Nationwide Study of Factors Impacting Survival Outcome and Consequences in Children with Reactivation/Refractory Langerhans Cell Histiocytosis.

BACKGROUND: Disease reactivation/refractory remains a major challenge in managing Langerhans cell histiocytosis (LCH). Outcomes and late sequelae should be explored. METHODS: A multi-institutional retrospective study was conducted to describe clinical characteristics, predictive factors, outcomes and late sequelae of pediatric reactivation/refractory LCH in Thailand. RESULTS: In all, 47 patients were studied, 25 (53.2%) patients had disease reactivation and 22 (46.8%) patients had refractory LCH. The median reactivation and refractory time were 1.59 and 0.33 years from diagnosis, respectively (p <0.001). The most common site of reactivation/refractory was the bone (n = 26, 55%), and 20 (42.6%) patients developed late sequelae. The 5-year overall survival (OS) was 76.1%. Patients with reactivation and refractory LCH performed similarly in 5-year OS (88% vs. 63%, p = 0.055). Prognostic factors associated with mortality were liver, spleen, hematopoietic system and lung reactivation (p <0.05). Lung reactivation was the only independent risk factor associated with the survival outcome (p = 0.002). CONCLUSIONS: The outcomes of pediatric patients between reactivation and refractory LCH in Thailand were similarly desirable and mortality was minimal although late sequelae may evolve. Pulmonary reactivation/refractory was an independent risk factor associated with survival.

Current Challenges of Asian National Children's Cancer Study Groups on Behalf of Asian Pediatric Hematology and Oncology Group.

In Asia, a few countries have a long and established history of collaborative clinical trials successfully formed national children's cancer study groups, but many still do not have such groups. The process of forming national children's cancer groups is fraught with many hurdles, which varies among the countries. One of the basic requirements for running clinical trials is an affordable health care system in which most of the children with cancer can receive the proposed treatment. The health insurance coverage for children with cancer varies from <20% to as high as 100% among Asian countries, and the operation of clinical trials must also be adjusted accordingly. Shortage of research personnel is common, including medical, nursing, research coordinators, and data managers. The establishment of the Asian Pediatric Hematology and Oncology Group aims to provide a good platform for promotion of international clinical trials in the Asian countries.

Treatment outcomes of high-dose chemotherapy plus stem cell rescue in high-risk neuroblastoma patients in Thailand.

BACKGROUND: In 2013, the Thai Pediatric Oncology Group (ThaiPOG) introduced a national protocol in which high-dose chemotherapy plus stem cell rescue is performed without immunotherapy. METHODS: This study aimed to elucidate the outcomes of high-risk neuroblastoma (HR-NB) patients treated with the ThaiPOG protocol. This retrospective cohort review included 48 patients (30 males, 18 females) with a median age of 3 years (range, 8 months to 18 years) who were treated at 5 ThaiPOG treatment centers in Thailand in 2000-2018. RESULTS: Eight of the 48 patients showed MYCN amplification. Twenty-three patients (48%) received 131I-meta-iodobenzylguanidine prior to high-dose chemotherapy and stem cell rescue. The majority of patients achieved a complete or very good response prior to consolidation treatment. The 5-year overall survival (OS) and event-free survival (EFS) rates were 45.1% and 40.4%, respectively. Patients aged >2 years had a nonsignificantly higher mortality risk (hazard ratio [HR], 2.66; 95% confidence interval [CI], 0.92-7.68; P=0.07). The MYCN amplification group had lower OS and EFS rates than the MYCN nonamplification group, but the difference was not statistically significant (45% OS and 37.5% EFS vs. 33.3% OS and 16.6% EFS; P=0.67 and P=0.67, respectively). Cis-retinoic acid treatment for 12 months was a strong prognostic factor that could reduce mortality rates among HR-NB patients (HR, 0.27; 95% CI, 0.09-0.785; P=0.01). CONCLUSION: High-dose chemotherapy plus stem cell rescue followed by cis-retinoic acid for 12 months was well tolerated and could improve the survival rates of patients with HR-NB.

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.

Clinical outcomes and screening for organ involvement in pediatric Langerhans cell histiocytosis in Thailand: multicenter study on behalf of the Thai Pediatric Oncology Group.

Langerhans cell histiocytosis (LCH) is a rare disease across all age groups and is characterized by various degrees of severity and organ system involvement. A multi-institutional retrospective study of pediatric patients with LCH treated between 1999 and 2018 at five pediatric oncology centers was conducted to describe the clinical characteristics, prognostic factors, and outcomes of LCH and to validate screening tools for organ system involvement in pediatric LCH in Thailand. A total of 127 patients with a median age of 2.7 years were studied. The single-to-multisystem (MS) LCH ratio was 1:1. Forty-seven patients (71%) with MS-LCH had risk-organ involvement (RO +), whereas 19 (29%) patients had no risk-organ involvement (RO -). The 5-year overall and event-free survival rates were 91.3% and 73.6%, respectively, which were comparable to those in developed countries. Prognostic factors included age < 2 years, RO + MS-LCH, and number of RO + . Abnormal complete blood count was a highly sensitive indicator of bone marrow involvement. Plain radiography is an appropriate screening tool to detect bone involvement.

A Pharmacokinetic Study of Native E.coli Asparaginase for Acute Lymphoblastic Leukemia Treated with ThaiPOG Protocol.

BACKGROUND: Asparaginase is one of the essential chemotherapies used to treat acute lymphoblastic leukemia (ALL). Asparaginase antibody production may cause a subtherapeutic level and result in an inferior outcome. The aim of this study was to prove the efficacy of current native E.coli asparaginase-based protocol. Moreover, does subtherapeutic result appeared in small group of the trial?. METHODS: A prospective study of asparaginase activity among patients who received native E.coli asparaginase 10,000 IU/m2 intramuscularly according to The Thai Pediatric Oncology Group (ThaiPOG) protocol was done. The plasma asparaginase activity was measured by the coupled enzymatic reaction. Pharmacokinetic data including peak activity (Cmax), time to maximum concentration (Tmax), area under the curve (AUC0-48h) being elucidated. RESULTS: Eight patients (five males and three females), median age 9.5 years, were enrolled. The median asparaginase activity of seven cases who were eligible for calculation reached Tmax within 24 hours (range 6-48 hours) with mean±SD of Cmax 3.60±0.34 (range 3.02-4.11) IU/ml. Mean±SD of AUC0-48h is 143.23±36.94 IU.h/mL (range 71.07 - 180.12 IU.h/mL). The post-48-hour activity showed a mean±SD of 3.19±0.24 IU/ml (range 2.77-3.51 IU/ml) which implied an adequacy of activity over 48 hours and proper for the 12-day period. One relapsed ALL patient showed an extremely low AUC of asparaginase activity which coincided with urticaria after asparaginase injection. Subsequently, the asparaginase antibody was demonstrated in this patient. CONCLUSION: Native E. coli asparaginase-based protocol provides a compelling pharmacokinetic effect. Asparaginase activity and/or antibody testing is recommended for all cases especially in a relapsed patient, history of high accumulative dose of asparaginase or suspected allergic reaction. Patients with low asparaginase activity or allergy may benefit from switching to an alternative form of asparaginase to maintain treatment efficacy.

Subcutaneous Panniculitis-like T-Cell Lymphoma With Hemophagocytic Lymphohistiocytosis Syndrome in Children and Its Essential Role of HAVCR2 Gene Mutation Analysis.

BACKGROUND: We identified 3 adolescents with alpha-beta subtype subcutaneous panniculitis-like T-cell lymphoma. CASE PRESENTATION: Three patients presented with prolonged fever, abnormal skin lesions, and cytopenia described in the context. All had the same disease entity, which showed the prolonged duration of B systemic symptoms till diagnosis, difficulty to distinguish from autoimmune diseases, presence of hemophagocytic lymphohistiocytosis syndrome, good response, and remained on long-term remission with nonchemotherapy treatment, which included oral corticosteroid and cyclosporin. CONCLUSIONS: Although diagnosis can only be "highly suspected" with pathologic review, some cases may need multiple serial skin biopsy to clarify diagnosis because of the discrete distribution of specific histology. T-cell receptor gene rearrangement, which demonstrates a monoclonal pattern of alpha and beta chain gene, is the essential requirement for specific diagnosis. The role of molecular analysis by identification of germline hepatitis A virus cellular receptor 2 (HAVCR2) gene mutation can be much valuable in classifying susceptible patients.

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.

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

Management of intracranial germ cell tumors at the King Chulalongkorn Memorial Hospital.

OBJECTIVE: To study the outcome of less aggressive radiotherapy combined with surgery and chemotherapy to reduce radiation complication in the treatment of intracranial germ cell tumor (ICGCT) at the King Chulalongkorn Memorial Hospital. MATERIAL AND METHOD: A descriptive study was established by reviewing patients' records from the Division of Therapeutic Radiology and Oncology admitted between 2001 and 2008. Median follow-up time was 65 months. Patient characteristics, investigations, and treatment modalities were presented in proportion. Survival analysis was evaluated by Kaplan-Meier method. The results were compared with the previous study in done in 1990 to 2000. RESULTS: Forty-two records were reviewed and 71% were male. The median age was 16 years. Pineal region was the most common site in 55%. Interestingly, 12% had synchronous lesions at both pineal and suprasellar regions. Out of 41 patients who had histopathological confirmation, 71% were germinoma. Out of 37 patients who had MRI spine or CSF cytology, 43% had CNS dissemination. Less aggressive radiotherapy combined with surgery and chemotherapy was increasingly utilized; however five-year overall survival rate in all patients was 83%, comparable to 82% from the previous study. Survival rates of patients without CNS dissemination were 88% in the present study and 83% in the previous study. Survival rates adjusted for histopathology were 86% for germinoma and 76% for non-germinoma. CONCLUSION: Less aggressive radiotherapy combined with surgery and chemotherapy to reduce radiation complication is an effective treatment for ICGCT.

Reference values for thrombotic markers in children.

Thromboembolic events are an increasingly common problem encountered in children. The laboratory diagnosis of thrombotic disorders in children differs from that in adults. To establish the normal reference of natural anticoagulant parameters in children of different age groups, plasma from healthy children between the ages of 2 months and 16 years (n = 127) and adults (n = 30) were assayed for a disintegrin-like and metalloprotease with thrombospondin type 1 domain 13 (ADAMTS-13), von Willebrand factor collagen-binding activity (vWF:CB), tissue factor pathway inhibitor (TFPI), homocyteine and natural anticoagulants. Children were divided into four age groups: less than 1 year, 1-5 years, 6-10 years, and 11-16 years. The reference values for ADAMTS 13, homocysteine, and protein C activity were significantly lower in children of all age groups compared with those in the adults. Similarly, those for protein C antigen, total protein S, free protein S and antithrombin III (AT III) for children less than 1 year were significantly lower than in the adults. On the contrary, TFPI levels were significantly higher in the children for all age groups when compared with the adults. vWF:CB levels were comparable across all groups. There are age-related physiologic differences in ADAMTS-13, TFPI, homocysteine and natural anticoagulants between children and adults. Our data will provide physicians with a useful reference guide in interpreting test results of inhibitors of hemostatic parameters in children suspected of thrombotic disorders.

Childhood cancer incidence and survival 2003-2005, Thailand: study from the Thai Pediatric Oncology Group.

BACKGROUND: Previous population-based incidences of childhood cancer in Thailand were achieved by extrapolating from data limited to a small number of cancer registries, not from the whole country. In addition, survival of childhood cancer patients is often described in specialized hospitals and/or institutions, but not in the general population. METHODS: All children aged 0-15 years who were newly diagnosed as having cancer were registered from 18 treatment centers during 2003-5 and classified into 12 diagnostic groups according to the International Classification of Childhood Cancer. Incidences were calculated by a standard method and survival was investigated using the ThaiPOG (Thai Pediatric Oncology Group) population-based registration data. Overall survival was calculated by the Kaplan Meier method. RESULTS: In the study period (2003-5) 2,792 newly diagnosed cases of childhood cancer were registered, with mean and median ages of 6.5 (SD=0.13) and 5.0 (0-14) years, respectively. The age-peak was between 1 and 4 years and the age-standardized rate (ASR) was 74.9 per million. Leukemia was the most common cancer (N=1421, ASR 38.1) followed by lymphoma (N=266, ASR 6.4) and neoplasms of the central nervous system (CNS, N=246, ASR 6.3). The follow-up duration totaled 101,250 months. The death rate was 1.11 per 100 person-months (95%CI: 1.02 -1.20). The 5-year overall survival was 54.9% (95%CI: 53.0%-56.9%) for all cancers. The respective, 5-year overall survival for (1) acute lymphoblastic leukemia (ALL), (2) acute non-lymphoblastic leukemia (ANLL), (3) lymphoma, (4) retinoblastoma, (5) renal tumors, (6) liver tumors, (7) germ cell tumors, (8) CNS tumors, (9) neuroblastoma, (10) soft tissue tumors and (11) bone tumors were (1) 64.5%, (2) 35.1%, (3) 59.5%, (4) 73.1%, (5) 70.4%, (6) 44.5%, (7) 70.6%, (8) 41.7%, (9) 33.6%, (10) 50.1%, and (11) 33.7%. CONCLUSIONS: The incidence of childhood cancer is lower than in western countries. Respective overall survival for ALL, lymphoma, renal tumors, liver tumors, retinoblastoma, soft tissue tumors is lower than those reported in developed countries while for CNS tumors, neuroblastoma and germ cell tumors the figures are comparable.

Activation of endothelial cells, coagulation and fibrinolysis in children with Dengue virus infection.

Dengue virus causes a febrile illness: Dengue fever (DF), and less frequently a life-threatening illness: Dengue hemorrhagic fever (DHF). Although severe bleeding remains a major cause of death in DHF, the pathogenesis of bleeding is poorly understood. This prospective cohort study was designed to determine the extent of activation of endothelial cells and the hemostatic system in correlation with clinical severity, and also to detect the best prognostic factor(s) for DHF. Endothelial cell activation, coagulation, anticoagulant and fibrinolysis parameters were measured in 42 children with Dengue infections (20 with DF and 22 with DHF) during three phases of illness. In DHF patients, during the febrile phase, von Willebrand factor antigen (vWF:Ag), tissue factor (TF) and plasminogen activator inhibitor (PAI-1) were significantly elevated, while platelet counts and ADAMTS 13 (a disintegrin and metalloprotease with thrombospondin repeats) were significantly low compared to DF patients. During the toxic phase, soluble thrombomodulin (sTM), tissue plasminogen activator (t-PA) and PAI-1 were also significantly increased, while ADAMTS 13 and thrombin activatable fibrinolysis inhibitor (TAFIa) were significantly low compared to DF patients. Abnormal vWF multimers were seen only in DHF patients. For endothelial cell injury and release of procoagulant components, activation of the coagulation cascade with thrombin generation, increased antifibrinolytic factors and consumption of natural anticoagulants, each appeared to play an important role in the development of hemorrhage in Dengue patients. Using logistic regression analysis, we found plasma VWF:Ag to be the best indicator of progression to DHF.

Pediatric reference values for molecular markers in hemostasis.

BACKGROUND: The hemostatic system is a developing and changing process relative to age. OBJECTIVES: To distinguish the differences in hemostatic parameters between children and adults, and to establish the normal range of these parameters in children of different age groups. DESIGN/METHODS: Blood was obtained from healthy children aged 1 to 18 years (n=70) and adults (n=26). Children were categorized into 3 age groups: 1 to 5 years, 6 to 10 years, and 11 to 18 years. Several coagulation and fibrinolysis parameters were determined. RESULTS: Children in all age groups showed no significant difference in mean levels of von Willebrand factor antigen and activity, activated partial thromboplastin time, fibrinogen, activated factor VII, tissue plasminogen activator, plasminogen activator inhibitor-1, and thrombin activatable fibrinolysis inhibitor compared with adults. However, children aged 1 to 5 years had significantly higher mean values of soluble thrombomodulin (P=0.001), prothrombin time (P=0.03), tissue factor (P<0.001), thrombin-antithrombin complex (P<0.001), and D-dimer (P=0.009) whereas they had significantly lower mean levels of protein C activity (P=0.02) than did adults. CONCLUSIONS: These data indicate physiologic differences in the hemostatic system between children and adults and should serve as a useful reference guide in interpreting test results for children with suspected bleeding disorders.

Diffuse Neonatal Hemangiomatosis: report of 5 cases.

Diffuse Neonatal Hemangiomatosis (DNH) is a rare, life-threatening condition associated with a few to hundreds of small, cutaneous and visceral hemangiomas. The authors reported 5 cases of DNH in which hepatic hemangioma were the most common visceral involvement. Response to prednisolone in these cases was not good, one died and four required second line therapy. Of these four cases, one case with embolisation; one with interferon and two with vinblastine. Response to vinblastine was good, but long-term follow-up of the side effects are needed.

Restrictive lung disease and serum TGF-beta1 in thalassemia major children.

A cross sectional study was performed in 21 thalassemia major (TM) children at King Chulalongkorn Memorial Hospital during March to August, 2003 to determine whether restrictive lung disease (RLD) was related to serum transforming growth factor-beta 1 (TGF-beta1). All studied patients (57% female, age 11.2 +/- 2.6 yrs, duration of transfusion 7.7 +/- 4.1 yrs) never had desferoxamine treatment and their pulmonary function, serum ferritin and serum TGF-beta1 were evaluated. Five (24%) had RLD. RLD patients had significantly longer durations of transfusion and higher serum ferritin levels than non-RLD patients (9.1 +/- 1.9 vs 5.5 +/- 3.2 yrs; p = 0.03 and 3,816.6 +/- 1,715.9 vs 2,084.5 +/- 1,504.8 ng/ml; p = 0.04, respectively). TM children had lower serum TGF-beta1 levels than normal children (7.9 vs 78.8 pg/ml; p < 0.001). The serum TGF-beta1 level was not different between RLD and non-RLD patients (13.3 vs 4.2 pg/ml; ns), concluding that RLD was related to longer duration of transfusion and higher serum ferritin but not related to serum TGF-beta1 levels.

Outcome of pediatric hematopoietic stem cell transplantations from Thai unrelated donors matched with high-resolution HLA typing.

The authors evaluated the outcome of ten children given hematopoietic stem cell transplantations from Thai unrelated donors (URD-HSCT) selected using DNA high-resolution typing of both HLA class I and II loci. Six patient/donor pairs (60%) were fully matched; four (40%) were 5/6 matched. Patients had either non-malignant (n=9) or malignant (n=1) diseases. In most cases, graft-versus-host disease (GVHD) prophylaxis composed of cyclosporine and short-term methotrexate. The probability of hematopoietic recovery at day 30 was 90%. The cumulative probability of acute GVHD and of chronic GVHD equaled 44.4 and 0%, respectively. Three patients died of transplant-related complications. The probability of transplant-related mortality (TRM) at 30, 100, and 180 days were 10, 30, and 30%, respectively. The overall and disease-free survival rates were 70 and 70%, respectively. URD-HSCT with donor selection based on high-resolution HLA typing is associated with a low incidence of both severe acute GVHD and graft failure. The observed outcome is comparable to that of children transplanted from HLA-identical siblings.