Can knowledgeable experts assess costs and outcomes as if they were ignorant? An experiment within precision medicine evaluation.

OBJECTIVES: The purpose of this study is to evaluate the validity of the standard approach in expert judgment for evaluating precision medicines, in which experts are required to estimate outcomes as if they did not have access to diagnostic information, whereas in fact, they do. METHODS: Fourteen clinicians participated in an expert judgment task to estimate the cost and medical outcomes of the use of exome sequencing in pediatric patients with intractable epilepsy in Thailand. Experts were randomly assigned to either an "unblind" or "blind" group; the former was provided with the exome sequencing results for each patient case prior to the judgment task, whereas the latter was not provided with the exome sequencing results. Both groups were asked to estimate the outcomes for the counterfactual scenario, in which patients had not been tested by exome sequencing. RESULTS: Our study did not show significant results, possibly due to the small sample size of both participants and case studies. CONCLUSIONS: A comparison of the unblind and blind approach did not show conclusive evidence that there is a difference in outcomes. However, until further evidence suggests otherwise, we recommend the blind approach as preferable when using expert judgment to evaluate precision medicines because this approach is more representative of the counterfactual scenario than the unblind approach.

Carboplatin-based regimen in pediatric intracranial germ-cell tumors (IC-GCTs): effectiveness and ototoxicity.

BACKGROUND: Induction chemotherapy with carboplatin followed by radiotherapy has been used for many years for treating intracranial germ-cell tumors (IC-GCTs) in Thailand. The objective of this study was to assess treatment outcomes, focusing on survival and ototoxicity. METHODS: The outcomes of all patients with IC-GCT treated at Ramathibodi Hospital and the Prasat Neurological Institute between 2000 and 2017 were reviewed and analyzed, including all patient characteristics and treatment modalities. Five-year overall survival (OS) and event-free survival (EFS) were analyzed using the Kaplan-Meier method, and factors affecting survival were compared using the log-rank test. RESULTS: Fifty-three patients age 1-14 years (median, 11 years) were included in this study. The median follow-up time was 63 months. The 5-year EFS and OS rates were 94.3% and 96.2% for all patients, respectively. No statistical difference in OS or EFS was observed between the data of recipients in the carboplatin-based and historical cisplatin-based therapies in our institutes. Concerning radiotherapy, omission of radiotherapy or focal irradiation results in worse long-term survival outcomes, but reduction in dose of radiotherapy to less than 40 Gy did not cause any negative impact on survival rates. Furthermore, carboplatin was associated with lower rates of hearing loss than cisplatin (5.7% vs 87.5%). CONCLUSIONS: Induction chemotherapy with carboplatin-based regimens was associated with excellent survival rates and low ototoxicity in patients with IC-GCT. Radiotherapy should be given to all patients with a minimal volume equivalent to whole-ventricular radiotherapy, during which doses of lower than 40 Gy can be effectively used.

Reported outcomes of children with newly diagnosed high-grade gliomas treated with nimotuzumab and irinotecan.

PURPOSE: The outcome of children with high-grade gliomas (HGGs) treated with radiation and adjuvant chemotherapy remains poor. The expression of epidermal growth factor receptor (EGFR) has been established in children with HGGs. This report demonstrated the outcomes of adjuvant nimotuzumab, an EGFR inhibitor, with irinotecan in pediatric HGGs. METHODS: Children with newly diagnosed HGGs were enrolled. Two weeks after surgery, nimotuzumab with a dose of 150 mg/m2 was given every week during radiation. After completion of radiation, a 4-week cycle of nimotuzumab (150 mg/m2) at week 1 and 3 and irinotecan (125 mg/m2) at week 1, 2, and 3 was given. RESULTS: Sixteen patients (5 females, 11 males), with a mean ± SD age of 8.2 ± 3.5 years were included. Tumors were located at the supratentorial region (50.0%), infratentorial region (43.8%), and both locations (6.2%). The 5-year PFS and OS were 19.9 ± 11.6 and 31.5 ± 13.0%, respectively. Median times of PFS and OS were 1.8 and 1.9 years, respectively. Prognostic factors related to good outcome were the location of tumor at the supratentorial region or outside brainstem and the extension of surgery. Side effects were minimal, with grade 1 anemia in three patients and diarrhea in one patient. Although, the adjuvant regimen of nimotuzumab and irinotecan slightly increases the overall outcome when compared to the historical study, the advantages of this protocol were minimal side effect, short period of hospitalization, and improved OS in patients who received extensive surgery.

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.

Mutation screening of the CDKL5 gene in cryptogenic infantile intractable epilepsy and review of clinical sensitivity.

PURPOSES: To perform CDKL5 mutation screening in Thai children with cryptogenic infantile intractable epilepsy and to determine the clinical sensitivity of CDKL5 screening when different inclusion criteria were applied. METHODS: Children with cryptogenic infantile intractable epilepsy were screened for CDKL5 mutation using multiplex ligation-dependent probe amplification and DNA sequencing. The clinical sensitivity was reviewed by combining the results of studies using similar inclusion screening criteria. RESULTS: Thirty children (19 girls and 11 boys) with a median seizure onset of 7 months were screened. Almost a half had infantile spasms and one fifth had stereotypic hand movements. A novel c.2854C>T (p.R952X) was identified in an ambulatory girl who had severe mental retardation, multiple types of seizures without Rett-like features. Her mother had a mild intellectual disability, yet her grandmother and half sister were normal despite having the same genetic alteration (random X-inactivation patterns). The pathogenicity of p.R952X identified here was uncertain since healthy relatives and 6 female controls also harbor this alteration. The clinical sensitivity of CDKL5 mutation screening among females with Rett-like features and negative MECP2 screening was 7.8% while the clinical sensitivity among females having cryptogenic intractable seizures with an onset before the ages of 12, 6 and 3 months were 4.7, 11.6 and 14.3%, respectively.

Carotid dissection causing stroke in a 13-year-old boy with mild hyperhomocysteinemia: case report.

The author describes a 13-year-old Thai boy who developed stroke caused by carotid dissection and found mild elevation of plasma homocysteine (tHcy). The patient improved after anticoagulation therapy and his plasma tHcy decreased after vitamin supplement. With long-term follow-up, he is having normal neurological condition. This case proposes that the pathogenesis of carotid dissection may associate with mild hyperhomocysteinemia.

Outcome of medulloblastoma in children treated with reduced-dose radiation therapy plus adjuvant chemotherapy.

Medulloblastoma is the most common malignant brain tumor in children. Post-surgical craniospinal irradiation (CSI; 30-36 Gy) plus local boost radiation therapy (RT; 54-56 Gy) is a standard treatment for children with medulloblastoma who are over 3 years old, resulting in a 5-year overall survival (OS) rate of 46% to 65% in average-risk patients and 50% in high-risk patients. The addition of chemotherapy has the benefit of reducing complications from radiation and improving the OS rate. Using this approach, the estimated 5-year OS rates for patients with average- and high-risk medulloblastomas treated with different protocols are 65% to 85% and 16% to 70%, respectively. In this study, we determined the outcome of patients with average- and high-risk medulloblastomas treated with reduced dosage CSI and chemotherapy with an oral etoposide-based regimen. The study included 49 patients, with a mean age of 7.7 ± 3.4 years. Twenty-six patients (53%) were classified as average-risk and 23 patients (47%) as high-risk. In the average-risk group, the 5-year progression free survival (PFS) rate was 62.9% ± 10% and the 5-year OS rate was 70.4% ± 9.5%. In the high-risk group the 5-year PFS rate was 48.9% ± 13% and the 5-year OS rate was 49.7% ± 13%. In the average-risk group, patients who received CSI of either 24 Gy (n=20) or 36 Gy (n=9) showed no difference in their 5-year PFS and OS rates. We found that patients who were ≤ 10 years old and patients who were female had a significantly better 5-year PFS rate.

Hypothalamic-pituitary dysfunction in survivors of childhood brain tumors in Prasat Neurological Institute.

OBJECTIVE: To assess hypothalamic-pituitary dysfunction in childhood brain tumor survivors in Prasat Neurological Institute. MATERIAL AND METHOD: Between October 2007 and September 2008, 19 brain tumor survivor children in Prasat Neurological Institute without recurrence at least 2 years after complete treatment were included in the present study. The patients were categorized according to brain tumor location into directly (DHPA) (9 cases) and indirectly (IDHPA) (10 cases) involving hypothalamic-pituitary axis. All patients were treated by surgery. Furthermore, six cases were combined with radiation and chemotherapy and 10 cases were combined with radiation therapy only. Growth Hormone (GH) stimulation test by clonidine and/or L-Dopa, ACTH stimulation test and thyroid function test (TFT) were done. RESULTS: The mean age at diagnosis was 9.9 +/- 4.6 years old and the interval from diagnosis to study was 5.8 +/- 2.2 years. Seven DHPA (77%) and seven IDHPA patients (70%) had low peak GH with significant lower level in the former group (p < 0.05). Six of seven DHPA (85%) and one IDHPA patients (10%) had low response to ACTH stimulation test. All DHPA (100%) and 10% IDHPA patients had central hypothyroidism. By ACTH stimulation test in DHPA patients, hypocortisolism was detected in five and excluded in one who later stopped prednisolone after prolonged continuation. The central hypothyroidism was newly detected in two DHPA patients and replacement therapy was initiated GH deficiency (GHD) was detected by GH stimulation test in 73% of overall brain tumors. Growth hormone therapy would be considered in the appropriate GHD patients. CONCLUSION: With effective therapy and improving survival rates of brain tumor children, hypothalamic-pituitary dysfunction in either DHPA or IDHPA group should be regularly monitored to prevent further morbidity and improve quality of life.

Folate pathway genetic polymorphisms and susceptibility of central nervous system tumors in Thai children.

BACKGROUND: Folate is an important micronutrient molecule participating in DNA synthesis, methylation and repair mechanisms. Genetic polymorphisms in folate pathway related enzymes including methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, thymidylate synthase (TS) 28-bp tandem repeat, and reduced folate carrier (RFC) G80A have been shown to be associated with increased susceptibility for several cancers. The aim of the present study was to evaluate whether single nucleotide polymorphisms in the genes encoding enzymes of the folate pathway predispose to any CNS tumors in Thai children. METHODS: In the present case-control study, we investigated these polymorphisms in genomic DNA from peripheral blood mononuclear cells in 73 Thai children with various types of central nervous system tumors and in 205 age and sex matched controls. RESULTS: Thirty-one out of 73 patients were diagnosed with glial tumors (astrocytoma, oigodendroglioma and ependymoma), 28 with embryonal CNS tumors (medulloblastoma, pinealoblastoma and primitive neuroectodermal tumor), 13 with germ cell tumors and 1 with meningioma. We found that the homozygous CC allele of MTHFR A1298C conferred an increased risk of embryonal CNS tumors (OR: 3.9; 95% CI: 1.3-11.4, p=0.02). CONCLUSION: Our findings thus suggest that folate metabolism may play a role in the pathogenesis of certain specific subtypes of pediatric brain tumor in Thai children, especially embryonal CNS tumors.

Flunarizine for prophylactic treatment of childhood migraine.

OBJECTIVE: To determine the effectiveness of flunarizine for migraine prophylaxis in children. PATIENTS AND METHOD: Children aged between 7 and 15 years who had the indication for prophylactic treatment of migraine were recruited into a prospective study at the Department of Pediatrics, Ramathibodi Hospital, from January 1st to December 31st 1999. After verbal consent was obtained, flunarizine was administered either at 5-mg daily in those who had never received it or at 10-mg daily in those who previously took this drug within one year Serial evaluation for the severity of migraine including duration, intensity, and frequency of headache attacks was performed every 2 weeks for 6 months. RESULTS: Twenty-one children (10 boys, 11 girls) with a mean age of 11.3+/-2.48 years (range 7-15 years) were enrolled in the study. There were ten children who had migraine with aura. Initially, 5-mg daily and 10-mg daily of flunarizine were administered in 19 and 2 patients respectively. The dosage was increased to 10-mg daily after two weeks in 5 patients because of the unresponsiveness to the initial dose. Improvement was observed in 14 patients (66%) including 13 of 14 patients who received 5-mg daily and 1 of 7 patients who received 10 mg daily. Five patients (23%) had no recurrent attack. Nine patients (42%) had more than 50%-reduction of frequency of migraine and 3 of these had either shorter duration or less intensity of the attack. Clinical improvement was observed between 2 and 4 weeks after initiation of treatment. There was no adverse effect observed CONCLUSION: This is a preliminary result demonstrating that flunarizine is one of the effective drugs for migraine prophylaxis in children.