Treatment outcomes among high-risk neuroblastoma patients receiving non-immunotherapy regimen: Multicenter study on behalf of the Thai Pediatric Oncology Group.

BACKGROUND: Neuroblastoma is the most common extracranial malignant solid tumor during childhood. Despite intensified treatment, patients with high-risk neuroblastoma (HR-NBL) still carry a dismal prognosis. The Thai Pediatric Oncology Group (ThaiPOG) proposed the use of a multimodality treatment to improve outcomes of HR-NBL in non-immunotherapy settings. METHODS: Patients with HR-NBL undergoing ThaiPOG protocols (ThaiPOG-NB-13HR or -18HR) between 2013 and 2019 were retrospectively reviewed. Patient demographic data, treatment modalities, outcomes, and prognostic factors were evaluated and analyzed. RESULTS: A total of 183 patients with HR-NBL undergoing a topotecan containing induction regimen were enrolled in this study. During the consolidation phase (n = 169), 116 patients (68.6%) received conventional chemotherapy, while 53 patients (31.4%) underwent hematopoietic stem cell transplantation (HSCT). The 5-year overall survival (OS) and event-free survival (EFS) were 41.2% and 22.8%, respectively. Patients who underwent HSCT had more superior 5-year EFS (36%) than those who received chemotherapy (17.1%) (p = .041), although they both performed similarly in 5-year OS (48.7% vs. 39.8%, p = .17). The variation of survival outcomes was observed depending on the number of treatment modalities. HSCT combined with metaiodobenzylguanidine (MIBG) treatment and maintenance with 13-cis-retinoic acid (cis-RA) demonstrated a desirable 5-year OS and EFS of 65.6% and 58.3%, respectively. Poorly or undifferentiated tumor histology and cis-RA administration were independent factors associated with relapse and survival outcomes, respectively (p < .05). CONCLUSION: A combination of HSCT and cis-RA successfully improved the outcomes of patients with HR-NBL in immunotherapy inaccessible settings.

Pediatric primary central nervous system tumors registry in Thailand under National Health Security Office schemes.

BACKGROUND: Few epidemiological studies of pediatric central nervous system (CNS) tumors have been performed using data from Southeast Asian national registries. Therefore, we aimed to examine data on CNS tumors from the first national childhood CNS tumor registry in Thailand. METHODS: Newly diagnosed children with benign and malignant primary CNS tumors from 20 nationwide hospitals were included. Two eras in the Thai registry were studied to compare national protocol effectiveness, including 2003-2005 (before establishment of a pediatric CNS tumor protocol) and 2011-2012 (post-establishment). RESULTS: The first study period had 300 patients with an incidence of 7.5/1,000,000 person-years and the second had 168 patients with an incidence of 13.24/1,000,000 person-years. The three most common tumors were gliomas, medulloblastoma/primitive neuroectodermal tumor (PNET), and germ cell tumors. The most common tumor site was the cerebellum, followed by the brainstem and pineal region. Five- and 10-year overall survival (OS) rates were 46.62% (95% confidence interval [CI] 40.85-52.18) and 41.78% (95% CI 36.11-47.34), respectively, for the first period. The second period had a 5-year OS of 64.75% (95% CI 56.70-71.68). OS rates for gliomas, germ cell tumors, medulloblastoma/PNET, and ependymomas were better in the second period than in the first period. CONCLUSIONS: The incidence of primary childhood CNS tumors in our study is lower compared with other reports. Improvement of OS in the second study period might be because of establishment of the Thai Pediatric Oncology Group, and national protocols for childhood CNS tumors.

Clinical outcomes and prognostic factors to predict treatment response in high risk neuroblastoma patients receiving topotecan and cyclophosphamide containing induction regimen: a prospective multicenter study.

BACKGROUND: Neuroblastoma is the most common extra-cranial solid tumor among children. Despite intensive treatment, patients with advanced disease mostly experience dismal outcomes. Here, we proposed the use of topotecan and cyclophosphamide containing induction regimen as an upfront therapy to high risk neuroblastoma patients. METHODS: Patients with high risk neuroblastoma undergoing ThaiPOG high risk neuroblastoma protocol from 2016 to 2017 were studied. All patients received 6 cycles of induction regimen consisting of 2 cycles topotecan (1.2 mg/m2/day) and cyclophosphamide (400 mg/m2/day) for 5 days followed by cisplatin (50 mg/m2/day) for 4 days combined with etoposide (200 mg/m2/day) for 3 days on the third and fifth cycles and cyclophosphamide (2100 mg/m2/day) for 2 days combined with doxorubicin (25 mg/m2/day) and vincristine (0.67 mg/m2/day) for 3 days on the fourth and sixth cycles. Treatment response after the 5th cycle before surgery and treatment-related toxicities after each topotecan containing induction cycle were evaluated. Relevant prognostic factors were analyzed to measure the treatment response among those patients. RESULTS: In all, 107 high risk neuroblastoma patients were enrolled in the study. After the 5th cycle of induction regimen, the patients achieved complete response (N = 2), very good partial response (N = 40), partial response (N = 46) and mixed response (N = 19). None of the patients experienced stable disease or disease progression. The most significant prognostic factor was type of healthcare system. The most common adverse effect was febrile neutropenia followed by mucositis, diarrhea and elevated renal function. CONCLUSION: The topotecan and cyclophosphamide containing induction regimen effectively provides favorable treatment response. The regimen is well tolerated with minimal toxicity among patients with high risk neuroblastoma in Thailand.

Genotypes and phenotypes of protein S deficiency in Thai children with thromboembolism.

The prevalence of protein S (PS) deficiency in Asian patients with venous thromboembolism is around 8-30%, higher than that in Caucasian populations. The present study reports the genotypes (including one novel mutation) and phenotypes of children with PS deficiency at a tertiary care institute. A total of six patients were included, three with arterial ischemic stroke, two with cerebral venous sinus thrombosis, and one with deep vein thrombosis. PS mutations were identified in four patients: p.R355C, p.G336D, p.E67A, and p.N188KfsX9. p.N188KfsX9 is a novel mutation with less than 20% PS activity noted in heterozygotes.

Outcome of acute lymphoblastic leukemia treatment using national protocols at the Queen Sirikit National Institute of Child Health.

OBJECTIVE: To evaluate the outcome of acute lymphoblastic leukemia (ALL) treatment at the Queen Sirikit National Institute of Child Health (QSNICH) after using national protocols. MATERIAL AND METHOD: Seventy-six pediatric patients with newly diagnosed with ALL, who were treated in Queen Sirikit National Institute of Child Health using the national protocols during March 2006 and February 2008, were enrolled. The national protocols were sub-classified by clinical risk factors and morphology of leukemic cells of the patients at initial presentation into 3 groups as standard risk (ALL-01-05), high-risk (ALL-02-05), and mature B-ALL or L3 (NHL-04-06) protocol. Overall survival (OS) and event-free survival (EFS) were determined by using Kaplan-Meier survival curves. RESULTS: The overall survival rate of ALL patients treated using the national protocols was 83.85% (88.06% in standard group, 82.01% in high-risk group, and 75% in L3 protocol). The mortality rate and event-free survival of ALL patients was 13.33% and 72.50%, respectively. CONCLUSION: The national protocols for ALL showed benefit in the improvement of outcomes from treatment in childhood ALL.

Natural course of low risk neuroblastoma.

BACKGROUND: Neuroblastoma is characterized by heterogeneity of histology, biology, and clinical behavior. Most epidemiology studies are based on Western and Japanese populations; there are very few studies on neuroblastoma from Southeast Asia. PROCEDURE: Cases of Thai children with neuroblastoma were retrospectively reviewed to determine if the epidemiology of the disease differs from Western populations. Sixty-two cases were assembled from two pathology centers in Bangkok. Histologic prognostic category and MYCN copy number were determined. RESULTS: The median age at diagnosis was 2.9 years. Only 11% of cases presented at less than 1 year of age and 12% cases had low stage disease (1, 2, and 4S). The majority of tumors had unfavorable histology (48/62); this was at least partly due to the higher age at diagnosis for most patients. MYCN amplification was detected in 18/52 (35%) tumors, all in stage 3 or 4 tumors. We assigned patients to high, intermediate and low risk categories using the Children's Oncology Group risk stratification criteria. In contrast to Western studies, the majority of cases (50/59 or 85%) in our series had high risk disease. CONCLUSIONS: Since there is no evidence to date that the biology of neuroblastoma varies by geographic region, the paucity of low risk cases in our study may reflect spontaneous resolution/differentiation of tumors that are not clinically detected. Moreover, a delay in diagnosis of intermediate risk cases could result in higher tumor burden at the time of diagnosis, increasing the proportion of high risk cases observed.

Report 2 cases of congenital factor XII deficiency: a rare coagulation disorder.

Factor XII (F.XII, Hageman factor) is one of the contact system factors which initiates an intrinsic coagulation pathway. But its definite role is still unclear, because many cases of severe F.XII deficiency experience thrombotic events instead of a bleeding problem. Moreover most of them are asymptomatic. There have only been a few reports of F.XII deficiency in Thailand. The author reports two cases of congenital F.XII deficiency in Thai children.

Absence of platelet recovery following Helicobacter pylori eradication in childhood chronic idiopathic thrombocytopenic purpura: a multi-center randomized controlled trial.

OBJECTIVE: To investigate the effect of Helicobacter pylori eradication on platelet recovery in childhood chronic idiopathic thrombocytopenic purpura (ITP). PATIENTS AND METHODS: A multi-center randomized controlled trial was conducted. Patients aged 4-18 years, diagnosed with chronic ITP, defined by platelet count below 100 x 10(9)/L lasting more than 6 months without identified causes, were enrolled and underwent (13)C-urea breath test for diagnosis of H. pylori infection. Patients who received prednisolone more than 0.5 mg/kg per day or received other platelet-enhancing therapy were excluded. Patients with H. pylori infection were randomized into two groups: treatment and control groups. Treatment group received a standard protocol for H. pylori eradication and repeated (13)C-UBT at 4-6 weeks to confirm successful therapy while the control group received no specific treatment. Monthly platelet count was monitored for 6 months in both groups. Primary outcome was platelet recovery, defined by platelet count over 100 x 10(9)/L for at least 3 months. RESULTS: Of the 55 ITP children, 16 (29.1%) had H. pylori infection. There were no differences in age, sex, duration of disease, platelet count, and the dose of prednisolone between the treatment group (n = 7) and control group (n = 9). One patient in control group was withdrawn due to massive gastrointestinal bleeding requiring a high dose prednisolone. At 6 months, platelet recovery was demonstrated in one patient in the treatment group as well as one in the control group. CONCLUSION: No beneficial effect of H. pylori eradication on platelet recovery in childhood chronic ITP was identified.

A neonate with petechiae and pancytopenia at birth as uncommon presentation of congenital HIV infection.

The authors describe a Thai newborn boy who was presented with petechiae, hepatosplenomegaly and pancytopenia at birth caused by congenital HIV infection. His clinical presentations were appeared on the early onset after birth. The bone marrow finding has shown hypocellularity which was also rare in HIV-infected children.

R147W in PROC Gene Is a Risk Factor of Thromboembolism in Thai Children.

The p.R147W mutation, the c.C6152T in exon 7, causing a change in amino acid from arginine to tryptophan of the PROC gene has been reported as a common mutation in Taiwanese populations with venous thromboembolism (VTE). The present study aimed to identify the prevalence of p.R147W in the Thai population and children with TE and the risk of developing TE. Patients aged ≤18 years diagnosed with TE were enrolled. The PROC gene was amplified by polymerase chain reaction using a specific primer in exon 7. The restriction fragment length polymorphism was designed using MwoI restriction enzyme. A total of 184 patients and 690 controls were enrolled. The most common diagnosis of TE was arterial ischemic stroke (AIS), at 100 (54.3%), followed by VTE, at 38 (20.6%), and cerebral venous sinus thrombosis (CVST), at 23 (12.5%). The prevalence of heterozygous and homozygous p.R147W in patients and controls was 9.5% versus 5.8% and 2.7% versus 0.1%, respectively. Heterozygous p.R147W had odds ratios (ORs) of 1.8 (95% confidence interval [CI]: 1.0-3.2, P = .04), 3.2 (95% CI: 1.2-8.2, P = .009), and 4.5 (95% CI: 1.6-12.8, P = .002) of developing overall TE, VTE, and CVST, respectively. Homozygous p.R147W had ORs of 20.2 (95% CI: 2.3-173.7, P < .001), 21.4 (95% CI: 2.2-207.9, P < .001), and 43.3 (95% CI: 3.8-490.6, P < .001) of developing overall TE, AIS, and CVST, respectively. This study suggested that p.R147W is a common mutation and increased risk of TE in Thai children.

Chediak-Higashi syndrome: report of a case with uncommon presentation and review literature.

Chediak-Higashi syndrome (CHS) is a very rare autosomal recessive immunodeficiency disorder characterized by partial albinism, recurrent pyogenic infections, and large granules in all granule-containing cells. The author describes a Thai girl who was the first case of CHS in Thailand. She presented in the accelerated phase of CHS, which leads to repeated infections and bleeding, often resulting in fatal outcome. Pancytopenias, hepatosplenomegaly, lymphohistiocytic infiltration in bone marrow and the abnormal characteristic granules in leukocyte clinched the diagnosis.

Hospital-based epidemiologic survey of malignancies in children infected with human immunodeficiency virus in Thailand.

To determine the incidence and spectrum of malignancies in human immunodeficiency virus-infected children, we surveyed 48 hospitals in Thailand between 1996 and 2000. There were 23 children (14 boys and 9 girls; average age at diagnosis of malignancy, 4.2 years), and the incidence rate was 0.6 per 1000 person-years. The most common malignancy was lymphoma (87.0%). The prognosis was poor.

Outcome of Childhood Acute Lymphoblastic Leukemia Treated Using the Thai National Protocols.

BACKGROUND: In recent decades, the prognosis for childhood leukemia has improved, especially for acute lymphoblastic leukemia (ALL). In Thailand, though, the survival rate for ALL is unimpressive. In 2006, standard national protocols for childhood leukemia treatment were implemented. We herein report the outcome of the ALL national protocols and explanations behind discrepancies in outcomes between institutions. MATERIALS AND METHODS: Between March 2006 and February 2008, 486 children with ALL from 12 institutions were enrolled in the Thai national protocols. There were 3 different protocols based on specific criteria: one each for standard risk, high risk and Burkitt's ALL. We classified participating centers into 4 groups of institutions, namely: medical schools in Bangkok, provincial medical schools, hospitals in Bangkok and provincial hospitals. We also evaluated supportive care, laboratory facilities in participating centers, socioeconomics, and patient compliance. Overall and event-free survival were determined for each group using the Kaplan Meier method. Statistical differences were determined using the log-rank test. Previous outcomes of Thai childhood ALL treatment between 2003 and 2005 served as the historic control. RESULTS: Five-year overall survival of ALL treated using the Thai national protocol was 67.2%; an improvement from the 63.7% of the 12-institute historical control (p-value=0.06). There were discrepancies in event-free survival of ALL between centers in Bangkok and up-country provinces (69.9% vs 51.2%, p-value <0.01). Socioeconomics and patient compliance were key elements in determining the outcome (65.5% vs 47.5%, 59.4% vs 42.9%) (p-value < 0.02). CONCLUSIONS: Implementation of standard national protocols for childhood leukemia in Thailand did not significantly improve the outcome of ALL. Factors leading to better outcomes included (a) improvement of treatment compliance (b) prevention of treatment abandonment and

Molecular analysis of factor XII gene in Thai patients with factor XII deficiency.

Factor XII is the initiating protein of the intrinsic coagulation pathway. It activates factor X after being activated by the so called 'contact system'. Both congenital factor XII deficiency, usually without bleeding symptoms, and several factor XII polymorphisms with possible thrombotic tendency have been described. In the presented work, two Thai patients with congenital factor XII deficiency have been studied by utilizing a PCR single-stranded conformation polymorphism (PCR-SSCP) method followed by direct sequencing. A new mutation of factor XII gene in the exon 7, c.583delC or p.H195fsX250, has been discovered and variable factor activities resulting from different mutations with or without polymorphisms are demonstrated. The other case had a homozygous missense mutation, c.G218C. Heterozygotes of this mutation, found in 1.9% (2/107) of healthy Thai volunteers, showed low factor XII activities suggesting that it is a deleterious mutation.

Late effects in survivors of childhood acute lymphoblastic leukemia: a study from Thai Pediatric Oncology Group.

Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk of long-term late effects. Therefore, systematic screenings of the late complications are essential. The objective of this study was to determine the prevalence of late effects of Thai children and adolescents after completion of ALL therapy. We performed a cross-sectional study for evaluation of the late effects in ALL survivors who came for follow-up at 10 pediatric oncology centers in Thailand. We evaluated the treatment-related late complications of children and adolescents who had finished ALL treatment for at least 2 years. Demographic data, treatment modalities, and late effects were recorded and analyzed. There were 258 survivors with a median age of 12.2 years (range 3.6-23.3 years). The median follow-up time was 7.2 years (range 2-17.5 years). Forty-seven percent (122 cases) suffered from at least one late effect. Overweight/obesity was the most common late effect. Radiation of central nervous system was a significant risk factor for overweight/obesity (OR 1.97, 95% CI 1.02-3.81) and educational problems (OR 4.3, 95% CI 1.32-14.02). Our data have demonstrated a significant prevalence of late effects after childhood ALL therapy. A long-term follow-up program for survivors of childhood cancer is therefore needed in our country.