Positional information plays a crucial role in embryonic pattern formation, yet its role in tooth development remains unexplored. In this study, we investigated the regional specification of lingual and buccal dental mesenchyme during tooth development. Tooth germs at the cap stage were dissected from mouse mandibles, and their lingual and buccal mesenchymal regions were separated for bulk RNA sequencing. Gene ontology analysis revealed that odontogenesis, pattern specification, and proliferation-related genes were enriched in the lingual mesenchyme, whereas stem cell development, mesenchymal differentiation, neural crest differentiation, and regeneration-related genes were predominant in the buccal mesenchyme. Reaggregation experiments using Wnt1^creERT/+; R26R^tdT/+ and WT mouse models demonstrated that lingual mesenchyme contributes to tooth formation, while buccal mesenchyme primarily supports surrounding tissues. Furthermore, only the lingual part of tooth germs exhibited odontogenic potential when cultured in vitro and transplanted under the kidney capsule. Bulk RNA transcriptomic analysis further validated the regional specification of the lingual and buccal mesenchyme. These findings provide novel insights into the molecular basis of positional information in tooth development and pattern formation.
Animals ; Mice ; Odontogenesis/genetics* ; Tooth Germ/cytology* ; Mesoderm/cytology* ; Cell Differentiation ; Mesenchymal Stem Cells ; Tooth/embryology*

Background: Active surveillance (AS) has emerged as a viable management strategy for low-risk papillary thyroid microcarcinoma (PTMC), following pioneering trials at Kuma Hospital and the Cancer Institute Hospital in Japan. Numerous prospective cohort studies have since validated AS as a management option for low-risk PTMC, leading to its inclusion in thyroid cancer guidelines across various countries. From 2016 to 2020, the Multicenter Prospective Cohort Study of Active Surveillance on Papillary Thyroid Microcarcinoma (MAeSTro) enrolled 1,177 patients, providing comprehensive data on PTMC progression, sonographic predictors of progression, quality of life, surgical outcomes, and cost-effectiveness when comparing AS to immediate surgery. The second phase of MAeSTro (MAeSTro-EXP) expands AS to low-risk papillary thyroid carcinoma (PTC) tumors larger than 1 cm, driven by the hypothesis that overall risk assessment outweighs absolute tumor size in surgical decision-making. Methods: This protocol aims to address whether limiting AS to tumors smaller than 1 cm may result in unnecessary surgeries for low-risk PTCs detected during their rapid initial growth phase. By expanding the AS criteria to include tumors up to 1.5 cm, while simultaneously refining and standardizing the criteria for risk assessment and disease progression, we aim to minimize overtreatment and maintain rigorous monitoring to improve patient outcomes. Conclusion This study will contribute to optimizing AS guidelines and enhance our understanding of the natural course and appropriate management of low-risk PTCs. Additionally, MAeSTro-EXP involves a multinational collaboration between South Korea and Australia. This cross-country study aims to identify cultural and racial differences in the management of low-risk PTC, thereby enriching the global understanding of AS practices and their applicability across diverse populations.

Background/Aims: Inaccurate prediction of lymph node metastasis (LNM) may lead to unnecessary surgery following endoscopic resection of T1 colorectal cancer (CRC). We aimed to validate the usefulness of artificial intelligence (AI) models for predicting LNM in patients with T1 CRC. Methods: We analyzed the clinical data, laboratory results, pathological reports, and endoscopic findings of patients who underwent radical surgery for T1 CRC. We developed AI models to predict LNM using four algorithms: regularized logistic regression classifier (RLRC), random forest classifier (RFC), CatBoost classifier (CBC), and the voting classifier (VC). Four histological factors and four endoscopic findings were included to develop AI models. Areas under the receiver operating characteristics curves (AUROCs) were measured to distinguish AI model performance in accordance with the Japanese Society for Cancer of the Colon and Rectum guidelines. Results: Among 1,386 patients with T1 CRC, 173 patients (12.5%) had LNM. The AUROC values of the RLRC, RFC, CBC, and VC models for LNM prediction were significantly higher (0.673, 0.640, 0.679, and 0.677, respectively) than the 0.525 suggested in accordance with the Japanese Society for Cancer of the Colon and Rectum guidelines (vs RLRC, p<0.001; vs RFC, p=0.001; vs CBC, p<0.001; vs VC, p<0.001). The AUROC value was similar between T1 colon versus T1 rectal cancers (0.718 vs 0.615, p=0.700). The AUROC value was also similar between the initial endoscopic resection and initial surgery groups (0.581 vs 0.746, p=0.845). Conclusions AI models trained on the basis of endoscopic findings and pathological features performed well in predicting LNM in patients with T1 CRC regardless of tumor location and initial treatment method.

Purpose: Hematopoietic stem cell transplantation (HSCT) has been an important method of treatment in the advance of pediatric acute lymphoblastic leukemia (ALL). The indications for HSCT are evolving and require updated establishment. In this study, we aimed to investigate the efficacy of HSCT on the treatment outcome of pediatric ALL, considering the indications for HSCT and subgroups. Materials and Methods: A retrospective analysis was conducted on ALL patients diagnosed and treated at a single center. Risk groups were categorized based on age at diagnosis, initial white blood cell count, disease lineage (B/T), and cytogenetic study results. Data on the patients’ disease status at HSCT and indications of HSCT were collected. Indications for HSCT were categorized as upfront HSCT at 1st complete remission, relapse, and refractory disease. Results: Among the 549 screened patients, a total of 418 patients were included in the study; B-cell ALL (n=379) and T-cell ALL (T-ALL) (n=39). HSCT was conducted on a total of 106 patients (25.4%), with a higher frequency as upfront HSCT in higher-risk groups and specific cytogenetics. The overall survival (OS) was significantly better when done upfront than in relapsed or refractory state in T-ALL patients (p=0.002). The KMT2A-rearranged ALL patients showed superior event-free survival (p=0.002) and OS (p=0.022) when HSCT was done as upfront treatment. Conclusion HSCT had a substantial positive effect in a specific subset of pediatric ALL. In particular, frontline HSCT for T-ALL and KMT2A-rearranged ALL offered a better prognosis than when HSCT was conducted in a relapsed or refractory setting.

Background: Mass spectrometry (MS) methods exhibit higher accuracy and comparability in measuring serum C-peptide concentrations than immunoassays. We developed and validated a novel isotope dilution-ultraperformance liquid chromatography-tandem MS (IDUPLC-MS/MS) assay to measure serum C-peptide concentrations. Methods: Sample pretreatment involved solid-phase extraction, ion-exchange solid-phase extraction, and derivatization with 6-aminoquinolyl-N-hydroxysuccinimidylcarbamate (Cayman Chemical, Ann Arbor, Michigan, USA). We used an ExionLC UPLC system (Sciex, Framingham, MA, USA) and a Sciex Triple Quad 6500 + MS/MS system (Sciex) for electrospray ionization in positive-ion mode with multiple charge states of [M+3H]3+ and multiple reaction monitoring transitions. The total run time was 50 mins, and the flow rate was 0.20 mL/min. We evaluated the precision, trueness, linearity, lower limit of quantitation (LLOQ), carryover, and matrix effects. Method comparison with electrochemiluminescence immunoassay (ECLIA) was performed in 138 clinical specimens. Results: The intra- and inter-run precision coefficients of variation were < 5% and the bias values for trueness were < 4%, which were all acceptable. The verified linear interval was 0.050–15 ng/mL, and the LLOQ was 0.050 ng/mL. No significant carryover or matrix effects were observed. The correlation between this ID-UPLC-MS/MS method and ECLIA was good (R = 0.995, slope = 1.564); however, the ECLIA showed a positive bias (51.8%). Conclusions The developed ID-UPLC-MS/MS assay shows acceptable performance in measuring serum C-peptide concentrations. This will be useful in situations requiring accurate measurement of serum C-peptide in clinical laboratories.

Background: Graft failure (GF) is a major complication of allogeneic hematopoietic cell transplantation (allo-HCT). Secondary transplantation has been recognized as a potential curative intervention. Methods: This study aimed to investigate the characteristics and outcomes of salvage transplantation by analyzing the patients who underwent a second HCT for GF following the initial allo-HCT between 1998 and 2020. Results: Overall, 23 recipients were identified, including 14 and 9 individuals with primary and secondary GF, respectively. Nine recipients underwent a second transplant from the same donor. Familial mismatched donors predominated in the second HCT (86.9%), with reduced-intensity conditioning as the prevailing approach (60.9%). Neutrophil engraftment occurred in 17 patients (73.9%) following the second HCT at a median of 17 days (range: 9–58 days) post-transplantation. However, secondary GF subsequently occurred in 5 patients, and successful engraftment following salvage transplantation was achieved in 12 (52.2%) patients. In the entire study population, the estimated 5-year probability of overall survival (OS) and treatment-related mortality (TRM) were 30.4% and 58.5%, respectively. Among patients who achieved successful engraftment following a second transplantation, the OS and TRM rates were 41.7% and 33.3%, respectively, indicating a trend toward better OS and significantly lower TRM compared to those with GF. Notably, 17 patients died, with infection being the most common cause (n = 12), irrespective of the engraftment status. Conclusion A successful engraftment following a second allo-HCT reduced the TRM; however, the OS remained suboptimal. The effective control of infectious diseases remains crucial for patients with GF, regardless of the engraftment status following salvage transplantation.

Background: Graft failure (GF) is a major complication of allogeneic hematopoietic cell transplantation (allo-HCT). Secondary transplantation has been recognized as a potential curative intervention. Methods: This study aimed to investigate the characteristics and outcomes of salvage transplantation by analyzing the patients who underwent a second HCT for GF following the initial allo-HCT between 1998 and 2020. Results: Overall, 23 recipients were identified, including 14 and 9 individuals with primary and secondary GF, respectively. Nine recipients underwent a second transplant from the same donor. Familial mismatched donors predominated in the second HCT (86.9%), with reduced-intensity conditioning as the prevailing approach (60.9%). Neutrophil engraftment occurred in 17 patients (73.9%) following the second HCT at a median of 17 days (range: 9–58 days) post-transplantation. However, secondary GF subsequently occurred in 5 patients, and successful engraftment following salvage transplantation was achieved in 12 (52.2%) patients. In the entire study population, the estimated 5-year probability of overall survival (OS) and treatment-related mortality (TRM) were 30.4% and 58.5%, respectively. Among patients who achieved successful engraftment following a second transplantation, the OS and TRM rates were 41.7% and 33.3%, respectively, indicating a trend toward better OS and significantly lower TRM compared to those with GF. Notably, 17 patients died, with infection being the most common cause (n = 12), irrespective of the engraftment status. Conclusion A successful engraftment following a second allo-HCT reduced the TRM; however, the OS remained suboptimal. The effective control of infectious diseases remains crucial for patients with GF, regardless of the engraftment status following salvage transplantation.

Background: Active surveillance (AS) has emerged as a viable management strategy for low-risk papillary thyroid microcarcinoma (PTMC), following pioneering trials at Kuma Hospital and the Cancer Institute Hospital in Japan. Numerous prospective cohort studies have since validated AS as a management option for low-risk PTMC, leading to its inclusion in thyroid cancer guidelines across various countries. From 2016 to 2020, the Multicenter Prospective Cohort Study of Active Surveillance on Papillary Thyroid Microcarcinoma (MAeSTro) enrolled 1,177 patients, providing comprehensive data on PTMC progression, sonographic predictors of progression, quality of life, surgical outcomes, and cost-effectiveness when comparing AS to immediate surgery. The second phase of MAeSTro (MAeSTro-EXP) expands AS to low-risk papillary thyroid carcinoma (PTC) tumors larger than 1 cm, driven by the hypothesis that overall risk assessment outweighs absolute tumor size in surgical decision-making. Methods: This protocol aims to address whether limiting AS to tumors smaller than 1 cm may result in unnecessary surgeries for low-risk PTCs detected during their rapid initial growth phase. By expanding the AS criteria to include tumors up to 1.5 cm, while simultaneously refining and standardizing the criteria for risk assessment and disease progression, we aim to minimize overtreatment and maintain rigorous monitoring to improve patient outcomes. Conclusion This study will contribute to optimizing AS guidelines and enhance our understanding of the natural course and appropriate management of low-risk PTCs. Additionally, MAeSTro-EXP involves a multinational collaboration between South Korea and Australia. This cross-country study aims to identify cultural and racial differences in the management of low-risk PTC, thereby enriching the global understanding of AS practices and their applicability across diverse populations.

Background/Aims: Inaccurate prediction of lymph node metastasis (LNM) may lead to unnecessary surgery following endoscopic resection of T1 colorectal cancer (CRC). We aimed to validate the usefulness of artificial intelligence (AI) models for predicting LNM in patients with T1 CRC. Methods: We analyzed the clinical data, laboratory results, pathological reports, and endoscopic findings of patients who underwent radical surgery for T1 CRC. We developed AI models to predict LNM using four algorithms: regularized logistic regression classifier (RLRC), random forest classifier (RFC), CatBoost classifier (CBC), and the voting classifier (VC). Four histological factors and four endoscopic findings were included to develop AI models. Areas under the receiver operating characteristics curves (AUROCs) were measured to distinguish AI model performance in accordance with the Japanese Society for Cancer of the Colon and Rectum guidelines. Results: Among 1,386 patients with T1 CRC, 173 patients (12.5%) had LNM. The AUROC values of the RLRC, RFC, CBC, and VC models for LNM prediction were significantly higher (0.673, 0.640, 0.679, and 0.677, respectively) than the 0.525 suggested in accordance with the Japanese Society for Cancer of the Colon and Rectum guidelines (vs RLRC, p<0.001; vs RFC, p=0.001; vs CBC, p<0.001; vs VC, p<0.001). The AUROC value was similar between T1 colon versus T1 rectal cancers (0.718 vs 0.615, p=0.700). The AUROC value was also similar between the initial endoscopic resection and initial surgery groups (0.581 vs 0.746, p=0.845). Conclusions AI models trained on the basis of endoscopic findings and pathological features performed well in predicting LNM in patients with T1 CRC regardless of tumor location and initial treatment method.

Purpose: Hematopoietic stem cell transplantation (HSCT) has been an important method of treatment in the advance of pediatric acute lymphoblastic leukemia (ALL). The indications for HSCT are evolving and require updated establishment. In this study, we aimed to investigate the efficacy of HSCT on the treatment outcome of pediatric ALL, considering the indications for HSCT and subgroups. Materials and Methods: A retrospective analysis was conducted on ALL patients diagnosed and treated at a single center. Risk groups were categorized based on age at diagnosis, initial white blood cell count, disease lineage (B/T), and cytogenetic study results. Data on the patients’ disease status at HSCT and indications of HSCT were collected. Indications for HSCT were categorized as upfront HSCT at 1st complete remission, relapse, and refractory disease. Results: Among the 549 screened patients, a total of 418 patients were included in the study; B-cell ALL (n=379) and T-cell ALL (T-ALL) (n=39). HSCT was conducted on a total of 106 patients (25.4%), with a higher frequency as upfront HSCT in higher-risk groups and specific cytogenetics. The overall survival (OS) was significantly better when done upfront than in relapsed or refractory state in T-ALL patients (p=0.002). The KMT2A-rearranged ALL patients showed superior event-free survival (p=0.002) and OS (p=0.022) when HSCT was done as upfront treatment. Conclusion HSCT had a substantial positive effect in a specific subset of pediatric ALL. In particular, frontline HSCT for T-ALL and KMT2A-rearranged ALL offered a better prognosis than when HSCT was conducted in a relapsed or refractory setting.