Background
Cerebral injury and long‐term neurodevelopmental impairment is common in extremely preterm infants. Cerebral near‐infrared spectroscopy (NIRS) enables continuous estimation of cerebral ...oxygenation. This diagnostic method coupled with appropriate interventions if NIRS is out of normal range (that is cerebral oxygenation within the 55% to 85% range) may offer benefits without causing more harms. Therefore, NIRS coupled with appropriate responses to abnormal findings on NIRS needs assessment in a systematic review of randomised clinical trials and quasi‐randomised studies.
Objectives
To evaluate the benefits and harms of interventions that attempt to alter cerebral oxygenation guided by cerebral NIRS monitoring in order to prevent cerebral injury, improve neurological outcome, and increase survival in preterm infants born more than 8 weeks preterm.
Search methods
We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 8), MEDLINE via PubMed (1966 to 10 September 2016), Embase (1980 to 10 September 2016), and CINAHL (1982 to 10 September 2016). We also searched clinical trial databases, conference proceedings, and the reference lists of retrieved articles for randomised clinical trials and quasi‐randomised studies.
Selection criteria
Randomised clinical trials and quasi‐randomised clinical studies comparing continuous cerebral NIRS monitoring for at least 24 hours versus blinded NIRS or versus no NIRS monitoring.
Data collection and analysis
Two review authors independently selected, assessed the quality of, and extracted data from the included trials and studies. If necessary, we contacted authors for further information. We conducted assessments of risks of bias; risks of design errors; and controlled the risks of random errors with Trial Sequential Analysis. We assessed the quality of the evidence with GRADE.
Main results
One randomised clinical trial met inclusion criteria, including infants born more than 12 weeks preterm. The trial employed adequate methodologies and was assessed at low risk of bias. One hundred and sixty‐six infants were randomised to start continuous cerebral NIRS monitoring less than 3 hours after birth until 72 hours after birth plus appropriate interventions if NIRS was out of normal range according to a guideline versus conventional monitoring with blinded NIRS. There was no effect of NIRS plus guideline of mortality until term‐equivalent age (RR 0.50, 95% CI 0.29 to 1.00; one trial; 166 participants). There were no effects of NIRS plus guideline on intraventricular haemorrhages: all grades (RR 0.93, 95% CI 0.65 to 1.34; one trial; 166 participants); grade III/IV (RR 0.57, 95% CI 0.25 to 1.31; one trial; 166 participants); and cystic periventricular leukomalacia (which did not occur in either group). Likewise, there was no effect of NIRS plus guideline on the occurrence of a patent ductus arteriosus (RR 1.96, 95% CI 0.94 to 4.08; one trial; 166 participants); chronic lung disease (RR 1.27, 95% CI 0.94 to 1.50; one trial; 166 participants); necrotising enterocolitis (RR 0.83, 95% CI 0.33 to 1.94; one trial; 166 participants); and retinopathy of prematurity (RR 1.64, 95% CI 0.75 to 3.00; one trial; 166 participants). There were no serious adverse events in any of the intervention groups. NIRS plus guideline caused more skin marks from the NIRS sensor in the control group than in the experimental group (unadjusted RR 0.31, 95% CI 0.10 to 0.92; one trial; 166 participants). There are no data regarding neurodevelopmental outcome, renal impairment or air leaks.
The quality of evidence for all comparisons discussed above was assessed as very low apart from all‐cause mortality and adverse events: these were assessed as low and moderate, respectively. The validity of all comparisons is hampered by a small sample of randomised infants, risk of bias due to lack of blinding, and indirectness of outcomes.
Authors' conclusions
The only eligible randomised clinical trial did not demonstrate any consistent effects of NIRS plus a guideline on the assessed clinical outcomes. The trial was, however, only powered to detect difference in cerebral oxygenation, not morbidities or mortality. Our systematic review did not reach sufficient power to prove or disprove effects on clinical outcomes. Further randomised clinical trials with low risks of bias and low risks of random errors are needed.
Abstract
Background
The established association between acute lymphoblastic leukemia (ALL) and hyperlipidemia has, in some studies, been linked to toxicities such as pancreatitis, thrombosis, and ...osteonecrosis. However, a systematic review investigating the incidence, management, and clinical implications of hyperlipidemia during childhood ALL treatment is lacking.
Objectives
Systematically assess the incidence of hyperlipidemia during ALL treatment, explore associations with risk factors and severe toxicities (osteonecrosis, thrombosis, and pancreatitis), and review prevalent management strategies.
Methods
A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement. Data synthesis was descriptive, and a meta‐analysis of hypertriglyceridemia and risk of severe toxicities was performed.
Results
We included 13 studies with 3,425 patients. Hyperlipidemia incidence varied widely (6.7%‐85%) but with inconsistent definitions and screening strategies across studies. Evidence regarding risk factors was conflicting, but age (> 10 years) and treatment with asparaginase and glucocorticosteroids seem to be associated with hyperlipidemia. Hypertriglyceridemia (grade 3/4) increased the risk for osteonecrosis (odds ratio (OR): 4.27, 95% confidence interval (CI): 2.77‐6.61). No association could be established for pancreatitis (OR: 1.60, 95% CI: 0.53‐4.82) or thrombosis (OR: 2.45, 95% CI: 0.86‐7.01), but larger studies are needed to confirm this.
Conclusion
The overall evidence of this systematic review is limited by the small number of studies and risk of bias. Our review suggests that hypertriglyceridemia increases the risk for osteonecrosis. However, larger studies are needed to explore the clinical implications of hyperlipidemia and randomized trials investigating hyperlipidemia management and its impact on severe toxicities.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
Posterior reversible encephalopathy syndrome (PRES) is a distinct entity with incompletely known predisposing factors. The aim of this study is to describe the incidence, risk factors, ...clinical course, and outcome of PRES in childhood acute lymphoblastic leukemia (ALL).
Procedure
Patients aged 1.0 to 17.9 years diagnosed with ALL from July 2008 to December 2015 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol were included. Patients with PRES were identified in the prospective NOPHO leukemia toxicity registry, and clinical data were collected from the medical records.
Results
The study group included 1378 patients, of whom 52 met the criteria for PRES. The cumulative incidence of PRES at one month was 1.7% (95% CI, 1.1–2.5) and at one year 3.7% (95% CI, 2.9–4.9). Older age (hazard ratios HR for each one‐year increase in age 1.1; 95% CI, 1.0–1.2, P = 0.001) and T‐cell immunophenotype (HR, 2.9; 95% CI, 1.6–5.3, P = 0.0005) were associated with PRES. Central nervous system (CNS) involvement (odds ratios OR = 2.8; 95% CI, 1.2–6.5, P = 0.015) was associated with early PRES and high‐risk block treatment (HR = 2.63; 95% CI, 1.1–6.4, P = 0.033) with late PRES. At follow‐up of the PRES patients, seven patients had epilepsy and seven had neurocognitive difficulties.
Conclusion
PRES is a neurotoxicity in the treatment of childhood ALL with both acute and long‐term morbidity. Older age, T‐cell leukemia, CNS involvement and high‐risk block treatment are risk factors for PRES.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
Socioeconomic differences in survival among children with acute lymphoblastic leukemia (ALL) have been reported in high‐income countries and there is an unmet need for strategies to ...identify vulnerable patient subgroups. Reported differences in survival for children from families with different socioeconomic positions seem to arise when starting maintenance therapy. This could reflect reduced physician's compliance or family adherence to maintenance therapy.
Methods
This nationwide cohort study with extensive monitoring of systemic methotrexate (MTX)/6‐mercaptopurine (6MP) dosing and metabolite levels, retrospectively investigated 173 Danish children treated according to The Nordic Society for Pediatric Hematology and Oncology ALL2008 protocol from 2008 to 2016.
Results
Significantly lower prescribed doses of MTX and 6MP were seen in the children in families with short parental education (short vs. medium vs. higher education: mMTX: 13.8, 16.2, and 18.6 mg/m2/week; p < .01; m6MP: 47.4, 64.9, and 66.1 mg/m2/day; p = .03) or parents unemployed/not in workforce (unemployed/not in workforce vs. mixed vs. at work: mMTX: 15.0, 19.9, and 17.2 mg/m2/week; p < .01; m6MP: 54.8, 72.0, and 65.1 mg/m2/day; p < .01). When assessing family adherence by analyzing MTX and 6MP metabolite levels, including per prescribed dose of MTX and 6MP, we found no significant differences by levels of parental education, affiliation to work market, or income (p > .05 for all comparisons).
Conclusions
These results indicate that inferior physician compliance to protocol recommendations on drug dosage rather than families’ adherence to therapy may contribute to the association between socioeconomic position and cure rates in childhood ALL, although precise mechanisms remain to be explored.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Central nervous system (CNS) involvement in childhood acute lymphoblastic leukemia (ALL) implicates enhanced intrathecal chemotherapy, which is related to CNS toxicity. Whether CNS involvement alone ...contributes to CNS toxicity remains unclear. We studied the occurrence of all CNS toxicities, seizures, and posterior reversible encephalopathy syndrome (PRES) in children with ALL without enhanced intrathecal chemotherapy with CNS involvement (n = 64) or without CNS involvement (n = 256) by flow cytometry. CNS involvement increased the risk for all CNS toxicities, seizures, and PRES in univariate analysis and, after adjusting for induction therapy, for seizures (hazard ratio HR = 3.33; 95% confidence interval CI: 1.26–8.82; p = 0.016) and PRES (HR = 4.85; 95% CI: 1.71–13.75; p = 0.003).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Therapeutic drug monitoring (TDM) can improve clinical care when using drugs with pharmacokinetic variability and a narrow therapeutic window. Rapid, reliable, and easy-to-use detection methods are ...required in order to decrease the time of analysis and can also enable TDM in resource-limited settings or even at bedside. Monitoring methotrexate (MTX), an anticancer drug, is critical since it is needed to follow the drug clearance rate and decide how to administer the rescue drug, leucovorin (LV), in order to avoid toxicity and even death. We show that with the optimized nanopillar-assisted separation (NPAS) method using surface-enhanced Raman scattering, we were able to measure MTX in PBS and serum in the linear range of 5–150 μM and confirmed that MTX detection can be carried out even in the presence of LV. Additionally, when NPAS was combined with centrifugal filtration, a quantification limit of 2.1 μM for MTX in human serum sample was achieved. The developed detection method enables fast detection (10 min) and quantification of MTX from human serum (>90% accuracy). Furthermore, we show the potential of the developed method for TDM, when quantifying MTX from clinical samples, collected from patients who are undergoing high-dose MTX therapy.
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IJS, KILJ, NUK, PNG, UL, UM
Methotrexate/6-mercaptopurine maintenance therapy improves acute lymphoblastic leukemia (ALL) outcome. Cytotoxicity is mediated by DNA incorporation of thioguanine nucleotides (DNA-TG). We ...investigated the association of DNA-TG to relapse risk in 1 910 children and young adults with non-high risk ALL. In a cohort-stratified Cox regression analysis adjusted for sex, age, and white cell count at diagnosis, the relapse-specific hazard ratio (HRa) per 100 fmol/μg increase in weighted mean DNA-TG (
DNA-TG) was 0.87 (95% CI 0.78-0.97; p = 0.013) in the 839 patients who were minimal residual disease (MRD) positive at end of induction therapy (EOI), whereas this was not the case in EOI MRD-negative patients (p = 0.76). Validation analysis excluding the previously published Nordic NOPHO ALL2008 pediatric cohort yielded a HRa of 0.92 (95% CI 0.82-1.03; p = 0.15) per 100 fmol/μg increase in
DNA-TG in EOI MRD-positive patients. If also excluding the United Kingdom cohort, in which samples were taken non-randomly in selected patients, the HRa for the EOI MRD-positive patients was 0.82 (95% CI 0.68-0.99; p = 0.044) per 100 fmol/μg increase in
DNA-TG. The importance of DNA-TG as a biomarker for maintenance therapy intensity calls for novel strategies to increase DNA-TG, although its clinical value may vary by protocol backbone.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Published evidence suggests that aspects of trial design lead to biased intervention effect estimates, but findings from different studies are inconsistent. This study combined data from 7 ...meta-epidemiologic studies and removed overlaps to derive a final data set of 234 unique meta-analyses containing 1973 trials. Outcome measures were classified as "mortality," "other objective," "or subjective," and Bayesian hierarchical models were used to estimate associations of trial characteristics with average bias and between-trial heterogeneity. Intervention effect estimates seemed to be exaggerated in trials with inadequate or unclear (vs. adequate) random-sequence generation (ratio of odds ratios, 0.89 95% credible interval {CrI}, 0.82 to 0.96) and with inadequate or unclear (vs. adequate) allocation concealment (ratio of odds ratios, 0.93 CrI, 0.87 to 0.99). Lack of or unclear double-blinding (vs. double-blinding) was associated with an average of 13% exaggeration of intervention effects (ratio of odds ratios, 0.87 CrI, 0.79 to 0.96), and between-trial heterogeneity was increased for such studies (SD increase in heterogeneity, 0.14 CrI, 0.02 to 0.30). For each characteristic, average bias and increases in between-trial heterogeneity were driven primarily by trials with subjective outcomes, with little evidence of bias in trials with objective and mortality outcomes. This study is limited by incomplete trial reporting, and findings may be confounded by other study design characteristics. Bias associated with study design characteristics may lead to exaggeration of intervention effect estimates and increases in between-trial heterogeneity in trials reporting subjectively assessed outcomes.
Purpose
Methotrexate (MTX)/6-Mercaptopurine (6MP)-based maintenance therapy is crucial to cure childhood acute lymphoblastic leukemia (ALL). Cytotoxicity is mediated by incorporation of thioguanine ...nucleotides (TGN) into DNA (DNA-TG) with higher levels in leucocytes being associated with reduced relapse risk. To further understand the dynamics of DNA-TG formation, we measured DNA-TG levels in leucocyte subsets during maintenance therapy and in the months following its discontinuation.
Methods
DNA-TG levels were measured in leucocytes (DNA-TG
Total
), polymorph nucleated granulocytes (neutrophils, eosinophils, basophils DNA-TG
PMN
) and mononucleated cells (lymphocytes, monocytes DNA-TG
MNC
) in 1013 samples from 52 patients on ALL maintenance therapy (951 samples during therapy and 62 samples after therapy discontinuation, respectively).
Results
Median DNA-TG
Total
, DNA-TG
PMN
and DNA-TG
MNC
during maintenance therapy were 539, 563 and 384 fmol/µg DNA, respectively. DNA-TG
PMN
displayed more pronounced fluctuation than DNA-TG
MNC
(range 0–3084 interquartile range IQR 271–881 versus 30–1411 IQR 270–509 fmol/µg DNA). DNA-TG
Total
was more strongly correlated with DNA-TG
PMN
(
r
S
= 0.95,
p
< 0.0001) than DNA-TG
MNC
(
r
S
= 0.73,
p
< 0.0001). DNA-TG
PMN
correlated less with DNA-TG
MNC
(
r
S
= 0.64,
p
< 0.0001) and to a much lesser extent with absolute neutrophil count (
r
S
= 0.35,
p
< 0.0001). Following discontinuation of therapy, DNA-TG
PMN
was rapidly eliminated, and not measurable beyond day 22 after discontinuation, whereas DNA-TG
MNC
was slowly eliminated, and five patients demonstrated a measurable DNA-TG
MNC
more than 365 days after therapy discontinuation.
Conclusion
Fluctuations in DNA-TG
Total
are predominantly caused by corresponding fluctuations in DNA-TG
PMN
, thus DNA-TG
Total
measures recent TGN incorporation in these short-lived cells. Measurement of DNA-TG
Total
at 2–4 weeks intervals provides a reliable profile of DNA-TG levels.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose
Mercaptopurine (6MP) is essential to cure childhood acute lymphoblastic leukemia (ALL). A liquid 6MP formulation was recently introduced to facilitate oral 6MP administration, especially to ...children. Its approval and bioequivalence with 6MP tablet were based on comparative pharmacokinetics in 60 healthy adults. Due to potential pharmacokinetic differences between healthy adults and children with ALL, we compared pharmacokinetics of tablet and liquid 6MP formulations in children with ALL.
Methods
Pharmacokinetics of 50 mg 6MP tablet (Puri-Nethol
®
) and 20 mg/ml 6MP liquid suspension (Xaluprine
®
) were compared in a non-blinded, random order, single-dose, cross-over study in 16 children with ALL (eight males). 6MP was administered after a 12 h fast, and 6MP plasma concentrations measured consecutively over seven hours post-dose. Pharmacokinetic outcomes were as follows: Area under the curve (AUC), maximum plasma concentration (
C
max
), time to maximum plasma concentration (
T
max
), and terminal half-life (
T
½
).
Results
Liquid 6MP formulation resulted in a 26% lower AUC (
p
= 0.02) compared with tablet (median 1215 vs. 1805 h × nmol/l). No significant differences were observed for
C
max,
T
max
and
T
½
(
p
= 0.28,
p
= 0.09,
p
= 0.41, respectively). Based on criteria declared by the World Health Organization the results did not establish non-inferiority of liquid 6MP formulation compared with 6MP tablet.
Conclusion
Non-inferiority of liquid 6MP formulation compared with 6MP tablet was not demonstrated. Yet, maintenance therapy doses are adjusted by degree of myelosuppression and not by 6MP dose. Thus, in spite of a lower bioavailability, a liquid 6MP formulation is still desirable in a clinical setting, especially for children. However, if shifting between 6MP formulation is indicated, dose adjustments should be anticipated to maintain equivalent treatment intensity in children with ALL.
The study is registered on clinicaltrials.gov (NCT01906671). Date of registration: 24.07.13.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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