A role for surgery in the treatment of relapsed Hodgkin lymphoma.

Treatment of Hodgkin lymphoma (HL) has advanced over time, rendering a fatal disease now largely curable. Multiagent chemotherapy regimens, hematopoietic stem cell transplantation, and radiotherapy are the mainstays of care. Surgical intervention is rarely indicated other than for biopsy at diagnosis. However, for patients with recurrent relapsed HL isolated to one anatomical location, refractory to all other therapy, there may be a beneficial role for surgical excision. Herein, we report the surgical management of three relapsed patients with stage IVB HL who were refractory to multiple other therapeutic approaches, who all achieved good event-free survival after operative management.

Single nucleotide polymorphism in IL1B is associated with infection risk in paediatric acute myeloid leukaemia.

We evaluated single nucleotide polymorphisms (SNPs) associated with infection risk in children with newly diagnosed acute myeloid leukaemia (AML). We conducted a multicentre, prospective cohort study that included children aged ≤18 years with de novo AML. DNA was isolated from blood lymphocytes or buccal swabs, and candidate gene SNP analysis was conducted. Primary outcome was the occurrence of microbiologically documented sterile site infection during chemotherapy. Secondary outcomes were Gram-positive and -negative infections, viridans group streptococcal infection and proven/probable invasive fungal infection. Interpretation was guided by consistency in risk alleles and microbiologic agent with previous literature. Over the study period 254 children and adolescents with AML were enrolled. Overall, 190 (74.8%) had at least one sterile site microbiologically documented infection. Among the 172 with inferred European ancestry and DNA available, nine significant associations were observed; two were consistent with previous literature. Allele A at IL1B (rs16944) was associated with decreased microbiologically documented infection, and allele G at IL10 (rs1800896) was associated with increased risk of Gram-positive infection. We identified SNPs associated with infection risk in paediatric AML. Genotype may provide insight into mechanisms of infection risk that could be used for supportive-care novel treatments.

Understanding the healthcare experiences of teenaged cancer patients and survivors.

BACKGROUND: Despite literature supporting a client and family-centred approach to healthcare delivery in paediatric facilities, there is little information about healthcare delivery from the perspective of teenagers in the oncology setting. The objective of this study is to describe the healthcare experiences of teenagers with cancer. METHODS: As part of a larger study on teen-centred care delivery in paediatric oncology, a survey included several open-ended questions to learn about the following: (1) what teenagers liked about the cancer care they received; (2) what they disliked about the cancer care received; and (3) what they would include if they could design the perfect cancer centre for teenagers. The survey was completed by 200 teenagers (aged 12-20 years) from three paediatric hospitals in Canada. Answers to these questions were coded and developed into themes and subthemes using a thematic analysis approach. RESULTS: The number of patients providing answers was 89% for question 1, 63% for question 2 and 68.5% for question 3. Likes and dislikes were conceptualized in terms of four key themes as follows: (1) staff at the treatment centre; (2) the cancer care they received; (3) the treatment centre itself; and (4) social activities. The most common suggestions for the perfect cancer centre included having access to better entertainment, more social opportunities to interact with peers, and a more comfortable environment for themselves and their families. CONCLUSION: Understanding teenagers' experiences in the paediatric oncology setting provides information that could be used to shape the delivery of healthcare in a way that is tailored to their needs. Further research in this area is required in order to improve existing oncology care.

Caregiving, single parents and cumulative stresses when caring for a child with cancer.

BACKGROUND: Single parents whose children have cancer are a marginalized group who report less family centred care, and therefore, less quality cancer care for their children. As such, the aims of this study were to explore how single parents of children with cancer describe their caregiving experiences and to understand their contextual life stressors. METHODS: A constructivist grounded theory method was used. Qualitative interviews with 29 single parents of children with cancer who were at least 6 months post-diagnosis were recruited between November 2009 and April 2011 from four hospitals across Canada. Line-by-line coding was used to establish codes and themes and constant comparison was used to establish relationships among emerging codes and conceptual themes. RESULTS: The first set of findings report on caregiving duties including: emotional tasks, informational tasks and physical tasks. The second set of findings report on the contextual picture of parent's lives including their living conditions, their physical and mental health and their family histories of disruption, trauma and disease. CONCLUSIONS: Single parents caring for children with cancer were found to experience several cumulative stressors in addition to the current strain of caring for a child with cancer. The synergy of these cumulative stresses with the added strain of caregiving for a child with cancer may have long-term health and financial implications for parents. Broad-based policy interventions should focus on relieving the chronic strains associated with being a single parent of a child with cancer.

Invasive fungal infections in paediatric acute myeloid leukaemia.

Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in paediatric acute myeloid leukaemia (AML). This study describes risk factors for IFI and IFI-related sepsis in this population. We conducted a population-based, retrospective cohort study of children with AML in Canada. IFIs during chemotherapy and prior to haematopoietic stem cell transplantation, relapse, persistent disease or death were identified. Risk factors for proven or probable IFI were examined. Among courses complicated by IFI, risk factors for sepsis were also evaluated. There were 341 children with AML included of which 41 (12.0%) experienced 46 different episodes of IFI. Candida species accounted for 23 (50.0%) of IFIs and Aspergillus spp. accounted for 14 (30.4%). Days of broad-spectrum antibiotics, days of corticosteroids and neutropenia at start of the course were independently associated with IFI. Only days of fever were independently associated with IFI-related sepsis. Invasive fungal infections occurred in 12.0% of paediatric AML patients. Risk factors for IFI and IFI-related sepsis were identified. This knowledge may help to consider targeted strategies.

Family-centred care: a qualitative study of Chinese and South Asian immigrant parents' experiences of care in paediatric oncology.

BACKGROUND: Over the past two decades, there is increasing emphasis being placed upon providing family-centred care (FCC) in paediatric oncology settings. However, there is a lack of knowledge of FCC in paediatric oncology from the perspectives of immigrant parents. The purpose of this paper is to describe Chinese and South Asian immigrant parents' experiences of FCC in paediatric oncology settings in Canada. METHODS: This study adopted a constructivist grounded theory approach. Fifty first generation Chinese and South Asian parents of children with cancer who were at least 6 months post-diagnosis were recruited from six Canadian paediatric oncology centres. Interviews were conducted in English, Cantonese, Mandarin, Urdu, Punjabi or Hindi, and transcribed into English. Analysis involved line-by-line, focused and theoretical coding, and the use of the constant comparison method. RESULTS: Findings indicated that overall parents were highly satisfied with the care and services they received, and their experiences were reflective of the key elements of FCC. However, there were some areas of concern identified by participants: parents not perceiving themselves as a member of the medical team; inconsistency in the quality and co-ordination of services among healthcare providers; disrespectful and mechanical manner of a few healthcare providers; and parents' discomfort with healthcare providers communicating sensitive health-related information directly with their child. CONCLUSIONS: In order to successfully provide family-centred services to immigrant parents of children with cancer, better communication of the elements of FCC between healthcare staff and families is needed to negotiate a clear role for the parents as partners of the healthcare team. Moreover, a better understanding of how family relationships are structured in immigrant families will assist healthcare providers to balance the best interests of the child with that of the family as a unit.

The use of parenteral nutrition for the management of PKU patient undergoing chemotherapy for lymphoma: a case report.

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.

Zebrafish developmental screening of the ToxCast™ Phase I chemical library.

Zebrafish (Danio rerio) is an emerging toxicity screening model for both human health and ecology. As part of the Computational Toxicology Research Program of the U.S. EPA, the toxicity of the 309 ToxCast™ Phase I chemicals was assessed using a zebrafish screen for developmental toxicity. All exposures were by immersion from 6-8 h post fertilization (hpf) to 5 days post fertilization (dpf); nominal concentration range of 1 nM-80 µM. On 6 dpf larvae were assessed for death and overt structural defects. Results revealed that the majority (62%) of chemicals were toxic to the developing zebrafish; both toxicity incidence and potency was correlated with chemical class and hydrophobicity (logP); and inter-and intra-plate replicates showed good agreement. The zebrafish embryo screen, by providing an integrated model of the developing vertebrate, compliments the ToxCast assay portfolio and has the potential to provide information relative to overt and organismal toxicity.

Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and metabolomics.

Metabolomics analysis was performed on the supernatant of human embryonic stem (hES) cell cultures exposed to a blinded subset of 11 chemicals selected from the chemical library of EPA's ToxCast™ chemical screening and prioritization research project. Metabolites from hES cultures were evaluated for known and novel signatures that may be indicative of developmental toxicity. Significant fold changes in endogenous metabolites were detected for 83 putatively annotated mass features in response to the subset of ToxCast chemicals. The annotations were mapped to specific human metabolic pathways. This revealed strong effects on pathways for nicotinate and nicotinamide metabolism, pantothenate and CoA biosynthesis, glutathione metabolism, and arginine and proline metabolism pathways. Predictivity for adverse outcomes in mammalian prenatal developmental toxicity studies used ToxRefDB and other sources of information, including Stemina Biomarker Discovery's predictive DevTox® model trained on 23 pharmaceutical agents of known developmental toxicity and differing potency. The model initially predicted developmental toxicity from the blinded ToxCast compounds in concordance with animal data with 73% accuracy. Retraining the model with data from the unblinded test compounds at one concentration level increased the predictive accuracy for the remaining concentrations to 83%. These preliminary results on a 11-chemical subset of the ToxCast chemical library indicate that metabolomics analysis of the hES secretome provides information valuable for predictive modeling and mechanistic understanding of mammalian developmental toxicity.

Combined retrospective analysis of 498 rat multi-generation reproductive toxicity studies: on the impact of parameters related to F1 mating and F2 offspring.

The multi-generation reproductive toxicity study (OECD TG 416 and USEPA 870.3800) has been extensively used internationally to assess the adverse effects of substances on reproduction. Recently the necessity of producing a second generation to assess the potential for human health risks has been questioned. The present standardized retrospective analysis of the impact of the second generation on overall study outcome combines earlier analyses and includes 498 rat multi-generation studies representing 438 different tested substances. Detailed assessment of study reports revealed no critical differences in sensitivities between the generations on the basis of a consideration of all endpoints evaluated. This analysis indicates that the second generation mating and offspring will very rarely provide critical information. These findings are consistent with the conclusions of previous retrospective analyses conducted by RIVM, USEPA and PMRA and support adoption of the proposed OECD extended one-generation reproductive toxicity study protocol in regulatory risk assessment testing strategies.

Effect of season on fresh and cryopreserved stallion semen.

The objective of this study was to determine the effect of season on sperm quality variables, expression of the fertility-related protein SP22 and selected mRNA transcripts in fresh and cryopreserved stallion sperm. Four stallions were collected in each of the four seasons: summer, fall, winter and spring. Ejaculates were divided and then evaluated for motility, morphology, SP22 staining and expression of selected mRNAs as either fresh semen samples or cryopreserved samples. A significant interaction between season and cryopreservation status was found for total and progressive sperm motility. RNA yield from sperm was not affected by any variable examined. There was no effect of season or cryopreservation on the relative amounts of mRNA for PGK2, TPX1, TIMP3 or ACTB. There was a tendency (P=0.1) for an effect of stallion on the relative amount of ACTB mRNA. The proportion of sperm immunostained for SP22 over the equatorial segment was affected (P<0.05) by stallion. In addition, there was an interaction (P<0.05) between season and cryopreservation status on the percentage of sperm staining for SP22 on the equatorial segment. The correlation among total motility, progressive motility and SP22 immunostaining was much greater (P<0.05) during the breeding season (March and June) than during the non-breeding season (September and December). Based on data analyzed, semen collected in the Northern Hemisphere between March and June may be best suited for cryopreservation.

Evaluating family-centred service in paediatric oncology with the measure of processes of care (MPOC-20).

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 > or =0.93). 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.

Identification of paediatric cancer patients with poor quality of life.

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; P<0.0001) while intensive chemotherapy treatment (OR: 2.34, 95% CI: 1.42, 3.85; P=0.0008) and having a sibling with a chronic condition (OR: 2.53, 95% CI: 1.54, 4.15; P=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.

Prevalence of post-thrombotic syndrome following asymptomatic thrombosis in survivors of acute lymphoblastic leukemia.

BACKGROUND: Deep vein thrombosis (DVT) is a complication of treatment of acute lymphoblastic leukemia (ALL) in children but little is known about the long-term outcomes of these DVT. OBJECTIVE: To determine the incidence of post-thrombotic syndrome (PTS) in (i) children with ALL diagnosed with asymptomatic DVT using radiographic testing and (ii) an unselected group of ALL survivors. METHODS: Cross-sectional study in two populations. Group I comprised children in the Prophylactic Antithrombin Replacement in Kids with ALL treated with L-Asparaginase (PARKAA) study diagnosed with DVT by radiographic tests. Group II consisted of non-selected childhood ALL survivors <21 years. PTS was assessed using a standardized scoring sheet. RESULTS: Group I: 13 PARKAA patients (median age 12 years) were assessed, and 7 had PTS (54%; 95% CI, 25-81). All patients had collaterals, three also had increased arm circumference. Group II: 41 patients (median age 13 years) with a history of ALL were enrolled, and 10 had PTS (24%; 95% CI, 11-38). All patients had collaterals; five also had increased arm circumference. CONCLUSION: There is a high incidence of PTS in survivors of childhood ALL with radiographically diagnosed asymptomatic DVT. A significant proportion of ALL survivors develop PTS, indicating previously undiagnosed DVT.

Induction of cytochrome P450 enzymes in rat liver by two conazoles, myclobutanil and triadimefon.

This study was undertaken to examine the inductive effects of two triazole antifungal agents, myclobutanil and triadimefon, on the expression of hepatic cytochrome P450 (CYP) genes and on the activities of CYP enzymes in male Sprague Dawley rats. Rats were dosed with the conazoles at three dose levels by gavage for 14 days: myclobutanil (150, 75, and 10mgkg(-1) body weight day(-1); triadimefon (115, 50, and 10 mg kg(-1) body weight day-'), which included their maximum tolerated dose levels (MTD). Both myclobutanil and triadimefon significantly induced pentoxyresorufin O-depentylase activities at their MTD levels: myclobutanil, 8.1-fold at 150mgkg(-1) body weight day- ; and triadimefon, 18.5-fold at 115mgkg(-1) body weight day-'. Benzyloxyresorufin O-debenzylase activities were similarly increased: myclobutanil, 13.3-fold; triadimefon, 27.7-fold. Quantitative real-time reverse-transcription polymerase chain reaction assays were used to characterize the mRNA expression of specific CYP genes induced by these two conazoles. Myclobutanil and triadimefon treatment at their MTD levels significantly increased rat hepatic mRNA expression of CYP2B1 (14.3- and 54.6-fold), CYP3A23/3A1 (2.2- and 7.3-fold), and CYP3A2 (1.5- and 1.7-fold). Western immunoblots of rat hepatic microsomal proteins identified significantly increased levels of CYP isoforms after myclobutanil or triadimefon treatment at their MTD levels: CYP2BI/2 (4.8- and 5.3-fold), and CYP3A1 (2.2- and 2.9-fold). Triadimefon also increased CYP3A2 immunoreactive protein levels 1.8-fold. These results indicate that triadimefon and myclobutanil, like other triazole-containing conazoles, induced CYP2B and CYP3A families of cytochromes in rat liver.

Metabolism of myclobutanil and triadimefon by human and rat cytochrome P450 enzymes and liver microsomes.

Metabolism of two triazole-containing antifungal azoles was studied using expressed human and rat cytochrome P450s (CYP) and liver microsomes. Substrate depletion methods were used due to the complex array of metabolites produced from myclobutanil and triadimefon. Myclobutanil was metabolized more rapidly than triadimefon, which is consistent with metabolism of the n-butyl side-chain in the former and the t-butyl group in the latter compound. Human and rat CYP2C and CYP3A enzymes were the most active. Metabolism was similar in microsomes prepared from livers of control and low-dose rats. High-dose (115 mg kg-1 day-1 of triadimefon or 150 mg kg-1 day-1 of myclobutanil) rats showed increased liver weight, induction of total CYP, and increased metabolism of the two triazoles, though the apparent Km appeared unchanged relative to the control. These data identify CYP enzymes important for the metabolization of these two triazoles. Estimated hepatic clearances suggest that CYP induction may have limited impact in vivo.

Natural history of arterial and venous thrombosis in children treated with low molecular weight heparin: a longitudinal study by ultrasound.

Low molecular weight heparin (LMWH) is efficacious in preventing recurrent thromboembolic events (TEs) in children. The efficacy of LMWH in resolving thrombus in children is, however, unknown and may differ from what has been observed in adults due to known differences in the hemostatic system. We reviewed the ultrasound (US) scanning reports of children treated with LMWH in order to determine the rate and predictors of thrombus resolution. Of 245 children consecutively treated for a non-cerebral TE with enoxaparin (Lovenox, Aventis Pharma Inc., QC, Canada) for at least 5 consecutive days, 190 (78%) had serial ultrasound available for analysis. The mean follow-up time was 7 months (median 3 months, range 3 days to 6.6 years). The rate of complete thrombus resolution was 101/190 (53%, 95% confidence interval 46.2-60.2%). On univariate analysis, arterial and non-occlusive thrombus had an increased rate of resolution when compared with venous and occlusive thrombus. Age at time of TE (neonates vs. non-neonates), location of TE, initial treatment (unfractionated heparin vs. LMWH) and dose of enoxaparin were not related to outcome. On multivariate analysis, type of vessel (vein vs. artery) and occlusion (occlusive vs. non-occlusive thrombus) independently predicted outcome. In children, the rate of complete thrombus resolution is similar to the rate in adults. The clinical significance of residual abnormal vessels, specifically to the occurrence of post-thrombotic syndrome and for the diagnosis of recurrence, needs to be explored in prospective studies.

Effects of heat shock protein 70 (Hsp70) on arsenite-induced genotoxicity.

Arsenic, a human carcinogen, is genotoxic, although its mechanism(s) of action for tumorigenesis is not well understood. Among the toxicity-related properties of this chemical are its clastogenic and aneugenic activities, as well as its capacity for inducing stress-response in the form of elevated heat shock protein (HSP) expression. In the present study, we evaluated the effects of Hsp70 expression on arsenite (As)-induced structural and numerical chromosome anomalies in human cells. Human MCF-7 Tet-off cells stably transfected with a pTRE/Hsp70-1 transgene construct were used to regulate Hsp70 levels prior to in vitro As exposures. Separate cultures of relatively high vs. low Hsp70-expressing cells were established. A cytokinesis block micronucleus assay with kinetochore immunostaining was used to detect micronuclei (MN) derived from chromosome breakage (K-MN) or loss (K+MN). These studies demonstrated significant increases in micronucleus frequencies in response to As following either a long exposure (5 or 10 microM for 46 hr), or short exposure (10 or 40 microM for 8 hr) protocol. Overall, the long protocol was more efficient in producing K+MN and cells with multiple MN. Overexpressing Hsp70 resulted in significant reductions in the percent of cells positive for MN for both the long and short As exposure protocols. Both K+ and K- types of As-induced MN were lower in cells with elevated Hsp70 as compared to cells without overexpression of Hsp70. We conclude that the dose and duration of As exposure influence the type as well as amount of chromosomal alteration produced and that inducible Hsp70 protects against both the clastogenic and aneugenic effects of this chemical.

Genetic background but not metallothionein phenotype dictates sensitivity to cadmium-induced testicular injury in mice.

Sensitivity to cadmium (Cd)-induced testicular injury varies greatly among mouse strains. For instance, 129/SvJ (129) mice are highly sensitive while C57BL/6J (C57) mice are refractory to Cd-induced testicular injury. Metallothionein (MT), a Cd-binding protein, is thought to be responsible for the strain susceptibility to Cd toxicity. In this study, MT-I/II knockout (MT-null) and wild-type 129 mice were used to determine the role of MT in Cd-induced testicular injury. Two additional strains of mice (C57 and the C57 x 129 F1cross) were also used to help define the role of genetic background in Cd toxicity. Mice were given 5-20 micromol/kg ip CdCl(2) and testicular injury was examined 24 h later by histopathology and testicular hemoglobin concentration. Cd produced dose-dependent testicular injury in all strains of mice, except for C57 mice, in which testicular injury could not be produced. MT-null mice were more sensitive than C57 x 129 mice but were equally sensitive as 129 mice to Cd-induced testicular injury. Fourteen days after 15 micromol/kg ip Cd administration, testicular atrophy was evident in MT-null, 129, and C57 x 129 mice but was absent in C57 mice. The resistance of C57 mice to Cd-induced testicular injury could not be attributed solely to a decreased uptake of (109)Cd nor to a greater amount of testicular MT. Microarray analysis revealed a higher expression of glutathione peroxidase in the testes of C57 mice, as well as genes encoding antioxidant components and DNA damage/repair, but their significance to Cd-induced injury is not immediately clear. Thus, this study demonstrates that it is genetic strain, not MT genotype, that is mechanistically important in determining susceptibility to Cd-induced testicular injury.