Effectiveness of antibacterial prophylaxis during induction chemotherapy in children with acute lymphoblastic leukemia.

BACKGROUND: Pediatric patients receiving induction chemotherapy for newly diagnosed acute lymphoblastic leukemia (ALL) are at high risk of developing life-threatening infections. We investigated whether uniform antibacterial guidelines, including mandatory antibacterial prophylaxis in afebrile patients during induction, decreases the incidence of microbiologically documented bacteremia. METHODS: Between 2012 and 2015, 230 patients with newly diagnosed ALL (aged 1-21) were enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 11-001 (DFCI 11-001). Induction therapy, regardless of risk group, included vincristine, prednisone, doxorubicin, methotrexate, and PEG-asparaginase. Afebrile patients received fluoroquinolone prophylaxis at the initiation of induction and those presenting with fever received broad-spectrum antibiotics; antibiotics were continued until blood count recovery. Rates of documented bacteremias and fungal infections on DFCI 11-001 were compared to those on the predecessor protocol (DFCI 05-001), which included the same induction phase without antibiotic prophylaxis guidelines. RESULTS: Sixty-six (28.7%) patients received fluoroquinolone prophylaxis, the remaining patients received broad-spectrum antibiotics. Twenty-four (36.4%) patients on prophylaxis developed fever and seven (10.6%) developed bacteremia. The overall rate of infection during induction on DFCI 11-001 was lower than on DFCl 05-001 (14.3% vs. 26.3%, P < 0.0001) due to a decreased rate of bacteremia (10.9% vs. 24.4%, P < 0.0001). The rate of fungal infections (4.8% vs. 3.6%) and induction death (0.9% vs. 2%) was not significantly different. CONCLUSION: For children with newly diagnosed ALL, uniform antibiotic administration until blood count recovery, including fluoroquinolone prophylaxis for afebrile patients, reduced the incidence of bacteremia during the induction phase. Larger, randomized studies should be performed to confirm these findings.

Health-related quality of life in long-term survivors of acute lymphoblastic leukemia in childhood and adolescence.

PURPOSE: Children with acute lymphoblastic leukemia (ALL), the commonest form of cancer in this age group, suffer considerable morbidity during treatment, with the majority returning to good health soon after therapy has been completed, as reflected in health-related quality of life (HRQL). However, survivors are at risk of many adverse health outcomes later, including obesity, measured by body mass index (BMI), that is compounded by limited physical activity. This study examined the HRQL of long-term survivors of ALL and its relationship to BMI and physical activity. METHODS: A cohort of 75 subjects who were more than 10 years from diagnosis was assessed for BMI (weight in kg/height in m2) and completed two questionnaires. HRQL was measured by the multi-attribute, preference-based Health Utilities Index (HUI) instrument HUI23S4.15Q designed for self-report, and physical activity was quantified by the Habitual Activity Estimation Scale. RESULTS: The mean utility scores for overall HRQL (HUI2 = 0.88, HUI3 = 0.83) were similar to those in the Canadian and US general population segments of equivalent age (HUI2 = 0.86, HUI3 = 0.85). However, the minimum scores (HUI2 = 0.23, HUI3 = -0.09) revealed a group of survivors with notable disabilities in the attributes of hearing, emotion, cognition, and pain. There were no statistically significant correlations between HRQL and BMI or between HRQL and physical activity, except for deafness and inactivity on weekdays. CONCLUSIONS: Overall, long-term survivors of ALL in childhood enjoy good HRQL but some experience appreciable disability, though this is not associated with BMI or, in the main, with physical activity.

Transfusion-related alloimmunization in children: epidemiology and effects of chemotherapy.

BACKGROUND & OBJECTIVES: Alloimmunization rates following red blood cell (RBC) transfusion in paediatric oncology are not known. This study aimed to: (1) describe frequency and specificity of alloantibodies in paediatric oncology patients after RBC transfusions; (2) determine the effect of chemotherapy on alloimmunization rate. MATERIALS & METHODS: Retrospective cohort study of paediatric patients at a tertiary care hospital is evaluated by two groups: control group, paediatric patients without cancer; study group, paediatric oncology patients who received chemotherapy. Alloimmunization was defined as clinically significant IgG alloantibody formation against RBC antigens. RESULTS: A total of 1273 children were evaluated including 324 in study group, 909 controls, and 40 haemoglobinopathy patients. Overall, frequency of alloimmunization was 1·5%: 0·3% (95% CI: 0, 1·90) in study group; 1·3% (95% CI: 0·73, 2·32) in control group and 15% in haemoglobinopathies. The association between chemotherapy and alloimmunization was not significant; P value = 0·20 Fisher's exact test, OR 0·23 (95% CI: 0·03, 1·79). CONCLUSION: This is the first study exploring RBC alloimmunization in paediatric patients by diagnosis. Alloimmunization frequency was low. It was not possible to determine an association between chemotherapy and alloimmunization due to the low event rate.

Development and validation of a generic scale for use in transition programmes to measure self-management skills in adolescents with chronic health conditions: the TRANSITION-Q.

AIM: To develop a generic self-management skills scale for use with adolescents diagnosed with a chronic health condition who are aged 12 to 18 years. BACKGROUND: There is a lack of methodologically sound scales for healthcare teams to use to measure self-management skills in adolescents with chronic conditions transitioning to adult care. METHODS: Adolescents aged 12 to 18 years with a broad range of chronic health conditions, including neurodevelopmental conditions, were recruited from May to August 2013 from nine outpatient clinics at McMaster Children's Hospital (Canada). Thirty-two participated in a cognitive interview, and 337 completed a questionnaire booklet. Interviews were used to develop the TRANSITION-Q. Rasch measurement theory (RMT) analysis was used to identify items that represent the best indicators of self-management skills. Traditional psychometric tests of measurement performance were also conducted. RESULTS: The response rate was 92% (32/32 cognitive; 337/371 field test). RMT analysis resulted in a 14-item scale with three response options. The overall fit of the observed data to that expected by the Rasch model was non-significant, providing support that this new scale measured a unidimensional construct. Other tests supported the scale as scientifically sound, e.g. Person Separation Index = 0.82; good item fit statistics; no differential item function by age or gender; low residual correlations between items; Cronbach's alpha = 0.85; test-retest reliability = 0.90; and tests of construct validity that showed, as hypothesized, fewer skills in younger participants and in participants who required assistance to complete the scale. Finally, participants who agreed they are ready to transfer to adult healthcare reported higher TRANSITION-Q scores than did participants who disagreed. CONCLUSIONS: The TRANSITION-Q is a short, clinically meaningful and psychometrically sound scale. This generic scale can be used in research and in paediatric and adolescent clinics to help evaluate readiness for transition.

Genetic analysis of inherited bone marrow failure syndromes from one prospective, comprehensive and population-based cohort and identification of novel mutations.

INTRODUCTION: Inherited bone marrow failure syndromes (IBMFSs) often have substantial phenotypic overlap, thus genotyping is often critical for establishing a diagnosis. OBJECTIVES AND METHODS: To determine the genetic characteristics and mutation profiles of IBMFSs, a comprehensive population-based study that prospectively enrols all typical and atypical cases without bias is required. The Canadian Inherited Marrow Failure Study is such a study, and was used to extract clinical and genetic information for patients enrolled up to May 2010. RESULTS: Among the 259 primary patients with IBMFS enrolled in the study, the most prevalent categories were Diamond-Blackfan anaemia (44 patients), Fanconi anaemia (39) and Shwachman-Diamond syndrome (35). The estimated incidence of the primary IBMFSs was 64.5 per 10(6) births, with Fanconi anaemia having the highest incidence (11.4 cases per 10(6) births). A large number of patients (70) had haematological and non-haematological features that did not fulfil the diagnostic criteria of any specific IBMFS category. Disease-causing mutations were identified in 53.5% of the 142 patients tested, and in 16 different genes. Ten novel mutations in SBDS, RPL5, FANCA, FANCG, MPL and G6PT were identified. The most common mutations were nonsense (31 alleles) and splice site (28). Genetic heterogeneity of most IBMFSs was evident; however, the most commonly mutated gene was SBDS, followed by FANCA and RPS19. CONCLUSION: From this the largest published comprehensive cohort of IBMFSs, it can be concluded that recent advances have led to successful genotyping of about half of the patients. Establishing a genetic diagnosis is still challenging and there is a critical need to develop novel diagnostic tools.

Comparative analysis of Shwachman-Diamond syndrome to other inherited bone marrow failure syndromes and genotype-phenotype correlation.

Our knowledge of the phenotypes of inherited bone marrow failure syndromes (IBMFSs) derives from case reports or case series in which only one IBMFS was studied. However, the substantial phenotypic overlap necessitates comparative analysis between the IBMFSs. Shwachman-Diamond syndrome (SDS) is an IBMFS that the appreciation of what comprises its clinical phenotype is still evolving. In this analysis we used data on 125 patients from the Canadian Inherited Marrow Failure Study (CIMFS), which is a prospective multicenter population-based study. Thirty-four cases of SDS patients were analyzed and compared to other patients with the four most common IBMFSs on the CIMFS: Diamond Blackfan anemia, Fanconi anemia (FA), Kostmann/severe congenital neutropenia and dyskeratosis congenita (DC). The diagnosis of SDS, FA and DC was often delayed relative to symptoms onset; indicating a major need for improving tools to establish a rapid diagnosis. We identified multiple phenotypic differences between SDS and other IBMFSs, including several novel differences. SBDS biallelic mutations were less frequent than in previous reports (81%). Importantly, compared to patients with biallelic mutations, patients with wild type SBDS had more severe hematological disease but milder pancreatic disease. In conclusion, comprehensive study of the IBMFSs can provide useful comparative data between the disorders. SBDS-negative SDS patients may have more severe hematological failure and milder pancreatic disease.

Outcome of Acute Myeloid Leukemia in Children Adolescents and Young Adults Treated with an Uniform Protocol in Casablanca, Morocco.

Treatment of acute myeloblastic leukemia in children, adolescents and young adults (AYA) is a challenge in low-income countries. To evaluate treatment outcomes of children (≤ 15 years) and AYA (15-30 years) diagnosed with novo AML and treated in a single center according to the AML-MA 2011 protocol. From January 2011 to December 2015, eligible patients (age ≤ 30 years) with novo AML had been enrolled on a uniform treatment protocol. The diagnosis was confirmed according to the FAB classification using the WHO 2008 criteria. Patients with WBC ≥ 50 G/L had pretreated 4 days of hydroxyurea followed by two inductions and two consolidations. Supportive care consisted of transfusion of labile blood products, antibiotics and antifungals, and patient and family education by the hygiene team. 155 patients were recruited, 41 were < 15 years old (22 boys, median age 7.8 years). Of the 114 AYA enrolled, (48 women, median age 23 years). Complete remission after two inductions was 28/41 (68.3%) of the children, including 100% of the children in the favorable group and 71/114 (62.3%) of the AYA, 22 of whom (68.7%) were in the favorable group. The number of deaths among children was 6 (14.6%). The evaluation of the AML-MA-2011 National Protocol in the age groups of children and AYA reveals that the objective of treatment is almost achieved in terms of complete remission in the two age groups.

Chromosome investigations & clinical outcome in patients with myelodysplastic syndromes.

A total of 25 patients with primary myelodysplastic syndrome (p-MDS) were cytogenetically investigated. The incidence of abnormal karyotypes was higher, detected in 88 per cent of the patients and the most frequent abnormality was a terminal deletion of chromosome 7 (45% of the patients with abnormal karyotypes) followed by an i (17q) (18%), +21(14%), -5/5q (9%), del (11) (q22) (9%). Cytogenetic analysis after therapy/after leukaemic transformation indicated either stable clones (2 patients) or emergence of new clones such as inv(5) (q32q36), del (17) (p13), +20, +22 (1 patient each). It is to be noted that of the 8 patients with leukaemic transformation, 5 had del (7q). The leukaemic transformation (32% of the patients) was not related to the percentage of abnormal karyotypes not to the percentage of blasts at the time of the MDS presentation. Chromosome instability was shown by 10 (45%) patients. Our data indicate that higher frequency of chromosomal aberrations with involvement of chromosome 7 may be the result of underlying disease.

Clinical analysis of mortality in hospitalized Zambian children with sickle cell anaemia.

The hospital records of 62 Zambian children with sickle cell anaemia (SCA) who died during a 3 year period (January 1987 to December 1989) at the Paediatric Wing of the University Teaching Hospital, Lusaka, Zambia, were reviewed retrospectively. The SCA patients accounted for 2.92 percent of the total admissions and the average case fatality was 6.61 percent of the total SCA admissions. The case fatality rate has reduced considerably as compared to the one observed in 1970 in Zambia, although the major causes of death remain the same. The maximum mortality was noted in the age group of one to five years (54.84%). The common causes of death were infections (29.54%), vasoocclusive crises (22.72%) and splenic sequestration crises (20.45%). The problems of sub-Saharan Africa, like malaria, malnutrition and now the HIV infection also adde to the mortality (15.90%).

PIP: Physicians analyzed the hospital records of 62 sickle cell anemia (SCA) patients who were admitted to the pediatric wing of the University Teaching Hospital in Lusaka, Zambia, between January 1987 and December 1989 and who died. They examined the case fatality rate and the causes of death. During this period, SCA patients comprised 938 of the 31,843 pediatric admissions (2.95%). The case fatality rate of these 938 urban SCA patients was 6.61%, which is much lower than the 1970 rate of 18.57%. The researchers attributed the lower case fatality rate to the comprehensive health care provided by the hospital's sickle cell disease clinic, established in 1971. Sickle cell-related deaths during the study period made up 0.97% of all pediatric deaths. The case fatality rate was 20.17% for all pediatric admissions. SCA-related mortality peaked in the 1-5 year old age group (38.71%) followed by the 6-10 year old age group (20.97%). As for causes of death, the case records of only 44 sickle cell-related deaths were available. The pediatricians were not able to specify the exact clinical diagnosis in 18 case files (29.03%). The major categories of causes of death were infections (29.54%), vaso-occlusive crises (22.72%), and splenic sequestration crises (20.45%). The infections included 6 cases of bronchopneumonia, 4 cases of confirmed malaria, 1 case of pneumococcal meningitis, and 1 case of HIV infection with cardiomyopathy. The researchers were not sure whether the HIV infection or SCA caused cardiomyopathy. An earlier study at the hospital found HIV seroconversion in more and more SCA patients. This study's major obstacles were poor record keeping, poor communication channels, inability to conduct autopsies due to social and cultural reasons, procedural delays, and unavailability of pathologists. These obstacles must be addressed to improve knowledge on death in SCA patients.

Plasmodium falciparum malaria in vivo drug sensitivity in Lusaka, Zambia.

In most of sub-Saharan African, drug resistant falciparum malaria has become a major health care concern. Drug sensitivity was evaluated in vivo in Lusaka, Zambia, in 71 episodes in 61 patients with uncomplicated falciparum malaria, for Chloroquin (CQ), Pyrimethamine/sulfadoxine (PS) and halofantrine (HF). CQ resistance was found at R2 (16 pc) and R3 (24.5 pc) level in 37 patients, R3 (10.5 pc) resistance to PS was found among 19 subjects studied. The drug resistance to CQ was inversely related to age.

Aniridia--Wilms' tumour association--a case with 11p 13-14.1 deletion and ventricular septal defect.

A two year old female child with bilateral wilms tumor (WT) along with multiple congenital anomalies like bilateral aniridia with congenital cataracts and nystagmus, microcephaly, mental retardation and ventricular septal defect has been described. The karyotype analysis revealed 46 xx, del 11p 13-14.1. Association of ventricular septal defect with the classical features of 'Aniridia-Wilms' tumor association' is an unusual feature in this case.

Chronic myelomonocytic leukaemia (an analysis of fourteen consecutive cases).

Fourteen consecutive cases of chronic myelomonocytic leukaemia aged 6 to 73 (mean 40.5) years were reviewed to define the natural history of the disease and the risk of acute transformation. The common presenting features included anaemia, fever, purpura, and bleeding tendencies. Abnormal karyotypes were seen in 4 of 6 patients subjected to cytogenetic analysis. Low dose cytosine arabinoside achieved complete remission in two and partial remission in one, of the four patients treated with this modality. The mean survival was 5.6 (range 2-12) months and two patients) evolved to acute myeloid leukaemia. The long term survival with the present form of therapy in chronic myelomonocytic leukaemia is poor.

Childhood myelodysplastic syndromes: clinical features, cytogenetics and prognosis.

Sixteen children with myelodysplastic syndrome as defined by the French-American-British co-operative group are presented. The mean age was 10.5 (2.5 to 16) years, with a male predominance. All patients belonged to the more aggressive subtypes of myelodysplastic syndromes. Seven patients presented with refractory anaemia with excess blasts, six had refractory anemia with excess blasts in transformation, and three had chronic myelomonocytic leukemia. Cytogenetic analysis done in 7 of the 16 patients, revealed karyotype abnormalities involving chromosomes 7, 8 and 17. One patient with Down's syndrome had karyotype of 47, XY, +21 (major clone) and 46, XY (minor clone). Five of these patients evolved to acute leukemia. The mean duration of survival was 5.5 months. Aggressive chemotherapy as a primary line of treatment induced remission in five out of six patients. Predominance of aggressive types of myelodysplastic syndromes in children and their good but short-lived response to aggressive chemotherapy suggests the need for early bone marrow transplantation following chemotherapy.

Fanconi's anemia: a clinico-hematological and cytogenetic study.

Eleven patients with typical features of Fanconi's anemia with cytogenetic studies were evaluated. Cytogenetic abnormalities was seen in all but one patient. Two patients had acute non-lymphoblastic leukemia (ANLL) and nine had Fanconi's anemia (FA). All patients with FA responded to oxymetholone and are well with a median follow up of 38.6 months. Both patients with ANLL died. This study stresses the need of an accurate cytogenetic analysis in FA patients along with a clinicohematological correlation.

Tonsillectomy and adenoidectomy for obstructive sleep apnea in sickle cell anemia.

OBJECTIVE: To evaluate the effects of Tonsillectomy and Adenoidectomy (T&A) on Obstructive Sleep Apnea (OSA) secondary to Upper Airway Obstruction (UAO) in children with Sickle Cell Disease (SCD). METHODS: Twenty eight children with SCD and history of snoring, with or without adeno tonsillar hypertrophy, were evaluated for UAO and OSA. RESULTS: Eight children were confirmed to have OSA by multichannel polysomnography and underwent T&A. Follow up examination showed symptomatic clinical and objective improvement in sleep study parameters in OSA. CONCLUSIONS: T&A appears to be a safe, effective option to treat selected patients with OSA due to UAO in SCD children.

Tonsillectomy and adenoidectomy for obstructive sleep apnea in sickle cell anemia.

Objective. To evaluate the effects of Tonsillectomy and Adenoidectomy (T&A) on Obstructive Sleep Apnea (OSA) secondary to Upper Airway Obstruction (UAO) in children with Sickle Cell Disease (SCD). Methods. Twenty eight children with SCD and history of snoring, with or without adeno tonsillar hypertrophy, were evaluated for UAO and OSA. Results. Eight children were confirmed to have OSA by multichannel polysomnography and underwent T&A. Follow up examination showed symptomatic clinical and objective improvement in sleep study parameters in OSA. Conclusions. T&A appears to be a safe, effective option to treat selected patients with OSA due to UAO in SCD children.

Poland's syndrome and Wilms tumor: an unusual association.

Poland's syndrome, a rare congenital disorder with pectoralis muscular girdle defect, have been reported in association with lymphoreticular malignancies in the past. Childhood solid tumors in association with this congenital anomaly have not been reported so far. We describe this rare association of Poland's syndrome and Wilms tumor. Due to the possibility of increased risk of leukemogenesis in patients with Poland's syndrome, chemo-radiation therapy of Wilms tumor in our patient may increase the risk of secondary leukemia. Therapeutic modification of primary cancer in these patients may be necessary with careful long-term follow-up for early detection and treatment of secondary cancer.

Childhood cancers in Zambia before and after the HIV epidemic.

Human immunodeficiency virus (HIV) related cancers in children are not as common and as well described as in adults. An HIV epidemic has been prevalent in Zambia since 1983-1984. To study the effect of the epidemic on the epidemiology of cancers in children a retrospective study was undertaken at the University Teaching Hospital (UTH), Lusaka, Zambia. All the histopathological records from 1980 to 1992 were reviewed and all cases of cancers in children less than 14 years of age were analysed. In order to define the effect of the HIV epidemic, the epidemiological features of various childhood cancers occurring before (during the years 1980-1982) and after (during the years 1990-1992) the onset of the HIV epidemic were compared. A significant increase in the occurrence of total childhood cancers was found. This is mostly due to a highly significant increase in the incidence of paediatric Kaposi's sarcoma (p = 0.000016), which is causally related to HIV infection, and a significant increase in the incidence of retinoblastoma (p = 0.02), which has an unknown relation to HIV infection. Though not yet statistically significant, there has also been a gradual and sustained increase in the incidence of non-Hodgkin's lymphoma, nasopharyngeal carcinoma, and rhabdomyosarcoma. There has been a significant reduction in the incidence of Burkitt's lymphoma. A prospective in depth epidemiological study of HIV related childhood cancers in Africa is urgently needed.