Brain Microstructural Changes Associated With Neurocognitive Outcome in Intracranial Germ Cell Tumor Survivors.

BACKGROUND: Childhood intracranial germ cell tumor (GCT) survivors are prone to radiotherapy-related neurotoxicity, which can lead to neurocognitive dysfunctions. Diffusion kurtosis imaging (DKI) is a diffusion MRI technique that is sensitive to brain microstructural changes. This study aimed to investigate the association between DKI metrics versus cognitive and functional outcomes of childhood intracranial GCT survivors. METHODS: DKI was performed on childhood intracranial GCT survivors (n = 20) who had received cranial radiotherapy, and age and gender-matched healthy control subjects (n = 14). Neurocognitive assessment was performed using the Hong Kong Wechsler Intelligence Scales, and functional assessment was performed using the Lansky/Karnofsky performance scales (KPS). Survivors and healthy controls were compared using mixed effects model. Multiple regression analyses were performed to determine the effects of microstructural brain changes of the whole brain as well as the association between IQ and Karnofsky scores and the thereof. RESULTS: The mean Intelligence Quotient (IQ) of GCT survivors was 91.7 (95% CI 84.5 - 98.8), which was below the age-specific normative expected mean IQ (P = 0.013). The mean KPS score of GCT survivors was 85.5, which was significantly lower than that of controls (P < 0.001). Cognitive impairments were significantly associated with the presence of microstructural changes in white and grey matter, whereas functional impairments were mostly associated with microstructural changes in white matter. There were significant correlations between IQ versus the mean diffusivity (MD) and mean kurtosis (MK) of specific white matter regions. The IQ scores were negatively correlated with the MD of extensive grey matter regions. CONCLUSION: Our study identified vulnerable brain regions whose microstructural changes in white and grey matter were significantly associated with impaired cognitive and physical functioning in survivors of pediatric intracranial GCT.

Neurocognitive function, performance status, and quality of life in pediatric intracranial germ cell tumor survivors.

BACKGROUND: Intracranial germ cell tumors (GCT) are more common in Asia than in the West, accounting for about 15% of brain tumors in Asian children. The survival rate for intracranial GCT is excellent, but there are concerns about the effects of radiotherapy on neuropsychological function and quality of life of patients. METHODS: Intracranial germ cell tumors (GCT) are more common in Asia than in the West, accounting for about 15% of brain tumors in Asian children. The survival rate for intracranial GCT is excellent, but there are concerns about the effects of radiotherapy on neuropsychological function and quality of life of patients. Intracranial GCT survivors in Hong Kong aged ≥ 6 years who received cranial irradiation in the past 15 years were recruited. Neurocognitive function and performance status were assessed by the Hong Kong Wechsler Intelligence scale and Karnofsky/Lansky performance scales (KPS), respectively. Quality of life was assessed using the Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales. A chart review was performed for tumor characteristics and complications related to the tumor and its treatment. RESULTS: Twenty-five intracranial GCT survivors were recruited. Longer length of time since treatment was associated with lower IQ scores. Larger tumor size was associated with lower KPS scores. Hemiparesis, poor manual dexterity, and complications with multi-organ involvement were associated with significantly lower KPS scores. Higher irradiation dosage was associated with lower PedsQL physical scores. CONCLUSIONS: The majority of GCT survivors had average intellectual functioning, satisfactory performance status and relatively good quality of life, except in the physical aspect. Comprehensive evaluation and long-term follow-up of GCT survivors are essential to provide timely support and improve long-term outcomes.

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.

Recovery of humoral and cellular immunities to vaccine-preventable infectious diseases in pediatric oncology patients.

The recovery of antibodies to various vaccine-preventable infectious diseases, humoral and cellular immunity in pediatric oncology patients were evaluated by a prospective longitudinal study for 18 months. Lymphocyte subset (CD3+, CD4+, CD8+, CD16/56+, CD19+), CD4/CD8 ratio, immunoglobulin levels, antibodies to diphtheria, pertussis, tetanus, hepatitis B, measles, mumps, and rubella were measured serially at 6 months till 18 months after stopping all chemotherapy (including maintenance chemotherapy). Twenty-eight children (hematological malignancies, n = 14; solid tumors, n = 14) were studied. The median age was 7.0 +/- 3.8 years old (range 2.6-16.2 years old). Although there was significant increase in CD3+, CD4+, CD8+, CD19+ cells, IgG, IgA, and IgM levels (P < .05), CD4+ and CD8+ counts were still below the age-specific normal range at the end of study period. At 18 months after stopping chemotherapy, 11%, 15%, 60%, 30%, 49%, and 30% of subjects remained seronegative against diphtheria, tetanus, hepatitis B, measles, mumps, and rubella. This will evolve to a significant health care problem if no further intervention is implemented, as the survival rate of pediatric oncology patients improves significantly with the improvement in various cancer treatment protocols. Near complete immune recovery was demonstrated in the subjects. Significant proportion of subjects remained susceptible to vaccine-preventable infectious diseases up to 18 months after stopping all chemotherapy.

HHV-6 encephalitis in pediatric unrelated umbilical cord transplantation: a role for ganciclovir prophylaxis?

The role of ganciclovir as HHV-6 prophylaxis in unrelated HSCT setting remains controversial. We performed an eight-yr retrospective review of patients received unrelated HSCT from January 2000 to September 2008. From January 2002, ganciclovir prophylaxis 5 mg/kg twice daily for seven days for all unrelated HSCT before transplant was adopted. The prevalence of HHV-6 encephalitis was studied before and after the change in policy. Fifty-four unrelated HSCT were performed from January 2000 to September 2008. Four cases (7.4%) of HHV-6 encephalitis were diagnosed. All of them were due to variant B infection. Two cases out of 16 cases (12.5%) were diagnosed before adoption of the policy; two cases out of 38 cases (5.3%) were diagnosed afterward. All of them were unrelated UCB transplant recipients. They were all seropositive to HHV-6 before transplant. Two cases complicated with significant residual neurological deficit and refractory seizure. The other two cases died of other transplant-related mortalities. We conclude that HHV-6 encephalitis is still a rare complication of unrelated HSCT and may be more common in unrelated UCB transplant. Routine use of ganciclovir as HHV-6 prophylaxis in all unrelated HSCT recipients may not be justified but may have a role in unrelated UCB transplant.

Post-transplant EBV-related lymphoproliferative disorder complicating umbilical cord blood transplantation in patients of adrenoleukodystrophy.

EBV-associated post-transplant lymphoproliferative disorder (PTLD) is a well-recognized complication following solid organ transplantation and hematopoietic stem cell transplantation (HSCT) using bone marrow or peripheral blood as stem cell sources, but rarely reported in umbilical cord blood transplantation (UCBT). We report two cases in unrelated UCBT setting and added the following new information to the literature: (i) EBV-related PTLD can be presented late in recipients of unrelated UCBT; (ii) in contrast to reported literatures that PTLD is a serious complication with unfavorable outcome, especially in monomorphic form, our cases showed that the clinical course may be relatively benign if treatment is initiated promptly.

Humoral immune response after post-chemotherapy booster diphtheria-tetanus-pertussis vaccine in pediatric oncology patients.

BACKGROUND: The role of post-chemotherapy booster vaccination in pediatric oncology children remains to be established. In this randomized controlled study, we studied the effect of immune responses to diphtheria-tetanus-pertussis (DTP) booster vaccination in children 6 months after completing chemotherapy. METHODS: Children 1-18 years old with chemotherapy completed for 6 months (baseline) were eligible. Subjects were randomized into vaccine and control group. In the former, three doses of DTP vaccine (Aventis Pasteur Inc., Lyon, France) were administered. IgG antibody titers against diphtheria, tetanus, pertussis, hepatitis B, measles, mumps, and rubella antibodies were measured serially in vaccine and control groups. Subsets of circulating lymphocytes (CD3(+), CD4(+), CD8(+), CD19(+), and CD16/56(+)) were quantified by flow cytometry using fluorescence-labeled monoclonal antibodies. RESULTS: Fifty-six children (28 vaccinees; 28 controls) were enrolled. Protective antibody levels against diphtheria, tetanus, pertussis were found at baseline in 83.6%, 96.5%, 96.1% of them respectively. After three doses of DTP, all vaccinees demonstrated a sustain rise in antibody levels and the antibody titers were significantly higher than control group. 35.8% of subjects were susceptible to measles mumps and rubella infection and 69% showed anti-HBs antibody titer less than protective level up to 18 months after stopping chemotherapy. CONCLUSIONS: Post-chemotherapy booster vaccinations produced a strong and sustained effect in humoral immunity against vaccine-preventable infectious diseases.