cycles of cyclophosphamide/etoposide in addition to DD4A drugs. The overall AREN0533 treatment strategy yielded EFS and OS estimates that were superior to previous studies.
Research with parents of children with cancer has identified factors related to their adjustment ... more Research with parents of children with cancer has identified factors related to their adjustment and coping, but it is not fully understood why some parents do well and others do not. Guided by a stress process model, we examined the interrelationships among a comprehensive set of factors to identify the most important determinants of health-related quality of life (HRQoL) in parents of children in active treatment for cancer. A cross-sectional survey of 411 parents (80% response rate) of children receiving cancer treatment in Canada was conducted between November 2004 and February 2007. The following constructs were measured: background and context factors, child characteristics, family-centered service delivery, caregiver strain, intrapsychic factors, coping/supportive factors and parental HRQoL. The model was evaluated using structural equation modeling. Analysis was stratified by time since diagnosis (i.e., <12 months and !12 months). For those within 12 months of their child's diagnosis, family-centred service provision, caregiver strain, and self-perception accounted for 58% of the variation in psychosocial health, whereas caregiver strain and social support explained 50% of the variation in physical health. For parents in the >12 month group, caregiving strain was the only factor with a direct relationship with parental psychosocial and physical health, accounting for 66% and 55% of the variance in these constructs, respectively. Our findings reinforce the need for health professionals to be particularly attuned to family caregivers in the early stages of treatment and identify potential areas for interventions to promote parental health.
BackgroundPatients with stage IV favorable histology Wilms tumor (FHWT) with extrapulmonary metas... more BackgroundPatients with stage IV favorable histology Wilms tumor (FHWT) with extrapulmonary metastases (EPM) constitute a small subset of patients with FHWT. Because of their rarity and heterogeneity, optimal FHWT treatment is not well understood. Children’s Oncology Group protocol AREN0533 assigned patients with FHWT and EPM to intensified chemotherapy, regimen M, after initial DD‐4A chemotherapy. To improve understanding of prognostic factors and best therapies, experiences of patients with EPM on AREN0533, as well as on protocols AREN03B2 and NWTS‐5, were reviewed.MethodsCombined outcomes for patients with EPM from NWTS‐5, AREN0533, and AREN03B2 were determined. Those treated on AREN0533 were compared with those treated on NWTS‐5. Prognostic factors were explored in the pooled cohort.ResultsForty‐seven patients with FHWT with EPM enrolled on AREN0533, 37 enrolled on NWTS‐5, and 64 were followed only on AREN03B2. The pooled cohort of all 148 patients demonstrated a 4‐year event‐fr...
Journal of Pediatric Hematology Oncology, Sep 1, 2004
Objective: To evaluate the ability of published dosage guidelines for enoxaparin to achieve thera... more Objective: To evaluate the ability of published dosage guidelines for enoxaparin to achieve therapeutic anticoagulation and to determine whether the routine monitoring of anti-Xa levels is still necessary at a tertiary care pediatric institution. Methods: Consecutive charts and laboratory records were reviewed for all patients receiving treatment doses of enoxaparin for thrombosis in the authors' institution over a 4-year period (1998-2002). Results: Sixty-six percent (25/38) of the anti-Xa levels were within the recommended therapeutic range (0.5-1.0 [± 10%] U/mL) after two doses. The success rates of achieving therapeutic levels were 1/6, 2/3, 6/9, 10/11, and 6/9, for patients 2 months or younger, more than 2 months to 1 year, more than 1 year to 6 years, more than 6 years to 12 years, and more than 12 years of age, respectively. Patients with cardiac or renal disease were more likely to achieve high anti-Xa levels. Thirty-seven percent of patients reported adverse effects. The most common effects were injection site-related bruising and minor bleeding. One patient experienced a major bleed that was not lifethreatening. Conclusions: Most patients achieved therapeutic anticoagulation when dosed according to the published guidelines. Children with cardiac conditions or renal insufficiency or those younger than 2 months were more likely to require dosage adjustments to achieve the therapeutic range. Routine monitoring of anti-Xa levels is still necessary in these patient populations, particularly when the early establishment of therapeutic anticoagulation may be critical. Enoxaparin appears to be well tolerated in the authors' patient population.
To the Editor: Rare cases of ocular findings have been reported with hemophagocytic lymphohistioc... more To the Editor: Rare cases of ocular findings have been reported with hemophagocytic lymphohistiocytosis (HLH) [1–4]. We report a 7-year-old patient with Epstein-Barr virus (EBV)-associated HLH with subhyaloid hemorrhages requiring bilateral vitrectomies. HLH is a rare and sometimes life-threatening disorder in which macrophages are activated due to uncontrolled T-lymphocyte activation and pro-inflammatory signaling [1,5]. This activation may be due to infectious or other stimuli, or as a result of an inherited T-cell or natural killer cell defect (e.g. perforin deficiency), and may result in diffuse inflammation [6]. The classic syndrome of HLH includes fevers, hepatosplenomegaly and bicytopenia or pancytopenia. Only a few cases of retinal findings associated with HLH have been reported [1–4], including two patients with retinal hemorrhages [2,4]. A previously well patient presented with a 2-month history of fevers, rash, arthralgias and anorexia. She was pancytopenic with marked hepatosplenomegaly. A bone marrow aspirate and biopsy showed extensive hemophagocytosis. Biochemical studies were supportive of the diagnosis of HLH: lactate dehydrogenase >20,000 U/L; triglyceride level 8.48 mmol/L; peak ferritin level 119,000 mg/L; fibrinogen level 3.06 g/L. She had no cerebral involvement. Active infection with EBV was documented by blood polymerase chain reaction (pcr) testing. Therapy was initiated as per the Histiocyte Society HLH-2004 protocol. No specific anti-EBV therapy was given after consultation with our Infectious Disease service. Genetic studies for familial HLH were negative. However, it is recognized that many cases of familial HLH are precipitated by infectious agents such as EBV [7]. At presentation, multiple subhyaloid hemorrhages were discovered with macular involvement. The optic discs were normal, with no vasculitis seen. Decreased visual acuity was documented bilaterally. Despite a response to treatment, continued ophthalmologic follow-up confirmed that the multiple subhyaloid hemorrhages were not clearing and were impairing her vision to 20/400 OD and 20/200 OS (Supplemental Fig. 1). Two months after diagnosis the child underwent vitrectomy, membrane peeling and hyaloid stripping of the right eye with air fluid exchange and endolaser application. Three weeks later the left eye required vitrectomy, air fluid exchange, membrane peeling and endolaser application. The patient’s vision improved to 20/20 in the right eye and 20/25þ in the left eye, uncorrected. Increased pressure in the right eye required prostaglandin analogue topical therapy, possibly due to subtenons steroids injected during a previous procedure. Unfortunately she relapsed with EBV reactivation while on continuation therapy. This unusual reactivation may have been due to immunosuppressive therapy. As previously noted, no anti-EBV therapy had been given initially. Re-induction chemotherapy was given as per HLH-2004 in addition to ganciclovir and rituximab, and she subsequently underwent an unrelated donor 5/6 antigen match cord blood stem cell transplant. Full donor engraftment was achieved, but the patient developed multi-organ failure due to transplant-related toxicity. She died on day þ56, autopsy was declined. Reports of ocular findings in HLH are rare [1–4]. However, we suggest careful ophthalmologic examination in all patients with HLH as eye findings may warrant close monitoring and intervention to preserve vision.
10009 Background: In National Wilms Tumor Study-5, tumor-specific combined loss of heterozygosity... more 10009 Background: In National Wilms Tumor Study-5, tumor-specific combined loss of heterozygosity (LOH) of chromosomes 1p and 16q was associated with adverse outcome in patients with favorable histology Wilms Tumor (FHWT): stage I/II patients treated with Regimen EE4A (vincristine (VCR)/dactinomycin (DACT)) had 4-year EFS of 91.2% without LOH and 74.9% with LOH; stage III/IV patients treated with Regimen DD4A (VCR/ DACT/doxorubicin(DOX)) and radiotherapy (RT) had 4-year EFS of 83% without LOH and 65.9% with LOH. The AREN0533/AREN0532 studies assessed whether augmenting therapy would improve EFS for FHWT with combined 1p/16q LOH. Stage I/II patients were treated with the addition of DOX (Regimen DD4A) but no RT. Stage III/IV patients were treated with Regimen M (VCR/DACT/DOX alternating with cyclophosphamide/etoposide) and RT. Methods: Patients were enrolled through the AREN03B2 Biology and Classification study between10/2006 and 7/2013. All patients underwent central review of pathology, surgical reports ...
Wilms tumor is the fourth most common malignancy of childhood; its pathogenesis, however, remains... more Wilms tumor is the fourth most common malignancy of childhood; its pathogenesis, however, remains largely unknown. With advancements in cytogenetic techniques, such as array comparative genomic hybridization (aCGH), there is new hope for uncovering small chromosomal microdeletions or microduplications that may contribute to our understanding of Wilms tumor. We performed aCGH on 10 samples of Wilms tumor with normal conventional cytogenetic and chromosomal CGH findings. Array CGH revealed abnormalities in 3 of the 10 samples, including microdeletions (2q37.1, 7q31 approximately q32, and 11q22.3), microduplication (18q21.1), and gains and losses of larger chromosomal areas (1q and 7q gain and loss of 7p, 11q, 14q, and 16q). Fluorescence in situ hybridization (FISH) analysis confirmed the abnormalities and revealed the majority of them existed only in a proportion cells (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =30% of cells). We also performed aCGH on three samples of Wilms tumor with previously identified translocations between chromosomes 1 and 16, to determine the breakpoints. The breakpoints were seen in the pericentromeric regions of both chromosomes. Array CGH is useful for identifying submicroscopic changes in Wilms tumor and is more sensitive for detecting clonal abnormalities than conventional methods.
Testicular cancer, specifically germ cell tumors, are the most common malignancy in young men and... more Testicular cancer, specifically germ cell tumors, are the most common malignancy in young men and are curable in up to 95 % of cases, but the incidence is on the rise. The key event in the transformation to malignancy is hypothesized to occur in early adulthood, and the carcinogenic pathway for germ cell tumors is thought to begin in fetal life due to maternal or environmental estrogen exposure. Intratubular Germ Cell Neoplasia (ITGCN), previously known as Carcinoma in Situ (CIS) of the testis, is a premalignant condition that can progress to testicular cancer and is associated with testicular germ cell tumors. ITGCN is rarely reported in prepubertal children, and it would be helpful to know the prognostic implications of this finding. We present a case report of a 4-month-old male with undifferentiated ITGCN, and a co-morbid mature teratoma, one of only a few cases currently published. This patient had a normal 46, XY karyotype and all normal laboratory result except for a slightly elevated AFP, which is considered a normal finding for his age. Our report contributes to the growing body of evidence of ITGCN in the pediatric population and how little is known about this diagnosis. We will also briefly review management options for these patients and how we will be following this patient.
The metabolic control of phenylalanine levels is a challenge during illness. We present the metab... more The metabolic control of phenylalanine levels is a challenge during illness. We present the metabolic management of a 6 year old boy with classical PKU who was diagnosed with stage III intraabdominal Burkit's lymphoma and underwent surgical resection and chemotherapy. The metabolic control during chemotherapy was achieved by the use of parenteral custom made amino acid solution and pro-active adjustment of intake. From the 94 obtained plasma phenylalanine (Phe) levels, 18.4% were above our clinic's recommended upper limit (360 μmol/L, 6 mg/dL) while 52.7% of Phe levels were below the recommended lower limit (120 μmol/L, 2 mg/dL). Phe levels above recommended range were associated with low caloric/protein intake, while levels below recommended range reflected the difficulty in achieving the full prescribed Phe intake. We recommend early institution of custom made amino acid solution with maximum amino acid content and caloric intake to provide optimal phenylalanine control. Administration of phenylalanine via regular intravenous amino acid solution may assist in avoiding low Phe levels when prescribed intake is compromised due to vomiting and other disease related illnesses. Use of custom made, phenylalanine free amino acid solution proved beneficial in the management of blood phenylalanine levels in a PKU patient during chemotherapy for Burkitt lymphoma.
BACKGROUND: It is questionable whether enrollment on clinical trials offers any survival advantag... more BACKGROUND: It is questionable whether enrollment on clinical trials offers any survival advantage at the population level over standard-of-care treatment. The objectives of this study were to describe the impact of trial enrollment on event-free survival and overall survival in pediatric acute myeloid leukemia (AML) using the Cancer in Young People in Canada (CYP-C) database. METHODS: Children were included if they had had AML newly diagnosed between ages birth and 14 years from 2001 to 2012. CYP-C is a national pediatric cancer population-based database that includes all cases of pediatric cancer diagnosed and treated at 1 of the 17 tertiary pediatric oncology centers in Canada. Univariate and Cox proportional hazards models were used to evaluate the impact of initial trial enrollment on survival. RESULTS: In total, 397 eligible children with AML were included in the analysis, of whom 94 (23.7%) were enrolled on a clinical trial at initial diagnosis. The most common reason for non-enrollment was that no trial was available. The eventfree survival rate at 5 years was 57.8% ± 5.2% for those enrolled versus 54.8% ± 2.9% for those not enrolled (P = .75). The overall survival rate at 5 years was 70.1% ± 4.9% for those enrolled versus 66.3% ± 2.8% for those not enrolled (P = .58). Enrollment on a trial was not associated with improved event-free or overall survival in multiple regression analyses. CONCLUSIONS: Enrollment on a clinical trial was not associated with improved survival for children with AML in a population-based cohort. Rationale for trial enrollment should not include the likelihood of benefit compared with non-enrollment.
The assessment of quality of life (QOL) is key within pediatric oncology and requires a clearly d... more The assessment of quality of life (QOL) is key within pediatric oncology and requires a clearly defined construct of QOL. The purpose of our study was: (1) to conduct a qualitative study to inform the theoretical underpinnings of QOL and (2) to determine the appropriateness of patient-reported outcome (PRO) instruments to assess and evaluate QOL in pediatric cancer patients and survivors. The study used an interpretative description approach. Children diagnosed with childhood cancer, aged 8-18 years, were recruited from four Canadian hospitals. Semi-structured interviews were completed, transcribed verbatim and coded through methods of constant comparison. In-depth analysis facilitated a comparison between emerging themes and the content of commonly used PRO instruments. Thirty-seven children (19 females; 51 %) participated. The mean age was 13 years, and 19 (51 %) participants were post-treatment. Participant experiences reflected notions of positive and negative duality, including: maintaining physical functioning but longing for the ability to participate in activities; experiencing a new level of intimacy with family and friends amidst isolation; and developing positivity amidst anger, sadness and lingering worry. Analysis showed that existing PRO instruments are missing concerns specific to this population and contain content not reflective of the QOL experiences of childhood cancer patients and survivors. Our research highlights important problems with content validity of existing PRO scales, indicating that the tools we have to date have limited utility in research and clinical practice. The development of a new PRO instrument should be considered to ensure that content validity is achieved.
The primary objective was to describe predictors of physical, emotional and social quality of lif... more The primary objective was to describe predictors of physical, emotional and social quality of life (QoL) in children receiving active treatment for cancer. This Canadian multi-institutional cross-sectional study included children with cancer receiving any type of active treatment. The primary caregiver provided information on child physical, emotional and social QoL according to the PedsQL 4.0 Generic Core scales. Between November 2004 and February 2007, 376 families provided the data. In multiple regression, children with acute lymphoblastic leukemia had better physical health (OR: 0.37, 95% CI 0.23, 0.60; Po0.0001) while intensive chemotherapy treatment (OR: 2.34, 95% CI: 1.42, 3.85; P ¼ 0.0008) and having a sibling with a chronic condition (OR: 2.53, 95% CI: 1.54, 4.15; P ¼ 0.0002) were associated with poor physical QoL. Better emotional health was associated with good prognosis, less intensive chemotherapy treatment and greater household savings, whereas female children and those with a sibling with a chronic condition had poor social QoL. Physical, emotional and social QoL are influenced by demographic, diagnostic and treatment variables. Sibling and household characteristics are associated with QoL. This information will help to identify children at higher risk of poor QoL during treatment for cancer.
Background: Central venous lines (CVLs) are frequently associated with deep venous thrombosis (DV... more Background: Central venous lines (CVLs) are frequently associated with deep venous thrombosis (DVT) in children; however, little is known about the epidemiologic characteristics or outcome of CVL-related DVT. Methods: The Canadian Childhood ...
Etoposide‐based treatment is the standard of care for adult HLH in many centers, yet there remain... more Etoposide‐based treatment is the standard of care for adult HLH in many centers, yet there remains a paucity of data regarding treatment outcomes. We conducted a retrospective study of 23 adults treated with etoposide‐based therapy compared to 10 pediatric HLH cases at a single center. At diagnosis, the median serum ferritin was 20,071 µg/L and 937 µg/L in adults and children, respectively; median sIL‐2r was 14,524 U/mL and 4,478 U/mL. Biochemical response to treatment was high, with 21/23 adults achieving >75% reduction in serum ferritin, but one year survival was only 7/21 compared to 7/10 in pediatric cases.
Background In order to evaluate the family-centeredness of paediatric oncology services, a psycho... more Background In order to evaluate the family-centeredness of paediatric oncology services, a psychometrically sound measure of family-centred services is needed. We performed a comprehensive evaluation of the psychometric properties of the 20-item Measure of Processes of Care (MPOC-20) in parents of children undergoing treatment for cancer at five paediatric oncology centres in Canada. Methods The sample included 411 parents (80% response rate). Exploratory factor analysis was used to determine the best way to group the items into scales. Psychometric tests were used to examine data quality, targeting, internal consistency reliability, within-scale construct validity and known-groups validity. Results Exploratory factor analysis identified two factors: a summary measure of family-centred services and a scale measuring activities that meet parents' general informational needs. Scores spanned the entire scale range, floor and ceiling effects were low, and the sample distribution was not unduly skewed. Scales showed acceptable internal consistency reliability (Cronbach's alphas Ն0.93). Known-group hypotheses supported the scales' ability to differentiate between groups hypothesized to differ. Moderate effect sizes were found when MPOC-20 scale scores for parents and for children with good quality of life were compared with those with poor quality of life. Conclusions The MPOC-20 is the only evaluated instrument currently available to measure family-centred services in paediatric oncology. Paediatric cancer programmes can now use this tool to determine parental perception of the extent to which services are family-centred.
Journal of Pediatric Oncology Nursing, Mar 1, 2012
Research to understand the sources of stress and job satisfaction in pediatric oncology staff is ... more Research to understand the sources of stress and job satisfaction in pediatric oncology staff is limited. The aim of the authors’ qualitative study was to describe the key work-related demands and rewards in relation to working closely with parents from the perspective of health care providers (HCPs). Semistructured interviews were conducted with 13 doctors, 9 nurses, 5 social workers, and 6 child life specialists. Line-by-line, focused, and theoretical coding was used to establish categories and themes. Constant comparisons were used to examine the relationships within and across codes and categories. Interviewing continued until no new themes emerged. HCPs found it rewarding when they established close or long-term relationships with parents and to helped families through the entire cancer journey, including palliative care. HCPs found it challenging to work with complex families; with parents who are demanding, rude, or angry; with parents who have differing views about the treatments and palliative care; and with having to relay bad news to parents. Future research could explore the relationship between the factors that the authors have identified and burnout syndrome.
The National Wilms Tumor Study (NWTS) treatment of favorable histology Wilms tumor with lung meta... more The National Wilms Tumor Study (NWTS) treatment of favorable histology Wilms tumor with lung metastases was vincristine/dactinomycin/doxorubicin (DD4A) and lung radiation therapy (RT). The AREN0533 study applied a new risk stratification and treatment strategy to improve event-free survival (EFS) while reducing exposure to lung RT. Methods Patients with favorable histology Wilms tumor and isolated lung metastases showing complete lung nodule response (CR) after 6 weeks of DD4A continued receiving chemotherapy without lung RT. Patients with incomplete response (IR) or loss of heterozygosity at chromosomes 1p/16q received lung RT and four cycles of cyclophosphamide/etoposide in addition to DD4A drugs (Regimen M). AREN0533 was designed to preserve a 4-year EFS of 85% for lung nodule CR and improve 4-year EFS from 75% to 85% for lung nodule IR. Results Among 292 assessable patients, 133 had CR and 159 had IR. For patients with CR, 4-year EFS and overall survival (OS) estimates were 79.5% (95% CI, 71.2% to 87.8%) and 96.1% (95% CI, 92.1% to 100%), respectively. Expected versus observed event rates were 15% and 20.2% (P = .052), respectively. For patients with IR, 4-year EFS and OS estimates were 88.5% (95% CI, 81.8% to 95.3%) and 95.4% (95% CI, 90.9% to 99.8%), respectively. Expected versus observed event rates were 25% and 12.2% (P , .001), respectively. Overall, 4-year EFS and OS were 85.4% (95% CI, 80.5% to 90.2%) and 95.6% (95% CI, 92.8% to 98.4%) compared with 72.5% (95% CI, 66.9% to 78.1%; P , .001) and 84.0% (95% CI, 79.4% to 88.6%; P , .001), respectively, in the predecessor NWTS-5 study. Conclusion Excellent OS was achieved after omission of primary lung RT in patients with lung nodule CR, although there were more events than expected. EFS was significantly improved, with excellent OS, in patients with lung nodule IR using four cycles of cyclophosphamide/etoposide in addition to DD4A drugs. The overall AREN0533 treatment strategy yielded EFS and OS estimates that were superior to previous studies.
Research with parents of children with cancer has identified factors related to their adjustment ... more Research with parents of children with cancer has identified factors related to their adjustment and coping, but it is not fully understood why some parents do well and others do not. Guided by a stress process model, we examined the interrelationships among a comprehensive set of factors to identify the most important determinants of health-related quality of life (HRQoL) in parents of children in active treatment for cancer. A cross-sectional survey of 411 parents (80% response rate) of children receiving cancer treatment in Canada was conducted between November 2004 and February 2007. The following constructs were measured: background and context factors, child characteristics, family-centered service delivery, caregiver strain, intrapsychic factors, coping/supportive factors and parental HRQoL. The model was evaluated using structural equation modeling. Analysis was stratified by time since diagnosis (i.e., <12 months and !12 months). For those within 12 months of their child's diagnosis, family-centred service provision, caregiver strain, and self-perception accounted for 58% of the variation in psychosocial health, whereas caregiver strain and social support explained 50% of the variation in physical health. For parents in the >12 month group, caregiving strain was the only factor with a direct relationship with parental psychosocial and physical health, accounting for 66% and 55% of the variance in these constructs, respectively. Our findings reinforce the need for health professionals to be particularly attuned to family caregivers in the early stages of treatment and identify potential areas for interventions to promote parental health.
Uploads
Papers by David Dix