Reduced Dose Intensity of Daunorubicin During Remission Induction for Low-Risk Patients With Acute Lymphoblastic Leukemia: A Retrospective Cohort Study of the Chinese Children's Cancer Group.

It is urgently necessary to reduce the adverse effects of chemotherapy while maintaining their cure high rates for children with acute lymphoblastic leukemia (ALL). The present study aimed to determine whether the dose intensity of daunorubicin during the remission-induction phase could be reduced for low-risk patients with ALL. A total of 2396 eligible patients, who participated in CCCG-ALL-2015 study and were provisionally assigned to the low-risk group, were included and divided into single-dose group and double-dose group according to the dosage of daunorubicin during the remission-induction phase. For patients with ETV6-RUNX1 positive ALL or hyperdiploidy ALL, there were no significant differences in outcomes between the two groups. For other patients, the 5-year event-free survival rate was significantly better and the 5-year cumulative risk of any relapse was significantly lower in the double-dose group compared with the single-dose group. Both the 5-year overall survival rate and the risk of early deaths were not significantly different between the two groups. Our results suggested that only B-lineage ALL patients with ETV6-RUNX1 positivity or hyperdiploidy who achieved an early negative minimal residual disease status were suitable candidates for dosage reduction of daunorubicin during the remission-induction phase. Clinical Trial Registration: http://www.chictr.org.cn/showproj.aspx?proj=10115, identifier ChiCTR-IPR-14005706.

Prevalence and risk factors of fractures in transfusion dependent thalassemia - A Hong Kong Chinese population cohort.

OBJECTIVE: To delineate the prevalence and associated risk factors of low BMD, osteoporosis/bone fragility and fracture in transfusion-dependent thalassemia (TDT) in the Chinese population in Hong Kong. DESIGN, PATIENTS AND MEASUREMENTS: A retrospective cohort study design was employed. Patients of TDT who had serial Hologic dual-energy X-ray absorptiometry (DXA) from 2010 to 2016 and received regular transfusion for at least 5 years were recruited. Clinical and biochemical data, from 5 years before the first DXA scan, were retrieved from the electronic record system of the Hospital Authority, till 30 June 2020. Low bone mineral density and osteoporosis/bone fragility are defined by the ISCD 2019 position guidelines. RESULTS: Seventy-seven patients were included in the analysis. The fracture prevalence of TDT among the Chinese population in Hong Kong was 15.58%. Up to 55.84% of patients had low bone mineral density, and 5.19% patients had osteoporosis/bone fragility state. The median age at first fracture was 31.73 years (range 24.06-44.18 years). In the regression analysis, a higher log(10) transformation of average ferritin levels over 5 years before the first DXA scan was significantly associated with fracture occurrence regardless of bisphosphonate treatment (OR 310.73, 95% CI 3.99-24183.89, p = .010). Mean average ferritin level over 5 years was 6695.5 ± 2365.7 pmol/L (fracture group) versus 4350.7 ± 3103.2 pmol/L (non-fracture group), p = .016. Hip and spine BMD Z-score did not have statistically significant association with fracture occurrence. CONCLUSION: Iron overloading plays an important role in adverse bone health in TDT. Dual X-ray densitometry is insufficient in predicting fracture risk.

Drug resistant epilepsy with mesial temporal sclerosis as possible late neurological complication in two AML survivors after stem cell transplantation.

•Mesial temporal sclerosis (MTS) is a potential late complication of hematological malignancies.•Seizures are usually drug resistant with MTS yet seizure freedom may be achieved by surgery.•Early evaluation for epilepsy surgery is warranted for drug resistant seizures due to AML.

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.

The impact of positron emission tomography on primary tumour delineation and dosimetric outcome in intensity modulated radiotherapy of early T-stage nasopharyngeal carcinoma.

BACKGROUND: In intensity modulated radiotherapy (IMRT) of nasopharyngeal carcinoma (NPC), accurate delineation of the gross tumour volume (GTV) is important. Image registration of CT and MRI has been routinely used in treatment planning. With recent development of positron emission tomography (PET), the aims of this study were to evaluate the impact of PET on GTV delineation and dosimetric outcome in IMRT of early stage NPC patients. METHODS: Twenty NPC patients with T1 or T2 disease treated by IMRT were recruited. For each patient, 2 sets of NP GTVs were delineated separately, in which one set was performed using CT and MRI registration only (GTVCM), while the other set was carried out using PET, CT and MRI information (GTVCMP). A 9-field IMRT plan was computed based on the target volumes generated from CT and MRI (PTVCM). To assess the geometric difference between the GTVCM and GTVCMP, GTV volumes and DICE similarity coefficient (DSC), which measured the geometrical similarity between the two GTVs, were recorded. To evaluate the dosimetric impact, the Dmax, Dmin, Dmean and D95 of PTVs were obtained from their dose volume histograms generated by the treatment planning system. RESULTS: The overall mean volume of GTVCMP was greater than GTVCM by 4.4 %, in which GTVCMP was slightly greater in the T1 group but lower in the T2 group. The mean DSC of the whole group was 0.79 ± 0.05. Similar mean DSC values were also obtained from the T1 and T2 groups separately. The dosimetric parameters of PTVCM fulfilled the planning requirements. When applying this plan to the PTVCMP, the average Dmin (56.9 Gy) and D95 (68.6 Gy) of PTVCMP failed to meet the dose requirements and demonstrated significant differences from the PTVCM (p = 0.001 and 0.016 respectively), whereas the doses to GTVCMP did not show significant difference with the GTVCM. CONCLUSION: In IMRT of early stage NPC, PET was an important imaging modality in radiotherapy planning so as to avoid underdosing the PTV, although its effect on GTV delineation was not significant. It was recommended that PET images should be included in the treatment planning of NPC patients.

Neonatal Abdominal Hemangiomatosis: Propranolol beyond Infantile Hemangioma.

Hemangioma is the most common vascular tumor of infancy; presentation is often as cutaneous infantile hemangioma (IH). Cutaneous hemangioma is a clinical diagnosis. Most IHs follow a benign course, with complete involution without treatment in the majority of cases. Visceral hemangioma often involves the liver and manifests as a life-threatening disorder. Hepatic hemangiomas may be associated with high output cardiac failure, coagulopathy, and hepatomegaly which generally develop between 1 and 16 weeks of age. Mortality has been reportedly high without treatment. We report a rare case of a male infant with neonatal hemangiomatosis with diffuse peritoneal involvement, which mimicked a malignant-looking tumor on imaging, and discuss therapeutic options and efficacy. Propranolol is efficacious for IH but generally not useful for other forms of vascular hemangiomas, tumors, and malformations. In our case of neonatal peritoneal hemangiomatosis, propranolol appears to have halted the growth and possibly expedite the involution of the hemangiomatosis without other treatments.

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.

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.

Long-term effects of pamidronate in thalassemic patients with severe bone mineral density deficits.

Osteoporosis is a common complication in thalassemia major (TM). Our previous study demonstrated severe bone mineral density (BMD) deficits at spine and hip in 62 and 35% of TM patients. This study assessed the effects of different treatments (calcium, vitamin D and bisphosphonate) on patients' BMD, which was measured at baseline and after 3-year treatments by dual energy X-ray absorptiometry (DEXA). Twenty-one untreated patients, 11 patients on calcium/vitamin D and seven patients on additional pamidronate, were recruited. They were comparable for gender (p = 0.630) and serum ferritin levels (p = 0.412). The median BMD Z-scores at lumbar spine and left hip improved only in patients with standard plus pamidronate treatments (baseline: -3.01 and -3.05, end-of-study: -2.12 and -2.09; p = 0.018 and 0.028, respectively). In contrast, BMD Z-scores at hip worsened in untreated patients (p = 0.034). In conclusion, long-term improvement in BMD in TM patients was observed with bisphosphonate but not calcium and vitamin D treatment.

Neurologic and radiologic manifestations of three girls surviving acute carbon monoxide poisoning.

We report the neurologic and radiologic manifestations of three adolescent girls with acute carbon monoxide poisoning. The girls were found collapsed and unconscious in a bathroom where liquid petroleum gas was being used as heating fuel. As hyperbaric oxygen therapy was not available locally, they only received oxygen supplementation via nasal cannula (4 L/minute) as treatment in the first 2 days. On transfer to a tertiary center in Hong Kong, evolving neurologic manifestations of visual acuity and field deficits, confusion, and focal motor weaknesses were observed. Focal infarctions were evident in cerebral computed tomography in one patient and cortical lesions on magnetic resonance imaging in all three patients. [18F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) revealed additional decreased metabolism in the basal ganglia in two patients, which was typical of carbon monoxide poisoning. The neurologic deficits resolved completely at 3 weeks after the exposure, but psychologic symptoms succeeded. This report serves to alert clinicians to the varied neuro-ophthalmologic manifestations and psychologic impairment even with the same duration of carbon monoxide poisoning. PET might be more sensitive in detecting cerebral injuries specific for carbon monoxide poisoning.