Olanzapine for prevention of chemotherapy-induced nausea and vomiting in children and adolescents: a multi-center, feasibility study.

CONTEXT: There are no prospective pediatric trials evaluating olanzapine for chemotherapy-induced nausea and vomiting (CINV) prevention. OBJECTIVE: This study evaluated the feasibility of a trial of olanzapine to evaluate the contribution of olanzapine to CINV control in pediatric oncology patients. METHODS: Patients < 18 years receiving CINV prophylaxis with ondansetron/granisetron/palonosetron ± dexamethasone ± aprepitant were eligible to participate in this prospective, single-arm, open-label study. All patients received olanzapine (0.14 mg/kg/dose; max 10 mg/dose) once daily orally starting before the first chemotherapy dose and continuing for up to four doses after the last chemotherapy administration. A future trial was considered feasible if mean time to enroll 15 patients was ≤ 12 months/site, ≥ 12/15 took at least half of the planned olanzapine doses, and ≤ 3/15 experienced significant sedation or dizziness despite dose reduction. The proportion of children who experienced complete CINV control (no nausea, vomiting, or retching) was described. RESULTS: Fifteen patients (range 4.1-17.4 years) participated; mean recruitment period was 9.3 months/site. All patients took at least half of the planned olanzapine doses. Six patients experienced sedation which resolved with olanzapine dose reduction (N = 5) or bedtime administration (N = 1). Olanzapine was stopped in one patient with blurry vision and in another with increased plasma GGT values. In both the acute and delayed phases, eight patients experienced complete control of vomiting but almost all (14/15) had nausea. CONCLUSION: A pediatric trial of olanzapine for CINV control is feasible. Our findings will inform the design of a future study.

Overweight, obesity and adiposity in survivors of childhood brain tumours: a systematic review and meta-analysis.

Survivors of childhood brain tumours (SCBT) have increased cardiometabolic risks, but the determinants of these risks are unclear. This systematic review aims to compare the prevalence of overweight and obesity as well as adiposity measures between SCBT and non-cancer controls. The PubMed, EMBASE, MEDLINE, CINAHL and the Cochrane Library databases were searched. The primary outcomes were the prevalence of overweight and obesity based on body mass index. The secondary outcomes were adiposity measures including percent fat mass, waist-to-hip and waist-to-height ratios. Forty-one studies were included in the meta-analysis. The prevalence of overweight and obesity combined was similar between overall SCBT, SCBT excluding craniopharyngioma and non-cancer controls (42.6%, 95% CI 30.1-55.1 vs. 31.7%, 95% CI 20.4-43.0 vs. 40.4%, 95% CI 34.0-46.8). We also found that SCBT have higher percent fat mass (mean difference 4.1%, 95% CI 2.0-6.1), waist-to-hip ratio (mean difference 0.07, 95% CI 0.02-0.13) and waist-to-height ratio (mean difference 0.06, 95% CI 0.01-0.10) than non-cancer controls. We conclude that SCBT have similar overweight and obesity distribution but higher adiposity than non-cancer controls. More studies were needed to explore the determinants of adiposity and its contribution to cardiometabolic outcomes in SCBT.

Embryonal tumors in Canadian children less than 36 months of age: results from the Canadian Pediatric Brain Tumor Consortium (CPBTC).

Embryonal tumors are a heterogeneous group of central nervous system (CNS) tumors whose subgroups have varying incidence and outcome. Despite these differences, they are often grouped as a single entity for study purposes. To date, there are no Canadian multi-institutional studies examining the incidence and outcome of all embryonal subtypes. The current study is an observational study reviewing embryonal tumors in all patients less than 36 months of age diagnosed with a CNS tumor in Canada from 1990 to 2005. Embryonal tumors accounted for 26.9% of all CNS tumors. Medulloblastomas were the highest proportion of the embryonal tumors at 61.5%. Atypical teratoid/rhabdoid tumors (AT/RT) had the second highest proportion of embryonal tumors at 18%. The proportion of primitive neuroectodermal tumors (PNET) was 16%, with 2.6 and 1.9% for congenital medulloepithelioma and ependymoblastoma tumors, respectively. AT/RT and PNET were more common in younger age groups. Medulloblastoma became more prevalent with increasing age, with its highest prevalence in the 25 to 36 month age group. Survival rates for our Canadian population at 18 and 24 months were 0.74 and 0.68 for medulloblastoma, 0.64 and 0.60 for PNET, and 0.36 and 0.29 for AT/RT, respectively. Overall, our data are comparable with published international rates for embryonal tumors. These incidence and outcome figures can guide future research into these rare tumors.

The effectiveness of interventions to treat hypothalamic obesity in survivors of childhood brain tumours: a systematic review.

BACKGROUND: Survivors of childhood brain tumours (SCBT) are at risk of type 2 diabetes and cardiovascular diseases. Obesity is a major driver of cardiometabolic diseases in the general population, and interventions that tackle obesity may lower the risk of these chronic diseases. The goal of this systematic review was to summarize current evidence for the presence of interventions to manage obesity, including hypothalamic obesity, in SCBT. METHODS: The primary outcome of this review was the body mass index z-score change from baseline to the end of the intervention and/or follow-up. Literature searches were conducted in PsycINFO, CINAHL, the Cochrane Library, Medline, SPORTDiscus, EMBASE and PubMed. Two reviewers completed study evaluations independently. RESULTS: Eleven publications were included in this systematic review (lifestyle intervention n = 2, pharmacotherapy n = 6 and bariatric surgery n = 3). While some studies demonstrated effectiveness of interventions to manage obesity in SCBT and alter markers of obesity and cardiometabolic risk, the evidence base was limited and of low quality, and studies focused on hypothalamic obesity. We conclude that there is urgent need to conduct adequately powered trials of sufficient duration, using existing and novel therapies to manage obesity, reduce the burden of cardiometabolic disorders and improve outcomes in SCBT.

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.

Refinement of the symptom screening in pediatrics tool (SSPedi).

BACKGROUND: Objective was to evaluate and refine a new instrument for paediatric cancer symptom screening named the Symptom Screening in Pediatrics Tool (SSPedi). METHODS: Respondents were children 8-18 years of age undergoing active cancer treatment and parents of eligible children. Respondents completed SSPedi once and then responded to semi-structured questions. They rated how easy or difficult SSPedi was to complete. For items containing two concepts, we asked respondents whether concepts should remain together or be separated into two questions. We also asked about each item's importance and whether items were missing. Cognitive probing was conducted in children to evaluate their understanding of items and the response scale. After each group of 10 children and 10 parents, responses were reviewed to determine whether modifications were required. Recruitment ceased with the first group of 10 children in which modifications were not required. RESULTS: Thirty children and 20 parents were required to achieve a final version of SSPedi. Fifteen items remain in the final version; the score ranges from 0 to 60. CONCLUSIONS: Using opinions of children with cancer and parents of paediatric cancer patients, we successfully developed a symptom screening tool that is easy to complete, is understandable and demonstrates content validity.

Chemotherapy-induced Peripheral Neuropathy Among Paediatric Oncology Patients.

BACKGROUND: Vinca alkaloids and platinum-containing chemotherapeutic drugs have the potential to cause chemotherapy-induced peripheral neuropathy (CIPN). This study determined the frequency of CIPN among children who were treated for acute lymphoblastic leukemia (ALL), lymphoma, brain tumour or Wilms tumour. PROCEDURE: This retrospective cohort study reviewed 252 patients treated at the Children's hospital of Eastern Ontario from 2001-2011. Patients were considered to have CIPN if they developed clinical symptoms of CIPN such as limb paraesthesia, weakness and/or ataxia during chemotherapy and their treating neurologist or oncologist deemed that their symptoms were due to a peripheral cause. Patients were excluded if their treatment regime did not include chemotherapy. RESULTS: The overall frequency of CIPN was 18.3% (46/252). Tumour-specific CIPN rates were: 18.9% (29/154) for ALL; 9.4% (3/32) for lymphoma; 17.9% (5/28) for Wilms tumour; and 23.7% (9/38) for brain tumour patients. Nerve conduction studies were completed for 17% of patients (all tumour types) and were abnormal in all but one patient. Among surviving CIPN patients (41/46), 93% showed no clinical deficits at their last examination, which was on average 56 months from time of diagnosis to last follow-up visit. CONCLUSIONS: The frequency of CIPN was less than that previously reported in adults receiving chemotherapy. Children with CIPN have a favourable outcome with most showing clinical improvement during the maintenance phase of treatment or after chemotherapy completion.

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.

Adolescents with acute lymphoblastic leukemia treated at pediatric versus adult hospitals.

BACKGROUND: The objective was to compare 5-year overall survival (OS) between adolescent and young adult (AYA) patients (age 15-19) with acute lymphoblastic leukemia (ALL) treated at a pediatric versus an adult center. PATIENTS AND METHODS: This was a population-based analysis using administrative data of Ontario ALL AYA patients diagnosed between 1986-2009. We calculated predicted survival proportions (PSPs) and 95% confidence intervals (CI). We also surveyed sites to determine whether pediatric or adult-based protocols were used in each period. RESULTS: Overall, 290 patients between 15-19 years of age were diagnosed with ALL during the study period; 144 patients (49.7%) were treated at an adult center. When adjusted for gender, age, income quintile and time period, AYA patients treated at a pediatric center did not have a significantly different PSP (0.65, 95% CI: 0.56-0.75) in comparison to those treated at an adult center (0.62, 95% CI 0.52-0.73; P = 0.87). Most AYA patients treated at adult centers received pediatric protocols in the recent periods. CONCLUSIONS: Using population-based data, AYA ALL patients had similar outcomes whether treated at a pediatric or an adult center. Early introduction of aggressive treatment protocols in adult centers may have negated differences in outcomes among AYA patients by site of care.

A paediatric palliative care programme in development: trends in referral and location of death.

PURPOSE: To describe the formation of a paediatric palliative care programme providing care in hospital, at home or in hospice, ensuring continuity of care where the child and family desire. STUDY DESIGN: Descriptive analysis was performed on referral source, diagnosis and reason for discharge for patients referred to the Palliative Care Team at the Children's Hospital of Eastern Ontario in Ottawa, Ontario, Canada from 1999 to 2007. RESULTS: 341 children were referred. 24% had a neurological condition, 21% had genetic disorders or congenital anomalies, 20% had cancer, 18% had metabolic or neurodegenerative conditions and 17% had another diagnosis. The major sources of referral included paediatricians, neonatologists, oncologists and intensivists. 55% of the children have died. 58% of these died in hospital, 27% at home and 15% in hospice. Of the remaining 152 children, 7% were discharged from the programme after clinical improvement, 4% were moved to another geographic location or an adult centre, 2% were not eligible, 1% declined services and 4% were lost to follow-up. The remaining 90 children continue to be followed-up. In the hospitalised patients who died, the annual referral rate increased from 20% to >50%. IMPLICATIONS: Referral to the palliative care team has increased over time in all diagnostic categories and from all sources. Most children died in hospital; however, a significant number of families chose end-of-life care at home or in a hospice.

Neuronal apoptosis inhibitory protein expression after traumatic brain injury in the mouse.

Apoptosis of brain cells is triggered by traumatic brain injury (TBI) and is blocked by caspase inhibitors. The neuronal apoptosis inhibitor protein (NAIP), which has been shown to inhibit apoptosis by both caspase-dependant and caspase-independent mechanisms, is neuroprotective in rat models of cerebral ischemia and axotomy. In order to gain a better appreciation of CNS apoptosis following head injury in general and the possible involvement of NAIP specifically, we have configured a mouse model of TBI. In addition to demonstrating apoptosis, the spatiotemporal expression or levels of a number of proteins with apoptosis modulating effects have been determined. Apoptosis of neurons and oligodendrocytes following TBI was observed in brain sections which were triple-stained with in situ end labeling, bisbenzimide and immunofluorescent stain for neuron specific nuclear protein and myelin-associated glycoprotein, respectively. Further evidence for apoptosis following TBI in this model was obtained in brain samples using ligation-mediated PCR amplification of DNA fragments and gel electrophoresis. The temporal profile of apoptosis was similar to the temporal profile of microglial activation determined by CD11b staining and TNFa expression induced by TBI. NAIP staining in sections of cerebral cortex and subcortical white matter increased at 6 h and decreased towards control levels at 24 h post-TBI. Temporal changes in the expression of NAIP were also observed using Western blot analysis of brain samples removed from injured cortex and sub-cortical white matter. At the time that NAIP expression decreased markedly (24 h post-TBI), procaspase-3 levels also decreased, PARP cleavage increased, and the highest levels of apoptosis were observed. These findings have implications in our understanding of traumatically induced programmed cell death and may be useful in the configuration of therapies for this common injury state.

Deep soft tissue infections in the neutropenic pediatric oncology patient.

PURPOSE: Necrotizing fasciitis and myonecrosis can be rapidly fatal without prompt and aggressive medical and surgical therapy. We reviewed our experience with necrotizing fasciitis and myonecrosis in neutropenic pediatric oncology patients to describe associated clinical characteristics and outline therapeutic interventions. PATIENTS AND METHODS: A retrospective chart review was performed for all cases of deep soft tissue infection found in neutropenic pediatric oncology patients during an 11-year period. RESULTS: Seven cases of necrotizing fasciitis and/or myonecrosis associated with chemotherapy-induced neutropenia were diagnosed during the study period. Deep soft tissue infection was diagnosed a median of 14 days after the initiation of chemotherapy. All of the patients presented with fever and pain, generally out of proportion to associated physical findings. Most patients (86%) also had tachycardia and subtle induration at the site of soft tissue infection. The pathogenic organism in four of seven patients originated in the gastrointestinal tract. Patients were treated with antibiotics, surgical debridements, granulocyte colony-stimulating factor, and hyperbaric oxygen. Granulocyte transfusions were administered if there were no signs of neutrophil recovery. Five patients survived their deep soft tissue infection. CONCLUSIONS: The diagnosis of necrotizing fasciitis and/or myonecrosis should be considered in any neutropenic patient with fever, tachycardia, and localized pain out of proportion to the physical findings. Appropriate therapy includes broad-spectrum intravenous antibiotics and urgent surgical intervention. Granulocyte colony-stimulating factor should be administered to all patients to enhance neutrophil recovery. Granulocyte transfusions should be considered if a prolonged period of neutropenia is anticipated.

Contrast-enhanced 3D MR breathhold imaging of porcine coronary arteries using fluoroscopic localization and bolus triggering.

The purpose of this study was to develop cardiac-gated contrast-enhanced 3D MRA for imaging the coronary arteries of pigs. Each major coronary artery was imaged individually in a single 3D slab in one breathhold. To permit acquisition within a breathhold, a limited number of partitions (12-16) were collected in a single, oblique, thin 3D slab. Typical resolution of the acquisition was 0.8 (X) x 1.6 (Y) x 1.6 (Z) mm. MR fluoroscopic localization was used to establish the 3D double-oblique orientation. Real-time MR fluoroscopy was also used to instantaneously trigger the 3D scan after detection in the aortic root of the intravenously administered contrast bolus. Six pigs were used in the study. Each pig was scanned on two separate days. Images routinely show the majority of the length of the three principal coronary arteries. Magn Reson Med 42:1159-1165, 1999.

Pulmonary function monitoring during adenosine myocardial perfusion scintigraphy in patients with chronic obstructive pulmonary disease.

OBJECTIVE: To determine whether adenosine could be safely administered to patients with chronic obstructive pulmonary disease (COPD) for coronary vasodilatation during perfusion scintigraphy without causing bronchospasm. MATERIAL AND METHODS: The study was divided into two phases. In the monitoring phase, patients with COPD were pretreated with an inhaled bronchodilator (albuterol) and had pulmonary function monitored during the infusion of a graduated dose of adenosine. Eligibility for entry into this phase of the study was determined on the basis of results of pulmonary function testing (PFT) during resting. Once we had shown that adenosine could be safely administered to patients with COPD, an implementation phase was begun. Entry did not require resting PFT, and patients were administered adenosine without monitoring of pulmonary function. Differences between patients with normal pulmonary function or mild COPD and those with more severe COPD were analyzed statistically. RESULTS: Of 94 patients entered into the monitoring phase, none had obvious bronchospasm. The dosage of adenosine was reduced in four patients because of a decrease in forced expiratory volume in 1 second (FEV1) of 20% in comparison with baseline (FEV1 before administration of albuterol). The mean FEV1 decreased slightly from 1.83 L after administration of albuterol to 1.78 L during the maximal adenosine dose. Patients with a remote history of asthma, positive result of a methacholine challenge test, or mild COPD (FEV1 60 to 80% of the maximal predicted value for age) did not differ significantly in their response to infusion of adenosine from those with moderate or severe COPD (FEV1 30 to 59% of the maximum predicted for age). Of 117 patients in the implementation phase, 2 had bronchospasm during infusion of adenosine that was quickly terminated by stopping the administration in one patient and reducing the dose of adenosine in the other. CONCLUSION: This study shows that adenosine can be safely administered intravenously to selected patients with known or suspected COPD to produce coronary vasodilatation for myocardial perfusion imaging. Patients who are within the guidelines established for this study should be considered for adenosine coronary vasodilatation with use of bronchodilator pretreatment, a graduated dose of adenosine, and regular chest auscultation during the infusion.

An optimal dual-size vial system for the cost-effective usage of Adenoscan.

BACKGROUND: Adenoscan (Fujisawa USA, Inc., Deerfield, Ill.) has been initially packaged in a 30 ml glass vial for single use only because it contains no preservative. This restricted usage has generated considerable waste and high cost for the patient. Although the new 20 ml vial of Adenoscan provides some reduction in waste, the savings offered by the 20 ml and 30 ml vial system is still not optimal. The purpose of this study was to investigate an optimal dual-size vial system that would provide limited amounts of waste while maintaining its practicality to satisfy different patient populations. MATERIALS AND RESULTS: The least waste for each potential combination (n = 344) of two vials was calculated by assuming that patient weights (30 to 200 kg) follow a normal distribution. The 6 ml and 15 ml vial combination had the least expected waste for lighter patient populations, and the 9 ml and 15 ml vial system had the least expected waste for heavier populations. The calculated wastes for 4207 patients (83 +/- 19 kg) undergoing adenosine stress myocardial perfusion studies at the Mayo Clinic were 10.5 +/- 9.3 ml (30 ml vial), 5.1 +/- 2.9 ml (20 ml and 30 ml vial system), 1.6 +/- 1.0 ml (6 ml and 15 ml vial system), and 1.8 +/- 1.2 ml (9 ml and 15 ml vial system). CONCLUSIONS: In general, both the 6 ml and 15 ml and 9 ml and 15 ml vial systems perform better than either the single 30 ml vial or the 20 ml and 30 ml vial system. Furthermore, the 6 ml and 15 ml vial combination offers the lowest expected waste for the actual patient population that underwent the adenosine stress myocardial perfusion imaging studies at our institution.

Clinical determinants of hemodynamic and symptomatic responses in 2,000 patients during adenosine scintigraphy.

OBJECTIVE: To determine whether subsets of patients referred for a clinically indicated radionuclide adenosine stress study respond differently to a standard infusion of adenosine. MATERIAL AND METHODS: We assessed multiple clinical and hemodynamic variables in the first 2,000 patients who underwent adenosine perfusion studies in our laboratory. A relevant clinical variable was defined as one that was significantly associated with changes in heart rate and blood pressure during adenosine infusion. Relevant clinical variables that were most significantly related to hemodynamic variables included age, gender, rhythm (atrial fibrillation), diabetes, and left ventricular function. These variables were then related to symptomatic responses (adverse effects) to adenosine infusion. To determine whether the different peripheral responses to adenosine reflected clinically important differences in coronary vasodilatation, we compared perfusion imaging with coronary angiographic findings in the 408 patients who underwent both studies within 6 months of each other. RESULTS: The decrease in systolic blood pressure was greater and the reflex tachycardia was less in patients 70 years of age or older and in those with insulin-dependent diabetes in comparison with younger patients and those without type 1 diabetes. Men had smaller decreases in blood pressure and smaller increases in heart rate than did women. Patients with atrial fibrillation and those with left ventricular ejection fraction less than 40% had smaller decreases in blood pressure and smaller increases in heart rate than did those in sinus rhythm or those with an ejection fraction of 40% or more. Age 70 years or older, male gender, atrial fibrillation, and left ventricular ejection fraction less than 40% were associated with fewer symptoms and less severe chest pain in comparison with patients without these variables. For patients with coronary angiograms, the relationship between coronary artery disease evident on angiography and perfusion abnormalities noted on scintigraphy was not different for any of the relevant clinical variables. CONCLUSION: Common clinical patient subsets are associated with different peripheral hemodynamic and symptomatic responses to infusion of adenosine. Despite these observations, however, the ability to detect coronary artery disease with perfusion imaging is not obviously altered.

Determination of ventricular ejection fraction: a comparison of available imaging methods. The Cardiovascular Imaging Working Group.

Knowledge of left ventricular ejection fraction has been shown to provide diagnostic and prognostic information in patients with known or suspected heart disease. In clinical practice, the ejection fraction can be determined by using one of the five currently available imaging techniques: contrast angiography, echocardiography, radionuclide techniques of blood pool and first pass imaging, electron beam computed tomography, and magnetic resonance imaging. In this review, we discuss the clinical application as well as the advantages and disadvantages of each of these methods as it relates to determination of ventricular ejection fraction.