CD9 shapes glucocorticoid sensitivity in pediatric B-cell precursor acute lymphoblastic leukemia.

Resistance to glucocorticoids (GCs), the common agents for remission induction in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), poses a significant therapeutic hurdle. Therefore, dissecting the mechanisms shaping GC resistance could lead to new treatment modalities. Here, we showed that CD9- BCP-ALL cells were preferentially resistant to prednisone and dexamethasone over other standard cytotoxic agents. Concordantly, we identified significantly more poor responders to the prednisone prephase among BCP-ALL patients with a CD9- phenotype, especially for those with adverse presenting features including older age, higher white cell count and BCR-ABL1. Furthermore, gain- and loss-of-function experiments dictated a definitive functional linkage between CD9 expression and GC susceptibility, as demonstrated by the reversal and acquisition of relative GC resistance in CD9low and CD9high BCP-ALL cells, respectively. Despite physical binding to the GC receptor NR3C1, CD9 did not alter its expression, phosphorylation or nuclear translocation but potentiated the induction of GC-responsive genes in GCresistant cells. Importantly, the MEK inhibitor trametinib exhibited higher synergy with GCs against CD9- than CD9+ lymphoblasts to reverse drug resistance in vitro and in vivo. Collectively, our results elucidate a previously unrecognized regulatory function of CD9 in GC sensitivity, and inform new strategies for management of children with resistant BCP-ALL.

Remote Ischemic Conditioning in Pediatric Cancer Patients Receiving Anthracycline Chemotherapy: A Sham-Controlled Single-Blind Randomized Trial.

Background: Anthracycline cardiotoxicity is a concern in survivors of childhood cancers. Recent evidence suggests that remote ischemic conditioning (RIC) may offer myocardial protection. Objectives: This randomized sham-controlled single-blind study tested the hypothesis that RIC may reduce myocardial injury in pediatric cancer patients receiving anthracycline chemotherapy. Methods: We performed a phase 2 sham-controlled single-blind randomized controlled trial to determine the impact of RIC on myocardial injury in pediatric cancer patients receiving anthracycline-based chemotherapy. Patients were randomized to receive RIC (3 cycles of 5-minute inflation of a blood pressure cuff placed over 1 limb to 15 mm Hg above systolic pressure) or sham intervention. The intervention was applied within 60 minutes before initiation of the first dose and before up to 4 cycles of anthracycline therapy. The primary outcome was the plasma high-sensitivity cardiac troponin T (hs-cTnT) level. The secondary outcome measures included echocardiographic indexes of left ventricular systolic and diastolic function and the occurrence of cardiovascular events. Results: A total of 68 children 10.9 ± 3.9 years of age were randomized to receive RIC (n = 34) or sham (n = 34) intervention. Plasma levels of hs-cTnT showed a progressive increase across time points in the RIC (P < 0.001) and sham (P < 0.001) groups. At each of the time points, there were no significant differences in hs-cTnT levels or LV tissue Doppler and strain parameters between the 2 groups (all P > 0.05). None of the patients developed heart failure or cardiac arrhythmias. Conclusions: RIC did not exhibit cardioprotective effects in childhood cancer patients receiving anthracycline-based chemotherapy. (Remote Ischaemic Preconditioning in Childhood Cancer [RIPC]; NCT03166813).

The incidence, risk factors, and outcomes of symptomatic avascular necrosis of bone among Chinese pediatric patients with acute lymphoblastic leukemia.

BACKGROUND: Avascular necrosis (AVN) of bone is a debilitating complication of pediatric patients with acute lymphoblastic leukemia (ALL). While it is extensively studied and reported in Western population, studies focused on Orientals are limited. This study aims to evaluate the incidence, risk factors, and clinical outcomes of AVN among Chinese children with ALL. METHODS: This study is a retrospective, territory-wide population-based cohort study of pediatric patients with ALL enrolled on one of the three consecutive ALL study protocols (ALL-IC-BFM 2002, CCLG-ALL 2008, and CCCG-ALL 2015). RESULTS: A total of 24 out of 533 pediatric subjects with ALL (4.5%) had symptomatic AVN. Age was the single most important risk factor associated with the development of AVN. Only three patients were below age of 10 at the time of diagnosis of ALL. The incidences of AVN in patients aged above and below 10 years were 18.2% ± 3.6% and 0.8% ± 0.5%, respectively, and were significantly different (p < 0.005). Treatment protocol, immunophenotype, and gender were not predictive of AVN. Among the 24 patients, five required orthopedic interventions in view of progressive and severe disease. For subjects with hip joints involvement, follow-up assessments showed 12 of 22 hip joints had radiological progression over a median duration of 3.63 years. Seventeen of them did not have pain at the latest follow-up and among patients with pain (n = 7), five did not experience any limitation on activities of daily living while two required use of walking aids or wheelchair. CONCLUSION: The incidence of symptomatic AVN in Chinese ALL patients was comparable to other studies in Western population. Adolescent age more than 10 years old was recognized to be the most important factor for development of AVN. Significant proportion of patients had radiological progression over time with a small percentage of subjects had daily activities affected.

Pharmacogenomic Profiling of Pediatric Acute Myeloid Leukemia to Identify Therapeutic Vulnerabilities and Inform Functional Precision Medicine.

Despite the expanding portfolio of targeted therapies for adults with acute myeloid leukemia (AML), direct implementation in children is challenging due to inherent differences in underlying genetics. Here we established the pharmacologic profile of pediatric AML by screening myeloblast sensitivity to approved and investigational agents, revealing candidates of immediate clinical relevance. Drug responses ex vivo correlated with patient characteristics, exhibited age-specific alterations, and concorded with activities in xenograft models. Integration with genomic data uncovered new gene-drug associations, suggesting actionable therapeutic vulnerabilities. Transcriptome profiling further identified gene-expression signatures associated with on- and off-target drug responses. We also demonstrated the feasibility of drug screening-guided treatment for children with high-risk AML, with two evaluable cases achieving remission. Collectively, this study offers a high-dimensional gene-drug clinical data set that could be leveraged to research the unique biology of pediatric AML and sets the stage for realizing functional precision medicine for the clinical management of the disease. SIGNIFICANCE: We conducted integrated drug and genomic profiling of patient biopsies to build the functional genomic landscape of pediatric AML. Age-specific differences in drug response and new gene-drug interactions were identified. The feasibility of functional precision medicine-guided management of children with high-risk AML was successfully demonstrated in two evaluable clinical cases. This article is highlighted in the In This Issue feature, p. 476.

Outcome prediction of chronic myeloid leukemia (CML) in children.

We evaluated the feasibility of existing risk assessment tools for chronic myeloid leukemia (CML) in children. Fifty-five patients with newly diagnosed CML between 1996 and 2019 were included. Forty-nine patients presented in chronic phase, thirty-six of whom were treated with upfront tyrosine kinase inhibitor (CP-TKI group); one presented in accelerated phase and four in blastic phase. Treatment, survival, responses, and tolerance were evaluated. All patients in the CP-TKI group received imatinib as their first TKI treatment. The 10-year overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) of TKI-treated group was 97%, 91.4%, and 72.3%, respectively. At 60 months, the rates of major molecular response were 81.2% and deep molecular response was 67.5%. The EUTOS long-term survival (ELTS) risk grouping did not predict OS, PFS, or EFS. The IMAFAIL risk groups were correlated with the risk of imatinib failure. Further studies are required to modify the existing risk assessment tools for children.

CD9 blockade suppresses disease progression of high-risk pediatric B-cell precursor acute lymphoblastic leukemia and enhances chemosensitivity.

CD9 has been implicated in cancer progression but its prognostic relevance and therapeutic potential in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are largely unknown. In a cohort of pediatric BCP-ALL patients, we found that CD9+ cases had a significantly lower 5-year relapse-free survival rate than CD9- cases. Multivariate analysis demonstrated that CD9 positivity independently predicted inferior survival outcomes, and could be applied with established prognostic features, including prednisone response and cytogenetic status, to refine patient stratification. Administration of CD9 antibody substantially suppressed disease progression in NOD/SCID mice xenografted with CD9+ cell lines and primary leukemic blasts from patients with high-risk and refractory BCP-ALL, without compromising hematopoietic stem cell engraftment. Combination of anti-CD9 with conventional chemotherapy further reduced leukemic burden and prolonged animal survival. Mechanistically, CD9 blockade inhibited leukemic cell proliferation, induced G0/G1 cell cycle arrest, activated p38, and enhanced chemotherapeutic agent-induced apoptosis. Further, CD9 physically interacted with integrin very late antigen-4, regulated affinity to vascular cell adhesion molecule-1, and was involved in leukemia-stroma interaction. Collectively, our study established CD9 as a new prognostic marker, validated the preclinical efficacy of CD9 antibody, and laid the foundation for clinical development of CD9-targeted therapy for high-risk and refractory pediatric BCP-ALL.

Late outcomes in children with Langerhans cell histiocytosis.

INTRODUCTION: Langerhans cell histiocytosis (LCH) is a rare disease with diverse clinical courses. Despite improvement in survival outcomes in the recent decades, sequelae of the disease remain a concern. This study aimed to provide information on the long-term outcomes in patients with LCH, particularly on the sequelae and any associated factors. METHOD: Medical records of patients with diagnosis of LCH and being managed in our centre were retrospectively reviewed. Data on the courses of illness, mortality, intervention, types and time of late events were collected and analysed. RESULTS: 70 patients were included with a mean observation time of 12 years (median 10.7 years, range 1-31.3 years). Sequelae related to LCH were present in 56% (n=39), being more common in multisystem diseases and patients with reactivations. Prevalence of sequelae is as follows: orthopaedic related 27%, diabetes insipidus 19%, growth retardation 13%, cosmetic 10%, neurological 7%, hearing 7%, anterior pituitary hormone deficiency 7%, hepatobiliary 4% and ophthalmological 3%. Neurological sequelae could manifest even 10 years after initial diagnosis of LCH. Reactivations, presence of central nervous system (CNS) risk lesions and treatment with radiotherapy were associated with a higher rate of sequelae. The cumulative incidence of reactivation was 34%. Most reactivations occurred in the first 2.5 years after diagnosis. CONCLUSION: Sequelae were common after LCH, although some were mild. Neurological sequelae could be particularly severe and debilitating. Vigilant long-term follow-up would be essential for optimising patient outcomes. Further studies on the prevention and treatment of CNS disease of LCH are warranted.

Myocardial stiffness as assessed by diastolic wall strain in adult survivors of childhood leukaemias with preserved left ventricular ejection fraction.

AIMS: We tested the hypothesis that myocardial stiffness as assessed by diastolic wall strain (DWS) is altered in adult survivors of childhood leukaemias with preserved left ventricular (LV) ejection fraction and explored its association with myocardial fibrosis and diastolic deformation. METHODS AND RESULTS: Ninety-four (53 males) adult survivors of childhood leukaemias aged 22.2 ± 5.5 years and 66 (36 males) healthy controls were studied retrospectively. Diastolic wall strain and calibrated integrated backscatter (cIB) were measured as indices of myocardial stiffness and fibrosis, respectively. Left and right ventricular (RV) diastolic and torsional mechanics were interrogated using speckle tracking echocardiography. Patients had significantly lower LV DWS, and hence stiffer LV myocardium, and greater myocardial cIB in patients than controls (all P < 0.001). Left ventricular longitudinal, radial, and circumferential early diastolic strain rates, circumferential late diastolic strain rate, and peak twisting and untwisting velocities, tricuspid annular early diastolic velocity, and RV-free wall longitudinal early diastolic strain rate were significantly lower in patients than controls (all P < 0.05). Diastolic wall strain correlated inversely with myocardial cIB, and positively with LV longitudinal, radial, and circumferential early diastolic strain rates (all P < 0.05), while myocardial cIB correlated inversely with LV radial and circumferential early diastolic strain rates, circumferential late diastolic strain rate, peak twisting and untwisting velocities, and tricuspid annular e velocity (all P < 0.05). CONCLUSION: In adult survivors of childhood leukaemias, despite the preservation of LV ejection fraction, increased stiffness of the LV myocardium is evident and is associated with myocardial fibrosis and impaired ventricular diastolic function.

Neonatal Haemophagocytic Lymphohistiocytosis Associated with Maternal Adult-Onset Still's Disease.

Neonatal haemophagocytic lymphohistiocytosis (HLH) is a rare but potentially lethal condition. We recently encountered a preterm infant who developed severe HLH associated with maternal adult-onset Still's disease, which to our knowledge has not been previously reported. The infant presented with fever, generalised lymphadenopathy, transient erythematous skin rash, hepatosplenomegaly, ascites, pancytopenia, marked hyperferritinaemia, and hypofibrinogenaemia, which were features similar to maternal presentation during late pregnancy. Whole gene exome sequencing screening for familial HLH (PRF1, STX11, STXBP2, and MUNC13D genes) was negative. We postulated that factors such as auto-antibodies, antigens, or inflammatory mediators transmitted vertically from the mother could have triggered the intense inflammation in the infant. The infant responded promptly to dexamethasone, etoposide, and cyclosporin A, without the need for bone marrow transplantation. Neonatologists should be alerted to the rare diagnosis of HLH in the presence of active maternal diseases, including infection or autoimmune conditions, especially in association with fever, cytopenia, and hepatosplenomegaly.

Indiscernible Benefit of Double-Unit Umbilical Cord Blood Transplantation in Children: A Single-Center Experience From Hong Kong.

Double-unit umbilical cord blood (DU-UCB) may extend the use of UCB transplantation and improve clinical outcomes. Data in the literature show that single-unit dominance happened in a vast majority of recipients, and the mechanism is unknown. We examined the clinical relevance and engraftment kinetics of DU-UCB transplant in 65 consecutive children who underwent unrelated single-unit (n = 25) and double-unit (n = 40) UCB transplantation for various hematological malignancies (n = 45) and nonmalignant disorders (n = 20). Our result showed no discernible benefit to children receiving double-unit transplant over those receiving single-unit transplant when the total nucleated cell (TNC) doses are ≥2.5 × 10(7)/kg, in terms of the hastening of the engraftment of neutrophils and platelets, reduction of nonengraftment, disease recurrence, early mortality, and graft-versus-host disease, despite significantly higher numbers of TNCs in double units. Further analyses demonstrated that the phenomena were not associated with underlying disease, duration of UCB storage, postthaw viability, HLA disparity, ABO incompatibility, gender, or doses of TNCs, CD34(+) cells, CD3(+) cells, or colony-forming units. Engrafting units in DU-UCB transplants were notably associated with higher CD34(+) cell dose. Chimerism studies demonstrated that single-unit dominance started before neutrophil engraftment in DU-UCB transplants. Data from the study suggested no advantage of infusing double-unit UCB, if an adequately dosed single-unit UCB is available. Successful prediction of the dominant graft would optimize algorithms of UCB selection and maximize the long-term engraftment of chosen units.

Myocardial iron load and fibrosis in long term survivors of childhood leukemia.

BACKGROUND: We sought to assess myocardial iron load and fibrosis, which may potentially affect cardiac function, in adult survivors of childhood leukemias and their relationships with left (LV) and right ventricular (RV) function. PROCEDURE: Fifty-eight (33 males) adult survivors, aged 24.5 ± 4.4, underwent cardiac magnetic resonance (CMR) at 16.6 ± 5.8 years after completion of treatment. Myocardial iron load and fibrosis were quantified using respectively T2* scan and late gadolinium enhancement. Right and left ventricular ejection fraction (EF) was measured by CMR, while myocardial function was assessed using tissue Doppler imaging. RESULTS: None of the survivors had significant myocardial iron overload (T2*<20 msec). The prevalence of LV and RV fibrosis was 9% (5/58) and 38% (22/58), respectively. Left ventricular EF was subnormal (EF 45-<55%) in 9% (5/58), while RV EF was abnormal (EF <45%) in 12% (7/58) and subnormal in 34% (20/58) of survivors. Patients with LV fibrosis had significantly lower mitral annular early diastolic velocity (P = 0.01) and smaller LV end-systolic volume (P = 0.02), while those with RV fibrosis had significantly lower tricuspid late diastolic annular velocity (P = 0.02) and early to late diastolic annular velocity ratio (P = 0.02) compared to those without. Cumulative anthracycline dose correlated with early diastolic mitral (r = -0.28, P = 0.038) and tricuspid (r = -0.40, P = 0.002) annular velocities, but not LV and RV EF or fibrosis (all P > 0.05). CONCLUSION: Ventricular fibrosis may occur in long term survivors of childhood leukemias and is related to diastolic function in the absence of significant myocardial iron overload.

Variants of cardiomyopathy and hypertension in neuroblastoma.

Catecholamine-associated cardiomyopathies caused by neuroblastoma have rarely been reported. We are reporting 2 cases of neuroblastoma associated with hypertension and severe cardiomyopathic changes in different extremes. One case was dilated cardiomyopathy with heart failure, and the other showed echocardiographic features simulating hypertrophic obstructive cardiomyopathy. Both girls had high levels of urine catecholamines on presentation. Anthracycline group of chemotherapy was avoided. Chemotherapy and tumor resection resulted in successful normalization of blood pressure and regression of cardiomyopathic changes. Blood pressure and cardiomyopathic changes should be monitored not only at presentation, but also during the treatment for neuroblastoma.

Plasma high sensitivity troponin T levels in adult survivors of childhood leukaemias: determinants and associations with cardiac function.

BACKGROUND: We sought to quantify plasma high sensitivity cardiac troponin (hs-cTnT) levels, their determinants, and their associations with left ventricular (LV) myocardial deformation in adult survivors of childhood acute leukaemias. METHODS AND RESULTS: One hundred adult survivors (57 males) of childhood acute leukaemias, aged 24.1 ± 4.2 years, and 42 age-matched controls (26 males) were studied. Plasma cTnT was determined using a highly sensitive assay. Genotyping of NAD(P)H oxidase and multidrug resistance protein polymorphisms was performed. Left ventricular function was assessed by conventional, three-dimensional, and speckle tracking echocardiography. The medians (interquartile range) of hs-cTnT in male and female survivors were 4.9 (4.2 to 7.2) ng/L and 1.0 (1.0 to 3.5) ng/L, respectively. Nineteen survivors (13 males, 6 females) (19%) had elevated hs-cTnT (>95(th) centile of controls). Compared to those without elevated hs-TnT levels, these subjects had received larger cumulative anthracycline dose and were more likely to have leukaemic relapse, stem cell transplant, and cardiac irradiation. Their LV systolic and early diastolic myocardial velocities, isovolumic acceleration, and systolic longitudinal strain rate were significantly lower. Survivors having CT/TT at CYBA rs4673 had higher hs-cTnT levels than those with CC genotype. Functionally, increased hs-cTnT levels were associated with worse LV longitudinal systolic strain and systolic and diastolic strain rates. CONCLUSIONS: Increased hs-cTnT levels occur in a significant proportion of adult survivors of childhood acute leukaemias and are associated with larger cumulative anthracycline dose received, history of leukaemic relapse, stem cell transplant, and cardiac irradiation, genetic variants in free radical metabolism, and worse LV myocardial deformation.

Prognosis and outcome of relapsed acute lymphoblastic leukemia: a Hong Kong Pediatric Hematology and Oncology Study Group report.

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.

Intact survival of refractory CMV limbic encephalitis in a patient with severe aplastic anemia after unrelated bone marrow transplantation.

We described a patient of refractory cytomegalovirus (CMV) limbic encephalitis who received matched unrelated bone marrow transplantation. Pyrosequencing study on serial cerebrospinal fluid samples revealed the emergence of resistant strains associated with exposure of antiviral agents. Combinations of antiviral agents had a role in partial suppression of CMV viral load but the clearance of virus mainly relied on the recovery of host's immunity and resulted in intact survival of host. Donor's CMV-seronegative status may contribute to the delay in controlling this serious infection. Prompt identification of drug-resistant mutant helps in selection of antiviral agents.

Humoral response to conjugate pneumococcal vaccine in paediatric oncology patients.

OBJECTIVE: Pneumococcal conjugate vaccine (PCV) is an effective way to prevent invasive pneumococcal diseases in high risk populations. The efficacy of this vaccine in paediatric oncology patients remains unknown. DESIGN AND SETTING: The authors evaluated the antibody response to seven pneumococcal serotypes in paediatric oncology patients given two doses of heptavalent PCV (PCV-7). RESULTS: Forty-four patients (20 males; 24 females) with median age 9.5 years were studied. After two doses of PCV-7, 86-100% of patients had protective antibody titres against the seven vaccine serotypes. Increases in geometric mean antibody concentrations ranged from 3.8-fold for serotype 19F to 85.8-fold for serotype 14. There was no documented invasive pneumococcal disease in our cohort during the study period. CONCLUSION: PCV can elicit protective antipneumococcal antibody responses in paediatric oncology patients.

Improved survival outcome of childhood acute myeloid leukemia with intensified chemotherapy in Chinese children.

With the use of intensive chemotherapy and hematopoietic stem cell transplantation (HSCT), the prognosis of childhood acute myeloid leukemia (AML) improved over the last 2 decades. Survival data of Chinese pediatric patients were seldom reported. The authors adopted modified UK Medical Research Council (MRC) AML protocols for treatment of childhood AML since 1994. From 1994 to 2008, the outcomes of Chinese AML patients were studied. Sixty-eight patients were studied. The median age at diagnosis was 9.9 years. Twenty-five patients (36.8%) had favorable cytogenetic karyotypes, including t(15;17), t(8;21) and inv(16). Complete remission (CR) rate was 91.2%. The relapse rate was 29.4%. For non-M3 patients, the 5-year overall survival (pOS) was 64% ± 7% and event-free survival (pEFS) was 53% ± 7%. For those non-good-risk patients who achieved CR, there were no significant differences in outcomes between patients who received HSCT in CR1 and those received chemotherapy alone (5-year pOS 80% ± 13% and 69% ± 9%, P = .52), 5-year pEFS 69% ± 15% and 55% ± 10%, P = .40). The pOS of the 20 relapsed patients was 29% ± 11%. Sixteen patients with t(8;21) and inv(16) had similar outcome with those without favorable cytogenetics (pOS 66% ± 12% versus 65% ± 7%, P = .39; pEFS 60% ± 11% versus 54% ± 8%, P = .45). Patients who achieved CR after 2 or more courses of chemotherapy and presenting white blood cell count (WBC) ≥ 100 × 10(9)/L had poorer outcome (pOS 40% versus 80%P < .01; 43% versus 70%, P = .02, respectively). Intensified chemotherapy improved outcome of Chinese AML children. CR after first course of chemotherapy and WBC at diagnosis were important prognostic factors.

Second malignant neoplasms in childhood cancer survivors in a tertiary paediatric oncology centre in Hong Kong, China.

BACKGROUND: Childhood cancer survivors were at risk of development of second malignant neoplasms. The aim of this study is to evaluate the incidence, risk factors and outcome of second malignant neoplasms in childhood cancer survivors in a tertiary paediatric oncology centre in Hong Kong, China. METHODS: We performed a retrospective review of patients with childhood cancer treated in Children's Cancer Centre in Prince of Wales Hospital, Hong Kong, China between May 1984 and June 2009. Case records of patients who developed second malignant neoplasms were reviewed. RESULTS: Totally 1374 new cases aged less than 21-year old were treated in our centre in this 25-year study period. Twelve cases developed second malignant neoplasms with 10-year and 20-year cumulative incidence of 1.3% (95% confidence interval 0.3% - 2.3%) and 2.9% (95% confidence interval 1.1% - 4.7%) respectively. Another 4 cases were referred to us from other centres for the management of second malignant neoplasms. In this cohort of 16 children with second malignant neoplasms, the most frequent second malignant neoplasms were acute leukemia or myelodysplastic syndrome (n = 6) and central nervous system tumor (n = 4). Median interval between diagnosis of primary and second malignant neoplasms was 7.4 years (range 2.1 - 13.3 years). Eight patients developed second solid tumor within the previous irradiated field. Radiotherapy significantly increased the risk of development of second solid tumor in patients with acute lymphoblastic leukemia (P = 0.027). Seven out of 16 patients who developed second malignant neoplasms had a family history of cancer among the first or second-degree relatives. Nine patients died of progression of second malignant neoplasms, mainly resulted from second central nervous system tumor and osteosarcoma. CONCLUSIONS: Cumulative incidence of second cancer in our centre was comparable to western countries. Radiotherapy was associated with second solid tumour among patients with acute lymphoblastic leukemia. Patients who developed second brain tumor and osteosarcoma had a poor outcome.

Lymphoproliferative response to herpes simplex virus type 1, cytomegalovirus, Epstein-Barr virus, varicella zoster virus, human herpes virus 6, 7, and 8 antigen stimulation in pediatric allogeneic stem cell transplant recipients.

We evaluate the recovery of CMI to various herpes viruses by measuring in vitro LPR to specific recall antigens. CMI was evaluated by the in vitro LPR of PBMC to specific purified HSV-1, VZV, CMV, EBV, HHV-6, -7, -8, antigens. Results were expressed as SI. SI > or = 3 was regarded as positive LPR. Serial measurements were taken prospectively from pretransplant till 12-month post-transplant. Thirty-six patients (M = 19; F = 17) with median age 10.5 yr old were recruited. Most transplants were from MSD with PBSC as the stem cell source. Altogether 50% of subjects started to show positive LPR to HSV-1, CMV, and VZV antigens at two-month post-transplant, major upsurges were noted until 6-month post-transplant. Subjects showed positive LPR to EBV, HHV-6, HHV-7, and HHV-8 antigens were all along <50% throughout the study period. The antibody status of donor and recipient for HSV-1, CMV, and VZV were associated with the timing of recovery of CMI. Choice of donor and stem cell source were important determinants of eventual LPR to various herpes viruses at 3-month post-transplant. At 12-month post-transplant, there was no statistical difference in any parameters in affecting LPR to different herpes viruses.