Successful haploidentical hematopoietic stem cell transplantation (HSCT) and durable engraftment by repeated donor lymphocyte infusions for a Chinese patient with transfusion-dependent hemoglobin (Hb) Hammersmith and massive splenomegaly.

BACKGROUND: Hemoglobin (Hb) Hammersmith is a rare form of unstable ß-chain hemoglobinopathy causing hemolytic anemia. This rare event led to a more serious transfusion-dependent phenotype in a patient. It was successfully cured by haploidentical hematopoietic stem cell transplantation (HSCT). METHODS AND RESULTS: A 9-year-old mainland Chinese male with a history of neonatal unconjugated hyperbilirubinemia was diagnosed to have hemoglobin (Hb) Hammersmith. He required regular blood transfusion but was unable to be transfused to desired parameters for 8 years prior to transplant due to social and geographical reasons. He subsequently developed marrow hyperplasia and progressive splenomegaly (down to umbilicus level), suggestive of extramedullary hematopoiesis. Eventually, the family came to Hong Kong and complied to a more intensive transfusion regimen and preconditioning chemotherapy 3 months prior to transplant. He underwent haploidentical HSCT using paternal TCRαß/CD45RA-depleted graft but suffered from graft rejection, despite splenic irradiation for massive splenomegaly. It was successfully salvaged with second HSCT with unmanipulated graft from the same donor with additional serotherapy and donor lymphocyte infusions. CONCLUSION: Allogenic haploidentical HSCT for hemoglobin Hammersmith is feasible but adequate immunosuppression during conditioning is crucial. Precise adoptive cell therapy can promote durable engraftment.

Repeated CD45RA-depleted DLI successfully increases donor chimerism in a patient with beta-thalassemia major after haploidentical stem cell transplant.

Allogeneic hematopoietic stem cell transplantation is curative for transfusion-dependent thalassemia, but mixed chimerism (MC) may herald graft rejection. We report a child who failed bone marrow transplant (BMT) from matched unrelated donor (MUD) successfully salvaged with haploidentical peripheral blood stem cell transplant (PBSCT), but had MC in T-lymphocyte compartment despite near-complete donor chimerism in myeloid compartment. MC was successfully improved by repeated CD45RA-depleted donor lymphocyte infusion (DLI). A 2-year-old Chinese girl with beta-thalassemia major underwent 12/12-MUD BMT with HU/AZA/Cy/Flu/Bu/TT conditioning resulted in graft rejection. As donor refused second donation, rescue haploidentical PBSCT was performed with alemtuzumab/fludarabine/treosulfan conditioning. Harvest product was CD3/CD45RA depleted with extra products cryopreserved. Split cell chimerism performed 1-month after haplo-transplant showed 97% mother, 3% MUD, and 0% host for granulocytes but 38% mother, 62% MUD, and 0% host for CD3 + T cells. In view of low haploidentical donor chimerism in T-lymphocyte compartment, CD45RA-depleted DLI using cryopreserved product was performed on day + 38, after thymoglobulin 3 mg/kg given as T-cell depletion 3 days beforehand. T-cell chimerism improved to 51% mother and 49% MUD post-DLI. Second cryopreserved CD45RA-depleted DLI was given 17 days after the first DLI (day + 55), and 100% full chimerism of mother's T cells was gradually established without significant graft-versus-host disease (GVHD) or viral reactivation. To conclude, split lineage chimerism determination is beneficial to guide management strategy. For MC in T-cell compartment, CD45RA-depleted DLI is a potential alternative to unselected T cells as it carries lower risk of GVHD and infection.

Outcomes of allogeneic transplantation for hemoglobin Bart's hydrops fetalis syndrome in Hong Kong.

BACKGROUND: Hemoglobin Bart's hydrops fetalis syndrome (BHFS) was once considered a fatal condition universally. Medical advances over the past three decades have resulted in increasing numbers of BHFS survivors. This retrospective review summarized local territory-wide experience and outcomes of BHFS patients who received allogeneic hematopoietic stem cell transplantation (HSCT) in Hong Kong. METHODS: All BHFS patients who underwent allogeneic HSCT in Hong Kong, either in one of the two former pediatric transplant centers (Queen Mary Hospital and Prince of Wales Hospital) on or before 2019 or in the single territory-wide pediatric transplant center (Hong Kong Children's Hospital) since 2019, from January 1, 1996, till December 31, 2020, were included. Basic demographic data, perinatal history, transplant details, long-term outcomes, and morbidities were reviewed. RESULTS: Total five allogeneic HSCT were performed in two males and three females at a median age of 22 months, which include one 8/8 matched-sibling bone marrow transplant, one 5/6 matched-sibling cord blood transplant with HLA-DR antigenic mismatch, two 12/12 matched-unrelated peripheral blood stem cell transplant (PBSCT), and one haploidentical PBSCT with TCRαß/CD45RA depletion from maternal donor. Neutrophil and platelet engrafted (>20 × 109 /L) at a median of 15 and 22 days, respectively. All achieved near full donor chimerism at 1 month. All patients survived and remained transfusion-independent without significant morbidities with median follow-up duration of 10 years. CONCLUSION: To conclude, local data demonstrated favorable outcome of allogeneic HSCT for BHFS patients, but sample number is small. Non-directive approach in counseling and international collaboration is recommended.

Excellent outcome of acute lymphoblastic leukaemia with TCF3-PBX1 rearrangement in Hong Kong.

OBJECTIVE: The aim of this study was to review clinical outcomes and prognosis of paediatric patients with acute lymphoblastic leukaemia (ALL) with TCF3-PBX1 rearrangement. PATIENTS: All children in Hong Kong diagnosed with ALL with TCF3-PBX1 rearrangement over the past two decades were included. METHODS: Six hundred and twenty-four newly diagnosed patients with ALL from four consecutive studies were enrolled from 1997 to 2016. Patients carrying TCF3-PBX1 rearrangement and patients at intermediate risk without the gene expression were compared for clinical characteristics, overall survival and event-free survival (EFS). RESULTS: The TCF3-PBX1 rearrangement was detected in 30 of 624 patients (4.8%). Results were consistent across the consecutive clinical trials employed in the past two decades. Compared with 239 intermediate risk patients without TCF3-PBX1 rearrangement, the 5-year overall survival and EFS for patients with TCF3-PBX1 rearrangement was superior, with both at 100% (P = 0.12 and P = 0.029). CONCLUSION: This population-based study over the past 20 years demonstrated that patients with TCF3-PBX1 rearrangement had favourable EFS compared with other intermediate risk patients treated with a similar chemotherapy backbone.

Selective T cell-depleted haploidentical hematopoietic stem cell transplantation for relapsed/refractory neuroblastoma.

Relapsed/refractory NB carries a bleak outcome, warranting novel treatment options. HaploHSCT induces a graft-versus-NB effect via natural killer cell alloreactivity. Review of patients with relapsed/refractory NB who underwent haploHSCT with ex vivo T-cell depletion in our unit from 2013 through 2018. Ten patients were identified (male=5; median age at haploHSCT=6.45 y, range: 3.49-11.02 y). Indications were relapsed in 7 and refractoriness in 3; disease status at haploHSCT was CR in 2, PR in 6, and PD in 2. All patients received peripheral blood stem cell grafts after ex vivo T-cell depletion (CD3/CD19-depletion=1; TCR-αß/CD19-depletion=4; CD3/CD45RA-depletion=4; and TCR-αß/CD45RA-depletion=1). Conditioning regimens were fludarabine-based. Neutrophils engrafted on median D + 10 (range: D + 9 to +13), and platelets engrafted (≥20 × 109 /L) on median D + 8 (range: D + 5 to D + 14). Early T- and NK-cell recovery were evident. Of the 10 patients, acute rejection developed in 1 (who died of PD despite rescue HSCT), and 1 died of sepsis before engraftment; 8 experienced full donor-chimerism post-HSCT. Among the 8, 6 experienced CR, 1 died of PD, and 1 died of pulmonary hypertensive crisis before evaluation. At publication, 4 were in remission (2.8, 7.4, 28.5, and 58.9 months). No significant GvHD occurred. HaploHSCT with selective ex vivo T-cell depletion may be a safe and useful salvage strategy for relapsed/refractory NB.

Cyclosporin A for persistent or chronic immune thrombocytopenia in children.

Twenty percent of children with immune thrombocytopenia (ITP) develop a chronic course where treatment strategy is less established. Cyclosporin A (CSA) has been shown to be effective in small series of children with chronic ITP and might reduce the need for chronic steroid therapy and/or splenectomy. We reviewed consecutive patients below 18 years old with persistent or chronic ITP treated with CSA in our unit between January 1998 and June 2015. Thirty patients (14 boys and 16 girls) were included. The median age at initial diagnosis of ITP was 5 years (range 0.5-16.2 years). CSA was started at a median of 13.9 months (range 3.4-124 months) after initial diagnosis and given for a median duration of 9.3 months (range 0.2-63.9 months). The median platelet count before commencement was 12 × 10(9)/L (range 4-199 × 10(9)/L). The median dose of CSA was 6 mg/kg/day (range 2.4-7.5 mg/kg/day). Complete response (CR) or response (R) was achieved in 17 patients (57 %), and 7 (23 %) had sustained response. Side effects (most commonly hirsutism) were tolerable and reversible. CSA appeared effective in about half of persistent or chronic ITP patients and safe as a second-line agent in managing these children.

Medical interventions for treating anthracycline-induced symptomatic and asymptomatic cardiotoxicity during and after treatment for childhood cancer.

BACKGROUND: Anthracyclines are frequently used chemotherapeutic agents for childhood cancer that can cause cardiotoxicity during and after treatment. Although several medical interventions in adults with symptomatic or asymptomatic cardiac dysfunction due to other causes are beneficial, it is not known if the same treatments are effective for childhood cancer patients and survivors with anthracycline-induced cardiotoxicity. This review is an update of a previously published Cochrane review. OBJECTIVES: To compare the effect of medical interventions on anthracycline-induced cardiotoxicity in childhood cancer patients or survivors with the effect of placebo, other medical interventions, or no treatment. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2015, Issue 8), MEDLINE/PubMed (1949 to September 2015), and EMBASE/Ovid (1980 to September 2015) for potentially relevant articles. In addition, we searched reference lists of relevant articles, conference proceedings of the International Society for Paediatric Oncology (SIOP), the American Society of Clinical Oncology (ASCO), the American Society of Hematology (ASH), the International Conference on Long-Term Complications of Treatment of Children & Adolescents for Cancer, and the European Symposium on Late Complications from Childhood Cancer (from 2005 to 2015), and ongoing trial databases (the ISRCTN Register, the National Institutes of Health (NIH) Register, and the trials register of the World Health Organization (WHO); all searched in September 2015). SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing the effectiveness of medical interventions to treat anthracycline-induced cardiotoxicity with either placebo, other medical interventions, or no treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection. One review author performed the data extraction and 'Risk of bias' assessments, which another review author checked. We performed analyses according to the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: In the original version of the review we identified two RCTs; in this update we identified no additional studies. One trial (135 participants) compared enalapril with placebo in childhood cancer survivors with asymptomatic anthracycline-induced cardiac dysfunction. The other trial (68 participants) compared a two-week treatment of phosphocreatine with a control treatment (vitamin C, adenosine triphosphate, vitamin E, oral coenzyme Q10) in leukaemia patients with anthracycline-induced cardiotoxicity. Both studies had methodological limitations.The RCT on enalapril showed no statistically significant differences in overall survival, mortality due to heart failure, development of clinical heart failure, and quality of life between treatment and control groups. A post-hoc analysis showed a decrease (that is improvement) in one measure of cardiac function (left ventricular end-systolic wall stress (LVESWS): -8.62% change) compared with placebo (+1.66% change) in the first year of treatment (P = 0.036), but not afterwards. Participants treated with enalapril had a higher risk of dizziness or hypotension (risk ratio 7.17, 95% confidence interval 1.71 to 30.17) and fatigue (Fisher's exact test, P = 0.013).The RCT on phosphocreatine found no differences in overall survival, mortality due to heart failure, echocardiographic cardiac function, and adverse events between treatment and control groups. AUTHORS' CONCLUSIONS: Only one trial evaluated the effect of enalapril in childhood cancer survivors with asymptomatic cardiac dysfunction. Although there is some evidence that enalapril temporarily improves one parameter of cardiac function (LVESWS), it is unclear whether it improves clinical outcomes. Enalapril was associated with a higher risk of dizziness or hypotension and fatigue. Clinicians should weigh the possible benefits with the known side effects of enalapril in childhood cancer survivors with asymptomatic anthracycline-induced cardiotoxicity.Only one trial evaluated the effect of phosphocreatine in childhood cancer patients with anthracycline-induced cardiotoxicity. Limited data with a high risk of bias showed no significant difference between phosphocreatine and control treatments on echocardiographic function and clinical outcomes.We did not identify any RCTs or CCTs studying other medical interventions for symptomatic or asymptomatic cardiotoxicity in childhood cancer patients or survivors.High-quality studies should be performed.

Surgery for scoliosis in Duchenne muscular dystrophy.

BACKGROUND: Scoliosis in patients with Duchenne muscular dystrophy (DMD) is usually progressive and is treated with surgery. However, it is unclear whether the existing evidence is sufficiently scientifically rigorous to support a recommendation for spinal surgery for most patients with DMD and scoliosis. This is an updated review, and an updated search was undertaken in which no new studies were found for inclusion. OBJECTIVES: To determine the effectiveness and safety of spinal surgery in patients with DMD with scoliosis. We intended to test whether spinal surgery is effective in increasing survival and improving respiratory function, quality of life, and overall functioning, and whether spinal surgery is associated with severe adverse effects. SEARCH METHODS: On 16 June 2015 we searched the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL Plus. We also searched ProQuest Dissertation and Thesis database (January 1980 to June 2015), the National Institutes of Health Clinical Trials Database (6 January 2015), and the WHO International Clinical Trials Registry Platform (17 June 2015), and checked references. We imposed no language restrictions. SELECTION CRITERIA: We planned to include controlled clinical trials using random or quasi-random allocation of treatment evaluating all forms of spinal surgery for scoliosis in patients with DMD in the review. The control interventions would have been no treatment, non-operative treatment, or a different form of spinal surgery. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. Two review authors independently examined the search results and evaluated the study characteristics against inclusion criteria in order to decide which studies to include in the review. MAIN RESULTS: Of the 49 relevant studies we found, none met the inclusion criteria for the review because they were not clinical trials, but prospective or retrospective reviews of case series. AUTHORS' CONCLUSIONS: Since no randomized controlled clinical trials were available to evaluate the effectiveness of scoliosis surgery in patients with DMD, we can make no good evidence-based conclusion to guide clinical practice. Patients with scoliosis should be informed as to the uncertainty of benefits and potential risks of surgery for scoliosis. Randomized controlled trials are needed to investigate the effectiveness of scoliosis surgery, in terms of quality of life, functional status, respiratory function, and life expectancy.

Interventions for prophylaxis of hepatic veno-occlusive disease in people undergoing haematopoietic stem cell transplantation.

BACKGROUND: Hepatic veno-occlusive disease (VOD) is a severe complication after haematopoietic stem cell transplantation (HSCT). Different drugs with different mechanisms of action have been tried in HSCT recipients to prevent hepatic VOD. However, it is uncertain whether high-quality evidence exists to support any prophylactic therapy. OBJECTIVES: We aimed to determine the effects of various prophylactic therapies on the incidence of hepatic VOD, overall survival, mortality, quality of life (QOL), and the safety of these therapies in people undergoing HSCT. SEARCH METHODS: We searched the Cochrane Central Registe of Controlled Trials (CENTRAL), MEDLINE, EMBASE, conference proceedings of three international haematology-oncology societies and two trial registries in January 2015, together with reference checking, citation searching and contact with study authors to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing prophylactic therapies with placebo or no treatment, or comparing different therapies for hepatic VOD in people undergoing HSCT. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 14 RCTs. Four trials (612 participants) compared ursodeoxycholic acid with or without additional treatment versus placebo or no treatment or same additional treatment. Two trials (259 participants) compared heparin with no treatment. Two trials (106 participants) compared low molecular weight heparin (LMWH) with placebo or no treatment. One trial (360 participants) compared defibrotide with no treatment. One trial (34 participants) compared glutamine with placebo. Two trials (383 participants) compared fresh frozen plasma (FFP) with or without additional treatment versus no treatment or same additional treatment. One trial (30 participants) compared antithrombin III with heparin versus heparin. One trial compared heparin (47 participants) with LMWH (46 participants) and prostaglandin E1 (PGE1) (47 participants). No trial investigated the effects of danaparoid. The RCTs included participants of both genders with wide age range and disease spectrum undergoing autologous or allogeneic HSCT. Funding was provided by government sources (two studies), research fund (one study), pharmaceutical companies that manufactured defibrotide and ursodeoxycholic acid (two studies), or unclear source (nine studies). All RCTs had high risk of bias because of lack of blinding of participants and study personnel, or other risks of bias (mainly differences in baseline characteristics of comparison groups).Results showed that ursodeoxycholic acid may reduce the incidence of hepatic VOD (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.40 to 0.88; number needed to treat for an additional beneficial outcome (NNTB) 15, 95% CI 7 to 50, low quality of evidence), but there was no evidence of difference in overall survival (hazard ratio (HR) 0.83, 95% CI 0.59 to 1.18, low quality of evidence). It may reduce all-cause mortality (RR 0.70, 95% CI 0.50 to 0.99; NNTB 17, 95% CI 8 to 431, low quality of evidence) and mortality due to hepatic VOD (RR 0.27, 95% CI 0.09 to 0.87; NNTB 34, 95% CI 16 to 220, very low quality of evidence). There was no evidence of difference in the incidence of hepatic VOD between treatment and control groups for heparin (RR 0.47, 95% CI 0.18 to 1.26, very low quality of evidence), LMWH (RR 0.27, 95% CI 0.06 to 1.18, very low quality of evidence), defibrotide (RR 0.62, 95% CI 0.38 to 1.02, low quality of evidence), glutamine (no hepatic VOD in either group, very low quality of evidence), FFP (RR 0.66, 95% CI 0.20 to 2.17, very low quality of evidence), antithrombin III (RR 0.13, 95% CI 0.01 to 2.15, very low quality of evidence), between heparin and LMWH (RR 1.96, 95% CI 0.80 to 4.77, very low quality of evidence), between heparin and PGE1 (RR 1.20, 95% CI 0.58 to 2.50, very low quality of evidence), and between LMWH and PGE1 (RR 0.61, 95% CI 0.24 to 1.55, very low quality of evidence). There was no evidence of difference in survival between treatment and control groups for heparin (92.6% vs. 88.7%) and defibrotide (HR 1.04, 95% CI 0.54 to 2.02, low quality of evidence). There were no data on survival for trials of LMWH, glutamine, FFP, antithrombin III, between heparin and LMWH, between heparin and PGE1, and between LMWH and PGE1. There were no data on quality of life (QoL) for any trials. Eleven trials reported adverse events. There was no evidence of difference in the frequency of adverse events between treatment and control groups except for one trial showing that defibrotide resulted in more adverse events compared with no treatment (RR 18.79, 95% CI 1.10 to 320.45). These adverse events included coagulopathy, gastrointestinal disorders, haemorrhage and microangiopathy. The quality of evidence was low or very low due to bias of study design, and inconsistent and imprecise results. AUTHORS' CONCLUSIONS: There is low or very low quality evidence that ursodeoxycholic acid may reduce the incidence of hepatic VOD, all-cause mortality and mortality due to VOD in HSCT recipients. However, the optimal regimen is not well-defined. There is insufficient evidence to support the use of heparin, LMWH, defibrotide, glutamine, FFP, antithrombin III, and PGE1. Further high-quality RCTs are needed.

Normal karyotype is a poor prognostic factor in myeloid leukemia of Down syndrome: a retrospective, international study.

Myeloid leukemia of Down syndrome has a better prognosis than sporadic pediatric acute myeloid leukemia. Most cases of myeloid leukemia of Down syndrome are characterized by additional cytogenetic changes besides the constitutional trisomy 21, but their potential prognostic impact is not known. We, therefore, conducted an international retrospective study of clinical characteristics, cytogenetics, treatment, and outcome of 451 children with myeloid leukemia of Down syndrome. All karyotypes were centrally reviewed before assigning patients to subgroups. The overall 7-year event-free survival for the entire cohort was 78% (± 2%), with the overall survival rate being 79% (± 2%), the cumulative incidence of relapse 12% (± 2%), and the cumulative incidence of toxic death 7% (± 1%). Outcome estimates showed large differences across the different cytogenetic subgroups. Based on the cumulative incidence of relapse, we could risk-stratify patients into two groups: cases with a normal karyotype (n=103) with a higher cumulative incidence of relapse (21%± 4%) than cases with an aberrant karyotype (n=255) with a cumulative incidence of relapse of 9% (± 2%) (P=0.004). Multivariate analyses revealed that white blood cell count ≥ 20 × 10(9)/L and age >3 years were independent predictors for poor event-free survival, while normal karyotype independently predicted inferior overall survival, event-free survival, and relapse-free survival. In conclusion, this study showed large differences in outcome within patients with myeloid leukemia of Down syndrome and identified novel prognostic groups that predicted clinical outcome and hence may be used for stratification in future treatment protocols.

Acupuncture for epilepsy.

BACKGROUND: Acupuncture is increasingly used in people with epilepsy. It remains unclear whether existing evidence is rigorous enough to support its use. This is an update of a Cochrane review first published in 2008. OBJECTIVES: To determine the effectiveness and safety of acupuncture in people with epilepsy. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialised Register (June 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 5), MEDLINE, EMBASE, CINAHL, AMED and other databases (from inception to June 2013). We reviewed reference lists from relevant trials. We did not impose any language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing acupuncture with placebo or sham treatment, antiepileptic drugs or no treatment; or comparing acupuncture plus other treatments with the same other treatments, involving people of any age with any type of epilepsy. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included 17 RCTs with 1538 participants that had a wide age range and were suffering mainly from generalized epilepsy. The duration of treatment varied from 7.5 weeks to 1 year. All included trials had a high risk of bias with short follow-up. Compared with Chinese herbs, needle acupuncture plus Chinese herbs was not effective in achieving at least 50% reduction in seizure frequency (80% in control group versus 90% in intervention group, RR 1.13, 95% CI 0.97 to 1.31, 2 trials; assumed risk 500 per 1000, corresponding risk 485 to 655 per 1000). Compared with valproate, needle acupuncture plus valproate was not effective in achieving freedom from seizures (44% in control group versus 42.7% in intervention group, RR 0.97, 95% CI 0.72 to 1.30, 2 trials; assumed risk 136 per 1000, corresponding risk 97 to 177 per 1000) or at least 50% reduction in seizure frequency (69.3% in control group versus 81.3% in intervention group, RR 1.34, 95% CI 0.52 to 3.48, 2 trials; assumed risk 556 per 1000, corresponding risk 289 to 1000 per 1000) but may have achieved better quality of life (QOL) after treatment (QOLIE-31 score (higher score indicated better QOL) mean 170.22 points in the control group versus 180.32 points in the intervention group, MD 10.10 points, 95% CI 2.51 to 17.69 points, 1 trial). Compared with phenytoin, needle acupuncture was not effective in achieving at least 50% reduction in seizure frequency (70% in control group versus 94.4% in intervention group, RR 1.43, 95% CI 0.46 to 4.44, 2 trials; assumed risk 700 per 1000, corresponding risk 322 to 1000 per 1000). Compared with valproate, needle acupuncture was not effective in achieving seizure freedom (14.1% in control group versus 25.2% in intervention group, RR 1.75, 95% CI 0.93 to 3.27, 2 trials; assumed risk 136 per 1000, corresponding risk 126 to 445 per 1000) but may be effective in achieving at least 50% reduction in seizure frequency (55.3% in control group versus 73.7% in intervention group, RR 1.32, 95% CI 1.05 to 1.66, 2 trials; assumed risk 556 per 1000, corresponding risk 583 to 923 per 1000) and better QOL after treatment (QOLIE-31 score mean 172.6 points in the control group versus 184.64 points in the intervention group, MD 12.04 points, 95% CI 4.05 to 20.03 points, 1 trial). Compared with antiepileptic drugs, catgut implantation at acupoints plus antiepileptic drugs was not effective in achieving seizure freedom (13% in control group versus 19.6% in intervention group, RR 1.51, 95% CI 0.93 to 2.43, 4 trials; assumed risk 127 per 1000, corresponding risk 118 to 309 per 1000) but may be effective in achieving at least 50% reduction in seizure frequency (63.1% in control group versus 82% in intervention group, RR 1.42, 95% CI 1.07 to 1.89, 5 trials; assumed risk 444 per 1000, corresponding risk 475 to 840 per 1000) and better QOL after treatment (QOLIE-31 score (higher score indicated worse quality of life) mean 53.21 points in the control group versus 45.67 points in the intervention group, MD -7.54 points, 95% CI -14.47 to -0.61 points, 1 trial). Compared with valproate, catgut implantation may be effective in achieving seizure freedom (8% in control group versus 19.7% in intervention group, RR 2.82, 95% CI 1.61 to 4.94, 4 trials; assumed risk 82 per 1000, corresponding risk 132 to 406 per 1000) and better QOL after treatment (QOLIE-31 score (higher score indicated better quality of life) mean 172.6 points in the control group versus 191.33 points in the intervention group, MD 18.73 points, 95% CI 11.10 to 26.36 points, 1 trial) but not at least 50% reduction in seizure frequency (65.6% in control group versus 91.7% in intervention group, RR 1.31, 95% CI 0.94 to 1.84, 4 trials; assumed risk 721 per 1000, corresponding risk 677 to 1000 per 1000). Acupuncture did not have excess adverse events compared to control treatment in the included trials. AUTHORS' CONCLUSIONS: Available RCTs are small, heterogeneous and have high risk of bias. The current evidence does not support acupuncture for treating epilepsy.

Urate oxidase for the prevention and treatment of tumour lysis syndrome in children with cancer.

BACKGROUND: Tumour lysis syndrome (TLS) is a serious complication of malignancies and can result in renal failure or death. Preliminary reports suggest that urate oxidase is effective in reducing serum uric acid, the build-up of which causes TLS. It is uncertain whether high-quality evidence exists to support its routine use in children with malignancies. OBJECTIVES: To assess the effects and safety of urate oxidase for the prevention and treatment of TLS in children with malignancies. SEARCH METHODS: This is an update of the original review. We performed a comprehensive search of the Cochrane Central Register of Controlled Trials (CENTRAL) (in The Cochrane Library issue 1, 2013), MEDLINE (1966 to February 2013), Embase (1980 to February 2013), and CINAHL (1982 to February 2013). In addition, we searched the reference lists of all identified relevant papers. We also explored other internet sources (updated search on 26 February 2013): the NHS' National Research Register, the US National Institutes of Health Ongoing Trials Register, the metaRegister of Controlled Trials, and ProQuest Dissertations & Theses Database. We also screened conference proceedings of the American Society of Clinical Oncology, the European Society for Medical Oncology, and the International Society of Paediatric Oncology meetings from 1993 to 2012. Finally, we contacted experts in the field and the manufacturer of rasburicase, Sanofi-aventis. SELECTION CRITERIA: Randomised controlled trials (RCT) and controlled clinical trials (CCT) of urate oxidase for the prevention or treatment of TLS in children under 18 years with any malignancy. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted trial data and assessed individual trial quality. We used risk ratios (RR) for dichotomous data and mean difference (MD) for continuous data. MAIN RESULTS: We included seven trials, involving 471 participants in the treatment groups and 603 participants in the control groups. One RCT and five CCTs compared urate oxidase and allopurinol. Three trials tested Uricozyme, and three trials tested rasburicase for the prevention of TLS.The RCT showed no significant difference in mortality (both all-cause mortality and mortality due to TLS), renal failure, and adverse effects between the treatment and the control groups. The frequency of normalisation of uric acid at four hours (Fisher's exact test P < 0.001) and area under curve of uric acid at four days (MD -201.00 mg/dLhr, 95% confidence interval (CI) -258.05 mg/dLhr to -143.95 mg/dLhr; P < 0.00001) were significantly better in the treatment group. The trial did not evaluate the primary outcome (incidence of clinical TLS).Pooled results of three CCTs showed significantly lower mortality due to TLS in the treatment group (RR 0.05, 95% CI 0.00 to 0.89; P = 0.04); all-cause mortality was not significantly different between the groups. Pooled results from five CCTs showed significantly lower incidence of renal failure in the treatment group (RR 0.26, 95% CI 0.08 to 0.89; P = 0.03). Results of CCTs also showed significantly lower uric acid in the treatment group at two days (three CCTs), three days (two CCTs), four days (two CCTs), and seven days (one CCT) after therapy, but not one day (three CCTs), five days (one CCT), and 12 days (one CCT) after therapy. Pooled results from three CCTs showed higher frequency of adverse effects in participants who received urate oxidase (RR 9.10, 95% CI 1.29 to 64.00; P = 0.03). One CCT evaluated the primary outcome; no significant difference was identified.Another included RCT, with 30 participants, compared different doses of rasburicase (0.2 mg/kg versus 0.15 mg/kg), which demonstrated no significant difference in uric acid normalisation and uric acid level at four hours). Common adverse events of urate oxidase included hypersensitivity, haemolysis, and anaemia, but no significant difference between treatment groups was identified. No significant difference in mortality (all-cause mortality and mortality due to TLS) and renal failure was identified. The primary outcome was not evaluated.All included trials were highly susceptible to biases. AUTHORS' CONCLUSIONS: Although urate oxidase might be effective in reducing serum uric acid, it is unclear whether it reduces clinical tumour lysis syndrome, renal failure, or mortality. Adverse effects might be more common for urate oxidase compared with allopurinol. Clinicians should weigh the potential benefits of reducing uric acid and uncertain benefits of preventing mortality or renal failure from TLS against the potential risk of adverse effects.

Case report: Therapy-related myeloid neoplasms in three pediatric cases with medulloblastoma.

Introduction: Medulloblastoma is the most common malignant brain tumor in children, often requiring intensive multimodal therapy, including chemotherapy with alkylating agents. However, therapy-related complications, such as therapy-related myeloid neoplasms (t-MNs), can arise, particularly in patients with genetic predisposition syndromes. This case report presents three pediatric cases of medulloblastoma with subsequent development of t-MNs, highlighting the potential role of genetic predisposition and the importance of surveillance for hematological abnormalities in long-term survivors. Case presentation: We describe three cases of pediatric medulloblastoma who developed t-MNs after receiving chemotherapy, including alkylating agents. Two of the patients had underlying genetic predisposition syndromes (TP53 pathologic variants). The latency period between initial diagnosis of medulloblastoma and the development of secondary cancer varied among the cases, ranging from 17 to 65 months. The three cases eventually succumbed from secondary malignancy, therapy-related complications and progression of primary disease, respectively. Conclusions: This report highlights the potential association between genetic predisposition syndromes and the development of therapy-related myeloid neoplasms in pediatric medulloblastoma survivors. It underscores the importance of surveillance for hematological abnormalities among such patients.

Acupuncture for hypoxic ischemic encephalopathy in neonates.

BACKGROUND: Hypoxic ischemic encephalopathy (HIE) in the neonate is associated with high mortality and morbidity. Effective treatment options are limited and therefore alternative therapies such as acupuncture are increasingly used. OBJECTIVES: We sought to determine the efficacy and safety of acupuncture on mortality and morbidity in neonates with HIE. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), Cochrane Neonatal Specialized Register, MEDLINE, AMED, EMBASE, PubMed, CINAHL, PsycINFO, WHO International Clinical Trials Registry Platform, and various Chinese medical databases in November 2012. SELECTION CRITERIA: We planned to include randomized or quasi-randomized controlled trials comparing needle acupuncture to a control group that used no treatment, placebo or sham treatment in neonates (less than 28 days old) with HIE. Co-interventions were allowed as long as both the intervention and the control group received the same co-interventions. We excluded trials that evaluated therapy that did not involve penetration of the skin with a needle or trials that compared different forms of acupuncture only. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed trials for inclusion. If trials were identified, the review authors planned to assess trial quality and extract data independently. We planned to use the risk ratio (RR), risk difference (RD), and number needed to benefit (NNTB) or harm (NNTH) with 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) with 95% CI for continuous outcomes. MAIN RESULTS: No trial satisfied our predefined inclusion criteria. Existing trials only evaluated acupuncture in older infants who survived HIE. There are currently no randomized controlled trials evaluating the efficacy of acupuncture for treatment of HIE in neonates. The safety of acupuncture for HIE in neonates is unknown. AUTHORS' CONCLUSIONS: The rationale for acupuncture in neonates with HIE is unclear and the evidence from randomized controlled trial is lacking. Therefore, we do not recommend acupuncture for the treatment of HIE in neonates. High quality randomized controlled trials on acupuncture for HIE in neonates are needed.

Surgery for scoliosis in Duchenne muscular dystrophy.

BACKGROUND: Scoliosis in people with Duchenne muscular dystrophy is usually progressive and treated with surgery. However, it is unclear whether the existing evidence is sufficiently scientifically rigorous to support a recommendation for spinal surgery for most people with Duchenne muscular dystrophy and scoliosis. This is an updated review and an updated search was undertaken in which no new studies were found. OBJECTIVES: To determine the effectiveness and safety of spinal surgery in people with Duchenne muscular dystrophy with scoliosis. We intended to test whether spinal surgery is effective in increasing survival, improving respiratory function, improving quality of life and overall functioning; and whether spinal surgery is associated with severe adverse effects. SEARCH METHODS: We searched the specialized registers of the Cochrane Neuromuscular Disease Group (31 July 2012), MEDLINE (January 1966 to July 2012), EMBASE (January 1947 to July 2012), CENTRAL (2012, Issue 7 in the Cochrane Library), CINAHL Plus(January 1937 to July 2012), Proquest Dissertation and Thesis Database (January 1980 to July 2012), and the National Institute of Health Clinical Trials Database (July 2012). No language restrictions were imposed. SELECTION CRITERIA: We planned to include controlled clinical trials using random or quasi-random allocation of treatment evaluating all forms of spinal surgery for scoliosis in people with Duchenne muscular dystrophy in the review. The control interventions would have been no treatment, non-operative treatment, or a different form of spinal surgery. DATA COLLECTION AND ANALYSIS: Two authors independently examined the search results and evaluated the study characteristics against inclusion criteria to decide which ones would be included in the review. MAIN RESULTS: On searching, 47 studies were relevant but none met the inclusion criteria for the review, because they were not clinical trials but prospective or retrospective reviews of case series. AUTHORS' CONCLUSIONS: Since there were no randomized controlled clinical trials available to evaluate the effectiveness of scoliosis surgery in people with Duchenne muscular dystrophy, no evidence-based recommendation can be made for clinical practice. People with scoliosis should be informed about the uncertainty of benefits and potential risks of surgery for scoliosis. Randomized controlled trials are needed to investigate the effectiveness of scoliosis surgery, in terms of quality of life, functional status, respiratory function and life expectancy.

Acupuncture for acute management and rehabilitation of traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) can be life threatening depending on the severity of the insult to the brain. It can also cause a range of debilitating sequelae which require cognitive, motor, communication, emotional, or behavioral rehabilitation of varying intensity and duration. A number of studies conducted and published in China have suggested that acupuncture may be beneficial in the acute treatment and rehabilitation of TBI. OBJECTIVES: To determine the efficacy and safety of acupuncture in the acute management or rehabilitation (or both) of patients with a TBI, including cognitive, neurological, motor, communication, emotional, or behavioral complications, or a combination of such complications. SEARCH METHODS: We searched the Cochrane Injuries Group Specialised Register, Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, EMBASE, CINAHL, AMED, PsycINFO and others. We also searched the Chinese Acupuncture Studies Register, the Studies Register of the Cochrane Complementary Medicine Field, NCCAM, and NIH Clinical Studies Database. Three major Mainland Chinese academic literature databases (CNKI, VIP and Wang Fang Data) were also searched using keywords in simplified Chinese. We searched all databases through December 2009, and some searches have been updated to October 2012. SELECTION CRITERIA: Randomized controlled studies evaluating different variants of acupuncture and involving participants of any age who had suffered a TBI. Included trials compared acupuncture with placebo or sham treatment, or acupuncture plus other treatments compared with the same other treatments. We excluded trials that only compared different variants of acupuncture or compared acupuncture alone against other treatments alone, as they did not yield the net effect of acupuncture. DATA COLLECTION AND ANALYSIS: Two review authors identified potential articles from the literature search and extracted data independently using a data extraction form. We performed methodological assessment of included studies using the Cochrane Collaboration's tool for assessing risk of bias. We were unable to perform quantitative data analysis due to insufficient included studies and available data. MAIN RESULTS: Four RCTs, including 294 participants, reported outcomes specified by this review. Three investigated electro-acupuncture for TBI while one investigated acupuncture for acute TBI. The results seem to suggest that acupuncture is efficacious for these indications, however the low methodological quality of these studies renders the results questionable. No adverse effects of acupuncture were reported in any of the studies. AUTHORS' CONCLUSIONS: The low methodological quality of the included studies does not allow us to make conclusive judgments on the efficacy and safety of acupuncture in either the acute treatment and/or rehabilitation of TBI. Its beneficial role for these indications remains uncertain. Further research with high quality trials is required.

Malignancies in Chinese patients with neurofibromatosis type 1.

OBJECTIVE: To investigate the pattern of malignancies in Chinese patients with neurofibromatosis type 1. DESIGN: Historical cohort study. SETTING: Queen Mary Hospital and Duchess of Kent Children's Hospital in Hong Kong. PATIENTS: Patients with neurofibromatosis type 1 seen between January 1995 and August 2011. RESULTS: We identified 123 Chinese patients with neurofibromatosis type 1, diagnosed at a median age of 4.9 years (range, 0.1-16.1 years); 75 (61%) were males. They were followed up for a median of 9.7 years (range, 0.2-27.6 years). Most (80%) of the patients participated in our surveillance programme. Twelve patients developed malignancies at the ages of 0.8 to 41.6 years. These malignancies included: peripheral nerve sheath tumours (n=3), juvenile myelomonocytic leukaemia (n=2), optic nerve glioma (n=1), thalamic pilocytic astrocytoma (n=1), rhabdomyosarcoma (n=1), osteosarcoma (n=1), neuroblastoma (n=1), anaplastic large cell lymphoma (n=1), and breast carcinoma and subsequently carcinoma of the ampulla of Vater (n=1). Among them, three had their tumours (optic glioma, thalamic astrocytoma, sacral malignant peripheral nerve sheath tumour) initially detected by surveillance imaging. Four patients survived without disease progression, three are alive with active disease, the remaining five died (when aged 3 to 56 years) with progressive or relapsed malignancies. The latter patients died from a neuroblastoma, a juvenile myelomonocytic leukaemia, a malignant peripheral nerve sheath tumour, a lymphoma, and a second primary tumour (carcinoma of ampulla of Vater, at the age of 56 years). In neurofibromatosis type 1 patients with malignancy, overall 30-year survival was significantly shorter than in those without malignancy (35% vs 93%, P<0.001). CONCLUSION: Chinese patients with neurofibromatosis type 1 are susceptible to different malignancies which contribute to mortality. These findings are similar to reports from overseas. Outcomes were unfavourable, except in patients having low-grade gliomas. Surveillance imaging may help early detection of deep-seated malignancies but the benefits accruing from such monitoring warrants prospective evaluation.