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Objective: The Direct Assessment of Nonvertebral Fractures in Community Experience (DANCE) study investigated the use of teriparatide in men and women with osteoporosis in the United States (US) and Puerto Rico (PR). In a sub-analysis, we evaluated whether the baseline characteristics of Latinas differed from those of white women in the study population and whether any patient attributes affected physicians' decisions to prescribe teriparatide., Methods: We assessed 3 patient cohorts treated with teriparatide 20 microg once daily for up to 24 months: 1) PR Latinas, 2) US Latinas, and 3) white women on the US mainland (white women). We analyzed differences related to ethnicity (Latina vs. white) and geography (PR vs. US mainland)., Results: Overall, 302 of the 3243 women (9%) enrolled in DANCE were Latina (205 of these 302 Latinas resided in PR). Significant differences were observed in 7 of 11 baseline characteristics. White women had more prior fragility fractures and family history of hip fracture than Latinas, while PR Latinas were generally older than US Latinas and had more comorbid conditions. A similar proportion of subjects in each cohort had received prior osteoporosis therapy. Physicians prescribed teriparatide more often for Latinas based on multiple risk factors for fracture and intolerance to previous osteoporosis therapy and to white women based on inadequate response to previous therapy or new (incident) fractures. Overall, Latinas were less persistent with teriparatide therapy than white women., Conclusion: We observed significant differences related to ethnicity and geography in the baseline demographics of Latinas enrolled in the DANCE study, criteria cited by physicians for initiating teriparatide therapy, and treatment persistence.

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.

Background: Renal tumors are one of the most common tumors in children. We aim at evaluating the characteristics and the outcome of Wilms tumor and other malignant kidney tumors in Hong Kong., Procedure: Between January 1990 to December 2010, 68 patients under the age of 18 with malignant renal tumors were diagnosed and received treatment in Hong Kong. Clinical records were updated regularly. Prognostic factors and survival rate were evaluated., Results: Fifty-four patients were diagnosed with Wilms tumor. The annual incidence was estimated to be 2.29 per million. The mean age was 38 months. Median follow-up was 9.2 years. The event-free survival and overall survival rate at 10 years were 85.2% and 92.6%, respectively. A pair of siblings with familial extrarenal Wilms tumor was included. Pulmonary metastasis did exhibit a significant difference in survival rate. Eight cases of clear cell sarcoma of the kidneys were reported and the survival rate was 100%., Conclusions: The clinical characteristics and outcome of the patients diagnosed Wilms tumor were comparable with other developed countries. Relatively high proportion and excellent outcome were found in clear cell sarcoma of the kidneys.

Background: The immunosuppressed state in patients undergoing hematopoietic stem cell transplantation (HSCT) predisposes them to activation of latent viral infections such as herpesvirus types 6 and 7 (HHV6 and HHV7). We aimed to evaluate the incidence, manifestations, outcomes, and risk factors of HHV 6 and HHV 7 infections after pediatric hematopoietic stem cell transplantation., Material and Methods: We performed 106 HSCTs (86 allogeneic and 20 autologous) on 94 children (56 boys, median age 7.1 years) during 2006-2012. Patients suspected to have HHV6 or HHV7 infections were tested using polymerase chain reaction on serum and/or cerebrospinal fluid., Results: Among the 63 patients tested for HHV, 10 patients (15.9%) were infected (HHV-6 (n=6), HHV-7 (n=4)) at a median of 18 days post-HSCT (cumulative incidence 11.5% at 1 year). Manifestations included fever (90%), rash (70%), hepatitis (80%), pneumonitis (50%), central nervous system (CNS) manifestations (40%), and graft failure (10%). One patient had persistent CNS infection despite treatment with foscarnet, ganciclovir, and cidofovir. Seven patients cleared herpesvirus after a median of 22 days. Four patients died (relapse of malignancy [n=3], acute graft-versus-host disease [aGVHD] [n=1]). Herpesvirus infections were associated with adenovirus infection (p=0.001) and severe (grade III-IV) aGVHD (p=0.037)., Conclusions: We concluded that HHV6 and HHV7 infections are common after pediatric HSCT. Most infections were self-limited and could be associated with adenovirus infection and severe aGVHD. Further studies are needed to evaluate predictors of severe morbidity or mortality, and define optimal prophylaxis and treatment.

Nasopharyngeal carcinoma is well known to be a viral driven malignancy. Despite high loco-regional control rate with modern radiotherapy, distant metastasis remains as a major threat to the patients highlighting the importance of effective systemic therapy. Recent advances in the understanding of tumor biology, host cell-virus interaction and genetics have paved new ways for targeted therapies. This review summarizes the recent advances into our knowledge and understanding of NPC and highlights potential novel therapeutic strategies that may prove useful to treat this disease., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Two clinical studies were conducted to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses (intravenous [iv] and subcutaneous [sc]) of blosozumab in postmenopausal women, including prior/current bisphosphonate (BP) users. In these phase 1, randomized, subject- and investigator-blind, placebo-controlled studies, subjects received escalating doses of blosozumab: single iv doses up to 750 mg, single sc doses of 150 mg, multiple iv doses up to 750 mg every 2 weeks (Q2W) for 8 weeks, multiple sc doses up to 270 mg Q2W for 8 weeks, or placebo. Six subjects were randomized to each dose in the single-dose study (12 to placebo) and up to 12 subjects to each arm in the multiple-dose study. Blosozumab was well tolerated with no safety concerns identified after single or multiple administrations up to 750 mg. Dose-dependent responses were observed in sclerostin, N-terminal propeptide of procollagen type 1, bone-specific alkaline phosphatase, osteocalcin, C-terminal fragment of type 1 collagen, and bone mineral density (BMD) after single and multiple (up to 5) administrations of blosozumab. There was up to a 3.41% (p=0.002) and up to a 7.71% (p<0.001) change from baseline in lumbar spine BMD at day 85 after single or multiple administrations of blosozumab, respectively. Prior BP use did not appear to have a clear impact on the effects of single doses of blosozumab when considering bone biomarker and BMD responses. Antibodies to blosozumab were detected by a screening assay, but no patterns with regard to dose or route of administration and no clear impact on blosozumab exposure or PD responses were identified. In summary, blosozumab was well tolerated and exhibited anabolic effects on bone. These findings support further investigation of blosozumab as a potential anabolic therapy for osteoporosis., (© 2014 American Society for Bone and Mineral Research.)

Cortical bone, the dominant component of the human skeleton by volume, plays a key role in protecting bones from fracture. We analyzed the cortical bone effects of teriparatide treatment in postmenopausal women with osteoporosis who had previously received long-term alendronate (ALN) therapy or were treatment naïve (TN). Tetracycline-labeled paired iliac crest biopsies obtained from 29 ALN-pretreated and 16 TN women were evaluated for dynamic histomorphometric parameters of bone formation at the periosteal, endocortical and intracortical bone compartments, before and after 24months of teriparatide treatment. At baseline, the frequency of specimens without any endocortical and periosteal tetracycline labeling, and the percentage of quiescent osteons, was higher in the ALN than the TN group. Endocortical and periosteal mineralizing surface (MS/BS%), periosteal bone formation rate (BFR/BS), mineral apposition rate (MAR) and the number of intracortical forming osteons were significantly lower in the ALN-pretreated patients than in the TN group. Following teriparatide treatment, the frequency of endocortical and periosteal unlabeled biopsies decreased; in the ALN-pretreated group the percentage of quiescent osteons decreased and, in contrast, forming and resorbing osteons were increased. Teriparatide treatment resulted in significant increases of MAR in the endocortical, and MS/BS% in the periosteal compartment in the ALN-pretreated group. Most indices of bone formation remained lower in the ALN-pretreated group compared with the TN group at study end. Endocortical wall width was increased in both ALN-pretreated and TN groups. Cortical porosity and cortical thickness were significantly increased in the ALN-pretreated group after teriparatide treatment. Our results suggest that 24months of teriparatide treatment increases cortical bone formation and cortical turnover in patients who were either TN or had previous ALN therapy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

A framework is proposed for making quality predictions in situations for which only systematically inaccurate data are available. The predictions are based on the systematically inaccurate data, complete data from similar situations, and expert knowledge. The proposed predictive model is well suited to functional data and is computationally simple, fast, and stable. We focus primarily on a particular problem presenting itself in the pharmaceutical industry. Predicting both side effect and endpoint dose responses before the initiation of a clinical trial has enormous ethical and financial importance in the pharmaceutical industry. The proposed Bayesian semiparametric predictive model is used to predict unobserved clinical dose-response curves conditional on preclinical data, data from similar compounds, and prior knowledge. The model allows for nonlinear dose-response curves and the incorporation of relevant prior information. Posterior sampling is achieved through a simple and computationally efficient Gibbs sampler. The predictions from the model are drawn from the posterior distribution of the average dose-response curve for the candidate compound, allowing straightforward incorporation into a risk assessment model unlike the deterministic predictions often used currently. The model is used on actual data from the pharmaceutical industry, showing that the model is capable of predicting lack or presence of trend with appropriate uncertainty.

Data on clinical features and outcome in pediatric follicular lymphoma (pFL) are scarce. The aim of this retrospective study including 13 EICNHL and/or i-BFM study group members was to assess clinical characteristics and course in a series of 63 pFL patients. pFL was found to be associated with male gender (3:1), older age (72 % ≥10 years old), low serum LDH levels (<500 U/l in 75 %), grade 3 histology (in 88 %), and limited disease (87 % stage I/II disease), mostly involving the peripheral lymph nodes. Forty-four out of sixty-three patients received any polychemotherapy and 1/63 rituximab only, while 17/63 underwent a "watch and wait" strategy. Of 36 stage I patients, 30 had complete resections. Only one patient relapsed; 2-year event-free survival and overall survival were 94 ± 5 and 100 %, respectively, after a median follow-up of 2.2 years. Conclusively, treatment outcome in pFL seems to be excellent with risk-adapted chemotherapy or after complete resection and an observational strategy only.

We retrospectively analysed the outcomes of 127 children with acquired severe aplastic anaemia (SAA) who had received haematopoietic stem cell transplantation (HSCT) between 2000 and 2011 in one of the 10 Asia Pacific institutions. Fifty-three were matched sibling donor (MSD) and 74 were alternative donor (AD), including 22 matched unrelated donor, 32 mismatched unrelated donor and 20 mismatched related donor. With a median follow up 45.5 months (13-139) and when compared to the MSD group, AD recipients had more grade II-IV acute graft-versus-host disease (aGVHD; 14.3% vs. 32.8%, P = 0.029), but similar grade III-IV aGVHD (10.2% vs. 12.5%, P = 0.774), graft failure (GF) (15.1% vs. 15.5%, P = 0.658) and 5-year overall survival (90.6% vs. 83.7%, P = 0.251). As a source of stem cell, peripheral blood stem cells (PBSC) resulted in less GF (18% vs. 9.1% P = 0.013), similar grade II-IV aGVHD (28.1% vs. 17.4%, P = 0.258), chronic GVHD (25.8% vs. 29.3%, P = 0.822) and similar outcomes (89.7% vs. 82.4%, P =0.665) when compared to bone marrow (BM). In univariate analysis, GF (P < 0.001) and grade II-IV aGVHD (P = 0.009) were predictors of poor survival. In multivariate analysis, only GF was associated with poor survival (P = 0.012). The outcome of AD and PBSC HSCT were comparable to that of MSD and BM HSCT in the Asia Pacific region., (© 2013 John Wiley & Sons Ltd.)

Background and Aims: Complications after liver transplantation are major factors that determine the prognosis of patients. In this study, we aimed at investigating an important though less frequently occurring complication, post-transplant lymphoproliferative disorders (PTLD), in a single institution after liver transplantation., Methods: 15 cases with a diagnosis of PTLD in post-liver transplant patients were retrieved from our archive and the clinicopathological features reviewed., Results: The overall incidence of PTLD was 2.3% (n=15/658), and the incidence was much higher in the paediatric than the adult age groups, being 11.1% (9/81) and 1% (6/577), respectively. The median time of presentation was 16 months after transplantation (occurrence time ranging from 2 to 87 months after transplantation). Lymph nodes, gastrointestinal tract and graft liver were the commonest sites of involvement. 11 cases were classified as monomorphic PTLD according to WHO classification and the majority (n=10/11) of them were of B cell differentiation. 12 of the total 15 PTLD cases showed a positive result for Epstein-Barr virus-encoded RNAs with in situ hybridisation. Eight patients were alive at the time of review, and two of them suffered from recurrence of the PTLD. Among the seven patients who died, six succumbed within 1 year from the diagnosis of PTLD., Conclusions: Despite its relative rarity as a complication for liver transplantation, PTLD imposes significant effects on the morbidity, mortality and treatment implications in postliver transplant patients. The clinicopathological data would hopefully provide better insight into the surveillance and management for susceptible patients.

A novel drug combination of a proteasome inhibitor, bortezomib, and a histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), was tested in nasopharyngeal carcinoma (NPC), both in vitro and in vivo. Dose-response of different concentrations of bortezomib and SAHA on inhibition of cell proliferation of NPC was determined. Mechanisms of apoptosis and effects on lytic cycle activation of Epstein-Barr virus (EBV) were investigated. Combination of bortezomib and SAHA (bortezomib/SAHA) synergistically induced killing of a panel of NPC cell lines. Pronounced increase in sub-G1, Annexin V-positive, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cell populations were detected after treatment with bortezomib/SAHA when compared with either drug alone. Concomitantly, markedly augmented proteolytic cleavage of PARP, caspase-3, -7, -8, and -9, reactive oxygen species (ROS) generation, and caspase-8-dependent histone acetylation were observed. ROS scavenger, N-acetyl cysteine, diminished the apoptotic effects of bortezomib/SAHA, whereas caspase inhibitor Z-VAD-FMK significantly suppressed the apoptosis without decreasing the generation of ROS. Bortezomib inhibited SAHA's induction of EBV replication and abrogated production of infectious viral particles in NPC cells. Furthermore, bortezomib/SAHA potently induced apoptosis and suppressed the growth of NPC xenografts in nude mice. In conclusion, the novel drug combination of bortezomib and SAHA is highly synergistic in the killing of NPC cells in vitro and in vivo. The major mechanism of cell death is ROS-driven caspase-dependent apoptosis. Bortezomib antagonizes SAHA's activation of EBV lytic cycle in NPC cells. This study provides a strong basis for clinical testing of the combination drug regimen in patients with NPC., (©2013 AACR)

Central diabetes insipidus (DI) is well-documented as a presenting feature of myelodysplastic syndrome and acute myeloid leukemia in adults. However, DI is unusual in pediatric patients with myeloid malignancies. We report here this rare complication in a child with neurofibromatosis type 1 who developed juvenile myelomonocytic leukemia and monosomy 7. Our case and previously reported cases of DI arising as a complication in myeloid malignancies demonstrate a close association with deletion of chromosome 7. The clinical characteristics and outcomes of these uncommon cases in children are reviewed and discussed.

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.

Norovirus infections are increasingly being recognized as important causes of diarrhea in hematopoietic stem cell transplantation (HSCT) recipients. This retrospective study aimed to evaluate the cumulative incidence, risk factors, and outcomes of norovirus infection in pediatric HSCT recipients. Among 55 patients age <21 years who underwent first HSCT between July 2007 and June 2011, 49 patients developed diarrhea and had stool tested for norovirus. Eight of these patients were found to be infected with norovirus. All were sporadic cases and manifested with nausea, vomiting, and diarrhea. The median age of these patients was 5.2 years (range, 0.5-18.5 years). Six were males. Seven patients underwent unrelated donor HSCT, and 1 patient underwent autologous cord blood HSCT. Two patients had norovirus infection before HSCT that persisted after transplantation. In the remaining 6 patients, norovirus developed at a median of 36.5 days posttransplantation (range, 5-517 days). The cumulative incidence of norovirus infection was 12.9% at 2 years posttransplantation. Risk factors for norovirus infection included the use of peripheral blood or cord blood as the stem cell source (P = .043) and administration of fludarabine (P = .002) and alemtuzumab (P = .011). The median time to viral clearance was 145 days (range, 13-263 days). Four-year survival was similar in norovirus-infected patients and noninfected patients (56.3% versus 58.3%)., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

aGVHD of the GI tract is common after allogeneic HSCT. Corticosteroids are the mainstay of treatment. Recent data suggest infliximab might be beneficial for steroid refractory aGVHD. We reviewed our experience in 10 pediatric patients who developed severe steroid refractory aGVHD (stage 3, n = 6; stage 4, n = 4), after an allogeneic matched unrelated HSCT for various hematological diseases (leukemia, n = 7; thalassemia, n = 3). The median age was 9.5 yr (range, 0.8-18.5 yr). All patients received 10 mg/kg infliximab weekly for 3-4 doses. Eight patients had CR and two had partial response. None of the patients developed therapy-related adverse effects. All patients developed infections subsequently, which may or may not be related to infliximab. Five patients developed chronic GVHD (cGVHD) (four severe, one mild). Six patients died at 66-1451 days post-transplant, from infection (n = 3), aGVHD (n = 1), lung cGVHD (n = 1), or idiopathic pneumonia (n = 1). Four patients were alive at 238-924 days post-transplant, all of whom had an increase in BMI by six months post-transplant. In conclusion, infliximab is well tolerated and appears effective in children with steroid refractory or dependent GI aGVHD. Infection is common and mortality remains high., (© 2012 John Wiley & Sons A/S.)

Nasopharyngeal carcinoma (NPC) is strongly associated with Epstein-Barr virus (EBV). We reported that suberoylanilide hydroxamic acid (SAHA) induced EBV lytic cycle in EBV-positive gastric carcinoma cells and mediated enhanced cell death. However, expression of EBV lytic proteins was thought to exert antiapoptotic effect in EBV-infected cells. Here, we examined the in vitro and in vivo effects of SAHA on EBV lytic cycle induction in NPC cells and investigated the cellular consequences. Micromolar concentrations of SAHA significantly induced EBV lytic cycle in EBV-positive NPC cells. Increased apoptosis and proteolytic cleavage of poly(ADP-ribose) polymerase and caspase-3, -7 and -9 in EBV-positive versus EBV-negative NPC cells were observed. More than 85% of NPC cells expressing immediate-early (Zta), early (BMRF1) or late (gp350/220) lytic proteins coexpressed cleaved caspase-3. Tracking of expression of EBV lytic proteins and cleaved caspase-3 over time demonstrated that NPC cells proceeded to apoptosis following EBV lytic cycle induction. Inhibition of EBV DNA replication and late lytic protein expression by phosphonoformic acid did not impact on SAHA's induced cell death in NPC, indicating that early rather than late phase of EBV lytic cycle contributed to the apoptotic effect. In vivo effects of SAHA on EBV lytic cycle induction and tumor growth suppression were also observed in NPC xenografts in nude mice. Taken together, our data indicated that activation of lytic cycle from latent cycle of EBV by SAHA leads to apoptosis and tumor growth suppression of NPC thereby providing experimental evidence for virus-targeted therapy against EBV-positive cancer., (Copyright © 2012 UICC.)

Background: In 2000, the Hong Kong Pediatric Hematology Oncology Study Group started a new relapsed acute lymphoblastic leukemia (ALL) treatment protocol based on modified ALL-REZ BFM 96 protocol aiming at improving the treatment outcome in Chinese children., Procedure: All patients in Hong Kong with first relapse of childhood ALL were included. Patients were stratified into four risk groups (S1, S2, S3, and S4) and the treatment consisted of intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation, if indicated., Results: Fifty-six patients were recruited and median age at diagnosis of ALL was 4.6 (range, 0.3-17) years. The median time from initial diagnosis to relapse was 2.5 (range, 0.3-9.1) years and follow-up time was 2.7 (range, 0-9.9) years. Forty-nine patients (87.5%) achieved second complete remission (CR2). CR2 rates for S1, S2, S3, and S4 groups were 100%, 93%, 90%, and 67%, respectively. Five-year overall survival (OS) was 50.5 ± 6.9% and event-free survival (EFS) was 41.5 ± 7.1%. There was no significant difference in survival among S1, S2, and S3 groups but S4 patients performed significantly worse with 5-year OS and EFS of 8% and 0%, respectively., Conclusion: Children with relapsed ALL of S1-S3 risk groups could be successfully treated with intensified treatment protocol. The S4 high risk group needs more innovative approach to improve treatment outcome., (Copyright © 2012 Wiley Periodicals, Inc.)

A combination drug product with two or more active compounds may be superior to each of its components with higher dose levels and, therefore, is preferred in terms of efficacy, cost, and safety. To study a combination drug, researchers often conduct trials by using a factorial design with combinations of dose levels of each drug component. By applying some bootstrap methods, we construct multiple testing procedures to simultaneously identify combinations superior to each drug component with any dose level. These multiple testing procedures are more powerful than Holm's step-down procedure that is known to be very conservative. When there is only one study endpoint, applying the bootstrap is straightforward. In many studies, however, there are two or more study endpoints and it is not simple to apply the bootstrap. We apply one version of the bootstrap and then use an upper bound to control the familywise error defined as the probability of rejecting at least one true null hypothesis. Properties of the bootstrap multiple testing procedures are discussed and examined in some simulation studies., (Copyright © 2012 John Wiley & Sons, Ltd.)

Whether certain Epstein-Barr virus (EBV) strains are associated with pathogenesis of nasopharyngeal carcinoma (NPC) is still an unresolved question. In the present study, EBV genome contained in a primary NPC tumor biopsy was amplified by Polymerase Chain Reaction (PCR), and sequenced using next-generation (Illumina) and conventional dideoxy-DNA sequencing. The EBV genome, designated HKNPC1 (Genbank accession number JQ009376) is a type 1 EBV of approximately 171.5 kb. The virus appears to be a uniform strain in line with accepted monoclonal nature of EBV in NPC but is heterogeneous at 172 nucleotide positions. Phylogenetic analysis with the four published EBV strains, B95-8, AG876, GD1, and GD2, indicated HKNPC1 was more closely related to the Chinese NPC patient-derived strains, GD1 and GD2. HKNPC1 contains 1,589 single nucleotide variations (SNVs) and 132 insertions or deletions (indels) in comparison to the reference EBV sequence (accession number NC007605). When compared to AG876, a strain derived from Ghanaian Burkitt's lymphoma, we found 322 SNVs, of which 76 were non-synonymous SNVs and were shared amongst the Chinese GD1, GD2 and HKNPC1 isolates. We observed 88 non-synonymous SNVs shared only by HKNPC1 and GD2, the only other NPC tumor-derived strain reported thus far. Non-synonymous SNVs were mainly found in the latent, tegument and glycoprotein genes. The same point mutations were found in glycoprotein (BLLF1 and BALF4) genes of GD1, GD2 and HKNPC1 strains and might affect cell type specific binding. Variations in LMP1 and EBNA3B epitopes and mutations in Cp (11404 C>T) and Qp (50134 G>C) found in GD1, GD2 and HKNPC1 could potentially affect CD8(+) T cell recognition and latent gene expression pattern in NPC, respectively. In conclusion, we showed that whole genome sequencing of EBV in NPC may facilitate discovery of previously unknown variations of pathogenic significance.

T cells simultaneously producing multiple cytokines and possessing cytotoxic capacity termed polyfunctional cells (PFCs) are increasingly recognized as the immune correlate of protection against pathogenic viruses. We investigated co-expression of four cytokines (interferon-γ, macrophage inflammatory protein 1-α, tumour necrosis factor-α and interleukin-2) and degranulation capacity (CD107a surface expression) of Epstein-Barr virus (EBV) -specific CD4(+) and CD8(+) T cells upon stimulation by overlapping peptides of EBV lytic (BZLF1) and latent (EBNA1, EBNA3 and LMP2) proteins, in 20 healthy Chinese long-term carriers. Two patients with post-transplant lymphoproliferative disorder (PTLD), who had impaired T-cell immunity, were studied for comparison. Both EBV-specific CD4(+) and CD8(+) PFCs were readily generated in long-term carriers and showed immunodominance hierarchies of latent proteins (EBNA1 > EBNA3/LMP2 and EBNA3 > LMP2 > EBNA1 for CD4(+) and CD8(+) T cells, respectively), as evidenced by a higher proportion of PFCs generated by immunodominant EBV proteins than by subdominant viral proteins. In contrast, the proportion of EBV-specific PFCs was markedly decreased in patients with PTLD. The EBV-specific PFCs produced more cytokine per cell than single-functional T cells and comprised different subsets. Five-functional CD4(+) and CD8(+) T cells were detected and four-functional CD4(+) T cells were mainly CD107a negative and expressed all four cytokines whereas four-functional CD8(+) T cells were mainly CD107a positive and expressed three of the four cytokines (interleukin-2-negative). We conclude that EBV-specific PFCs are generated in much higher proportions in the long-term carriers than in the patients with PTLD and maintain the immunodominant characteristics of the virus., (© 2011 The Authors. Immunology © 2011 Blackwell Publishing Ltd.)

Novel Epstein-Barr Virus (EBV) strains with deletion of either EBER1 or EBER2 and corresponding revertant viruses were constructed and used to infect B lymphocytes to make lymphoblastoid cell lines (LCLs). The LCLs were used in microarray expression profiling to identify genes whose expression correlates with the presence of EBER1 or EBER2. Functions of regulated genes identified in the microarray analysis include membrane signaling, regulation of apoptosis, and the interferon/antiviral response. Although most emphasis has previously been given to EBER1 because it is more abundant than EBER2, the differences in cell gene expression were greater with EBER2 deletion. In this system, deletion of EBER1 or EBER2 had little effect on the EBV transformation frequency of primary B cells or the growth of the resulting LCLs. Using the recombinant viruses and novel EBER expression vectors, the nuclear redistribution of rpL22 protein by EBER1 in 293 cells was confirmed, but in LCLs almost all of the cells had a predominantly cytoplasmic expression of this ribosomal protein, which was not detectably changed by EBER1. The changes in LCL gene expression identified here will provide a basis for identifying the mechanisms of action of EBER RNAs.

Background: Viral infections cause significant morbidity and mortality in patients with hematological malignancies. It remains uncertain whether viral vaccinations in these patients are supported by good evidence., Objectives: We aimed to determine the effectiveness and safety of viral vaccines in patients with hematological malignancies., Search Strategy: We searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL (June 2010), reference lists of relevant papers, abstracts from scientific meetings and contacted vaccine manufacturers., Selection Criteria: Randomized controlled trials (RCTs) evaluating viral vaccines in patients with hematological malignancies were included., Data Collection and Analysis: Relative risk (RR) was used for binary data and mean difference (MD) for continuous data. Primary outcome was incidence of infection. Secondary outcomes were mortality, incidence of complications and severe viral infection, hospitalization, immune response and adverse effects. Fixed-effect model was used in meta-analyses., Main Results: Eight RCTs were included, with 305 patients in the intervention groups and 288 in the control groups. They evaluated heat-inactivated varicella zoster virus (VZV) vaccine (two trials), influenza vaccines (five trials) and inactivated poliovirus vaccine (IPV) (one trial). Seven trials had high and one trial had moderate risk of bias.VZV vaccine might reduce herpes zoster compared to no vaccine (RR 0.54, 95% CI 0.3 to 1.0, P=0.05), but not statistically significant. Vaccination also demonstrated efficacy in immune response but frequently caused local adverse effects. One trial reported severity score of zoster, which favored vaccination (MD 2.6, 95% CI 0.94 to 4.26, P=0.002).Two RCTs compared inactivated influenza vaccine with no vaccine and reported lower risk of lower respiratory infections (RR 0.39, 95% CI 0.19 to 0.78, P=0.008) and hospitalization (RR 0.17, 95% CI 0.09 to 0.31, P<0.00001) in vaccine recipients. However, vaccine recipients more frequently experienced irritability and local adverse effects. There was no significant difference in seroconversion between one and two doses of influenza vaccine (one trial), or between recombinant and standard influenza vaccine (one trial), or influenza vaccine given with or without re-induction chemotherapy (one trial).The IPV trial comparing vaccination starting at 6 versus 18 months after stem cell transplant (SCT) found no significant difference in seroconversion., Authors' Conclusions: Inactivated VZV vaccine might reduce zoster severity in adult SCT recipients. Inactivated influenza vaccine might reduce respiratory infections and hospitalization in adults with multiple myeloma or children with leukemia or lymphoma. However, the quality of evidence is low. Local adverse effects occur frequently. Further high-quality RCTs are needed.

A standardized chelation protocol was applied by stratifying transfusion-dependent thalassemic patients into three groups, namely well chelated group (A), inadequately chelated group without (B) or with (C) risk of cardiac complications based on serum ferritin (SF) levels and magnetic resonance imaging (MRI) cardiac T2* measurements. Group A patients were advised to continue with deferoxamine (DFO) (Regimen Ic). Group B patients were given options of either intensification of DFO alone (Regimen Ii), deferiprone (L1) alone (Regimen II) or combined therapy with L1 and DFO (Regimen III). Group C patients were advised to take either Regimen Ii or Regimen III. The 1-year result showed that the combined therapy (Regimen III) significantly reduced SF level, cardiac and liver iron in the groups of inadequately chelated patients. The same set of outcome parameters was repeated at 2.5 years of treatment so as to evaluate the intermediate-term effects of this risk stratified chelation protocol. The number of patients with cardiac T2* <20 ms decreased from 34 (60%) at baseline to 17 (30%) of the whole cohort of 57 patients at the end of the study. There were further improvements in SF, cardiac and liver T2* in Group C patients. Significant improvement in left ventricular ejection fraction (LVEF) was demonstrated after 2.5 years of the combined therapy group in which the change was not initially apparent after the first year of assessment.

Positive controls have often been used in nonclinical and clinical cardiovascular safety studies to evaluate the study's assay sensitivity with respect to drug-induced prolongation of the QT interval of the electrocardiogram (ECG). If the study is able to detect such QT prolongation by the control, then a finding of negative QT effect of comparable size for the test drug will constitute evidence that the test drug does not in fact prolong the QT interval by the amount of regulatory concern. Current regulatory guidance regarding QT interval prolongation includes ICH S7B (nonclinical) and ICH E14 (clinical). However, the underlying null hypothesis settings of the two documents are quite different. This paper quantitatively evaluates the utility of positive controls in nonclinical and clinical studies in which a test drug and a positive control are simultaneously assessed in a study. The results show that positive controls, when powered at 80%, can be beneficial in 58% of nonclinical QT studies with Prob(S)=0.8; when powered at 90%, positive controls can be beneficial 73% of clinical QT studies with Prob(S)=0.9, where Prob(S) represents the probability of success with no QT risk at the stage of development., (2010. Published by Elsevier Inc.)

Summary: Zygomycetes are widely distributed in the environment as inhabitants of soil and decaying matter. On rare occasions, these organisms can cause invasive infections in immunocompromised hosts. As zygomycetes are resistant to most conventional antifungal agents, its infection is often fatal. We report 2 cases of unusual intra-abdominal Rhizopus microsporus infection in children with acute leukemia as a result of an unprecedented outbreak due to oral intake of contaminated allopurinol tablets and ready-to-eat food items. Among the 2 patients, one of them survived after aggressive combined surgical, antifungal (AmBisome, Caspofungin, and Posaconazole) and iron chelation therapy.

Background: Tumor lysis syndrome (TLS) is a serious complication of malignancies and can result in renal failure or death. Preliminary reports suggest that urate oxidase is highly effective in reducing serum uric acid. It is uncertain whether high quality evidence exists to support its routine use in children with malignancies., Objectives: We aimed to determine the effectiveness and safety of urate oxidase in the prevention and treatment of TLS in children with malignancies., Search Strategy: We performed a comprehensive search of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library issue 2, 2009), MEDLINE (1966 to 2009), EMBASE (1980 to 2009) and CINAHL (1982 to 2009)., Selection Criteria: Randomized controlled trials (RCT) and controlled clinical trials (CCT) evaluating 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 relative risk (RR) for binary data and mean difference (MD) for continuous data., Main Results: We included five trials, involved 336 patients in the treatment groups and 458 patients in the control groups. One RCT and three CCTs compared urate oxidase and allopurinol. Two trials tested Uricozyme and two tested rasburicase for the prevention of TLS. The RCT showed no significant difference in mortality or renal failure between the treatment and the control groups. The frequency of normalization of uric acid (RR 19.09, 95% CI 1.28 to 285.41) and area under curve of uric acid (MD -201, 95% CI to -258.05 to -143.95) were significantly better in the treatment group. One patient developed hemolysis. One CCT reported significantly lower mortality due to TLS (RR 0.05, 95% CI 0.00 to 0.89) and lower incidence of renal failure (RR 0.13, 95% CI 0.05 to 0.35) in the treatment group. Another CCT found significantly lower uric acid in the treatment group at 72 hours (MD -98.33, 95% CI -170.66 to -26) and 168 hours (MD -103.67, 95% CI -179.00 to -28.34). All included trials are highly susceptible to biases.Another included RCT with 30 patients compared different doses of rasburicase (0.2 mg/kg versus 0.15 mg/kg), which demonstrated similar efficacy in the reduction of uric acid. Adverse events occurred in 20% of patients, including hemolysis, hypersensitivity and anemia., Authors' Conclusions: Although urate oxidase might be effective in reducing serum uric acid, it is still unclear whether this translates into a reduction in mortality or renal failure. Clinicians should weigh the potential benefits of reducing uric acid and uncertain benefits of preventing renal failure or mortality from TLS against the potential risk of adverse effects.

In Epstein-Barr virus (EBV)-associated malignancies, the virus is harbored in every tumor cell and persists in tightly latent forms expressing a very limited number of viral latent proteins. Induction of EBV lytic cycle leads to expression of a much larger number of viral proteins, which may serve as potential therapeutic targets. We found that 4 histone deacetylase inhibitors, trichostatin A (TSA), sodium butyrate (SB), valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA), all significantly induced EBV lytic cycle in EBV-positive gastric carcinoma cells (AGS/BX1, latency II) but only weakly induced in Burkitt lymphoma cells (AK2003, latency I) and did not induce in lymphoblastoid cells (LCLs, latency III). Interestingly, SAHA potently induced viral lytic cycle in AGS/BX1 cells at micromolar concentrations (evidenced by 8-fold increase in viral DNA replication, strong expression of viral lytic proteins and production of infectious virus particles) and mediated enhanced cell death of EBV-positive AGS/BX1 cells when compared with that of EBV-negative AGS cells, possibly related to cell cycle arrest at G2/M phase. Furthermore, SAHA effected strong induction of EBV lytic cycle in nasopharyngeal carcinoma but not in NK lymphoma cells (both expressing EBV latency II pattern), indicating preferential viral lytic induction in epithelial rather than lymphoid malignancies. In conclusion, SAHA is found to be a potent EBV lytic cycle inducing agent, which warrants further investigation into its potential application as a novel virus-targeted drug for treatment of EBV-associated epithelial malignancies.

Chronic treatment with suprapharmacologic doses of peroxisome proliferator-activated receptor (PPAR) agonists has a known potential for causing left ventricular hypertrophy (LVH). The mechanism by which LVH develops is not well understood nor are biomarkers of it well characterized. Natriuretic peptides are important regulators of cardiac growth, blood volume, and arterial pressure and may be useful biomarkers of LVH and hemodynamic changes that precede it. We measured amino-terminal pro-atrial natriuretic peptide (NTproANP), amino-terminal pro-brain natriuretic peptide (NTproBNP), and cardiac troponin I (cTnI) concentrations in serum and plasma, as well as transcripts in left ventricular heart tissue for atrial natriuretic peptide precursor (Nppa), brain natriuretic peptide precursor (Nppb), and myosin heavy chain-beta (Myh7) as potential biomarkers of LVH induced by a PPARalpha/gamma dual agonist in Sprague-Dawley rats. We used magnetic resonance imaging, echocardiography, and hemodynamics to identify structural and functional cardiovascular changes related to the biomarkers. Heart-to-brain weight ratios (HW:BrW) were correlated with NTproANP, NTproBNP, and cTnI concentrations in serum as well as fold change in expression of Nppa and Nppb. LVH was characterized by increased left ventricular wall thickness and inner diameter, increased cardiac output, decreased arterial blood pressure, and increased heart rate. In these studies, each end point contributed to the early detection of LVH, the ability to monitor its progression, and demonstrated the ability of NTproANP concentration in serum to predict LVH and hemodynamic changes.

Tendons and entheses are magnetic resonance (MR) "invisible" when imaged with conventional clinical pulse sequences. When the highly ordered, collagen-rich fibers in tendons and entheses are placed at the magic angle, dipolar interactions are decreased and their T2s are often considerably increased. The bulk magnetic susceptibility of tendons and entheses also varies with orientation to B(0), leading to a direction-dependent resonance frequency shift. Ultrashort echo time (UTE) sequences with a minimum TE of 8 mus provide high signal from both tendons and entheses. The combination of a UTE sequence with an interleaved undersampled variable TE acquisition scheme provides a new approach for fast spectroscopic imaging of short T2 tissues. This UTE spectroscopic imaging (UTESI) technique provides quantitative information including T2, chemical shift and resonance frequency shift due to bulk susceptibility effect. In this article, the orientational effects on tendons and entheses were investigated using a UTESI sequence on a clinical 3-T scanner. T2 was found to increase fivefold for tendons and twofold for entheses due to the magic angle effect. A resonance frequency shift up to 1.2 ppm was observed for both tendons and entheses due to the bulk susceptibility effect when their orientation was changed from 0 degree to 90 degrees relative to B(0)., (Copyright 2010 Elsevier Inc. All rights reserved.)

Mesial temporal lobe epilepsy (MTLE) is a severe neurological condition of unknown pathogenesis for which several animal models have been developed. To obtain a better understanding of the underlying molecular mechanisms and identify potential biomarkers of lesion progression, we used a rat kainic acid (KA) treatment model of MTLE coupled with global gene expression analysis to examine temporal (four hours, days 3, 14, or 28) gene regulation relative to hippocampal histopathological changes. The authors recommend reviewing the companion histopathology paper (Sharma et al. 2008) to get a better understanding of the work presented here. Analysis of filtered gene expression data using Ingenuity Pathways Analysis (Ingenuity Systems, http://www.ingenuity.com) revealed that a number of genes pertaining to neuronal plasticity (RhoA, Rac1, Cdc42, BDNF, and Trk), neurodegeneration (Caspase3, Calpain 1, Bax, a Cytochrome c, and Smac/Diablo), and inflammation/immune-response pathways (TNF-alpha, CCL2, Cox2) were modulated in a temporal fashion after KA treatment. Expression changes for selected genes known to have a role in neuronal plasticity were subsequently validated by quantitative polymerase chain reaction (qPCR). Notably, canonical pathway analysis revealed that a number of genes within the axon guidance signaling canonical pathway were up-regulated from Days 3 to 28, which correlated with aberrant mossy fiber (MF) sprouting observed histologically beginning at Day 6. Importantly, analysis of the gene expression data also identified potential biomarkers for monitoring neurodegeneration (Cox2) and neuronal/synaptic plasticity (Kalrn).

Cardiac troponin I is a useful biomarker of myocardial injury, but its use in mice and application to early drug discovery are not well described. The authors investigated the relationship between cTnI concentration in serum and histologic lesions in heart tissue from mice treated with isoproterenol (ISO). Cardiac TnI concentrations in serum increased in a dose-dependant manner and remained increased twenty-four to forty-eight hours after a single administration of isoproterenol. Increased cTnI concentration was of greater magnitude and longer duration than increased fatty acid binding protein 3 concentration, aspartate aminotransferase activity, and creatine kinase activity in serum. Isoproterenol-induced increases in cTnI concentrations were both greater and more sustained in BALB/c than in CD1 mice and correlated with incidence and severity of lesions observed in heart sections from both strains. In drug development studies in BALB/c mice with novel kinase inhibitors, cTnI concentration was a reliable stand-alone biomarker of cardiac injury and was used in combination with measurements of in vivo target inhibition to demonstrate an off-target contribution to cardiotoxicity. Additional attributes, including low cost and rapid turnaround time, made cTnI concentration in serum invaluable for detecting cardiotoxicity, exploring structure-activity relationships, and prioritizing development of compounds with improved safety profiles early in drug discovery.

Our previous study showed that combined therapy with deferiprone (L1) and deferoxamine (DFO) was safe and efficacious in reducing iron overload in poorly-chelated thalassemia major patients for the short-term but the magnetic resonance imaging (MRI) T2* evaluation was not available at that time. Since October 2006, we applied a standardized chelation protocol by stratifying transfusion-dependent thalassemic patients into three groups, namely well-chelated group (A), poorly-chelated group without (B) or with (C) risk of cardiac complications, based on their serum ferritin (SF) levels and magnetic resonance imaging (MRI) cardiac T2* measurements. The patients in each group were given options of chelation regimens to improve their iron overload status. Chelation regimens included continuation or intensification of DFO alone (Regimen Ic or Ii, respectively), L1 alone (Regimen II), and combined therapy with L1 and DFO (Regimen III). Group A patients continued with Regimen Ic. Group B patients could opt for either Regimen Ii or II/III. Group C patients could opt for either Regimen Ii or III. Serum ferritin levels and MRI cardiac and liver T2* measurements were evaluated after 1 year of treatment. Fifty-seven patients (27 males, 30 females; age range 5-34 years, median: 25 years) were categorized into Group A (n = 3), B (n = 20) and C (n = 34). All Group A patients continued with DFO treatment. In Group B, seven were on Regimen Ii, five on Regimen II and five on Regimen III. In Group C, five were on Regimen Ii, two on Regimen II and 26 on Regimen III. Significant improvement was noted only for Group C patients using Regimen III (combined therapy) in SF levels, cardiac T2* and liver T2* measurements.

Introduction: Adrenergic blockade as a treatment for chronic heart failure (CHF) has proved effective, but its pharmacological mechanism on CHF remains unclear. In the past two decades, studies on heart rate variability (HRV) have reported that CHF patients generally have a reduced temporal complexity in heart rate variability. On the other hand, adrenergic blockers have been shown to restore such complexity. Fractal analysis is a novel and efficient tool to explore the adrenergic blockade effect on HRV. This paper applies the detrended fluctuation analysis (DFA) and multifractal DFA (MF-DFA) methods in an attempt to understand the effect of adrenergic blockade on cardiac dynamics in conscious beagle dogs., Methods: DFA and MF-DFA analysis are conducted on RR interval data generated from telemetry instrumented dogs receiving a combination of 15 mg/kg nadolol and 5 mg/kg phenoxybenzamine orally administered at the 22nd and 34th hour in a parallel design (n=12). All dogs had approximately 48 h of beat-to-beat heart rate measurements recorded in the left ventricle. Complexity measures for heartbeat series are compared between the blocker and vehicle group. We also compute traditional statistics for HRV and spectral parameters and examine their correlation with fractal analysis., Results: When compared to the vehicle group, the adrenergic blocker group had: 1) longer RR intervals (p=0.02) and lower beat-to-beat variability (p=0.04); 2) decreased low frequency (LF) and high frequency (HF) power (p=0.03), and higher LF-to-HF ratio; 3) larger middle-range scaling exponents (p<0.01); 4) broader multifractal spectra (p=0.03) with higher dominant singularity indices (p=0.02)., Discussion: Our results show that 1) adrenergic blockade alters the sympathovagal balance; 2) adrenergic blockers enhance the complexity of the cardiac dynamics; 3) the adrenergic blockade effect on cardiac dynamics is primarily the attenuation of small fluctuations in RR intervals. Fractal analysis also has the potential to be applied to early QT diagnosis.

Objectives: To review the treatment outcome of rhabdomyosarcoma in Hong Kong Chinese children., Design: Retrospective review., Setting: University teaching hospital, Hong Kong., Patients: Consecutive cases of rhabdomyosarcoma diagnosed and treated by the Department of Paediatrics and Adolescent Medicine of Queen Mary Hospital between 1989 and 2005. Each patient was staged and treated according to the Intergroup Rhabdomyosarcoma Study guidelines., Main Outcome Measures: Overall and event-free survival rates, and toxicity data., Results: Of 19 patients (8 males and 11 females), 14 (74%) were younger than 10 years old. The median age at diagnosis was 6 (range, 0.5-17) years. Primary sites of rhabdomyosarcoma included: the head and neck (n=8; 6 classified as cranial parameningeal), genitourinary (3), extremity (3), pelvis (3), and trunk (2). Thirteen (68%) had embryonal and six (32%) had alveolar histology. Two, 2, 9, and 6 were classified as belonging to Intergroup Rhabdomyosarcoma Study groups 1, 2, 3, and 4, respectively. Respective 5-year overall and event-free survival rates of the entire cohort were 49% (95% confidence interval, 26-73%) and 32% (10-55%), with a median follow-up of 3.4 (range, 0.2-16.7) years. In non-metastatic cases (Intergroup Rhabdomyosarcoma Study groups 1-3), the 5-year overall survival rate was 66% (95% confidence interval, 39-93%) and in metastatic cases (group 4) it was 17% (0-46%). The 5-year overall survival rate for patients aged less than 10 years was 60% (95% confidence interval, 33-87%) compared to 20% (0-55%) in those aged 10 years and over. Significant treatment-related toxicities including myelosuppression, infections, peripheral neuropathy, and second cancers were encountered., Conclusions: Treatment outcome of rhabdomyosarcoma in this cohort of Chinese children was less favourable than that reported in international studies. Whilst the main reason could have been related to the high proportion of metastatic cases, also non-metastatic cases faired worse. Improved outcomes may be achieved by advances in multidisciplinary (paediatric oncology, pathology, radiotherapy, and surgery) management and supportive care.

Secondary malignancies are an important cause of morbidity and mortality in childhood cancer survivors. Salivary gland tumors account for about 6% of the second cancers. The majority of these are mucoepidermoid carcinomas (MEC) of the parotid gland. We report the clinical and pathological features of a rarer histological type, acinic cell carcinoma (ACC), in a childhood acute lymphoblastic leukemia (ALL) survivor. The behavior of secondary ACC appears similar to primary tumor and similar treatment may be adopted. Early recognition and complete resection is important for achieving a good outcome. Careful monitoring for recurrence or a third malignancy is needed., ((c) 2007 Wiley-Liss, Inc.)

Autologous hematopoietic stem cell transplant (AHSCT) has been advocated as a form of salvage therapy for children with high-risk or relapsed brain tumors but only limited data are available currently. We report the outcomes of pediatric brain tumors treated with AHSCT in a quaternary referral center in Hong Kong over 10 years (June 1996-May 2006). Thirteen patients with medulloblastoma (n = 9), cerebral primitive neuroectodermal tumor (n = 1), ependymoma (n = 1), germ cell tumor (n = 1) and cerebellar rhabdoid (n = 1) were transplanted because of tumor residual (n = 1) or recurrence (n = 12). Uniform upfront treatment protocols were adopted according to specific tumor types. Prior to AHSCT, 8 patients (61.5%) achieved complete remission and 5 (38.5%) were in partial remission. Conditioning employed thiotepa 300 mg/m2, etoposide 250 mg/m2)and carboplatin 500 mg/m2 daily for 3 days. Toxicity included mucositis and neutropenic fever in all patients, grade 4 hepatic toxicity in 4 patients (including hepatic veno-occlusive disease in 2 patients) and grade 4 renal toxicity in 1 patient. The 5-year event-free survival was 53.9%. Five patients died of disease recurrence or progression 8-21 months after transplant with a median disease-free period of 8 months post-transplant. One died of transplant-related complications in the early post-transplant period. Seven survived for a median of 5.4 years (maximum follow-up of 9.8 years), with six having Lansky-Karnofsky performance score above 80. All survivors had complete remission before transplant though 2 had leptomeningeal spread. We conclude that AHSCT can achieve long-term survival in children with recurrent brain tumor. However, those with macroscopic residual tumor before transplant cannot be salvaged.

Introduction: The evaluation of drug disposition properties of chemical entities in drug discovery research typically involves the conduct of pharmacokinetic studies in rodents that requires blood sampling over several time points, preferably without disrupting the physiological status of the animals. Several blood withdrawal methods have been employed throughout the industry, yet these methods have not been comprehensively evaluated with regard to their effects on pharmacokinetic profiles of the drug investigated to recommend best practices., Methods: In this paper, the pharmacokinetics of six marketed drugs from four distinct therapeutic classes were compared using tail-vein, femoral-artery cannula-, and retro-orbital sinus bleeding techniques. The marketed drugs used in these studies were pentoxifylline, gemfibrozil, glipizide, methotrexate, clonidine, and fluoxetine., Results: Following oral administration, peak plasma concentration (C(max)), and area under the curve (AUC(0-24)) values for all compounds were not significantly different with the tail-vein method when compared to cannula- or retro-orbital sinus bleeding, except for fluoxetine and gemfibrozil for which minor, but statistically significant differences were observed. The effect of arterial versus venous tail-bleeding on the pharmacokinetics of pentoxifylline indicated no statistical differences in either C(max) or AUC(0-24) values. However, for fluoxetine, higher exposures were observed with tail arterial than venous sampling (2-fold with respect to C(max) and 1.7-fold with respect to AUC(0-24), p<0.05)., Discussion: The observed differences with fluoxetine may be due to its pharmacological effects on thermoregulatory responses that influence tail blood flow, a hypothesis that remains to be tested. Based on these observations, we recommend the tail-bleeding technique for pharmacology or toxicology exposure and F% studies, particularly in early discovery work. Retro-orbital bleeding is controversial and is no longer considered a humane method. Cannula-bleeding, especially coupled with automated blood-collection techniques, has become the most efficient way for pharmaceutical industry to perform rat bioavailability studies.

Introduction: The Health and Environmental Sciences Institute of the International Life Sciences Institute (ILSI/HESI) Cardiovascular Safety Subcommittee outlined a set of in vivo telemetry studies to determine how well this preclinical model identified compounds known to cause torsades de pointes (TdP) and prolong QT interval in humans. In the original analysis of these data, QT, QTcB (Bazett model), QTcF (Fridericia model), and QTcQ (animal-specific model) were evaluated. We further evaluate the statistical properties of these measurements, using a method that can properly account for the sources of variability in the dataset., Methods: The ILSI/HESI telemetry studies were conducted as a double Latin square design where eight dogs each received a vehicle control and three dose levels of a compound on four separate dosing days. We statistically analyzed the QT/QTc intervals using a repeated measures analysis of covariance and evaluate the powers for QT, QTcF and QTcQ based on simulations., Results: The analyses for QTcF and QTcB intervals show that all six compounds which were known to cause TdP in humans were identified as positive and all six compounds known to be free of TdP events in their clinical use had no statistically significant treatment-related effects, while the analyses for QTcQ identified all positive compounds except pimozide. The power analysis shows that the method can detect a 7% increment of QT, a 5% increment of QTcF, and a 4% increment of QTcQ, with greater than 80% of power when n=8., Discussion: We describe a repeated measures procedure to perform statistical analysis of covariance on Latin square designs and show that it can be used to detect meaningful changes in the analysis of QT/QTc intervals.

Two cases of spinal epidural hematoma and two cases of intracranial subdural hematoma after lumbar puncture (LP) are reported in children receiving chemotherapy for acute lymphoblastic leukemia and non-Hodgkin lymphoma. The bleeding was asymptomatic but interfered with treatment in one case, and caused either severe backache or headache but no neurological deficit in the other three patients. The platelet counts were 8 and 46 x 10(9)/L in two patients and were normal in the other patients at the time of LP. All recovered without surgical treatment. There is an inherent, albeit uncommon, risk of bleeding into the central nervous system associated with LP in children with cancer and should be distinguished from postdural puncture headache (PDPH). Thrombocytopenia is not always an accompanying factor.

A retrospective cohort of 163 children with 171 hematopoietic stem cell transplantation (HSCT) performed during Mar. 1992-Dec. 2005 were analyzed to evaluate the incidence, risk factors, management, and outcome of hemorrhagic cystitis (HC). Fourteen patients (8.2%) developed HC (6 boys, median age 6.6 years) at 0-166 days after HSCT (median 25 days), and lasted for 3-96 days (median 26 days). Older age at transplant (median 11.0 vs. 6.4 years, P = 0.013), allogeneic transplant (OR = 4.4, P = 0.02), cyclophosphamide-containing conditioning (OR = 4.87, P = 0.008), moderate-to-severe acute graft-versus-host disease (GVHD) (OR = 3.56, P = 0.025) and hepatic GVHD (OR = 3.62, P = 0.017) were associated with higher risks of HC in univariate but not multivariate analyses. While estrogen was ineffective in most patients, intravesical formalin, which was used in five patients, was found to be a very effective yet safe treatment for intractable HC. Patients with HC had longer hospital stay (median 175 vs. 88 days, P = 0.004). HC resolved after treatments in all cases but eight of the 14 patients subsequently died of other complications of HSCT. In conclusion, HC is a serious complication of allogeneic HSCT. Treatment with intravesical formalin appears effective and safe and can be considered early in severe HC to reduce the risk of morbidity and mortality.

Introduction: To account for heart rate-induced changes in the QT interval, correction formulas are generally applied to normalize the QT interval for heart rate. None of these formulas is entirely accurate because correction or normalization of any parameter in biology may introduce an additional source of variation in estimating the parameter. In this article, a one-step approach for the statistical analysis of the QT interval was proposed based on modeling the functional relationship between the QT interval and heart rate., Methods: The QT-HR relationship was incorporated into the statistical analysis to provide a model-based correction. This was accomplished by including HR as a covariate in the QT interval analysis. The approach was demonstrated using data generated from Lilly Research Laboratories. We compared the false positive rate and statistical power of QT, QTcF, and the proposed one-step method., Results: We found the one-step method demonstrated the greatest sensitivity in detecting a QT interval change without an increase in the false positive rate. It was shown that the one-step QT analysis could detect a 5%-6% increment of the QT interval. This is approximately equivalent to an increase of 11-13 ms in QT interval in beagle dogs., Discussion: Several advantages and unique features of the one-step method are discussed. These include evaluating treatment effect on QT without applying a heart rate correction formula and estimating QT difference flexibly at any selected heart rate. In addition to the linear QT-HR relationship, other functional relationships can be easily implemented to this approach.

Normal turnover of body tissues yields apoptotic cells while infections cause tissue injuries and cell necrosis. The interaction of these dying cells with dendritic cells (DCs) may provide immunological instructions leading to either immune tolerance or activation. We hypothesize that neonatal and adult DCs differ in their responses to dying cells, thereby contributing to the observed differences in immune responses between neonates and adults. We compare the outcome of interaction of cord and adult blood-derived DCs with dying Epstein-Barr-virus-transformed lymphoblastoid cells (LCLs) and the responsiveness to lipopolysaccharide. While cord DCs were able to phagocytose both apoptotic and necrotic LCLs, the subsequent responses differed significantly from those of adult DCs. Interaction of adult DCs with necrotic but not early apoptotic LCLs resulted in high expression of DC costimulatory molecules (CD80/CD86) and activation markers (CD83), production of both proinflammatory and anti-inflammatory cytokines (tumour necrosis factor-alpha, interleukin-10), and strong T-cell-stimulating activities. In contrast, in response to either necrotic or apoptotic LCLs, cord DCs had minimal up-regulation of those DC functional markers, little cytokine production and poor stimulation on T-cell proliferation. In response to lipopolysaccharide, however, both adult and cord DCs produced comparable levels of tumour necrosis factor-alpha and interleukin-10, but only adult DCs produced interleukin-12(p70). Taken together, these results suggest that neonatal DCs generally favour immune tolerance with minimal activation and cytokine production, except in extremely dangerous situations, such as bacterial sepsis, when neonatal DCs may produce certain types of cytokines and stimulate T-cell proliferation.

Introduction: We studied the statistical power of a replicated Latin square design where eight animals each receive a vehicle control and three dose levels of a drug on four separate dosing days. Cardiovascular parameters evaluated in the study were systolic arterial pressure, diastolic arterial pressure, left ventricular heart rate, and dP/dt(max)., Methods: Observations were simulated based on historical data and drug response profiles from cardiovascular safety pharmacology studies conducted at Lilly Research Laboratories. Statistical analysis for treatment effects was performed using a linear mixed model. Monotonicity of dose response was examined using sequential linear trend tests based on ordinal spacing of dose levels., Results: The replicated Latin square design for cardiovascular safety pharmacology studies is shown to have at least an 80% power of detecting changes from control of at least a 10% increment in systolic and diastolic pressure and a 15% increment in heart rate and dP/dt(max). The power is not sensitive to the shape of dose response profile over time., Discussion: Several unique features of our statistical power evaluation include the comparison of different covariance structures and drug response profiles. The procedure can also be applied to future power evaluations of other cardiovascular parameters, such as the QT interval, and the loss of statistical power due to missing observations.

Background: Interleukin (IL)-12 plays a vital role in regulating cell-mediated immunity against tuberculosis (TB)., Methods: To test whether IL12B genetic polymorphisms might contribute to human TB susceptibility, we examined the genotype frequencies of 5 IL12B polymorphisms (at promoter, intron 2, intron 4, exon 5, and 3' untranslated region [UTR]) in 516 patients with TB and 514 healthy control subjects from the Hong Kong Chinese population., Results: Individuals homozygous for the IL12B intron 2-repeat marker (ATT)8 had a 2.1-fold increased risk of developing TB (P < .001) (odds ratio, 2.14 [95% confidence interval, 1.45-3.19]). Estimation of the frequencies of multiple-locus haplotypes composed of IL12B promoter, intron 2, intron 4, and 3' UTR alleles revealed potential risk haplotypes (designated "A" and "K") and protective haplotypes (designated "B") for TB. Furthermore, combining the genotype data of the 4 informative IL12B loci revealed a strong association between a specific genotype pattern, termed "diplotype I" (heterozygous A and K haplotypes), and TB. In contrast, diplotype II (homozygous BB haplotypes) appeared protective against TB., Conclusions: These findings support the association between IL12B intron 2 polymorphism and TB and between specific IL12B haplotypes and TB.

Background: According to seroprevalence studies the majority of children in Hong Kong are infected by Epstein-Barr virus (EBV) before 10 years of age, but the characteristics of EBV-associated infectious mononucleosis (IM) in Chinese children are largely unreported. This study aims at defining the clinical presentation and complications of Chinese childhood IM in relation to age of the children., Methods: A retrospective study was performed on 77 consecutive Chinese childhood IM patients who fulfilled the serologic criteria for the diagnosis of primary EBV infection (viral capsid antigen IgM+ viral capsid antigen IgG+ Epstein-Barr nuclear antigen-). The clinical, hematologic and biochemical findings were evaluated among four age groups of <2 years, 2 to 4 years, 5 to 9 years and 10 to 15 years., Results and Conclusions: EBV-associated IM occurred at all age groups with a peak incidence at 2 to 4 years, corresponding to the rapid rise in the seroprevalence of EBV in early childhood in the Hong Kong Chinese. The majority of children presented with fever, tonsillopharyngitis, lymphadenopathy and hepatosplenomegaly, similar to the adult IM patients, and recovered without major complications. Marked lymphocytosis with the presence of atypical lymphocytes was a consistent hematologic finding in all age groups. The occurrence of hepatitis showed a clear association with advancing age (P = 0.003). The age-related increase in IM-associated hepatitis may reflect difference in the host immune response against EBV between the infants and older children.