Outcomes of adolescents with acute lymphoblastic leukaemia.

INTRODUCTION: Compared with young children who have acute lymphoblastic leukaemia (ALL), adolescents with ALL have unfavourable disease profiles and worse survival. However, limited data are available regarding the characteristics and outcomes of adolescents with ALL who underwent treatment in clinical trials. The aim of this study was to investigate the causes of treatment failure in adolescents with ALL. METHODS: We retrospectively analysed the outcomes of 711 children with ALL, aged 1-18 years, who were enrolled in five clinical trials of paediatric ALL treatment between 1993 and 2015. RESULTS: Among the 711 children with ALL, 530 were young children (1-9 years at diagnosis) and 181 were adolescents (including 136 younger adolescents [10-14 years] and 45 older adolescents [15-18 years]). Compared with young children who had ALL, adolescents with ALL were less likely to have favourable genetic features and more likely to demonstrate poor early response to treatment. The 10-year overall survival and event-free survival rates were significantly lower among adolescents than among young children (77.9% vs 87.6%, P=0.0003; 69.7% vs 76.5%, P=0.0117). There were no significant differences in the 10-year cumulative incidence of relapse, but the 10-year cumulative incidence of treatment-related death (TRD) was significantly greater among adolescents (7.2%) than among young children (2.3%; P=0.002). Multivariable analysis showed that both younger and older adolescents (vs young children) had worse survival and greater incidence of TRD. CONCLUSION: Adolescents with ALL had worse survival because they experienced a greater incidence of TRD. There is a need to investigate optimal treatment adjustments and novel targeted agents to achieve better survival rates (without excessive toxicity) among adolescents with ALL.

Hepatic steatosis is highly prevalent across the paediatric age spectrum, including in pre-school age children.

BACKGROUND: The prevalence of non-alcoholic fatty liver disease (NAFLD) in children is 8% in the general population, and 34% in the context of obesity. There is a paucity of data on the prevalence of hepatic steatosis in healthy children in Ontario. AIMS: To determine the prevalence of hepatic steatosis using abdominal computed tomography (CT) scans in a cohort of previously healthy children across the paediatric age spectrum in Ontario, Canada, and to determine any association between measures of abdominal adiposity and hepatic steatosis. METHODS: Retrospective review of the SickKids Trauma Database from 2004-2015. Previously healthy children ages 1-17 years having undergone an abdominal CT scan as a part of routine trauma assessment were included, and those with an intra-abdominal injury excluded. Steatosis was defined as a difference between liver and spleen attenuation ≤-25HU. The percentage of the total area occupied by abdominal subcutaneous adipose and visceral adipose tissue was measured. Anthropometrics and baseline demographics were collected. RESULTS: A total of 503 (51% male) children with mean (±SD) age 9.5 ± 4.5 years and weight z-score of 0.37 ± 1.05 were studied. Seventy-seven (15%, 95% CI [12%-18%]) had hepatic steatosis; no differences found between sexes or across age quartiles. The abdominal subcutaneous adipose tissue area was greater in those with hepatic steatosis compared to those without (32% [22-42] vs 24% [17-36], P = 0.003). The visceral adipose tissue area was significantly greater in older children ≥9.8 years with hepatic steatosis (7.7% [5.1-10] vs 6.6% (4.9-8.5), P = 0.04). CONCLUSION: Hepatic steatosis was highly prevalent in previously healthy children in Ontario, including children of pre-school age. We found an association between hepatic steatosis and abdominal subcutaneous adipose tissue, and in older children with visceral adipose tissue.

Chronic hepatitis B virus (HBV) infection in children: 25 years' experience.

Whereas e-seroconversion represents the loss of hepatitis B e-antigen (HBeAg) followed by gain of antibody to HBeAg (anti-HBe), 'inactive chronic infection' extends this concept to include e-seroconversion with decreased serum viral load and biochemical remission. These events must be well-characterized before treatment outcomes can be evaluated. We examined the rates of e-seroconversion and achievement of inactive chronic infection among children with chronic HBV infection. Children who were HBsAg positive >6 months were identified retrospectively between 1983 and 2008 from the Hospital for Sick Children Liver Clinic. Inactive chronic infection was defined as loss of HBeAg, serum ALT ≤40 IU/mL, and HBV DNA <10(6 ) IU/mL. Both e-seroconversion and achievement of inactive chronic infection were characterized using survival analysis. The effect of transmission route, treatment, age at diagnosis, ethnicity, gender and baseline ALT on these rates was evaluated with univariate and multiple regression. Of 252 HBeAg-positive cases, 59.9% had HBV-infected mothers, 77% were Asian, and 33 received interferon-α. Untreated children were younger at last follow-up (mean 14.5 vs 17.6 years), had lower ALT (median 60 vs 116 IU/mL) and had shorter follow-up (6.6 vs 9.1 years, all P < 0.002) compared to treated children. Crude e-seroconversion rate was 41.7% over 0.5-19.1 years of follow-up, and this was not affected by transmission route (P = 0.93), gender (P = 0.62) nor treatment (P = 0.08). 49% achieved inactive chronic infection by age 19 years. Being non-Asian, age at diagnosis<3 years, and ALT ≥40 IU/mL were associated with a higher rate of e-seroconversion and achieving inactive chronic infection (P < 0.0001). Almost 50% of children achieved inactive chronic infection by early adulthood.

Biosynthesis of novel polyhydroxyalkanoate containing 3-hydroxy-4-methylvalerate by Chromobacterium sp. USM2.

AIMS: Polyhydroxyalkanoate (PHA) with enhanced physicochemical properties will be ideal for a wide range of practical applications. The incorporation of 3-hydroxy-4-methylvalerate (3H4MV) into the polymer backbone is known to improve the overall properties of the resulting polymer. However, the most suitable micro-organism and PHA synthase that can synthesize this monomer efficiently still remain unknown at present. Therefore, we evaluated the abilities of a locally isolated Chromobacterium sp. USM2 to produce PHA containing 3H4MV. METHODS AND RESULTS: The ability of Chromobacterium sp. USM2 to synthesize poly(3-hydroxybutyrate-co-3-hydroxy-4-methylvalerate) [P(3HB-co-3H4MV)] was evaluated under different culture conditions. It was found that Chromobacterium sp. USM2 can synthesize P(3HB-co-3H4MV) when glucose and isocaproic acid were fed as carbon source. However, the highest molar fraction of 3H4MV, 22 mol% was detected in Chromobacterium sp. USM2 when isocaproic acid was provided as the sole carbon source. In addition, aeration was identified as a crucial factor in initiating the accumulation of high 3H4MV molar fractions. CONCLUSIONS: Chromobacterium sp. USM2 was able to synthesize broad comonomer compositional distribution of P(3HB-co-3H4MV). SIGNIFICANCE AND IMPACT OF THE STUDY: Compared with Cupriavidus necator and Burkholderia sp., Chromobacterium sp. USM2 was found to have better ability to bioconvert isocaproic acid to form 3H4MV unit.

The changing face of hepatitis in boys with haemophilia associated with increased prevalence of obesity.

Hepatitis in children with haemophilia was historically most often associated with transfusion-transmitted infections. However, with the use of recombinant clotting factor concentrates, acquisition of such infections has now become rare. We studied the profile of hepatitis in North-American children with haemophilia in the modern era of safe blood products and excess childhood obesity. A total of 173 boys (<18 years) registered in the Pediatric Comprehensive Care Haemophilia Program were included in this retrospective study. Hospital records were reviewed for baseline data, serial height and weight measurements and serial alanine aminotransferase (ALT) levels. A body mass index (BMI) ranking was available for 170 boys, of whom 25 (14.7%, 95% CI 9.7-20.9%) were obese. The rate of obesity was higher in severe haemophilic boys. Compared with the general childhood population, the rate of obesity trended towards being higher in young haemophilic boys (2-5 years), but was similar in other age groups. A persistently high ALT (≥80 U L(-1) ) was documented in 5 boys and was associated with obesity. Three boys had clinical and imaging studies compatible with non-alcoholic fatty liver disease (NAFLD). Overweight and obesity are common among haemophilic boys, especially those who are younger and with severe disease. In this large group of haemophilic boys, chronic viral hepatitis was rare and NAFLD was a more common cause of liver disease. Overweight and obese haemophilic boys should be evaluated for NAFLD and interventional programmes should be designed to reduce the potential complications associated with obesity.

Pico-Salax versus polyethylene glycol for bowel cleanout before colonoscopy in children: a randomized controlled trial.

BACKGROUND AND STUDY AIMS: Comparison of bowel preparation for colonoscopy in children with either Pico-Salax (sodium picosulphate with magnesium citrate) or polyethylene glycol with electrolyte solution (PEG-ELS). PATIENTS AND METHODS: In this investigator-blinded, randomized controlled trial, 83 children (12.5 +/- 3.1 years) requiring elective colonoscopy at a referral hospital were randomly allocated to Pico-Salax (n = 43) or PEG-ELS (n = 40), and an intention-to treat analysis was applied. Pico-Salax was administered in two doses, one the evening before and one on the morning of the procedure. PEG-ELS was administered over 4 hours. Efficacy was scored using the Ottawa scale and other constructs. Tolerability and toxicity were measured by patient and nursing questionnaires and serum biochemistry. RESULTS: 35 of Pico-Salax patients (81 %) were satisfied or very satisfied with the cleanout, compared with 19 (48 %) in the PEG-ELS group (P = 0.001). No differences were found in bowel cleanout effectiveness, as judged by the Ottawa score (P = 0.24), completion rates (P = 0.69), colonoscopy duration (P = 0.59), need for enemas (P = 0.25), or physician's global impression (P = 0.7). Except for one case of mild dehydration in the Pico-Salax group, no clinically significant adverse events were recorded. Serum biochemistry results were similar between groups except for more hypermagnesemia associated with Pico-Salax and hypokalemia with PEG-ELS; neither was clinically significant. CONCLUSION: Children tolerate Pico-Salax better than PEG-ELS for bowel cleanout before colonoscopy. This study did not demonstrate superiority of effectiveness or safety for either regimen.

Long-term follow-up of portal hypertension after liver transplantation in children.

We aimed to describe the long-term changes in the imaging and clinical features of PHALT in children. A retrospective review was undertaken of consecutive children undergoing their first liver transplant between 1993 and 2003. Details of clinical progress and ultrasound imaging were recorded at one-yr post-transplantation and at last follow-up. Data were extracted on 83 children (median age at transplant 1.7 yr, range one month to 17.5 yr, 44 girls) who underwent 89 transplants. Four of these children died at a mean 5.6 yr (range 3.8-6.9 yr) after transplantation. Of the survivors, follow-up at one yr (n = 83) and at last follow-up (n = 71, median 4.3 yr post-transplant) revealed imaging evidence of splenomegaly in 46% and 44%, ascites in 6% and 4%, and portal systemic collaterals in 12% and 14%, respectively. Gastrointestinal hemorrhage associated with portal hypertension had occurred in no children at one yr and in four (6%) at latest follow-up. Features of portal hypertension on ultrasound scan are common in children before liver transplantation. An important minority of children will suffer clinically significant complications of PHALT during long-term follow-up, caused by both vascular and parenchymal disease.

Congenital cholestatic syndromes: what happens when children grow up?

Although advances in the management of children with congenital cholestasis have enabled many to survive into adulthood with their native livers, even the most common of these conditions remains rare in adult hepatology practice. Among four congenital cholestatic syndromes (biliary atresia, Alagille syndrome, Caroli disease and congenital hepatic fibrosis, and progressive familial intrahepatic cholestasis), the published data on outcomes of the syndromes into adulthood suggest that a spectrum of severity of liver disease can be expected, from cirrhosis (almost universal in adults with biliary atresia who have not required liver transplantation) to mild and subclinical (eg, in the previously undiagnosed affected parent of an infant with Alagille syndrome). Complications associated with portal hypertension and nutritional deficiencies are common, and other associated features of the cholestatic syndrome may require appropriate attention, such as congenital heart disease in Alagille syndrome. Indications for liver transplantation include synthetic failure, progressive encephalopathy, intractable pruritus, recurrent biliary sepsis and recurrent complications of portal hypertension. Improved understanding of biliary physiology will hopefully translate into improved therapy for children and adults with cholestasis.

Improved outcome of acute lymphoblastic leukaemia treated by delayed intensification in Hong Kong children: HKALL97 study.

OBJECTIVE: To study the outcome of children with acute lymphoblastic leukaemia who were treated using a protocol including one or two delayed intensifications. DESIGN: Prospective single-arm multicentre study. SETTING: Five designated children cancer units of the Hospital Authority of Hong Kong. PATIENTS: Children aged between 1 and 17.9 years with newly diagnosed acute lymphoblastic leukaemia seen from November 1997 to December 2002. INTERVENTION: Chemotherapy was modified from a German Berlin-Frankfurt-Muenster 95 (BFM95) protocol that included a delayed intensification similar to the induction phase repeated 5 months after diagnosis. High-risk patients were given double delayed intensification. MAIN OUTCOME MEASURES: Overall survival and event-free survival of the whole group and the three risk groups (standard-, intermediate-, and high-risk groups), and comparison with historical controls. RESULTS: A total of 171 patients were recruited with a median age at diagnosis of 5.57 years (range, 1.15-17.85 years). The induction remission rate was 95.3% and non-leukaemia mortality during remission was 2.3%. At 4 years, the relapse rate of this (HKALL97) study was significantly lower than that of the HKALL93 study (15.7 vs 37.3%; P<0.001). The 4-year overall survival of HKALL97 and HKALL93 studies were 86.5% and 81.8%, respectively (P=0.51). The 4-year event-free survival for HKALL97 and HKALL93 studies were 79% and 65%, respectively (P=0.007). Nonetheless the difference of event-free survival was most remarkable in the intermediate-risk group: 75.6% and 53.1% for HKALL97 and HKALL93 studies, respectively (P=0.06). CONCLUSION: A more intensive delayed consolidation phase improved the outcome for children with acute lymphoblastic leukaemia by reducing relapses at 4 years. The early treatment complications were manageable and non-leukaemia mortality during remission remained low.

Role of imaging in management of hemophilic patients.

OBJECTIVE: The purpose of this study was to evaluate the role of symptomatology and conventional radiographic scoring in predicting synovial hypertrophy, which could affect the clinical management of hemophilic patients. MATERIALS AND METHODS: Twenty males (mean age, 14.3 years old) with hemophilic arthropathy, including 34 symptomatic joints and 26 asymptomatic joints (16 knees, 20 ankles, and 24 elbows) had conventional radiographs of individual joints obtained that were rated according to the Arnold-Hilgartner stage and the Pettersson score. The patients also underwent MRI for the detection of synovial hypertrophy. The association of synovial hypertrophy and symptomatology was evaluated using the chi-square or Fisher's exact test. The best sensitivity, specificity, and positive and negative predictive values in detection of synovial hypertrophy using symptomatology and radiographic scoring were calculated. RESULTS: A significant association was seen between symptomatology and synovial hypertrophy of the knee and ankle joints (p < 0.05). The sensitivity, specificity, and positive and negative predictive values of symptomatology in detection of synovial hypertrophy of the knee were 100%, 78%, 78%, and 100%, respectively, and for the ankle were 83%, 75%, 83%, and 75%, respectively. The Arnold-Hilgartner stage and Pettersson score of the radiograph had a significant association with synovial hypertrophy of the knee and ankle joints (p < 0.05). Arnold-Hilgartner staging provided a better prediction of synovial hypertrophy, with sensitivity, specificity, positive predictive value, and negative predictive value of 100%, 100%, 100%, and 100% for knees and 82%, 100%, 100%, and 82% for ankles. CONCLUSION: In hemophilic patients, the presence of symptomatology in the knee and ankle joints is associated with synovial hypertrophy, and scoring of the conventional radiographs using Arnold-Hilgartner staging is useful for the prediction of synovial hypertrophy.

Use of hair analysis in the diagnosis of heavy metal poisoning: report of three cases.

We report three paediatric cases of suspected heavy metal poisoning that presented with non-specific symptoms. Hair samples of the three patients were sent overseas for analysis; results showed abnormal levels of many elements, including some heavy metals. A diagnosis of heavy metal poisoning was made and chelation therapy was offered to each patient. Blood levels for some heavy metals were subsequently checked and all were within the normal range. The original diagnosis of heavy metal poisoning was therefore not substantiated. The patients did not have a history of exposure to heavy metals or specific clinical features of heavy metal poisoning. The non-invasive nature of hair analysis is tempting, but the validity of such testing in diagnosing heavy metal poisoning is questionable.

Bone mineral assessment by dual energy X-ray absorptiometry in children with inflammatory bowel disease: evaluation by age or bone area.

BACKGROUND: Abnormal linear growth and deficient bone mineral acquisition may coexist in children with inflammatory bowel disease (IBD). Traditionally, bone mineral assessment by dual energy x-ray absorptiometry (DXA) involves comparison to age- and gender-matched reference ranges, and these studies in children with IBD show a high prevalence of osteopenia. AIMS: To compare the prevalence of osteopenia using two methods of interpretation; one adjusted for age and gender and the other adjusted for bone size and gender. PATIENTS: Forty-seven patients with Crohn disease (CD) and 26 patients with ulcerative colitis (UC) with a median age of 13.5 years (range, 5.5-18.2 years) were evaluated. METHODS: Lumbar spine (LS) and total body (TB) bone mineral content (BMC) were measured by DXA and converted to bone mineral density (BMD, g/cm) corresponding to BMC divided by the bone area. Age and gender-matched BMD standard deviation scores (SDS) were based on reference data providing age- and gender-matched BMC and bone area. These data also allowed calculation of percentage of predicted bone area for age and gender (ppBone Area) and percentage of predicted BMC for Bone Area (ppBMC). RESULTS: Patients with CD were shorter than those with UC (median height, SDS, -0.9 v 0, P < 0.05). Median ppBone Area for LS and TB for the whole group was 85% (10th centile, 68; 90th centile 99) and 81% (10th centile 66; 90th centile, 97), respectively. The ppBone Area at both sites was directly related to height SDS and BMI SDS (r > 0.5; P < 0.005). Median BMD SDS for LS and TB was -1.6 (10th centile -3.6; 90th centile, -0.2) and -0.9 (10th centile, -2.4; 90th centile, 0.4), respectively. Median ppBMC for LS and TB was 98% (10th centile, 84%; 90th centile, 113%) and 101% (10th centile 94%; 90th centile, 107%), respectively. The ppBMC showed no relationship to ppBone Area (r = 0.1, NS). Failure to account for bone area led to a label of moderate or severe osteopenia in 65% of cases. After adjustment for bone area, the proportion of children with osteopenia fell to 22%. CONCLUSIONS: The data suggest that children with IBD often have small bones for age because they have growth retardation. When DXA data are interpreted with adjustment for bone size, most children were found to have adequate bone mass. Correct interpretation of DXA is important for identifying children who may be at a real risk of osteoporosis.

Treatment of acute lymphoblastic leukemia in Hong Kong children: HKALL 93 study.

A population-based multicentre study for childhood acute lymphoblastic leukemia (ALL) was conducted in Hong Kong from 1993 to 1997. One hundred and forty-five newly diagnosed ALL patients were treated by the HKALL 93 protocol. Patients were stratified into three risk groups according to age, presenting white cell count, immunophenotyping and cytogenetic study. The patients received the same induction and early and late intensification at week 5 and week 20. Fifty-eight standard risk (SR) patients received regular intrathecal methotrexate as CNS preventive therapy, while 49 intermediate risk (IR) patients received high dose intravenous methotrexate and regular intrathecal methotrexate. Thirty-eight high risk (HR) patients were treated with prophylactic cranial irradiation and an additional intensification block at week 35. The induction remission rate was 97.2% with 2% induction death. Two patients died during first complete remission. Relapse occurred in 20.7, 42.9 and 42.1% of SR, IR and HR patients respectively. By multivariate logistic regression, age> or =10 years and white cell count> or =100 x 10(9)/l were the two significant variables accounting for mortality. The 5-year overall and event-free survival of the whole group was 81.3 and 62.6% respectively. According to risk groups, the event-free survival was 79, 49 and 61% for SR, IR and HR patients respectively, while the overall survival was 96, 73 and 68% for SR, IR and HR patients respectively. In conclusion, the treatment protocol had low treatment-related mortality but was associated with a rather high relapse rate, especially in IR patients. Salvage therapy achieved sustained second remission in some patients. More intensive treatment especially a late intensification is required to improve the outcome.

Analysis of 13C-mixed triacylglycerol in stool by bulk (EA-IRMS) and compound specific (GC/MS) methods.

This paper was presented in poster form at the 17th International Congress of Nutrition, August 27-31, Vienna, Austria (Annals of Nutrition & Metabolism 2001; 45(Suppl.1):349). Some of the data were also presented in poster form at the British Society of Gastroenterology Meeting, March 18-21, Glasgow, UK (Gut 2001; 48(Suppl.1):A91). The 13C-mixed triacylglycerol (MTG) breath test is used to measure intraluminal fat digestion. In normal digestion, 20-40% of the ingested 13C label is recovered in breath CO2. We aimed to identify the proportions of ingested label excreted in stool, as well as breath following ingestion of 13C-MTG by children with impaired exocrine pancreatic function and healthy controls. 13C enrichment of breath samples was measured by continuous flow isotope ratio mass spectrometry (IRMS) and cumulative percent dose recovered (cPDR) in 10 h was calculated. Total 13C of a faecal fat extract from each stool was measured by elemental analyser-IRMS, and 13C enrichment and concentration of the TBDMS derivative of octanoic acid was measured by GC/MS after hydrolysis of the fat extract. Stool 5-day cPDR was calculated. Mean breath cPDR was 35%. Mean cPDR in stool by combustion-IRMS and GC/ MS, respectively, was 0.8% and 1.0%. Therefore, the remaining 64% of the 13C label must remain in the body and variability in breath cPDR is due to postabsorptive rather than predigestive factors.

Morbidity and mortality patterns of thalassaemia major patients in Hong Kong: retrospective study.

OBJECTIVES: To study the morbidity and mortality patterns of transfusion-dependent thalassaemia major patients in Hong Kong, and compare the outcomes of these patients according to different periods of birth. DESIGN: Retrospective study. SETTING: Paediatric departments of three regional hospitals, Hong Kong. SUBJECTS AND METHODS: Medical records of thalassaemia major patients were reviewed. Data gathered included demographic and survival data, complications of iron overload, repeated transfusion, and bone marrow transplantation; the probability of survival of three cohorts was also estimated. RESULTS: Two hundred and thirty-two patients were studied at a median age of 15.5 years (range, 1.4-30.3 years). There were 60 patients born before 1980 (cohort 1), 117 patients born between 1980 and 1989 (cohort 2), and 55 patients born after 1989 (cohort 3). The median age of starting desferrioxamine was 8 years, 4 years, and 3 years for cohorts 1, 2, and 3, respectively. Cardiomyopathy, diabetes mellitus, and hypothyroidism occurred in 15.1%, 8.6%, and 6.9% of patients with thalassaemia major, respectively. The above complications developed in 5% to 12% of cohort 2 patients. Delayed puberty was present in 38.4% and hormonal replacement for gonadal failure was required in 29.7% of evaluable patients. Short stature was common and the median height standard deviation score was -1.63. Twenty patients had died, and cardiomyopathy was the leading cause of death, followed by complications of bone marrow transplantation. The probability of survival beyond the age of 20 years was 87.6%. CONCLUSION: Despite the use of iron chelation in the past two decades, severe complications of iron overload still occurred even in those who started chelation therapy early. Cardiomyopathy was the leading cause of death, while endocrinopathies and short stature were common complications especially in teenagers and adults.