Worawut Choeyprasert

Cisplatin-induced ototoxicity in pediatric solid tumors: The role of glutathione S-transferases and megalin genetic polymorphisms

Cisplatin-induced ototoxicity, an important dose-limiting side effect, has proven high interindividual variability. Glutathione S-transferases (GSTs) are isoenzymes involved in cellular detoxification processes. Megalin has been demonstrated to bind aminoglycosides, known to be similar to cisplatin for their ototoxicity. The GSTs and megalin expression is genetically polymorphic, which might be responsible for the variability in cisplatin-induced ototoxicity. The genotyping of GSTM1, GSTT1 polymorphisms, and 2 nonsynonymous single nucleotide polymorphisms (SNPs) at megalin genes, rs2075252 and rs2228171, were performed in 68 children diagnosed with solid tumors who received cisplatin-based chemotherapy. After the end of treatment, audiometry demonstrated hearing loss in 79.4% of patients according to Brock classification. The cumulative cisplatin dose >400 mg/m2 is associated with increased risk of cisplatin-induced ototoxicity [odds ratio (OR), 17.5; 95% confidence interval (CI), 3.09-98.62]. GSTT1 wild genotype and C-allele of rs2228171 SNPs of megalin gene occurred with higher frequency in patients with ototoxicity (P=0.023; OR, 10; 95% CI, 1.80-56.00 and P=0.034; OR, 2.67; 95% CI, 1.22-5.82, respectively). In conclusion, our results suggested that GSTT1 wild genotype and C-allele of rs2228171 SNPs might be risk factors for ototoxicity. The cumulative cisplatin dose <400 mg/m2 should be beneficial in order to ameliorate ototoxicity.

Comparative outcome of Thai pediatric osteosarcoma treated with two protocols: the role of high-dose methotrexate (HDMTX) in a single institute experience.

BACKGROUND High-dose methotrexate (HD-MTX) is recognized as an efficient component of therapy against pediatric osteosarcoma in combination with other drugs such as cisplatin (CDP), carboplatin (CBDCA), doxorubicin (ADM), etoposide (VP-16) and ifosfamide (IFO). OBJECTIVES To demonstrate the feasibility and effectiveness of the HD-MTX/CDP/DOX/VP-16/IFO [MTX(+)] protocol comparable to CDP/ADM/CBDCA/IFO [MTX(-)] for treating childhood osteosarcoma at Ramathibodi Hospital (1999-2014). MATERIALS AND METHODS A retrospective analysis was conducted of osteosarcoma patients aged less than 18 years treated with two chemotherapeutic regimens between 1999 and 2014. A total of 45 patients received the MTX(-) and 21 the MTX(+) protocol. RESULTS Overall limb-salvage and amputation rate were 12.9% and 77.7%, respectively. Kaplan- Meier analysis results for 3-year disease free survival (DFS) and overall survival (OS) regardless of treatment regimens were 43.4±6.0% and 53.2±6.1% respectively. The 3-year DFS and OS were improved significantly with the MTX(+) protocol compared to MTX(-) protocol (p=0.010 and p=0.009, log rank test) [69.8±10.5%, 79.8±9.1% for MTX(+) and 31.1±6.9%, 42.2±7.4% for MTX(-) protocol, respectively]. Patients with metastatic osteosarcoma treated with the MTX(+) protocol had statistically significant higher 3-year DFS and OS than those treated with the MTX(-) protocol (66.7±13.6% and 15.0±8.0% for 3-year DFS, p=0.010, 73.3±13.2% and 20±8.9% for 3-year OS, p=0.006, respectively). The independent risk factors for having inferior 3-year DFS and OS were poor histological response (tumor necrosis <90%) and treatment with the MTX(-) protocol. The multivariate analysis identified only the treatment with the MTX(-) protocol as an independent predictor of inferior OS with a hazard ratio (HR) of 3.53 (95% confidence interval of 1.2-10.41, p=0.022). CONCLUSIONS Our study demonstrated the tolerability, feasibility and efficacy of the HDMTX-based regimen improving the survival rate in pediatric osteosarcoma cases, in line with reports from developed countries.

Carboplatin and Doxorubicin in Treatment of Pediatric Osteosarcoma: A 9-year Single Institute Experience in the Northern Region of Thailand

BACKGROUND Osteosarcoma is the most common primary bone tumor in childhood and adolescence. Carboplatin, a platinum-derived agent, is used as neoadjuvant chemotherapy for pediatric osteosarcoma because of its anti-tumor activity and had low toxicity as compared to cisplatin. OBJECTIVE To determine demographic data, prognostic factors and outcome of childhood osteosarcoma treated with a carboplatin-based chemotherapeutic protocol at Chiang Mai University. METHOD A retrospective analysis was conducted on 34 osteosarcoma patients aged less than 18 years and treated between 2003 and 2011. RESULTS Overall limb-salvage and amputation rates were 23.5% and 70.6%, respectively. With the mean follow-up time of 29.5 months (1.5-108.9), the Kaplan-Meier analysis for 3-year disease-free survival (DFS) and 3-year overall survival (OS) were 20.2±7.7% and 47.1±9.5% respectively. Patients who had initial pulmonary metastasis were at significantly greater risk for developing recurrence (p=0.02, OR=7; 1.2-40.1) and had a tendency to have lower 3-year OS compared to those without initial pulmonary metastasis (28.1±13%, 63.1±12.3%, respectively, p=0.202). On univariate analysis, age at diagnosis and patients who were declined surgery were significantly associated with lower 3-year OS (p=0.008 and <0.05, respectively). However, age at diagnosis, sex, tumor size and histological subtypes were not found to significantly affect recurrence or survival. CONCLUSIONS In our study, the survival rate was far lower than those reported from developed countries. These might indicate the ineffectiveness of carboplatin in combination with doxorubicin as frontline treatment of pediatric osteosarcoma, especially in those with initial pulmonary metastasis. Refinement in risk and treatment stratification and dose intensification for pediatric osteosarcoma constitutes a future challenge to improve outcomes, especially in metastatic patients who may need a more intensive regimen.

Health-Related Quality of Life in Adolescents with Thalassemia.

Children and adolescents with thalassemia suffer from chronicity of the disease and its treatment, including transfusion dependence and complications of iron overload. This study aimed to assess the health-related quality of life of adolescents with thalassemia compared with healthy controls. Sixty-four adolescents with thalassemia aged 13 to18 years and their parents were enrolled in this cross-sectional study, as well as their age- and gender-matched those of the healthy controls (64 participants and their parents). The Pediatric Quality of Life Inventory 4.0 Scales (PedsQL 4.0) self-report form was administered to the adolescents in both groups. Parents were also asked to complete the PedsQL 4.0, parent proxy-report form. The self-reported total, psychosocial, and school functioning scores of the thalassemia patients were significantly lower than those of the healthy controls (p = 0.03, 0.04, and <0.001, respectively). The parent-reported psychosocial and school functioning scores of the thalassemia group were also significantly lower than those of the controls (p = 0.03 and 0.003, respectively). Among adolescents with thalassemia, the serum ferritin level and comorbidity were the only variables associated with quality of life scores. This study showed that thalassemia negatively affected quality of life. For a better quality of life, thalassemia patients should be monitored for serum ferritin levels and treated for comorbidity as part of their comprehensive health care.

Pulmonary hypertension in non-transfusion-dependent thalassemia: Correlation with clinical parameters, liver iron concentration, and non-transferrin-bound iron

Abstract Background Pulmonary hypertension is a major cardiac complication in non-transfusion-dependent thalassemia (NTDT). Several clinical and laboratory parameters, including iron overload, have been shown to have a positive correlation with the incidence of pulmonary hypertension. Non-transferrin-bound iron (NTBI) is a form of free-plasma iron that is a good indicator of iron overload. Objectives The aim of this study was to determine the prevalence of pulmonary hypertension in patients with NTDT and to investigate its correlation with the clinical parameters, liver iron concentration (LIC) and NTBI. Methods Patients with NTDT were evaluated using echocardiography, and magnetic resonance imaging for cardiac T2* and LIC. Pulmonary hypertension was defined as peak tricuspid regurgitation velocity ≥2.9 m/s measured using trans-thoracic echocardiography. Clinical parameters and the status of iron overload as determined by LIC, serum ferritin, and NTBI level were evaluated for their association with pulmonary hypertension. Results Of 76 NTDT patients, mean age 23.7 ± 8.5 years, seven patients (9.2%) had pulmonary hypertension. Previous splenectomy (71.4 vs. 24.6%, P-value 0.019), higher cumulative red blood cell (RBC) transfusions (received ≥10 RBC transfusions 85.7 vs. 33.3%, P-value 0.011), higher nucleated RBCs (353 ± 287 vs. 63 ± 160/100 white blood cells, P-value <0.001), and a high NTBI level (5.7 ± 3.0 vs. 3.3 ± 2.8 µmol/l, P-value 0.034) were associated with pulmonary hypertension. There was no significant correlation between LIC or serum ferritin and pulmonary hypertension. Conclusion Pulmonary hypertension in NTDT is common, and is associated with splenectomy and its related factors. NTBI level shows a significant correlation with pulmonary hypertension.

Successful treatment of mild pediatric kasabach-merritt phenomenon with propranolol monotherapy.

Kasabach-Merritt phenomenon (KMP) is relatively rare in childhood and adolescents with high mortality rate because of its hemorrhagic complications and unresponsiveness to treatments such as corticosteroids, vincristine, intravascular embolization, and/or surgery. Propranolol, a β-adrenergic receptor blocker, has a promising efficacy against vascular tumors such as infantile hemangiomas. But limited and variable data has been reported regarding the role of propranolol in treatment of KMP. We herein reported the successful treatment of mild pediatric KMP with propranolol monotherapy in a case of a five-week-old child with kaposiform hemangioendothelioma with successful treatment of both clinical and hematologic responses. After eight months of follow-up, patient still had stable cutaneous lesion while receiving propranolol monotherapy. Regular hematologic monitoring was done in order to detect any late relapse of the disease. Six months after discontinuation of propranolol, patient has still remained free of hematologic relapse, and primary cutaneous lesion has become a pale pink, 1 cm sized skin lesion.

Adverse effects of imatinib in children with chronic myelogenous leukemia

Imatinib mesylate (IM) is a selective tyrosine kinase inhibitor and is approved for indefinite treatment of pediatric chronic myelogenous leukemia (CML). Potential side‐effects regarding growth failure and bone metabolism have been reported but data are still scarce in pediatric CML.

Coinheritance of Hereditary Elliptocytosis and Deletional Hemoglobin H Disease

Hereditary elliptocytosis is an inherited red blood cell membrane disorder characterized by typical peripheral blood smear findings of elliptocytes or rod-like red blood cells. Hemoglobin H disease is a form of α-thalassemia disease resulting in mild to moderate hemolytic anemia. The authors report 1 case of a girl who was diagnosed with oculo-auriculo-vertebral spectrum and a coinheritance of hereditary elliptocytosis and deletional hemoglobin H disease. She had moderate, non-transfusion-dependent anemia. The red blood cells showed marked poikilocytosis and fragmentation. The parents were α-thalassemia carriers and the father had the typical red blood cell morphology of common hereditary elliptocytosis.

Incidences, Trends and Long Term Outcomes of Retinoblastoma in Three Cancer Registries, Thailand.

BACKGROUND Retinoblastoma (RB) is rare, albeit the most common primary intraocular malignancy among children. To elucidate the true incidence, trend and survival, we studied incidences and trends of retinoblastoma in a large population with long-term follow-up using data from 3 population-based cancer registries. OBJECTIVE To describe the incidence, trends and survival of RB between 1990 and 2009 in Khon Kaen, Songkhla and Chiang Mai, Thailand. MATERIALS AND METHODS We sourced the data from the cancer registries in Khon Kaen, Songkhla and Chiang Mai on children with retinoblastoma, diagnosed between 1990 and 2009. Retinoblastoma was defined as per the International Classification of Disease for Oncology version 3 using the code 9510/3. Incidence was analyzed using the standard method with the criteria of the International Association of Cancer Registries. The Kaplan-Meier method was applied to calculate cumulative survival. Trends were calculated using the log rank test. RESULTS We identified 75 cases of children between 0 and 15 years of age diagnosed with RB (Khon Kaen 31, Chiang Mai 20, Songkhla 24). Males and females were equally affected. The most common age group was 0-4 years. The morphological verification of the disease was 90.7%. The respective ASR in Khon Kaen, Chiang Mai and Songkhla was 4.4, 4.0 and 4.6 per million; for which the overall ASR for all 3 areas was 4.3 per million. The respective trend in incidence was 4, 2.8, 5.8 and 5.4 during 1990-4, 1995-9, 2000-4 and 2005-9. Overall, incidence trended gradually upward by 2% annually. The respective survival rate in Khon Kaen, Chiang Mai and Songkhla was 50, 40 and 75% (differences not significantly different at p=0.14) and the overall survival for all centers was 60%. CONCLUSIONS Over the last two decades, the incidence and overall survival of retinoblastoma has increased. The ASRs and survival in Thailand were less than those in resource-rich countries.

Vincristine-induced polyneuropathy in a child with stage I Wilms’ tumour presenting with unilateral abducens nerve palsy

A 4-year-old boy presented with right esotropia while receiving vincristine and dactinomycin for stage I Wilms’ tumour according to the National Wilms Tumour Study-5 protocol. On examination, he had isolated limitation of his right lateral gaze. CT of the brain and cerebrospinal fluid examination were normal. A nerve conduction velocity study which was performed on the peripheral nerves revealed predominant motor polyneuropathy compatible with axonal loss involving the upper limbs. The patient had received a cumulative vincristine dose of 17 mg/m2 before developing esotropia. Vincristine-induced abducens nerve mononeuropathy and subclinical motor polyneuropathy was suspected. Unilateral esotropia markedly improved after the discontinuation of vincristine and a short course of oral pyridoxine treatment.