Predictive factors for L-asparaginase hypersensitivity in pediatric acute lymphoblastic leukemia.

BACKGROUND: L-Asparaginase is a crucial component of acute lymphoblastic leukemia (ALL) treatment. However, hypersensitivity is a common adverse event. This study aimed to identify risk factors for L-asparaginase hypersensitivity in childhood ALL. METHODS: Children treated for ALL at Chiang Mai University Hospital, Thailand, between 2005 and 2020 were included. Demographic data, clinical characteristics, and factors related to L-asparaginase were retrospectively reviewed. RESULTS: L-Asparaginase hypersensitivity was observed in 24 of 216 children with ALL (11.1%). All patients received native L-asparaginase intramuscularly, and events occurred exclusively during the post-induction phase without concurrent corticosteroid use. Univariable analysis showed that relapsed ALL, higher accumulated doses, increased exposure days, and longer interval between drug administrations were potential risk factors. In multivariable logistic regression analysis, interruption of L-asparaginase administration for ≥ 52 weeks and exposure duration of ≥ 15 days were independent risk factors, with adjusted odds ratio of 16.481 (95% CI 3.248-83.617, p = 0.001) and 4.919 (95% CI 1.138-21.263, p = 0.033), respectively. CONCLUSIONS: Children with ALL who require re-exposure to L-asparaginase after 52-week interruption or who have received L-asparaginase for ≥ 15 exposure days are at risk of developing L-asparaginase hypersensitivity. Further management strategies in this setting should be evaluated.

Rotational Thromboelastometry and Clot Waveform Analysis as Point-of-Care Tests for Diagnosis of Disseminated Intravascular Coagulation in Critically Ill Children in Thailand.

OBJECTIVES: This study aimed to determine the test performances of rotational thromboelastometry (ROTEM) and activated partial thromboplastin time-based clot waveform analysis (aPTT-CWA) compared with the International Society on Thrombosis and Hemostasis disseminated intravascular coagulation (ISTH-DIC) score for diagnosis of overt disseminated intravascular coagulation (ODIC) in critically ill children. Prognostic indicators of DIC complications were also evaluated. DESIGN: A prospective cross-sectional observational study was conducted. ROTEM and aPTT-CWA were assessed alongside standard parameters based on the ISTH-DIC score and natural anticoagulants. Both conventional and global hemostatic tests were repeated on days 3-5 for nonovert DIC. SETTING: PICU of the Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. SUBJECTS: Infants and children who were admitted to PICU with underlying diseases predisposed to DIC, such as sepsis, malignancy, major surgery, trauma, or severe illness, were included in the study between July 1, 2021, and November 30, 2022. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sixty-four children were enrolled in this study. The prevalence of ODIC was 20.3%. Regarding ROTEM parameters, using EXTEM clot formation time (CFT) cutoff of greater than 102 seconds provided sensitivity and specificity of 90.9% and 80.9%, respectively, for diagnosing ODIC, with the area under the curve (AUC) of 0.86. In the case of aPTT-CWA performance, no biphasic waveform was observed, whereas both maximum coagulation acceleration (Min2) of less than 0.35%/s2 and maximum coagulation deceleration of less than 0.25%/s2 demonstrated identical sensitivities of 76.9% and specificities of 79.6%. Combining two global hemostatic tests significantly improved the diagnostic performance (INTEM CFT + EXTEM CFT + Min2 AUC 0.92 [95% CI, 0.80-1.00] vs. EXTEM CFT AUC 0.86 [95% CI, 0.75-0.96], p = 0.034). Bleeding was the most common consequence. In multivariable logistic regression analysis, Min2 of less than 0.36%/s2 was an independent risk factor for bleeding complications, with an adjusted odds ratio of 15.08 (95% CI, 1.08-211.15, p = 0.044). CONCLUSIONS: ROTEM and aPTT-CWA were valuable diagnostic tools in critically ill children who might require point-of-care tests. Min2 showed significant clinical implications for predicting bleeding events in this population.

Cost and effectiveness comparison of sirolimus versus standard treatment in Kasabach-Merritt phenomenon: a real-world evidence study in Thailand.

The conventional treatment of Kasabach-Merritt Phenomenon (KMP) consists of corticosteroids with vincristine/vinblastine or others. The aim of the study is to compare the first-year direct costs and effectiveness between sirolimus and conventional treatment. A retrospective case-control study of KMP patients was conducted at a mean age of 9 months (1 day to 12 years) between 2000 and 2022 from four tertiary centers in Thailand. The direct costs, hematologic and clinical complete response (HCR, CCR), hospitalization, length of stay, and complications were compared. Of 29 patients, 13 underwent sirolimus (four upfront and nine were refractory to the conventional). The first-year total cost had no statistically significant difference between sirolimus VS conventional treatment (8,852.63 VS 9,083.56 USD: p value: 0.94). The therapeutics achievement was the same in both HCR (244.75 VS 168.94 days; p value: 0.60) and CCR (419.77 VS 399.87 days; p value: 0.90). The subgroup analysis of the first-line sirolimus (n = 4) compared with the conventional (n = 25) showed a more reduced total cost (4,907.84 VS 9,664.05 USD; p value: 0.26) rendered net total cost of -4,756.21 USD per patient (cost saving). A more significant contrast of therapeutic achievement by reduction of both HCR (11.67 VS 224.20 days; p value: 0.36) and CCR (38.50 VS 470.88 days; p value: 0.04) was shown. The sirolimus had no difference in hospitalization, length of stay, and complications. Even though, it was unable to identify significant differences in cost-effectiveness. Sirolimus is suitable for all patients who have diagnosis of KMP either for rescue therapy or first-line treatment.

Clinical prediction tool to identify children at risk of pulmonary embolism.

INTRODUCTION: The diagnosis of pediatric pulmonary embolism (PE) is often delayed due to non-specific symptoms, and clinical prediction tools designed for adults are unsuitable for children. This study aimed to create a PE predictive model and to evaluate the reported tools in the Thai pediatric population. MATERIALS AND METHODS: A multi-center retrospective study from 4 university hospitals included children ≤18 years of age undergoing computed tomography pulmonary angiogram from 2000 to 2020 with the suspicion of PE. Patients' clinical presentations and risk factors of venous thromboembolism (VTE) were compared between the PE-positive and PE-negative groups. Significant risk factors from univariate and multivariate logistic regression were included to create a clinical prediction tool. The performance of the model was demonstrated by sensitivity, specificity, area under the curve (AUC), Hosmer Lemeshow test, ratio of observed and expected outcomes and bootstrapping. RESULTS: Of the 104 patients included, 43 (41.3 %) were grouped as PE-positive and 61 (58.7 %) as PE-negative. Five parameters, including congenital heart disease/pulmonary surgery, known thrombophilia, previous VTE, nephrotic syndrome and chest pain showed significant differences between the two groups. Score ≥ 2 yielded a 74.4 % sensitivity and a 75.4 % specificity with an AUC of the model of 0.809. The model performance and validation results were within satisfactory ranges. CONCLUSION: The study created a clinical prediction tool indicating the likelihood of PE among Thai children. A score ≥2 was suggestive of PE.

Multicenter Study of Diagnostic Tool for Patients with Hemophilia: From Bedside to Comprehensive Investigations.

Background: Hemophilia cannot be diagnosed in most laboratories of economically less-developed countries leading to high mortality and morbidity rates. Aim: A diagnostic tool was established ranging from bleeding assessment and a simple bedside test of mixing venous clotting time (VCT) to comprehensive DNA analysis for patients with hemophilia. Methods: Patients with known (n=80) and suspected hemophilia (n=14) were included. Their bleeding symptoms were initially evaluated using verified translated-Thai ISTH bleeding assessment tool. Then, blood samples were drawn using a two-syringe technique, 2 mL each was placed in three tubes, for the mixing VCT and citrate blood was kept for coagulogram and coagulation factor assay. Finally, DNA analysis was determined. Results: A total of 94 patients with hemophilia (A68, B26) defined as severe (A 57, B 17), moderate (A 7, B 5), and mild degrees (A 4, B 4) with the mean (SD) age of 14.0 (11.7) years and 24 normal controls aged 25.5 (4.5), were enrolled in the study. The mean (SD) bleeding score of patients with hemophilia was 13.5 (5.5), which did not significantly differ between patients with hemophilia A and B. The mixing venous clotting time offered the presumptive diagnosis of hemophilia A and B, which were subsequently confirmed by the prolonged APTT, low FVIII:C and FIX:C and mutations on the factor VIII and IX genes. Conclusion: A diagnostic tool for bleeding assessment, mixing venous clotting time, coagulogram, coagulation factor assay, and DNA analysis for patients with hemophilia has been established in the existing health-care system.

Genetic variations of type 2 and type 3 von Willebrand diseases in Thailand.

AIMS: Von Willebrand disease (VWD) is an inherited haemostatic disorder with a wide range of bleeding phenotypes based on von Willebrand factor (VWF) levels. Multiple assays including VWF gene analysis are employed to correctly diagnose VWD and its subtypes. However, data on VWF mutations among Southeast Asian populations are lacking. We, therefore, aimed to explore genetic variations in Thai patients with type 2 and type 3 VWD by whole exome sequencing (WES). METHODS: In this multicentre study, Thai patients with type 2 and type 3 VWD, according to the definitions and VWF levels recommended by the international guidelines, were recruited. WES was performed using DNA extracted from peripheral blood in all cases. The novel variants were verified by Sanger sequencing. RESULTS: Fifteen patients (73% females; median age at diagnosis 3.0 years) with type 2 (n=12) and type 3 VWD (n=3) from 14 families were enrolled. All patients harboured at least one VWF variant. Six missense (p.Arg1374Cys, p.Arg1374His, p.Arg1399Cys, p.Arg1597Trp, p.Ser1613Pro, p.Pro1648Arg) and one splice-site (c.3379+1G>A) variants in the VWF gene were formerly described. Notably, six VWF variants, including three missense (p.Met814Ile, p.Trp856Cys, p.Pro2032Leu), one deletion (c.2251delG) and two splice-site (c.7729+4A>C, c.8115+2delT) mutations were novelly identified. Compound heterozygosity contributed to type 2 and type 3 VWD phenotypes in two and one patients, respectively. CONCLUSIONS: Type 2 and type 3 VWD in Thailand demonstrate the mutational variations among VWF exons/introns with several unique variants. The WES-based approach potentially provides helpful information to verify VWD diagnosis and facilitate genetic counselling in clinical practice.

National strategic advocacy to manage patients with inherited bleeding disorders in low and lower-middle income countries.

INTRODUCTION: Inherited bleeding disorders (IBDs) including hemophilia, von Willebrand disease, platelet disorders, mucocutaneous bleeding disorders and coagulation factor deficiencies are rarely found and under-recognized in low and lower-middle-income countries. Some patients succumbed to serious bleeding without diagnosis and treatment during childhood. AREA COVERED: Diagnosis, management, and prevention should be integrated into the existing health care system. Although some countries have not implemented appropriate health care infrastructure, an initiative plan should be set up by cooperation of experienced experts and health care providers. Identification of patients with IBDs should be started in the antenatal setting to search for females at risk of carrier state. The investigations include bleeding assessment, mixing venous clotting time, coagulogram, coagulation factor assay and mutation detection. Genotypic analysis is helpful for confirming the definite diagnosis, carrier detection as well as prenatal diagnosis for females at risk of bearing an offspring with severe bleeding manifestations. Management involves replacement therapy ranging from blood component to virus-inactivated factor concentrate. Appropriate research is an essential backbone for improving patients' care. EXPERT OPINION: Effective national strategic advocacy to manage patients with IBDs requires intensive collaboration among policy makers, health care providers, patients, and family members.

Practices and challenges for hemophilia management under resource constraints in Thailand.

Hemophilia is an inherited bleeding disorder caused by deficiency of a specific coagulation factor. Factor VIII deficiency is responsible for hemophilia A while factor IX deficiency is responsible for hemophilia B. As per the 2020 annual global survey by the World Federation of Hemophilia, only 1828 Thai hemophiliacs have been registered to the national healthcare system. The reason for the low number is the underdiagnosis which is a major concern in the real-world practice among Asian countries. In Thailand, most hemophiliacs are diagnosed by general practitioners, pediatricians or internists at rural hospitals and are referred to hemophilia specialists at the Hemophilia Treatment Centers (HTCs). Despite the challenges pertaining to infrastructure and cost of treatment, Thailand has progressed substantially in providing the required hemophilia care, as evidenced by an evolution in acquiring and sharing knowledge as well as collaborative efforts among multiple stakeholders over the past three decades. In this letter-to-the-editor, the authors have summarized the practices for and challenges faced with hemophilia management in Thailand.

Treatment modalities of ALK-positive relapsed/refractory inflammatory myofibroblastic tumor of the brain and lungs in 7-year-old girl: case-based reviews.

PURPOSE: Inflammatory myofibroblastic tumor (IMT) belongs to mesenchymal neoplasm of intermediate malignancy in WHO classification. Primary CNS disease or CNS metastases (CNS-IMT) occur in minority. We describe a case of relapsed/refractory IMT of lungs with multiple brain metastases in young child who achieved long-term complete response after alectinib. This systematic review also summarizes treatment modalities and outcome of children and adolescent with CNS-IMT. METHODS: PRISMA 2020 guideline was applied to select an article from PubMed, Scopus, and Cochrane databases without time limits. This review focused on children and adolescent 0-24 years of age with CNS-IMT or inflammatory pseudotumor (CNS-IPT). The clinical characteristics and treatment outcome were explored. RESULTS: A total of 51 patients in 49 publications were identified. Median age of patients with CNS-IMT/IPT was 15-year-old and 60.8% were male. The most common location of tumor was cerebral cortex (54.9%). Complete resection of CNS-IMT/IPT was performed in 27 cases with 100% complete response and 18.5% recurrence. Nearly half of patients who received partial resection without adjuvant therapy experienced progressive disease, while the contrast group totally achieved partial response. Overall responses in 7 patients treating with ALK inhibitors were 57.1% durable complete response and 42.9% transient partial response. CONCLUSION: First-line treatment of CNS-IMT/IPT is complete resection. Patients who received partial tumor removal might have benefit from adjuvant therapy. ALK inhibitors reveal a promising result in unresectable CNS-IMT/IPT. Our case has shown a success in treating relapsed and refractory CNS-IMT as well as the primary site using 2nd-generation ALK inhibitor.

Warburg effect mimicking inborn errors of metabolism in childhood hematologic malignancies: A case-based systematic review.

BACKGROUND: Type B lactic acidosis and hypoglycemia can occur in various pediatric conditions. In young children with a history of fasting preceding these metabolic derangements, inborn errors of metabolism should be primarily considered. However, the Warburg effect, a rare metabolic complication, can also manifest in children with hematologic malignancies. Only a few reports of this condition in children have been published in the literature. AIM: To identify the clinical course, treatment strategies, and outcomes of childhood hematologic malignancies with type B lactic acidosis. METHODS: We performed a comprehensive search of the PubMed, Scopus, and Cochrane databases without any time restriction but limited to English language articles. The databases were last accessed on July 1st, 2023. RESULTS: A total of 20 publications were included in the analysis, all of which were case reports or case series. No higher quality evidence was available. Among children with hematologic malignancies and Warburg effect, there were 14 cases of acute lymphoblastic leukemia and 6 cases of non-Hodgkin's lymphoma including our illustrative case. Lactic acidosis occurred in 55% of newly diagnosed cases and 45% of relapsed cases. The mean age was 10.3 ± 4.5 years, and 80% of cases were male. The mean serum lactate was 16.9 ± 12.6 mmol/L, and 43.8% of the cases had concomitant hypoglycemia. Lactic acidosis initially subsided in 80% of patients receiving chemotherapy compared to 60% in the contrast group. The mortality rate of newly diagnosed cases was 45.5%, while the relapsed cases represented a 100% mortality rate. All 8 patients reported before 2001 died from disease-related complications. However, patients described in reports published between 2003 and 2023 had a 54.5% rate of complete remission. CONCLUSION: This complication has historically led to fatal outcome; however, patients who received chemotherapy showed a more favorable response. Therefore, it is crucial to promptly initiate specific treatment in this context.

What information and the extent of information to be provided in an informed assent/consent form of pediatric drug trials.

BACKGROUND: This study aimed to determine the elements and the extent of information that child participants and their parents would like to read in an informed assent form (IAF)/informed consent form (ICF) of a pediatric drug trial. METHODS: A descriptive survey was conducted to determine the perceived importance of each element of the ICF content from child participants and their parents who underwent informed assent/consent of a multi-center pediatric drug trial. The respondents were asked to indicate the level of importance of each item in a questionnaire, by giving a rating scale from 1 (not important) to 5 (very important). RESULTS: A total of 22 families, 17 child participants with the diagnosis of hematology or oncology diseases and 27 parents, were enrolled. Among 30 items, risk-benefit aspects (i.e., direct health benefit [mean: 4.71 for child respondents, 4.89 for parent respondents], indirect/societal benefit [mean: 4.65, 4.85], major foreseeable risk [mean: 4.47, 4.78], post-trial benefit/provision [mean: 4.59, 4.74], and all adverse effects of the drug including uncommon adverse effects [mean: 4.53, 4.74]) were perceived to be of most concerning items from both child participants' and parents' viewpoint. None of the items were considered 'slightly important' or lower by more than 20% of the respondents. CONCLUSIONS: For pediatric drug trials, risk-benefit information (including direct health benefit, indirect/societal benefit, and post-trial benefit/provision, as well as major foreseeable risk and adverse effects of the drug) should be made a salient feature of an IAF/ICF. This empirical data could help related stakeholders arrange essential information in order of importance and tailor an IAF/ICF to better suit child participants' and parents' needs, particularly for pediatric drug trials involving children with the diagnosis of hematology or oncology diseases.

Reticulocyte hemoglobin concentration for screening iron deficiency in very low birth weight preterm neonates.

BACKGROUND: Preterm and low birth weight infants are at risk of iron deficiency. Reticulocyte hemoglobin concentration may be useful as a screening test to diagnose iron deficiency in preterm neonates. OBJECTIVE: To evaluate the accuracy and establish the reticulocyte hemoglobin concentration cutoff value for iron deficiency diagnosis in very low birth weight preterm neonates. METHOD: This study was conducted between May 2018 and March 2019 at Chiang Mai University Hospital. Preterm infants born at gestational age ≤34 weeks and birth weight ≤1500 g were enrolled. Blood samplings were obtained within the first 48 h of life. Iron deficiency was defined by using two or more of these following parameters: mean corpuscular volume <100 fL, transferrin saturation <16% and serum ferritin <30 µg/L. Neonatal anemia was defined as hemoglobin <15 g/dL. The optimum reticulocyte hemoglobin concentration cutoff values were performed by using predictive values and receiving operation characteristic analysis. RESULT: Fifty-seven preterm neonates were enrolled. Nine (15.7%) and three (5.3%) neonates had iron deficiency and iron deficiency anemia, respectively. The reticulocyte hemoglobin concentration cutoff value of <29 pg showed the optimum accuracy to diagnose iron deficiency in very low birth weight preterm neonates with sensitivity, specificity, positive and negative predictive values of 89%, 79%, 42% and 97%, respectively. CONCLUSION: Reticulocyte hemoglobin concentration can be used as a screening parameter to diagnose iron deficiency for VLBW preterm neonates. The optimum cutoff value which provided the acceptable accuracy was <29 pg.

Severe neonatal haemolytic anaemia caused by compound heterozygous KLF1 mutations: report of four families and literature review.

Mutations in the KLF1 gene, which encodes a transcription factor playing a role in erythropoiesis, have recently been demonstrated to be a rare cause of hereditary haemolytic anaemia. We described the genotypic and phenotypic spectra of four unrelated families with compound heterozygous class 2/class 3 KLF1 mutations. All patients had p.G176RfsX179 on one allele and either p.A298P, p.R301H or p.G335R on the other allele. All presented on the first day of life with severe haemolytic anaemia with abnormal red blood cell morphology, markedly increased nucleated red blood cells and hyperbilirubinaemia. Three patients later became transfusion-dependent. All parents with heterozygous KLF1 mutation without co-inherited thalassaemia had normal to borderline mean corpuscular volume (MCV) and normal to slightly elevated Hb F. Fifteen previously reported cases of biallelic KLF1 mutations were identified from a literature review. All except one presented with severe haemolytic anaemia in the neonatal period. Our finding substantiates that compound heterozygous KLF1 mutations are associated with severe neonatal haemolytic anaemia and expands the haematologic phenotypic spectrum. In carriers, the previously suggested findings of low MCV, high Hb A2 and high Hb F are inconsistent; thus this necessitates molecular studies for the identification of carriers.

MYH9 disorder: Identification and a novel mutation in patients with macrothrombocytopenia.

The diagnosis of MYH9 disorder is guided by recognizing granulocyte Döhle body-like inclusion bodies and large/giant platelets in the peripheral blood smear. Immunofluorescence study of nonmuscle myosin heavy chain IIA is a sensitive screening method for diagnosis of MYH9 disorder. The diagnosis can then be confirmed by genetic analysis. A total of 67 patients with macrothrombocytopenia were included, of which 11 patients (16%), aged 4 months to 22 years, were ultimately diagnosed with MYH9 disorder. One novel mutation in exon 30 at c.4338T>C (p.F1446A) was detected. This mutation was associated with nonhematologic manifestations presenting in late adolescence with cataracts, hearing loss, and hematuria.

Real-world evidence on health resource use among patients with haemophilia and inhibitor exhibiting severe bleeding episodes.

OBJECTIVE: This study aimed to explore real-world evidence on health resource use (HRU) spending on patients with haemophilia and inhibitor. MATERIALS AND METHODS: Medical records from 1990 to 2019 of patients with haemophilia and inhibitor from three comprehensive haemophilia treatment centres were retrospectively retrieved. RESULTS: In all, 31 patients with haemophilia (A = 30, B = 1) and inhibitor ≥5 BU were included. The mean initial inhibitor of 95.4 BU was detected at the mean age of 6.7 years. The mean number of annual hospitalisations was 3.9. A total of 795 bleeding episodes (major =125, minor =670) were evaluated. The treatment included bypassing agents or plasma exchange before administering high-dose factor VIII concentrate and intervention or surgery. Six patients succumbed to bleeding at the mean age of 17.2 years. Nineteen surviving patients experienced multiple morbidity except six patients with successful and partially successful immune tolerance induction (ITI). The mean (SD) annual total medical consumption for episodic treatment and successful ITI per patient with haemophilia A were 30,804 (81,332) USD and 55,531 (100,566) USD, respectively. Only episodic treatment was paid by the government budget for limited amounts of bypassing agents. CONCLUSION: Management for patients with haemophilia and inhibitor exhibiting severe bleeding is challenging for medical personnel in countries having limited resources over decades. The real-world data will be used to negotiate with the government to increase budget for adequate bypassing agents or nonreplacement therapy and to include ITI in the national haemophilia treatment.

Screening for Iron Deficiency Anemia in Infants in a Thalassemia-endemic Region.

Screening for iron deficiency anemia (IDA) in infants is usually carried out by hemoglobin (Hb) level and mean corpuscular volume (MCV). A coinherited thalassemia carrier may confound the diagnosis of IDA. This study aimed to characterize the hematologic parameters in infants with IDA and in thalassemia carriers, and to study the use of red cell parameters in IDA screening in a thalassemia-endemic area. Healthy infants, 6 to 12 months of age were enrolled. Blood samples were taken for complete blood count, ferritin level, Hb analysis, and polymerase chain reaction for alpha-thalassemia. IDA was defined as Hb <11.0 g/dL and ferritin <12 µg/L. Formulae calculated from red cell parameters to distinguish thalassemia carriers were analyzed. Eighty-five infants, 8.3±2.4 months of age, including 48 (56.5%) male infants were enrolled. Sixteen infants (18.8%) had IDA. There were 25 thalassemia carriers (29.4%), 1 Hb H disease, and 1 homozygous Hb E. Hb levels and MCV in the IDA and thalassemia carrier groups were significantly lower than those in the normal group. Area under the curve of Mentzer index (MCV/red blood cell count <13) to suggest thalassemia carriers was 0.867 (95% confidence interval: 0.784-0.951), and the sensitivity and specificity were 92.6% and 72.4%, respectively. In conclusion, both Hb level and Mentzer index are recommended for screening of IDA and thalassemia carriers in the population.

Phase II, multi-center, open-label, single-arm clinical trial evaluating the efficacy and safety of Mycophenolate Mofetil in patients with high-grade locally advanced or metastatic osteosarcoma (ESMMO): rationale and design of the ESMMO trial.

BACKGROUND: Clinical outcomes of patients with osteosarcoma remain unsatisfactory, with little improvement in a 5-year overall survival over the past three decades. There is a substantial need for further research and development to identify and develop more efficacious agents/regimens in order to improve clinical outcomes of patients for whom the prognosis is unfavorable. Recently, mycophenolate mofetil, a prodrug of mycophenolic acid, has been found to have anticancer activity against osteosarcoma in both in vitro and animal experiments, so that further investigation in humans is warranted. METHODS: A total of 27 patients with high-grade locally advanced or metastatic osteosarcoma will be enrolled into this phase II, multi-center, open-label, single-arm, two-stage clinical trial. The main objectives of this study are to determine the efficacy and safety of mycophenolate mofetil in the patients. The primary endpoint is progression-free survival at 16 weeks; the secondary endpoints include progression-free survival, overall survival, overall response rate, safety parameters, pharmacokinetic parameters, biomarkers, pain score, and quality of life. Mycophenolate mofetil at the initial dose of 5 g/day or lower will be administered for 4 cycles (28 days/cycle) or until disease progression or unacceptable toxicity. The dose of mycophenolate mofetil may be reduced by 1-2 g/day or withheld for some Grade 3 or Grade 4 toxicities whenever clinically needed. The duration of study participation is approximately 4-5 months, with a minimum of 12 study visits. If mycophenolate mofetil proves beneficial to some patients, as evidenced by stable disease or partial response at 16 weeks, administration of mycophenolate mofetil will continue in the extension period. DISCUSSION: This trial is the first step in the translation of therapeutic potential of mycophenolate mofetil emerging from in vitro and animal studies into the clinical domain. It is designed to assess the efficacy and safety of mycophenolate mofetil in patients with high-grade locally advanced or metastatic osteosarcoma. The results will provide important information about whether or not mycophenolate mofetil is worth further development. TRIAL REGISTRATION: This trial was prospectively registered on Thai Clinical Trials Registry (registration number: TCTR20190701001). The posted information will be updated as needed to reflect protocol amendments and study progress.

Unusual Presentation with Orbital Mass in a Child with Precursor B-Cell Acute Lymphoblastic Leukemia.

Orbital involvement is one of the extramedullary manifestations in acute leukemia. It is common in acute myeloid leukemia, but rare in acute lymphoblastic leukemia (ALL). We described a 3-year-old girl who presented with progressive proptosis of the right eye and was later diagnosed with precursor B-cell ALL. Initial blood count showed Hb 6.9 g/dL, WBC 42,000/mm3, lymphoblast 50%, and platelet count 185,000/mm3. Bone marrow aspiration revealed 90% lymphoblasts with positivity for CD10, CD19, CD20, CD22, and HLA-DR markers. Computed tomography (CT) scan of the brain and orbit revealed a homogeneous enhancing mass involving the right orbit with intracranial extension. The cytogenetic study showed 46,XX chromosomes. After 4 weeks of induction chemotherapy for very high-risk ALL, although the bone marrow was in remission, the proptosis was partially resolved. CT scan confirmed a decrease in size of the right orbital mass and degree of intracranial extension. Unfortunately, the patient abandoned the treatment after the induction chemotherapy. The actual incidence of orbital involvement in ALL is unknown. Previous case reports describe diverse manifestations of orbital involvement in ALL. The involvement may be unilateral or bilateral, may occur at first diagnosis or at relapse, and may be seen in isolation or with other systemic symptoms. There is no standard treatment protocol. Chemotherapy with or without radiotherapy is generally suggested. The role of upfront hematopoietic stem cell transplantation remains inconclusive. The previously reported prognosis of ALL with orbital involvement is poor.