Risk factors for symptomatic venous thromboembolism during therapy for childhood acute lymphoblastic leukemia.

BACKGROUND: Symptomatic venous thromboembolism (VTE) is an unpredictable and life-threatening toxicity, which occurs early in childhood acute lymphoblastic leukemia (ALL) therapy. Approximately 5% of children will experience VTE which is treated with anticoagulation. Asparaginase and corticosteroids are etiologic factors for VTE, however other clinical factors may modify this risk. PROCEDURE: We sought to i) assess published pre-treatment VTE risk factors ii) identify early clinical factors that were associated with VTE and iii) determine whether single nucleotide polymorphisms (SNPs) associated with VTE in non-cancer patients contributed to VTE in children with ALL. We performed a detailed, retrospective analysis of 1021 ALL patients treated between 1998 and 2013. Individual patient records were reviewed to ascertain VTE incidence and document treatment-related clinical variables. RESULTS: The incidence of VTE was 5.1%. Extremes of weight at diagnosis (<5th or >95th centile) was an independent risk factor in multivariable analysis, when added to published risk factors of age ≥10 years and mediastinal mass. When factors during induction/consolidation were considered separately: bacteremia, elevated serum gamma-glutamyl transferase and bilirubin were associated with VTE occurrence. None of the SNPs associated with VTE in non-cancer populations were significantly associated with VTE in our cohort. CONCLUSION: We found two known risk factors (age ≥ 10 years and mediastinal mass) in a large cohort of children treated for ALL and identified other factors associated with VTE such as weight extremes at diagnosis, bacteremia, and abnormal liver function which warrant further study. These VTE risk factors may form the basis of future thromboprophylaxis trials.

Stepped-wedge cluster randomised controlled trial to assess the effectiveness of an electronic medication management system to reduce medication errors, adverse drug events and average length of stay at two paediatric hospitals: a study protocol.

INTRODUCTION: Medication errors are the most frequent cause of preventable harm in hospitals. Medication management in paediatric patients is particularly complex and consequently potential for harms are greater than in adults. Electronic medication management (eMM) systems are heralded as a highly effective intervention to reduce adverse drug events (ADEs), yet internationally evidence of their effectiveness in paediatric populations is limited. This study will assess the effectiveness of an eMM system to reduce medication errors, ADEs and length of stay (LOS). The study will also investigate system impact on clinical work processes. METHODS AND ANALYSIS: A stepped-wedge cluster randomised controlled trial (SWCRCT) will measure changes pre-eMM and post-eMM system implementation in prescribing and medication administration error (MAE) rates, potential and actual ADEs, and average LOS. In stage 1, 8 wards within the first paediatric hospital will be randomised to receive the eMM system 1 week apart. In stage 2, the second paediatric hospital will randomise implementation of a modified eMM and outcomes will be assessed. Prescribing errors will be identified through record reviews, and MAEs through direct observation of nurses and record reviews. Actual and potential severity will be assigned. Outcomes will be assessed at the patient-level using mixed models, taking into account correlation of admissions within wards and multiple admissions for the same patient, with adjustment for potential confounders. Interviews and direct observation of clinicians will investigate the effects of the system on workflow. Data from site 1 will be used to develop improvements in the eMM and implemented at site 2, where the SWCRCT design will be repeated (stage 2). ETHICS AND DISSEMINATION: The research has been approved by the Human Research Ethics Committee of the Sydney Children's Hospitals Network and Macquarie University. Results will be reported through academic journals and seminar and conference presentations. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ANZCTR) 370325.

A new scale for the assessment of performance and capacity of hand function in children with hemiplegic cerebral palsy: reliability and validity studies.

BACKGROUND: In hemiplegic children, the recognition of the activity limitation pattern and the possibility of grading its severity are relevant for clinicians while planning interventions, monitoring results, predicting outcomes. OBJECTIVE: Aim of the study is to examine the reliability and validity of Besta Scale, an instrument used to measure in hemiplegic children from 18 months to 12 years of age both grasp on request (capacity) and spontaneous use of upper limb (performance) in bimanual play activities and in ADL. DESIGN: Psychometric analysis of reliability and of validity of the Besta scale was performed. SETTING: Outpatient study sample METHODS: Reliability study: A sample of 39 patients was enrolled. The administration of Besta scale was video-recorded in a standardized manner. All videos were scored by 20 independent raters on subsequent viewing. 3 raters randomly selected from the 20-raters group rescored the same video two years later for intra-rater reliability. Intra and inter-rater reliability were calculated using Intraclass Correlation Coefficient (ICC) and Kendall's coefficient (K), respectively. Internal consistency reliability was assessed using Alpha's Chronbach coefficient. Validity study: a sample of 105 children was assessed 5 times (at t0 and 2, 3, 6 and 12 months later) by 20 independent raters. Each patient underwent at the same time to QUEST and Besta scale administration and assessment. Criterion validity was calculated using rho-Pearson coefficient. RESULTS: Reliability study: The inter-rater reliability calculated with Kendall's coefficient resulted moderate K=0.47. The intra-rater (or test-retest) reliability for 3 raters was excellent (ICC=0.927). The Cronbach's alpha for internal consistency was 0.972. Validity study: Besta scale showed a good criterion validity compared to QUEST increasing by age and severity of impairment. Rho Pearson's correlation coefficient r was 0.81 (P<0.0001). Limitations. Besta scales in infants finds hard to distinguish between mild to moderately impaired hand function. CONCLUSIONS: Besta scale scoring system is a valid and reliable tool, utilizable in a clinical setting to monitor evolution of unimanual and bimanual manipulation and to distinguish hand's capacity from performance.

High-risk childhood acute lymphoblastic leukemia in first remission treated with novel intensive chemotherapy and allogeneic transplantation.

Children with acute lymphoblastic leukemia (ALL) and high minimal residual disease (MRD) levels after initial chemotherapy have a poor clinical outcome. In this prospective, single arm, Phase 2 trial, 111 Dutch and Australian children aged 1-18 years with newly diagnosed, t(9;22)-negative ALL, were identified among 1041 consecutively enrolled patients as high risk (HR) based on clinical features or high MRD. The HR cohort received the AIEOP-BFM (Associazione Italiana di Ematologia ed Oncologia Pediatrica (Italy)-Berlin-Frankfurt-Münster ALL Study Group) 2000 ALL Protocol I, then three novel HR chemotherapy blocks, followed by allogeneic transplant or chemotherapy. Of the 111 HR patients, 91 began HR treatment blocks, while 79 completed the protocol. There were 3 remission failures, 12 relapses, 7 toxic deaths in remission and 10 patients who changed protocol due to toxicity or clinician/parent preference. For the 111 HR patients, 5-year event-free survival (EFS) was 66.8% (±5.5) and overall survival (OS) was 75.6% (±4.3). The 30 patients treated as HR solely on the basis of high MRD levels had a 5-year EFS of 63% (±9.4%). All patients experienced grade 3 or 4 toxicities during HR block therapy. Although cure rates were improved compared with previous studies, high treatment toxicity suggested that novel agents are needed to achieve further improvement.

FBXW7 regulates glucocorticoid response in T-cell acute lymphoblastic leukaemia by targeting the glucocorticoid receptor for degradation.

Loss of function mutation in FBXW7, an E3 ubiquitin ligase, is associated with good prognosis and early glucocorticoid treatment response in childhood T-cell acute lymphoblastic leukemia (T-ALL) by unknown mechanisms. Here, we show that FBXW7 targets the glucocorticoid receptor α (GRα) for ubiquitylation and proteasomal degradation in a manner dependent on glycogen synthase kinase 3 ß-mediated phsophorylation. FBXW7 inactivation caused elevated GRα levels, and enhanced the transcriptional response to glucocorticoids. There was significant enhancement of GR transcriptional responses in FBXW7-deficient cell lines and primary T-ALL samples, in particular, for those pro-apoptotic regulatory proteins, BIM and PUMA. Reduced FBXW7 expression or function promoted glucocorticoid sensitivity, but not sensitivity to other chemotherapeutic agents used in T-ALL. Moreover, this was a general feature of different cancer cell types. Taken together, our work defines GRα as a novel FBXW7 substrate and demonstrates that favorable patient prognosis in T-ALL is associated with FBXW7 mutations due to enhanced GRα levels and steroid sensitivity. These findings suggest that inactivation of FBXW7, a putative tumor suppressor protein, may create a synthetic lethal state in the presence of specific anticancer therapies.

[The quality of interdisciplinary communication]. / La qualità della comunicazione interdisciplinare.

Because of a continued increase of complex patients and the development of many areas of sub-specialities in medicine, the use and quality of interdisciplinary communication has been found to be lacking, especially between hospital and primary care physicians, causing a significant gap in the documentation, coverage and care of individual patients. The study focuses on state of the art interdisciplinary communication, with consideration given to current used tools and priorities. An ad hoc questionnaire surveyed 118 physicians about their profession, the types of patients, the frequency of complex cases, the tools used to communicate with each patient and how the physicians rated these tools. The rate of patients needing interdisciplinary communication is 17% of the entire patient sample, all of this percentage having complex health care needs (terminally ill, disabled, often without a personal support network). Physicians frequently used paper documents, despite their lack of quality, as well as the telephone to communicate with other colleagues. Computer devices were scarcely used. Many Doctors (71%) value the actual interdisciplinary communication of low quality, despite the fact that it is considered to have a significant influence on the quality of health care. New tools and methods are needed. For example, dedicated standards of multidisciplinary and multi-professional Continuing Medical Education (CME), as well as the use of computer tools allowing for shared clinical records.

Features and outcomes of neonatal neuroblastoma.

PURPOSE: Neonatal neuroblastoma (NNBL) is a rare tumour with few reported cases in the literature. The prognosis of NNBL is unclear with reported survival between 76 and 91%. The growing use of ante-natal ultrasound (USS) in recent years has resulted in an increasing incidence of NNBL. The purpose of this study is to review our experience with incidence, clinical features and outcome of NNBL in those children diagnosed ante-natally compared to those diagnosed post-natally. METHODS: Twelve cases of NNBL were detected ante-natally or in the neonatal period (0-28 days) from a cohort of 120 children diagnosed with neuroblastoma (10%) over a 10-year period at the study institutions. Review of these 12 children forms the basis of this report. RESULTS: Ante-natal diagnosis (ADNB) was made in six children (50%) and post-natal diagnosis (PDNB) in six (50%). Tumour site in both cohorts were predominantly adrenal and tumour staging was similar in both groups. There was no difference in outcome in ADNB compared to PDNB with overall 100% survival for the entire group. CONCLUSIONS: NNBL is a subset of neuroblastoma with apparent excellent outcome irrespective of the time of diagnosis. Clinical features and outcomes of ADNB are no different to PDNB.

Reduced incidence of second solid tumors in survivors of childhood Hodgkin's lymphoma treated without radiation therapy.

BACKGROUND: We assessed the risk of developing second malignancies in children treated for Hodgkin's lymphoma (HL), the majority of whom received chemotherapy only. PATIENTS AND METHODS: The development of second malignancies in children with HL, treated between 1960 and 1999, was assessed. Results were obtained by both chart review and linkage with a centralized cancer registry. Tumor incidence was compared for patients treated with and without radiotherapy (RT) and with the general population. Risk factors for developing second tumors were assessed by multivariate analysis. RESULTS: Of 142 childhood HL patients, 63 had received RT and 79 had not. Overall survival was similar for both groups. Fourteen patients developed second solid tumors, 12 who had received RT and 2 treated with chemotherapy only (P <0.001), with a 30-year cumulative incidence of 24.7% [95% confidence interval (CI) 7.27-47.4] and 5.8% (95% CI 0-58.9), respectively (P = 0.01). The standardized incidence ratio for second solid tumors was 236 (95% CI 112.2-359.0) versus 43.6 (95% CI 0-103.9), respectively. Multivariate analysis showed treatment with RT was the only significant risks factor for developing second solid tumors. CONCLUSIONS: Children with HL without RT have a substantially lower incidence of second tumors than those treated with RT.

Indications to upper gastrointestinal endoscopy in children with dyspepsia.

OBJECTIVES: The objective of the study was to ascertain the appropriateness of indications for upper gastrointestinal (UGI) endoscopy in children with dyspepsia. METHODS: We used the RAND/University of California at Los Angeles method to investigate the appropriateness of the opinions of a panel of experts. The panel judged 2304 theoretical patient scenarios defined by a combination of demographic and clinical variables. Descriptive and multivariate logistic regression analyses were performed. RESULTS: The panel rated UGI endoscopy as appropriate in 27.2% of cases, inappropriate in 14.3%, and dubious in 58.5%. Disagreement emerged for 21% of cases. UGI endoscopy was considered increasingly appropriate in cases with a positive family history of peptic ulcer and/or Helicobacter pylori infection (odds ratio [OR] 8.518, P < 0.0001), when dyspepsia interfered with activities of daily living ("sleep" OR 7.540, P < 0.0001; "normal activities" OR 5.725, P < 0.0001), and when patients were older than 10 years ("

Clinical, subclinical and potential autoimmune diseases in an Italian population of children with coeliac disease.

BACKGROUND Several studies have suggested a link between coeliac disease and other autoimmune diseases. AIM To compare the presence of autoimmune disease in children with coeliac disease and in controls. METHODS When coeliac disease was diagnosed, 267 children were evaluated for clinical autoimmune disease (with signs/symptoms), subclinical autoimmune disease (with autoantibodies and subclinical impairment of the target organ) or potential autoimmune disease (with autoantibodies only) and compared with 220 healthy controls. 170 coeliac disease patients were followed up for a mean 47 +/- 31 months, in complete remission on a gluten-free diet. Ninety-nine controls were followed up for 45 +/- 33 months. RESULTS When coeliac disease was diagnosed, 71 (27%) children had autoimmune disease vs. 1% among the controls (P < 0.001): 31 had clinical autoimmune disease and 40 had subclinical or potential autoimmune disease. During the follow-up, the clinical autoimmune disease cases slightly decreased from 12% to 11%, while the potential autoimmune disease cases increased from 14% to 21%. Of the 99 controls, none had any variation in their autoantibody profile. CONCLUSIONS Gluten-free diet does not modify the natural history of autoimmunity in patients with coeliac disease. However, gluten-free diet seems to produce a favourable effect on the previously present clinical autoimmune disease and to prevent the development of new clinical autoimmune disease, but does not affect the onset of potential autoimmunity, which tends to increase with time.

Concurrent HIV infection and neuroblastoma.

An infant is reported who presented with Pneumocystis carinii pneumonia, secondary to HIV infection, diagnosed at 3 months of age, and who had concurrent paravertebral neuroblastoma. Although neuroblastoma cell lines support the growth of HIV in vitro, this is the first report of a clinical association between HIV infection and neuroblastoma. Although we do not think the conditions are causally linked, we report the case to raise awareness of a possible association between HIV and neuroblastoma. The case also raises the importance of starting antiretroviral treatment with three drugs.

A reliable method for total RNA extraction from frozen human bone marrow samples taken at diagnosis of acute leukaemia.

This report describes a newly developed method using Trizol LS reagent that can reliably extract high quality total RNA from frozen human leukaemic bone marrow samples. Extraction of total RNA from 71 frozen leukaemic bone marrow samples obtained at the time of diagnosis produced a median yield of 145 micro g/ml leukaemic bone marrow. Total RNA samples could be reverse transcribed into cDNA and used successfully in the reverse transcription polymerase chain reaction amplification of B2M transcripts in 68 of 71 cases. A multivariate linear regression analysis revealed that significant predictors of RNA yield were both sample volume (< 1 ml v > 1 ml; p = 0.003) and peripheral blood white cell count (< 5 x 10(9) v >or= 5 x 10(9) white blood cells/litre; p = 0.011). The percentage of blasts present, leukaemia subtype, and sample storage period at -80 degrees C (up to 945 days) were not predictors of total RNA yield. This method of total RNA extraction should be of interest to diagnostic and research staff using frozen bone marrow samples for molecular analyses. Similarly, the lack of association between sample storage period at -80 degrees C and total RNA yield should be of interest to the administrators of tumour banks housing frozen bone marrow samples.

Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines.

The gradual loss of DNA from the ends of telomeres has been implicated in the control of cellular proliferative potential. Telomerase is an enzyme that restores telomeric DNA sequences, and expression of its activity was thought to be essential for the immortalization of human cells, both in vitro and in tumor progression in vivo. Telomerase activity has been detected in 50-100% of tumors of different types, but not in most normal adult somatic tissues. It has also been detected in about 70% of human cell lines immortalized in vitro and in all tumor-derived cell lines examined to date. It has previously been shown that in vitro immortalized telomerase-negative cell lines acquire very long and heterogeneous telomeres in association with immortalization presumably via one or more novel telomere-lengthening mechanisms that we refer to as ALT (alternative lengthening of telomeres). Here we report evidence for the presence of ALT in a subset of tumor-derived cell lines and tumors. The maintenance of telomeres by a mechanism other than telomerase, even in a minority of cancers, has major implications for therapeutic uses of telomerase inhibitors.

Alterations in p53 and p16INK4 expression and telomere length during spontaneous immortalization of Li-Fraumeni syndrome fibroblasts.

Normal cells have a strictly limited growth potential and senesce after a defined number of population doublings (PDs). In contrast, tumor cells often exhibit an apparently unlimited proliferative potential and are termed immortalized. Although spontaneous immortalization of normal human cells in vitro is an extremely rare event, we observed this in fibroblasts from an affected member of a Li-Fraumeni syndrome kindred. The fibroblasts were heterozygous for a p53 mutation and underwent senescence as expected at PD 40. In four separate senescent cultures (A to D), there were cells that eventually recommenced proliferation. This was associated with aneuploidy in all four cultures and either loss (cultures A, C, and D) or mutation (culture B) of the wild-type (wt) p53 allele. Loss of wt p53 function was insufficient for immortalization, since cultures A, B, and D subsequently entered crisis from which they did not escape. Culture C has continued proliferating beyond 400 PDs and thus appears to be immortalized. In contrast to the other cultures, the immortalized cells have no detectable p16INK4 protein. A culture that had a limited extension of proliferative potential exhibited a progressive decrease in telomere length with increasing PD. In the culture that subsequently became immortalized, the same trend occurred until PD 73, after which there was a significant increase in the amount of telomeric DNA, despite the absence of telomerase activity. Immortalization of these cells thus appears to be associated with loss of wt p53 and p16INK4 expression and a novel mechanism for the elongation of telomeres.

Childhood acute myeloid leukemia: outcome in a single center using chemotherapy and consolidation with busulfan/cyclophosphamide for bone marrow transplantation.

PURPOSE: To report the impact of bone marrow transplantation (BMT) with busulfan/cyclophosphamide (BuCy) as end consolidation in a cohort of consecutively diagnosed children with acute myeloid leukemia (AML). PATIENTS AND METHODS: Between May 1987 and November 1992, 43 patients were diagnosed with AML. Tissue typing at diagnosis determined whether patients would proceed to autologous or allogeneic BMT as end consolidation after six cycles of chemotherapy. Conditioning for BMT was with BuCy, followed by allogeneic or unpurged autologous marrow infusion. RESULTS: Of 37 patients who received chemotherapy, 35 achieved remission (95%) after one to six courses of treatment and 34 (92%) were transplanted. Five relapsed before BMT, four were subsequently transplanted in second complete remission (CR2) (n = 3) or untreated first relapse (n = 1), and one failed to respond to further therapy. All other patients proceeded to BMT in first complete remission (CR1). Eleven patients received allografts: one relapsed and one died of graft-versus-host disease (GvHD), for a leukemia-free survival rate of 90% at a median of 41 months after BMT (range, 3 to 60). For 23 autografts, there were two toxic deaths and eight relapses, with a leukemia-free survival rate of 61% at a median of 11 months after BMT (range, 0 to 66). The high relapse rate following autologous BMT led us to escalate the dose of Bu from 16 mg/kg to 600 mg/m2 using a single daily dose of Bu. CONCLUSION: With modern supportive therapy, most newly diagnosed children with AML will enter remission and are eligible for intensification therapy. BuCy is well tolerated in children, which allowed us to escalate the dose of Bu in recent patients. Further follow-up is needed to determine whether this has an impact on the relapse rate following autologous BMT.

Acute myeloid leukaemia in patients with trisomy 21 (Down syndrome) treated by bone marrow transplantation.

Patients with trisomy 21 have an increased incidence of haematological disorders, including neonatal 'leukaemoid reaction' (transient myeloproliferative disorder [TMD]), and acute leukaemias. In the past it has been felt that patients with trisomy 21 and acute leukaemia do not tolerate, and hence may not warrant, therapy as intensive as those without the syndrome. The present authors' experience and the current literature do not support this view. Two cases are reported of acute myeloid leukaemia in children with trisomy 21, successfully treated with intensive chemotherapy and bone marrow transplantation.

In vitro transformation of Li-Fraumeni syndrome fibroblasts by SV40 large T antigen mutants.

Transfection of SV40 early region DNA into normal human diploid fibroblasts (NHDFs) increases their proliferative potential to a limited extent. We have investigated the roles of the SV40 large T antigen (LTAg) regions responsible for binding to the protein products of the retinoblastoma (Rb) and p53 genes in this temporary escape from senescence. Patients encoding LTAg mutants were transfected into NHDFs and into Li-Fraumeni syndrome (LFS) fibroblasts which are heterozygous wild-type (wt)/null-mutant for p53. A LTAg mutated in the p53-binding region (T402DE) had greatly reduced efficiency of focus formation, and a p110Rb-binding mutant was unable to induce any foci. T402DE-induced NHDF foci senesced at the same time as untransfected cells, but the equivalent LFS foci all had increased proliferative potentials, with the greatest increase being seen in clones that lost the wt p53 allele. One LFS clone expressed the T402DE mutant during focus formation, but later lost both the T402DE DNA and the wt p53 allele. We conclude that SV40-induced focus formation in NHDFs requires the LTAg p110Rb-binding region, and is enhanced by loss of normal p53 function. In contrast, increased proliferative potential is primarily due to loss of p53 function.

Pain and symptom control in paediatric palliative care.

Important differences become evident in a comparison of cancer pain between children and adults. Management of pain in children is commonly multidisciplinary, is less dependent on invasive measures and relies more on systemic therapy. Children are not little adults: their immaturity, developing cognition and dependence all influence their experience and interpretation of pain. Much progress has been made in altering practices such as under-prescribing and underdosing that have adversely affected adequate control of pain in children. The challenge for paediatric health care providers in the mid 1990s is not only to be informed of current practices in pain and symptom control in paediatric palliative care, but also to remember to establish those practices in day to day management. Even though pain and its effects in children are now better understood, it is often still not managed optimally. Good management of pain in children depends on accurate assessment. In the past 10 years, assessment of pain in children has advanced considerably. However, assessment of pain in the preverbal child is still inadequate and in need of attention. Sedation, tolerance and involuntary movements may occur as side effects of opioids in children and may cause significant problems in management of the dying child. Psychostimulants can diminish sedation to some extent, but there is little information as yet on the value of these drugs in children. Tolerance to opioids may develop quickly, leading to poor control of pain and distress for the child. Strategies to improve management of tolerance include use of regional anaesthetic techniques such as the epidural/intrathecal route for opioid administration. Involuntary movements induced by opioids are uncommon but have the potential to cause significant distress. The mechanisms underlying these side effects of opioids need to be established. Strategies are needed for the effective treatment and prevention of these side effects. Neuropathic pain can be severe, distressing and difficult to treat. Experience of its treatment in terminally ill children is limited. Effective use of tricyclic antidepressants and systemically administered local anaesthetics is still to be determined. Regional anaesthetic techniques may be of great benefit when neuropathic pain cannot be controlled with systemic therapy. Procedural pain is more common than pain related to disease in the management of paediatric cancer. Further research is needed to identify the best approach to its management. We have found nitrous oxide to be of great benefit in management of procedural pain in children. Non-pharmacological methods of treatment of pain in children, such as transcutaneous electrical nerve stimulation or acupuncture, may also be useful and should receive continuing evaluation. There are significant and current issues in paediatric palliative care besides management of pain. There are difficulties in the provision of home nursing care for children with cancer in the terminal phase of their illness, including lack of community nursing services at night and on weekends and lack of adequate home help for parents. Attitudes of staff involved in the care of the child and family and their commitment to working as a multidisciplinary team strongly influence the quality and success of care given. Pain control and palliative medicine are evaluable by measures of quality assurance or outcome, and adoption of such evaluations should improve standards of care. Euthanasia in children is even more difficult as an ethical dilemma than in adults. Optimum symptom control with current techniques should almost always obviate its consideration. We are opposed to euthanasia. Psychosocial and cultural issues all influence the family's experience of palliative care. Further research is necessary in all of these areas.(ABSTRACT TRUNCATED)