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Background: KBG syndrome is a rare autosomal dominant genetic disease characterized by facial dysmorphism, developmental disorders, and short stature. The syndrome is caused by the haploinsufficiency of the ankyrin repeat domain-containing protein 11 (ANKRD11). Recently, there have been concerns that ANKRD11 serves as a tumor suppressor gene. Herein, we report a patient with KBG syndrome, diagnosed with hepatoblastoma at 21 months of age, which required chemotherapy and liver transplantation. Case report: A male infant born by cesarean section at 29+1 weeks of gestation, weighing 1220 g, was diagnosed with pulmonary atresia with ventricular septal defect and large patent ductus arteriosus. Bilateral low-set ears with a preauricular skin tag, left microtia, swelling of left neck, single umbilical artery, bilateral undescended testis, large anterior fontanelle, and bilateral club foot were noted. At a corrected age (CA) of 7 months, exome sequencing was performed, and a heterozygous nonsense pathogenic variant of ANKRD11 was found (c.7195C > T, p.Gln2399∗). Therefore, KBG syndrome was confirmed. At CA of 18 months, the patient presented with lethargy, poor oral intake, and jaundice symptoms and was diagnosed with hepatoblastoma. He received 12 cycles of chemotherapy for 9 months, but multiple hepatic masses remained; therefore, liver transplantation was performed at 28 months of age. Conclusions: KBG syndrome is a rare genetic disorder that has been identified relatively recently, and not all characteristics have yet been identified. The study of our case may provide evidence of cancer risk in patients with KBG syndrome.

Abstract Background Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are found in 1% of gliomas across children and adults. TRK inhibitors are promising therapeutic agents for NTRK-fused gliomas because they are tissue agnostic and cross the blood–brain barrier (BBB). Methods We investigated twelve NGS-verified NTRK-fused gliomas from a single institute, Seoul National University Hospital. Results The patient cohort included six children (aged 1–15 years) and six adults (aged 27–72 years). NTRK2 fusions were found in ten cerebral diffuse low-grade and high-grade gliomas (DLGGs and DHGGs, respectively), and NTRK1 fusions were found in one cerebral desmoplastic infantile ganglioglioma and one spinal DHGG. In this series, the fusion partners of NTRK2 were HOOK3, KIF5A, GKAP1, LHFPL3, SLMAP, ZBTB43, SPECC1L, FKBP15, KANK1, and BCR, while the NTRK1 fusion partners were TPR and TPM3. DLGGs tended to harbour only an NTRK fusion, while DHGGs exhibited further genetic alterations, such as TERT promoter/TP53/PTEN mutation, CDKN2A/2B homozygous deletion, PDGFRA/KIT/MDM4/AKT3 amplification, or multiple chromosomal copy number aberrations. Four patients received adjuvant TRK inhibitor therapy (larotrectinib, repotrectinib, or entrectinib), among which three also received chemotherapy (n = 2) or proton therapy (n = 1). The treatment outcomes for patients receiving TRK inhibitors varied: one child who received larotrectinib for residual DLGG maintained stable disease. In contrast, another child with DHGG in the spinal cord experienced multiple instances of tumour recurrence. Despite treatment with larotrectinib, ultimately, the child died as a result of tumour progression. An adult patient with glioblastoma (GBM) treated with entrectinib also experienced tumour progression and eventually died. However, there was a successful outcome for a paediatric patient with DHGG who, after a second gross total tumour removal followed by repotrectinib treatment, showed no evidence of disease. This patient had previously experienced relapse after the initial surgery and underwent autologous peripheral blood stem cell therapy with carboplatin/thiotepa and proton therapy. Conclusions Our study clarifies the distinct differences in the pathology and TRK inhibitor response between LGG and HGG with NTRK fusions.

BackgroundMethotrexate (MTX) is the primary drug used in the treatment of pediatric acute lymphoblastic leukemia (ALL). However, some patients exhibit delayed clearance of high-dose (HD) MTX, which induces severe nephrotoxicity, mucositis, hepatotoxicity, and neurotoxicity. We sought to identify relevant variants associated with delayed clearance of HD-MTX in pediatric patients with ALL.MethodsWhole-exome sequencing of germline DNA was performed in 51 Korean pediatric patients with ALL. A total of 341 HD-MTX infusion data points from 51 patients were analyzed. MTX levels and laboratory measurements reflecting toxicity outcomes were obtained. Correlations between peak serum MTX levels at 24 h and toxicity outcomes were assessed. Analyses were performed to identify variants affecting delayed MTX clearance.ResultsThe 24 h MTX level strongly correlated with the subsequent creatinine (Cr) level. Moreover, rs2229866 in contactin 2 (CNTN2), rs200687372 in myotubularin Related Protein 9 (MTMR9), rs777260512 in polymerase iota (POLI), rs16954698 in polycystic kidney disease 1-like 2 (PKD1L2), rs117765468 in NSE1 Homolog, SMC5-SMC6 Complex Component (NSMCE1), and rs1800956 in endoglin (ENG) were identified as candidate variants associated with delayed MTX clearance. In particular, ENG rs1800956 was significantly associated with delayed MTX clearance in all analyses and PKD1L2 rs16954698 was replicated in an external dataset (phs000637.v1.p1) from the Database of Genotypes and Phenotypes (dbGaP).ConclusionThis is the first whole-exome sequencing-based analysis of delayed MTX clearance in pediatric patients with ALL. ENG rs1800956 and PKD1L2 rs16954698 were found to be potentially influential variants associated with delayed MTX clearance. These findings provide insights into HD-MTX-induced nephrotoxicity and may contribute to reducing adverse reactions through treatment modification.

Abstract Chemotherapy-induced alopecia (CIA) is a common and debilitating condition in children, with limited research on its characteristics and treatment. Therefore, this study aims to describe the characteristics of pediatric patients with CIA and the treatment outcomes of topical minoxidil and l-cystine, medicinal yeast, and pantothenic acid complex-based dietary supplements (CYP). This retrospective cohort study analyzed data from patients who underwent high-dose conditioning chemotherapy followed by hematopoietic stem cell transplantation and were treated with either topical minoxidil or CYP for CIA between January 2011 and January 2022. Among the 70 patients evaluated, 61 (87.1%) experienced clinical improvement. Patients in the groups with superior treatment outcomes received a greater cumulative amount of minoxidil and underwent treatment for a more extended duration (P

Autoimmune hemolytic anemia (AIHA) is a common complication after hematopoietic stem cell transplantation (HSCT). Although post-HSCT AIHA is associated with poor prognosis and is more resistant to treatment than primary AIHA, the standard treatment has not yet been determined. We report a case of post-HSCT AIHA, which occurred 9 years after unrelated donor bone marrow transplantation for acute biphenotypic leukemia. Steroid treatment was initially effective but prolonged steroid usage, due to recurrent relapses, caused avascular necrosis. Although rituximab was unsuccessful in preventing relapses, sirolimus was effective in allowing the discontinuation of steroid treatment and sustaining transfusion-free status. Sirolimus, previously reported to be effective in pediatric post-HSCT AIHA and AIHA after solid organ transplantation, may be effective in adult post-HSCT AIHA as well.

Summary: Perceptual learning improves our ability to interpret sensory stimuli present in our environment through experience. Despite its importance, the underlying mechanisms that enable perceptual learning in our sensory cortices are still not fully understood. In this study, we used in vivo two-photon imaging to investigate the functional and structural changes induced by visual stimulation in the mouse primary visual cortex (V1). Our results demonstrate that repeated stimulation leads to a refinement of V1 circuitry by decreasing the number of responsive neurons while potentiating their response. At the synaptic level, we observe a reduction in the number of dendritic spines and an overall increase in spine AMPA receptor levels in the same subset of neurons. In addition, visual stimulation induces synaptic potentiation in neighboring spines within individual dendrites. These findings provide insights into the mechanisms of synaptic plasticity underlying information processing in the neocortex.

Abstract Background Although various coronavirus disease 2019 (COVID‐19) vaccines have been delivered to the public worldwide, data on cancer populations are limited. Vaccine hesitancy related to safety concerns is observed among cancer patients. We report the perception of COVID‐19 vaccines and their safety profile after vaccination among cancer patients. Materials and Methods Between April and November 2021, a multicenter survey was conducted on 318 patients treated in any hemato‐oncology outpatient clinic among three hospitals under the Korea University Medical Center. The medical records of the patients were reviewed to obtain detailed clinical and hematological toxicity data. Results A perception survey was conducted among 293 patients. Among them, 53.9% were concerned about developing vaccine‐related adverse events (VRAEs) and 23.5%, about negative effects on cancer treatment. During the study period, 255 and 186 patients participated in a safety survey after the first and second doses, respectively. After the first dose, 62% of patients reported VRAEs (2.4%, grade 3), whereas 48.9% reported VRAEs (2.7%, grade 3) after the second dose. For both doses, injection‐site pain and sore arm pain were the most common VRAEs, followed by myalgia, fatigue, and headache. No grade 4/5 VRAEs were observed, and there were no differences in complete blood count after vaccination. Multivariate analysis revealed female sex, active cancer treatment, and mRNA vaccines as independent risk factors for VRAE development in cancer patients. Conclusion Despite high levels of concern, COVID‐19 vaccines were well tolerated by cancer patients, with a safety profile consistent with that of the general population.

BackgroundManaging complex vascular anomalies in pediatric care requires comprehensive approaches. Sirolimus, an mTOR inhibitor with immunosuppressive and anti-angiogenic properties, offers promise. We evaluated sirolimus's effectiveness and safety in pediatric patients with complex vascular anomalies at a tertiary children's hospital.MethodsOur study included 20 patients, aged 1 month to 19 years, with diverse vascular anomalies resistant to conventional therapies or located in high-risk areas precluding surgery. The evaluation of response encompassed measuring the reduction in the size of the targeted vascular or lymphatic lesions as observed on radiologic imaging, along with considering improvements reported by the patients.ResultsPatients used sirolimus for a median of 2.1 years, ranging from 0.6–4.3 years. Results indicated that 60% of patients achieved complete or partial response (CR/PR), whereas 40% had stable disease (SD). Notably, no disease progression occurred. Lesion size assessment was complex, yet patients' self-reported improvements were considered. Three patients reinitiated sirolimus after discontinuation due to worsening lesions. Sirolimus treatment demonstrated good tolerability, with minor complications except for one case of Pneumocystis jiroveci pneumonia. Group comparisons based on response highlighted better outcomes in patients with vascular tumors (CR/PR group 58.0% vs. SD group 0.0%, P = 0.015) or localized measurable lesions (83.3% vs. 12.5%, P = 0.005).ConclusionOur study underscores sirolimus's potential for treating complex vascular anomalies in pediatric patients. Challenges associated with optimal treatment duration and concurrent interventions necessitate a comprehensive approach and genetic testing to optimize outcomes.

Mitotane is an adrenolytic drug that exhibits therapeutic effects within a narrow target range (14–20 μg/dL). Various complications develop if the upper limit is exceeded. We present the case of a 5-year-old girl with breast development, acne, and pubic hair who was diagnosed with an adrenal mass that was subsequently excised. The pathological finding was adrenocortical carcinoma with a high risk of malignancy, and adjuvant therapy (combined mitotane and radiation therapy) was recommended. Mitotane was initiated at a low dose to allow monitoring of the therapeutic drug level, and high-dose hydrocortisone was also administered. However, the patient exhibited elevated adrenocorticotropic hormone levels and vague symptoms such as general weakness and difficulty concentrating. It was important to determine if these symptoms were signs of the neurological complications that develop when mitotane level is elevated. Encephalopathy progression and pubertal signs appeared 6 months after diagnosis, induced by high mitotane level. The mitotane decreased to subtherapeutic level several months after its discontinuation, at which time endocrinopathy (central hypothyroidism, hypercholesterolemia, and secondary central precocious puberty) developed. The case shows that low-dose mitotane can trigger neurological and endocrinological complications in a pediatric patient, indicating that the drug dose should be individualized with frequent monitoring of the therapeutic level.

We aimed to analyze the characteristics of serious adverse events following immunizations (AEFIs) to identify potential safety information and prediction features. We screened the individual case safety reports (ICSRs) in adults who received mRNA-based COVID-19 vaccines using the Vaccine Adverse Event Reporting System until December 2021. We identified the demographic and clinical characteristics of ICSRs and performed signal detection. We developed prediction models for serious AEFIs and identified the prognostic features using logistic regression. Serious ICSRs and serious AEFIs were 51,498 and 271,444, respectively. Hypertension was the most common comorbidity (22%). Signal detection indicated that the reporting odds ratio of acute myocardial infarction (AMI) was more than 10 times. Those who had experienced myocardial infarction (MI) were 5.7 times more likely to suffer from MI as an AEFI (95% CI 5.28–6.71). Moreover, patients who had atrial fibrillation (AF), acute kidney injury (AKI), cardiovascular accident (CVA), or pulmonary embolism (PE) were 7.02 times, 39.09 times, 6.03 times, or 3.97 times more likely to suffer from each AEFI, respectively. Our study suggests that vaccine recipients who had experienced MI, AF, AKI, CVA, or PE could require further evaluation and careful monitoring to prevent those serious AEFIs.

Background: The optimal conditioning regimen of tandem high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) for high-risk neuroblastoma (HR-NBL) has not been established. The efficacy of 131I-MIBG therapy is under exploration in newly diagnosed HR-NBL patients. Here, we compared the outcomes of tandem HDC/ASCT between the 131I-MIBG combination and non-MIBG groups. Methods: We retrospectively analyzed the clinical data of 33 HR-NBL patients who underwent tandem HDC/ASCT between 2007 and 2021 at the Seoul National University Children’s Hospital. Results: The median age at diagnosis was 3.6 years. 131I-MIBG was administered to 13 (39.4%) of the patients. Thirty patients (90.9%) received maintenance therapy after tandem HDC/ASCT, twenty-two were treated with isotretinoin ± interleukin-2, and eight received salvage chemotherapy. The five-year overall survival (OS) and event-free survival (EFS) rates of all patients were 80.4% and 69.4%, respectively. Comparing the 131I-MIBG combined group and other groups, the five-year OS rates were 82.1% and 79.7% (p = 0.655), and the five-year EFS rates were 69.2% and 69.6% (p = 0.922), respectively. Among the adverse effects of grade 3 or 4, the incidence of liver enzyme elevation was significantly higher in the non-131I-MIBG group. Conclusions: Although tandem HDC/ASCT showed promising outcomes, the 131I-MIBG combination did not improve survival rates.

(1) Background: Hospitalists are healthcare providers who focus on hospitalized patients, but research on the roles of pediatric hospitalists is lacking. This study investigates the role of a supervisor-type hospitalist in a pediatric hematology/oncology ward at a tertiary children’s hospital, assessing the impact on satisfaction levels among patient caregivers, resident physicians, and nurses. (2) Methods: A retrospective analysis and online surveys were conducted to assess satisfaction levels before and after the introduction of hospitalists in the Department of Pediatric Hematology/Oncology at Seoul National University Children’s Hospital in the Republic of Korea. (3) Results: The introduction of hospitalists led to a 19.3% reduction in prescription error interventions over six months. Unexpected transfers to the intensive care unit decreased from 1.4% to 0.7% (p = 0.229). Patient caregivers reported elevated satisfaction levels with physicians (rated 8.47/10), and there was a significant enhancement in overall satisfaction among nurses (increasing from 3.23 to 4.23/5, p < 0.001). The majority of resident physicians (83.3%) expressed contentment with the hospitalist system, with 77% indicating an interest in transitioning to a hospitalist role. However, these resident physicians also expressed concerns regarding job stability. (4) Conclusions: Supervisor-type pediatric hospitalists have the potential to elevate satisfaction levels not only among patient caregivers but also among nurses and resident physicians, showing promise in improving medical care quality. Nonetheless, ensuring favorable perception and securing job stability within the hospitalist system are pivotal for achieving successful implementation.

Abstract NUDT15 and TPMT variants are strong genetic determinants of thiopurine-induced hematological toxicity. Despite the impact of homozygous CRIM1 on thiopurine toxicity, several patients with wild-type NUDT15, TPMT, and CRIM1 experience thiopurine toxicity, therapeutic failure, and relapse of acute lymphoblastic leukemia (ALL). Novel pharmacogenetic interactions associated with thiopurine intolerance from hematological toxicities were investigated using whole-exome sequencing for last-cycle 6-mercaptopurine dose intensity percentages (DIP) tolerated by pediatric ALL patients (N = 320). 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). Among 19 carriers, 7 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%) variants. IL6 and CRIM1 variants showed marked inter-ethnic variability. Four-gene-interplay models revealed the best odds ratio (8.06) and potential population impact [relative risk (5.73), population attributable fraction (58%), number needed to treat (3.67), and number needed to genotype (12.50)]. Interplay between IL6 rs13306435 and CRIM1 rs3821169 was suggested as an independent and/or additive genetic determinant of thiopurine intolerance beyond NUDT15 and TPMT in pediatric ALL.

BackgroundA low-degree tumor necrosis after neoadjuvant chemotherapy is a poor prognostic factor for osteosarcoma (OSA). However, the role of high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation in OSA remains controversial. We analyzed the treatment outcomes and prognostic factors of nonmetastatic OSA and compared the HDC and conventional chemotherapy (CC) outcomes of patients with 90% (good response [GR]), whereas most cases with

Abstract 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

Abstract Background While ETV6- NTRK3 fusion is common in infantile fibrosarcoma, NTRK1/3 fusion in pediatric tumors is scarce and, consequently, not well known. Herein, we evaluated for the presence of NTRK1/3 fusion in pediatric mesenchymal tumors, clinicopathologically and immunophenotypically. Methods We reviewed nine NTRK fusion-positive pediatric sarcomas confirmed by fluorescence in situ hybridization and/or next-generation sequencing from Seoul National University Hospital between 2002 and 2020. Results One case of TPR-NTRK1 fusion-positive intracranial, extra-axial, high-grade undifferentiated sarcoma (12-year-old boy), one case of LMNA-NTRK1 fusion-positive low-grade infantile fibrosarcoma of the forehead (3-year-old boy), one case of ETV6-NTRK3 fusion-positive inflammatory myofibroblastic tumor (IMT) (3-months-old girl), and six cases of ETV6-NTRK3 fusion-positive infantile fibrosarcoma (median age: 2.6 months, range: 1.6–5.6 months, M: F = 5:1) were reviewed. The Trk immunopositivity patterns were distinct, depending on what fusion genes were present. We observed nuclear positivity in TPR-NTRK1 fusion-positive sarcoma, nuclear membrane positivity in LMNA-NTRK1 fusion-positive sarcoma, and both cytoplasmic and nuclear positivity in ETV6-NTRK3 fusion-positive IMT and infantile fibrosarcomas. Also, the TPR-NTRK1 fusion-positive sarcoma showed robust positivity for CD34/nestin, and also showed high mitotic rate. The LMNA-NTRK1 fusion-positive sarcoma revealed CD34/S100 protein/nestin/CD10 coexpression, and a low mitotic rate. The IMT with ETV6-NTRK3 fusion expressed SMA. Six infantile fibrosarcomas with ETV6-NTRK3 fusion showed variable coexpression of nestin (6/6)/CD10 (4/5)/ S100 protein (3/6). Conclusions All cases of NTRK1 and NTRK3 fusion-positive pediatric tumors robustly expressed the Trk protein. A Trk immunopositive pattern and CD34/S100/nestin/CD10/SMA immunohistochemical expression may suggest the presence of NTRK fusion partner genes. LMNA-NTRK1 fusion sarcoma might be a low-grade subtype of infantile fibrosarcoma. Interestingly, more than half of the infantile fibrosarcoma cases were positive for S100 protein and CD10. The follow-up period of TPR-NTRK1 and LMNA-NTRK1 fusion-positive tumors are not enough to predict prognosis. However, ETV6-NTRK3 fusion-positive infantile fibrosarcomas showed an excellent prognosis with no evidence of disease for an average of 11.7 years, after gross total resection of the tumor.

Abstract Background NUDT15 and TPMT variants are strong genetic determinants of thiopurine-induced hematological toxicity that results in therapeutic failure in pediatric acute lymphoblastic leukemia (ALL). However, many patients with both wild-type (WT) NUDT15 and TPMT still suffer from thiopurine toxicity and therapeutic failure. Methods Whole-exome sequencing was done for discovery (N = 244) and replication (N = 76) cohorts. Age- and sex-adjusted multiple regression analyses of both WT patients were performed to identify (p

The survival rates for pediatric patients with solid tumors have improved dramatically in recent decades. However, patients with metastatic disease at diagnosis or progressive solid tumors still have a poor prognosis. Recently, immunotherapy has emerged as a novel therapeutic strategy in the pediatric population. Although not widely used in Korea, the anti-GD2 treatment in neuroblastoma is one of the successes of immunotherapy. In addition, many early phase clinical trials for monoclonal and bispecific antibodies, immune checkpoint inhibitors (ICIs), chimeric antigen receptor T cell therapy and cancer vaccines are ongoing. According to results reported so far, a majority of pediatric solid tumors showed limited response to ICIs, except Hodgkin lymphoma and hypermutant pediatric tumors. These results indicate that children and adolescents need to be applied different immunotherapeutic approaches from adults. The aim of this review is to understand the immunological environment and immunotherapeutic challenges in pediatric solid tumors.

Circulating cell-free DNA (cfDNA) can be used to characterize tumor genomes through next-generation sequencing (NGS)-based approaches. We aim to identify novel genetic alterations associated with drug resistance in lung cancer and colorectal cancer patients who were treated with EGFR-targeted therapy and cytotoxic chemotherapy through whole exome sequencing (WES) of cfDNA. A cohort of 18 lung cancer patients was treated with EGFR TKI or cytotoxic chemotherapy, and a cohort of 37 colorectal cancer patients was treated with EGFR monoclonal antibody or cytotoxic chemotherapy alone. Serum samples were drawn before and after development of drug resistance, and the genetic mutational profile was analyzed with WES data. For 110 paired cfDNA and matched germline DNA WES samples, mean coverage of 138x (range, 52–208.4x) and 47x (range, 30.5–125.1x) was achieved, respectively. After excluding synonymous variants, mutants identified in more than two patients at the time of acquired resistance were selected. Seven genes in lung cancer and 16 genes in colorectal cancer were found, namely, APC, TP53, KRAS, SMAD4, and EGFR. In addition, the GPR155 I357S mutation in lung cancer and ADAMTS20 S1597P and TTN R7415H mutations in colorectal cancer were frequently detected at the time of acquired resistance, indicating that these mutations have an important function in acquired resistance to chemotherapy. Our data suggest that novel genetic variants associated with drug resistance can be identified using cfDNA WES. Further validation is necessary, but these candidate genes are promising therapeutic targets for overcoming drug resistance in lung cancer and colorectal cancer.

Abstract Background “End of life” is a difficult topic of conversation in East Asian cultures, even among patients and doctors who share a good rapport. In 2016, the Hospice, Palliative Care, and Life-Sustaining Treatment Decision-Making Act, which took the form of “Physician Orders for Life-Sustaining Treatment,” was introduced in South Korea. This study was conducted to investigate the completion rate of Physician Orders for Life-Sustaining Treatment in patients with advanced cancer on the active recommendation of physicians, as well as patients’ general attitudes toward end-of-life care. Methods We conducted a preliminary, cross-sectional descriptive survey on patients with advanced cancer. A total of 101 patients with advanced solid cancer agreed to participate in the study. The primary endpoint was the rate of completion of Physician Orders for Life-Sustaining Treatment based on a doctor’s suggestion. Written interviews were conducted to understand the perceptions and factors influencing patients’ decisions. Results Of the 101 patients, 72 (71.3%) agreed to prepare Physician Orders for Life-Sustaining Treatment. Patients who had an educational level of high school or higher were more likely to agree to complete Physician Orders for Life-Sustaining Treatment documentation as compared to the lower educational status group. More than half of the respondents who completed Physician Orders for Life-Sustaining Treatment documentation reported that they had more than a fair understanding of “life-sustaining care” or “Physician Orders for Life-Sustaining Treatment.” Participants’ reasons for Physician Orders for Life-Sustaining Treatment completion were diverse. Conclusions We found that highly educated patients, who understood the concept behind the policy well, tended to accept Physician Orders for Life-Sustaining Treatment without hesitation. Better education, information shared through the media, and conversations with health care providers might improve understanding of Physician Orders for Life-Sustaining Treatment in patients with cancer.

Primary enucleation is a life-saving treatment for advanced intraocular retinoblastoma, particularly in patients with poor visual potential and functional contralateral eyes. This single-center study presents the treatment outcomes of patients with unilateral retinoblastoma who received primary enucleation and adjuvant chemotherapy with cyclophosphamide, vincristine, doxorubicin, and intrathecal methotrexate (CVDM) between 2000 and 2020. Twenty patients were enrolled in the study. The median age at diagnosis was 26 months (range, 1–45). Eighteen patients (90%) were in group E and two (10%) were in group D, according to the intraocular classification of retinoblastoma guidelines. Excluding one patient with an inadequate specimen, 19 patients (95%) had optic nerve involvement (ONI) at least up to the lamina cribrosa. Eight patients (40%) had choroidal invasion in addition to ONI. Two patients (10%) were surgical resection margin positive. The overall and event-free survival rates were 100% and 95%, respectively, for a median follow-up duration of 102.24 months (range 24.2–202.9). There were no relapses or deaths due to any cause, but one patient developed secondary rhabdomyosarcoma 99.6 months after chemotherapy. Treatment was well tolerated, with minimal hematotoxicity and hepatotoxicity. CVDM as a post-enucleation chemotherapy for advanced intraocular retinoblastoma has excellent outcomes with tolerable toxicity. However, in line with updated treatment trends, further risk stratification and lowering the treatment intensity should be considered. Continued long-term follow-up is required to further determine late effects.

There are few data about Pneumocystis jirovecii pneumonia (PCP) in children, particularly in developed countries. This study investigated the clinical characteristics and prognosis of the clinical PCP in non-HIV-infected Korean children. Children with positive results for the staining and/or polymerase chain reaction (PCR) for P. jirovecii between 2001 and 2021 were identified. Patients were grouped into clinical PCP, which comprised proven and modified probable cases, and non-PCP groups. Modified probable PCP (mp-PCP) indicate the case which P. jirovecii was detected by conventional PCR rather than real-time PCR test. The differences in demographic and clinical characteristics were analyzed between the groups. A total of 110 pneumonia cases with positive results for P. jirovecii PCR and/or stain were identified from 107 children. Of these, 28.2% were classified as non-PCP, 12.7% of proven PCP, and 59.1% of mp-PCP. Compared with the non-PCP group, the mp-PCP group had a significantly higher rate of solid organ transplantation (3.2% vs. 24.6%), fever (58.1% vs. 76.9%), tachypnea (25.8% vs. 66.2%), dyspnea (48.4% vs. 83.1%), desaturation (48.4% vs. 80.0%), and bilateral ground-glass opacity on chest radiograph (19.4% vs. 73.8%). However, when the mp-PCP group was compared with the proven PCP group, there was no statistically significant difference. For children with clinical PCP, age under 5 years of age (odds ratio [OR] 10.7), hospital-onset (OR 6.9), and desaturation as initial symptom (OR 63.5) were significant risk factors for death in multivariable analysis. Modified probable PCP might reliably reflect true PCP in terms of patient’s demographic, clinical features, treatment response, and prognosis. Immunocompromised children with hospital-onset pneumonia who are younger than 5 years of age and have desaturation would be more cautiously and aggressively managed for survival through the screening for P. jirovecii by conventional PCR on appropriate lower respiratory specimens.

Summary: We systematically compare the contributions of two dopaminergic and two cholinergic ascending populations to a spatial short-term memory task in rats. In ventral tegmental area dopamine (VTA-DA) and nucleus basalis cholinergic (NB-ChAT) populations, trial-by-trial fluctuations in activity during the delay period relate to performance with an inverted-U, despite the fact that both populations have low activity during that time. Transient manipulations reveal that only VTA-DA neurons, and not the other three populations we examine, contribute causally and selectively to short-term memory. This contribution is most significant during the delay period, when both increases and decreases in VTA-DA activity impair short-term memory. Our results reveal a surprising dissociation between when VTA-DA neurons are most active and when they have the biggest causal contribution to short-term memory, and they also provide support for classic ideas about an inverted-U relationship between neuromodulation and cognition.

Purpose We investigated the clinical characteristics of patients who developed thyroid dysfunction and evaluated the risk factors for hypothyroidism following radiotherapy and chemotherapy in pediatric patients with medulloblastoma or primitive neuroectodermal tumor (PNET). Methods The medical records of 66 patients (42 males) treated for medulloblastoma (n=56) or PNET (n=10) in childhood between January 2000 and December 2014 at Seoul National University Children’s Hospital were retrospectively reviewed. A total of 21 patients (18 high-risk medulloblastoma and 3 PNET) underwent high-dose chemotherapy and autologous stem cell rescue (HDCT/ASCR) Results During the median 7.6 years of follow-up, 49 patients (74%) developed transient (n=12) or permanent (n=37) hypothyroidism at a median 3.8 years of follow-up (2.9–4.6 years). Younger age (

It is complicated to establish a consensus on the management and diagnosis of malignancy-triggered hemophagocytic lymphohistiocytosis (M-HLH) in children, as an initial presentation of malignancy is complicated. In this paper, we analyze the clinical characteristics and outcomes of eight pediatric patients in which M-HLH was the initial presentation of malignancy. All patients had hematologic malignancies: three subcutaneous panniculitis-like T-cell lymphomas, two acute lymphoblastic leukemias, two anaplastic large cell lymphomas, and a systemic EBV + T-cell lymphoma of childhood. The incidence rate of M-HLH among leukemia and malignant lymphoma patients in our institution was 1.9%. From the initial diagnosis of HLH, the median time taken to be diagnosed as a malignancy was about 1.3 months. The majority of patients received HLH-targeted immunosuppression and/or etoposide at first. The patients’ clinical response to treatment for HLH and malignancies were varied. Five out of the eight patients died, one of whom died due to HLH-related cerebral edema after the initiation of chemotherapy. The median overall survival was 1.6 years. In order to improve the survival rate, the early detection of M-HLH, rapid screening for malignancy, and complete control of M-HLH with HLH-directed therapy followed by a thorough response monitoring are required.

Abstract Objectives Paediatric and adolescent patients in need of allogeneic haematopoietic stem cell transplantation (HSCT) generally receive stem cells from older, unrelated or parental donors when a sibling donor is not available. Despite encouraging clinical outcomes, it has been suggested that immune reconstitution accompanied by increased replicative stress and a large difference between donor and recipient age may worsen immunosenescence in paediatric recipients. Methods In this study, paired samples were collected at the same time from donors and recipients of haploidentical haematopoietic stem cell transplantation (HaploSCT). We then conducted flow cytometry‐based phenotypic and functional analyses and telomere length (TL) measurements of 21 paired T‐cell sets from parental donors and children who received T‐cell‐replete HaploSCT with post‐transplant cyclophosphamide (PTCy). Results Senescent T cells, CD28− or CD57+ cells, were significantly expanded in patients. Further, not only CD4+CD28− T cells, but also CD4+CD28+ T cells showed reduced cytokine production capacity and impaired polyfunctionality compared with parental donors, whereas their TCR‐mediated proliferation capacity was comparable. Of note, the TL in patient T cells was preserved, or even slightly longer, in senescent T cells compared with donor cells. Regression analysis showed that senescent features of CD4+ and CD8+ T cells in patients were influenced by donor age and the frequency of CD28− cells, respectively. Conclusion Our data suggest that in paediatric HaploSCT, premature immunosenescent changes occur in T cells from parental donors, and therefore, long‐term immune monitoring should be conducted.

Nudix Hydrolase 15 (NUDT15) and Thiopurine S-Methyltransferase (TPMT) are strong genetic determinants of thiopurine toxicity in pediatric acute lymphoblastic leukemia (ALL) patients. Since patients with NUDT15 or TPMT deficiency suffer severe adverse drug reactions, star (*) allele-based haplotypes have been used to predict an optimal 6-mercaptopurine (6-MP) dosing. However, star allele haplotyping suffers from insufficient, inconsistent, and even conflicting designations with uncertain and/or unknown functional alleles. Gene-wise variant burden (GVB) scoring enables us to utilize next-generation sequencing (NGS) data to predict 6-MP intolerance in children with ALL. Whole exome sequencing was performed for 244 pediatric ALL patients under 6-MP treatments. We assigned star alleles with PharmGKB haplotype set translational table. GVB for NUDT15 and TPMT was computed by aggregating in silico deleteriousness scores of multiple coding variants for each gene. Poor last-cycle dose intensity percent (DIP < 25%) was considered as 6-MP intolerance, resulting therapeutic failure of ALL. DIPs showed significant differences ( p < 0.05) among NUDT15 poor (PM, n = 1), intermediate (IM, n = 48), and normal (NM, n = 195) metabolizers. TPMT exhibited no PM and only seven IMs. GVB showed significant differences among the different haplotype groups of both NUDT15 and TPMT ( p < 0.05). Kruskal–Wallis test for DIP values showed statistical significances for the seven different GVB score bins of NUDT15. GVBNUDT15 outperformed the star allele-based haplotypes in predicting patients with reduced last-cycle DIPs at all DIP threshold levels (i.e., 5%, 10%, 15%, and 25%). In NUDT15-and-TPMT combined interaction analyses, GVBNUDT15,TPMT outperformed star alleles [area under the receiver operating curve (AUROC) = 0.677 vs. 0.645] in specificity (0.813 vs. 0.796), sensitivity (0.526 vs. 0.474), and positive (0.192 vs. 0.164) and negative (0.953 vs. 0.947) predictive values. Overall, GVB correctly classified five more patients (i.e., one into below and four into above 25% DIP groups) than did star allele haplotypes. GVB analysis demonstrated that 6-MP intolerance in pediatric ALL can be reliably predicted by aggregating NGS-based common, rare, and novel variants together without hampering the predictive power of the conventional haplotype analysis.

Several lines of evidence suggest that the striatum has an important role in spatial working memory. The neural dynamics in the striatum have been described in tasks with short delay periods (1–4 s), but remain largely uncharacterized for tasks with longer delay periods. We collected and analyzed single unit recordings from the dorsomedial striatum of rats performing a spatial working memory task with delays up to 10 s. We found that neurons were activated sequentially, with the sequences spanning the entire delay period. Surprisingly, this sequential activity was dissociated from stimulus encoding activity, which was present in the same neurons, but preferentially appeared towards the onset of the delay period. These observations contrast with descriptions of sequential dynamics during similar tasks in other brains areas, and clarify the contribution of the striatum to spatial working memory.

This case study explores the use of CD45RA+ depleted lymphocyte infusion as a potential treatment for refractory cytomegalovirus (CMV) disease in an infant with complete DiGeorge syndrome (cDGS). The patient, who had a severe T cell deficiency, initially received ganciclovir but developed resistance. Infusing CD45RA+ depleted CMV-specific lymphocytes from the patient's father resulted in a decrease in CMV viral load. However, the patient ultimately passed away from pneumonia and sepsis. The study suggests that CD45RA+ depleted lymphocyte infusion may be a viable option for treating refractory CMV disease in cDGS patients, but further research is needed. [Extracted from the article]