Hee Young Shin

Background: We retrospectively assessed the long-term efficacy, safety, and functional outcome of chemotherapy and radiotherapy (RT) in patients with intracranial germinoma (iGE). Methods: A total of 160 patients with iGE treated between 1983 and 2013 were reviewed. Overall survival (OS) was estimated using Kaplan-Meier method. The cumulative incidence of recurrence (CIR), and secondary malignancies (CISM) were analyzed using cumulative incidence functions (CIFs), with death without the event of interest treated as a competing risk. Functional outcomes were assessed using the Karnofsky Performance Scale (KPS). Cox proportional hazards regression was used to analyze predictive factors. Results: The mean follow-up duration was 157.1 months. The 5-/10-year OS rates were 93.8% and 88.6%. The 5- and 10-year CIRs were both 5.6%, whereas the CISM were 0.6% and 2.1%, respectively. Secondary malignancies developed in 14 patients, most commonly glioblastoma. Thirty-one patients died from disease-, treatment-, or secondary malignancy-related causes. Additional causes of death were identified during long-term follow-up, even more than 20 years after treatment. Functional outcomes remained favorable (KPS ≥ 60) in 90.6% at 5 years and 88.5% at 10 years. Chemotherapy combined with reduced extent and reduced-dose RT significantly improved OS without increasing the CIR. Conclusions: Despite the generally favorable prognosis, secondary malignancies and disease- and treatment-related long-term adverse effects significantly affect patient outcomes in iGE. Long-term follow-up (over 20 years) is essential for detecting and managing these complications. Chemotherapy with reduced-extent and reduced-dose RT may help minimize long-term adverse effects.

Background: Invasive fungal diseases (IFDs) increase the mortality rate of patients with neutropenia who receive chemotherapy or have previously undergone hematopoietic stem cell transplantation (HSCT). Micafungin is a broad-spectrum echinocandin with minimal toxicity and low drug interactions. We therefore investigated the efficacy and safety of prophylactic micafungin in pediatric and adolescent patients who underwent autologous HSCT. Methods: This was a phase II, prospective, single-center, open-label, and single-arm study. From November 2011 to February 2017, 125 patients were screened from Seoul National University Children’s Hospital, Korea, and 112 were enrolled. Micafungin was administered intravenously at a dose of 1 mg/kg/day (maximum 50 mg/day) from day 8 of autologous HSCT until neutrophil engraftment. Treatment success was defined as the absence of proven, probable, or possible IFD up to 4 weeks after therapy. Results: The study protocol was achieved without premature interruption in 110 patients (98.2%). The reasons interrupting micafungin treatment included early death (n = 1) and patient refusal (n = 1). Treatment success was achieved in 109 patients (99.1%). Only one patient was diagnosed with probable IFD. No patients were diagnosed with possible or proven IFD. In the full analysis set, 21 patients (18.8%) experienced 22 adverse events (AEs); however, all AEs were classified as “unlikely” related to micafungin. No patient experienced grade IV AEs nor discontinued treatment, and none of the deaths were related to micafungin. Conclusions: Our study demonstrated that micafungin is a safe and effective option for antifungal prophylaxis in pediatric patients who underwent autologous HSCT, with promising efficacy without significant AEs.

Purpose Effectiveness and safety of clofarabine (one of the treatment mainstays in pediatric patients with relapsed/refractory acute lymphoblastic leukemia [ALL]) was assessed in Korean pediatric patients with ALL to facilitate conditional coverage with evidence development.Materials and Methods In this multicenter, prospective, observational study, patients receiving clofarabine as mono/combination therapy were followed up every 4-6 weeks for 6 months or until hematopoietic stem cell transplantation (HSCT). Response rates, survival outcomes, and adverse events were assessed.Results Sixty patients (2-26 years old; 65% B-cell ALL, received prior ≥ 2 regimen, 68.3% refractory to previous regimen) were enrolled and treated with at least one dose of clofarabine; of whom 26 (43.3%) completed 6 months of follow-up after the last dose of clofarabine. Fifty-eight patients (96.7%) received clofarabine combination therapy. Overall remission rate (complete remission [CR] or CR without platelet recovery [CRp]) was 45.0% (27/60; 95% confidence interval [CI], 32.4 to 57.6) and the overall response rate (CR, CRp, or partial remission [PR]) was 46.7% (28/60; 95% CI, 34.0 to 59.3), with 11 (18.3%), 16 (26.7%), and one (1.7%) patients achieving CR, CRp, and PR, respectively. The median time to remission was 5.1 weeks (95% CI, 4.7 to 6.1). Median duration of remission was 16.6 weeks (range, 2.0 to 167.6 weeks). Sixteen patients (26.7%) proceeded to HSCT. There were 24 deaths; 14 due to treatment-emergent adverse events.Conclusion Remission with clofarabine was observed in approximately half of the study patients who had overall expected safety profile; however, there was no favorable long-term survival outcome in this study.

Lee JM, et al. J Korean Med Sci. 2021 Jan;36(4):e37. https://doi.org/10.3346/jkms.2021.36.e37

Information regarding surgical diseases in North Korea is not fully reported despite their clear clinical significance. The current study aimed to indirectly assess the contemporary research trends and medical infrastructure related to surgical diseases in North Korea. We analyzed and categorized articles from the journal Surgery that were published during the Kim Jong-un era (2012–2018). The framework for categorization was primarily based on disease entities, surgical specialty, and research methodology. A total of 1792 articles in 28 issues were included in the current study. The frequency of detailed surgical cases and their associated characteristics based on their specialty were investigated. The types of medical imaging techniques and anesthetics that were commonly utilized in clinical fields in North Korea were also evaluated. A large proportion of essential surgeries were covered, with the exception of those for congenital diseases; however, a lack of surgical techniques and infrastructure was revealed. Going forward, further evaluation of the surgical system and a greater focus on non-communicable diseases in North Korea are needed.

Introduction: The demand for surgical diseases in North Korea is not fully reported despite its clinical significance. This study is to indirectly assess contemporary research trends and infrastructure status on surgical diseases in North Korea. Methods: We analyzed articles of journal ‘ Surgery ’ published in Kim Jong-un era (2012-2018). The framework for categorization was primarily based on the disease entities, surgery specialty, and research methodology. Results: 1,792 articles in 28 issues were included in the study. The frequency of detailed surgery cases and the characteristics of their specialty were investigated. The types of medical imaging techniques and anesthetics commonly utilized in clinical fields in North Korea were also evaluated. Conclusions: An obvious disjunction between actual disease prevalence and research trends mirrors the lack of surgical technique and infrastructure. Further evaluation and attention to the surgical system in North Korea are required.

A Pediatric Case of Long-term Untreated Distal Renal Tubular Acidosis Distal renal tubular acidosis (dRTA) is a rare renal tubular disorder characterized by normal anion gap metabolic acidosis, hypokalemia, and high urine pH. It can be inherited or acquired. In untreated pediatric patients with dRTA, rickets and growth retardation are common. We report the case of a 12-year-old Lao girl who presented with typical clinical features of dRTA with severe bone deformities that developed after a bedridden state due to a bicycle accident at the age of 8 years. Initial laboratory tests revealed metabolic acidosis with a normal anion gap, hypokalemia, and alkali urine. Renal ultrasonography revealed bilateral medullary nephrocalcinosis. Whole exome sequencing revealed no pathogenic mutations. After treatment with oral alkali, potassium, and vitamin D, she could walk and run. Later, she underwent corrective orthopedic surgeries for bony deformities. Thus, in pediatric dRTA patients, despite severe symptoms remaining untreated, accurate diagnosis and proper management can improve quality of life.

Background: Central nervous system germ cell tumors (CNS GCTs) are a heterogeneous group of brain tumors, which are more common in Asian countries. There have been different therapeutic strategies in treating germinoma and non-germinomatous germ cell tumors (NGGCT), depending on prognosis. Moreover, long-term follow up should be emphasized due to higher late complication rates. Here, we investigated long-term outcomes and complication profiles of 127 CNS GCT patients who received uniform upfront chemotherapy. Methods: We retrospectively evaluated outcomes of CNS GCT patients treated in Seoul National University Children’s Hospital from August 2004 to April 2019. Patients were classified as low risk (LR) or high risk (HR) based on pathologic diagnosis and tumor markers. Most patients received upfront systemic chemotherapy with carboplatin, cyclophosphamide, etoposide, and/or bleomycin, followed by either proton or photon radiation therapy according to patients’ choice. Results: The median age at diagnosis was 11.9 (range, 3.8–25.1) years, and 54.3% of patients were LR. Photon and proton radiation therapy were administered to 73.2 and 25.2% of patients, respectively. In both LR and HR groups, there were no significant differences in survival between photon and proton radiation therapy. The 10-year relapse incidences were 9.3 and 5.6% in the LR and HR groups, respectively. All recurrences, except one, were local relapse. Six secondary malignancies occurred; the 10-year incidences of secondary malignancy were 2.2 and 7.6% in the LR and HR groups, respectively. The 10-year overall survival rates were 98.3 ± 1.7 and 91.8 ± 3.9% in the LR and HR groups, respectively. In a subgroup analysis of HR group, pathologically diagnosed NGGCT patients (n = 20) showed worse 10-year EFS (65.9 ± 11.9%, p < 0.001) and OS (77.9 ± 9.8%, p = 0.024) rates compared to other HR patients who were not pathologically diagnosed or were confirmed as germinoma with elevated tumor markers. All mortalities were related to disease progression or secondary malignancy. Conclusion: The strategy of treating CNS GCTs with upfront chemotherapy according to risk groups resulted in good clinical outcomes and acceptable relapse incidence. However, further modification in the definition of the HR group is needed to reduce long-term complications.

Background: NUDT15 and TPMT variants are strong genetic determinants of thiopurine-induced hematological toxicity. Despite recent discovery of homozygous CRIM1 effect on thiopurine toxicity, many patients with wild-type NUDT15, TPMT , and CRIM1 still suffer from thiopurine toxicity, and therapeutic failure and relapse of acute lymphoblastic leukemia (ALL). Methods: Novel PGx interactions associated with thiopurine toxicity in 320 pediatric ALL patients were investigated using whole-exome sequencing technology for the last-cycle 6-Mercaptopurine dose intensity percentage (DIP) tolerated by pediatric ALL patients. Results: IL6 rs13306435 carriers ( N =19) exhibited significantly lower DIP (48.0±27.3%) than non-carriers ( N =209, 69.9±29.0%; p =0.0016 and 0.0028 by t -test and multiple linear regression, respectively). Of the 19 carriers, seven with both heterozygous IL6 rs13306435 and CRIM1 rs3821169 showed significantly decreased DIP (24.7±8.9%) than those with IL6 ( N =12, 61.6±25.1%) or CRIM1 ( N =94, 68.1±28.4%) variant only. Both IL6 and CRIM1 variants showed marked inter-ethnic variability. Significant interplay between IL6 and CRIM1 in thiopurine toxicity was suggested. GVB (Gene-wise Variant Burden)-based four-gene-interplay model showed the best odds ratio (8.06) and potential population impact (i.e., relative risk (5.73), population attributable fraction (58%), number needed to treat (3.67) and number needed to genotype (12.50)). Conclusions: Interplay of IL6 rs13306435 and CRIM1 rs3821169 was suggested as independent and/or additive genetic determinant of thiopurine toxicity beyond NUDT15 and TPMT in pediatric ALL.