Background: As nationwide government-led whole-genome sequencing (WGS) projects progress, optimizing the clinical integration of large-scale WGS results is crucial. We explored how the initial analysis from Korea’s First WGS Pilot Study for Rare Diseases was applied in clinical practice, and then we reanalyzed the data comprehensively at Samsung Medical Center (SMC) Seoul, Korea. Methods: A prospective cohort study designed to collect WGS data under a Korean national initiative was conducted from August 2020 to December 2021. We focused on patients with rare diseases recruited from 16 university hospitals. The participants included 5,000 individuals (2,200 probands and 2,800 family members). The initial WGS data and diagnostic reference reports (from 682 probands and 484 family members), generated based on the First Korean WGS Pilot Study for Rare Diseases, were subsequently reanalyzed by SMC. Results: The initial analysis of the First Korean WGS Pilot Study data revealed a diagnostic rate of 17%. Upon receiving these results, the SMC conducted two rounds of reanalysis, increasing the diagnostic rate from 15% in the first analysis, to 18% in the second, and finally to 24% in the third (P = 1.6 × 10 −5 ). Key factors in improving the genetic diagnosis included increased detection of novel (likely) pathogenic variants (P = 1.0 × 10 −4 ), improved diagnostic rates with larger family recruitment (P = 0.004), and refined clinical information for more precise genotype–phenotype correlation analysis (40%). Conclusions Although national WGS projects lay a foundation for rare disease diagnosis, hospital-level reanalysis and multidisciplinary collaborations are crucial for optimizing diagnostic outcomes.

Purpose: Persistent hypercalcemia after parathyroidectomy (PTx) remains a significant concern in patients with tertiary hyperparathyroidism (THPT) following kidney transplant (KT). Complete resection of hyperfunctioning glands is challenging due to ectopic or intrathyroidal glands. This study evaluated whether intraoperative parathyroid hormone (ioPTH) monitoring during PTx in KT patients with THPT reduces the surgical failure rate. Methods: We retrospectively analyzed 111 patients with THPT who underwent PTx at a single tertiary center. Patients were divided into 2 groups: those without ioPTH monitoring (n=98) and those with ioPTH monitoring (n=13). Surgical procedures included less than subtotal, subtotal, or total PTx with autotransplantation. Surgical failure was defined as persistent hypercalcemia (serum calcium ≥10.3 mg/dL and intact parathyroid hormone [PTH] >65 pg/mL) on postoperative day 1 (POD1) or at ≥6 months postoperatively. Results: The ioPTH group demonstrated a significantly lower mean PTH level on POD1 (21±15.3 pg/mL vs. 39±39 pg/mL; P=0.006). Although not statistically significant, the ioPTH group showed a higher biochemical cure rate at 3 months (53.8% vs. 30.6%) and no cases of persistent hyperparathyroidism, compared to 15.3% in the non-ioPTH group.Despite adequate intraoperative PTH reduction, some patients in both groups exhibited isolated PTH elevation without hypercalcemia. Conclusion Although ioPTH monitoring did not significantly reduce the surgical failure rate in PTx for THPT, the use of ioPTH may meaningfully improve surgical completeness and reduce the risk of persistent or recurrent hyperparathyroidism, suggesting its substantial potential value as an intraoperative.

Purpose: Hungry bone syndrome (HBS) is a common and critical postoperative complication in patients undergoing parathyroidectomy (PTX) for secondary hyperparathyroidism (SHPT) and tertiary hyperparathyroidism (THPT). We aimed to identify clinical predictors of HBS and assess its impact on bone mineral density (BMD) after PTX. Methods: We retrospectively analyzed data of patients with SHPT and THPT who underwent PTX at Asan Medical Center (2010–2022). Clinical characteristics, including biochemical markers and BMD, were investigated. HBS was defined as profound hypocalcemia of less than 8.4 mg/dL (2.1 mmol/L) or prolonged hypocalcemia for more than 4 days after PTX. Results: A total of 91 patients were included: 18 (19.8%) with SHPT and 73 (80.2%) with THPT. Subtotal PTX was performed in 80 patients (87.9%), while 11 patients (12.1%) underwent total PTX with autotransplantation (TPTX + AT). HBS occurred in 31 patients (34.1%), with a higher incidence in patients with SHPT (72.2%) and all patients who underwent TPTX + AT.Patients with HBS required more calcium supplementation and had higher ALP levels at all timepoints (P < 0.001). In the HBS group, BMD improved more significantly in the femur (P = 0.005) and showed a trend towards improvement in the spine (P = 0.059). Risk factors for HBS included younger age, SHPT, and elevated preoperative ALP and intact parathyroid hormone levels. Conclusion HBS is characterized by severe hypocalcemia due to calcium reabsorption into bone after PTX. Identifying risk factors for HBS may promote early risk stratification and tailored perioperative management, including surgical approach, especially for high-risk patients.

Purpose: This study evaluates the Korean Cancer Study Group Geriatric Score-7 (KG-7) frailty screening tool’s effectiveness in elderly multiple myeloma (MM) patients to prevent under and overtreatment. Materials and Methods: This prospective pilot cohort study included 100 elderly patients aged 70 and older with newly diagnosed MM who had not undergone transplantation from August 2020 to January 2022. Results: The median age was 77 years, and 73.0% of patients were classified at International Staging System stages 2 or 3. Using a 5-point cutoff on the KG-7 index (non-frail, score ≥ 5; frail, score < 5), 31% were categorized as frail. After a median follow-up of 26.8 months, the 3-year overall survival rate was 73.0%. There was no statistically significant association between any frailty index and the risk of death. However, frail patients defined by the simplified frailty index (hazard ratio [HR], 2.49; 95% confidence interval [CI], 1.09 to 5.95; p=0.030) and by KG-7 (HR, 2.43; 95% CI, 1.03 to 5.86; p=0.043) had a significantly higher risk of grade 3-4 non-hematologic toxicity, whereas the International Myeloma Working Group definition did not. Over a 24-month tracking period, vulnerability as measured by KG-7 either improved or deteriorated. Conclusion The pilot study, which had a limited number of participants, did not demonstrate KG-7’s effectiveness in predicting survival; however, it successfully predicted severe non-hematologic toxicities. We plan to conduct larger studies in elderly MM patients to determine whether KG-7 can help tailor their treatment regimens.

Purpose: Declines in masticatory function have been reported to be closely associated with cognitive impairment and reduced brain activity in older adults. This study aimed to investigate the effects of intraoral vibratory stimulation on masticatory function, cognitive performance, and brain activity in elderly individuals and to evaluate its potential efficacy. Materials and Methods: Participants were divided into a vibration-stimulation group (n=9) and a non-vibration control group (n=7). Baseline assessments were conducted at the first visit. Participants then received either vibratory stimulation or a wash-out (control) condition for two weeks, followed by the same assessments at the final visit. Evaluation measures were dental assessments (maximum bite force, masticatory performance, and salivary flow rate), cognitive tests (CANTAB, paper-based and computerized tests), quantitative electroencephalography (qEEG), and functional magnetic resonance imaging (fMRI) during a short-term memory task. Results: No significant long-term effects or statistically meaningful differences were observed between the two groups in cognitive performance or brain activity. Similarly, no pre- to post-intervention differences were found between groups in dental measures related to masticatory function (maximum bite force, masticatory performance, and salivary flow rate). Due to the limited sample size, this study functioned as a pilot study focusing on descriptive rather than inferential statistical analysis. Conclusion Intraoral vibratory stimulation did not demonstrate immediate or clear effects on cognitive function or brain activity in older adults, suggesting the need for optimization of stimulation parameters such as location and intensity. Future studies with larger sample sizes and improved stimulation methods replicating masticatory function are warranted to further explore the potential cognitive benefits.

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: MUTYH-associated polyposis is an autosomal recessive disorder associated with an increased lifetime risk of colorectal cancer and a moderately increased risk of ovarian, bladder, breast, and endometrial cancers. We analyzed the carrier frequency and estimated the incidence of MUTYH-associated polyposis in East Asian and Korean populations, for which limited data were previously available. Methods: We examined 125,748 exomes from the gnomAD database, including 9,197 East Asians, and additional data from 5,305 individuals in the Korean Variant Archive and 1,722 in the Korean Reference Genome Database. All MUTYH variants were interpreted according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines and the Sequence Variant Interpretation guidelines from ClinGen. Results: The global carrier frequency of MUTYH-associated polyposis was 1.29%, with Europeans (non-Finnish) having the highest frequency of 1.86% and Ashkenazi Jews the lowest at 0.06%. East Asians and Koreans had a carrier frequency of 0.35% and 0.37% and an estimated incidence of 1 in 330,409 and 1 in 293,304 in Koreans, respectively, which were substantially lower than the global average of 1 in 24,160 and the European (nonFinnish) incidence of 1 in 11,520. Conclusions This was the first study to investigate the frequency of carriers of MUTYH-associated polyposis in East Asians, including specific subgroups, utilizing gnomAD and a Korean genome database. Our data provide valuable reference information for future investigations of MUTYH-associated polyposis to understand the genetic diversity and specific variants associated with this condition in East Asian populations.

Background: Circulating tumor DNA (ctDNA) profiling from peripheral blood allows relatively noninvasive monitoring of solid tumors; however, its utility post-surgery or chemotherapy in colorectal cancer remains underexplored. We evaluated the clinical implications of a ctDNA next-generation sequencing (NGS) panel post-surgery or chemotherapy in patients with colorectal cancer. Methods: We collected samples from 23 patients with colorectal cancer (17 men, median age 65 yrs) at baseline and post-surgery or chemotherapy at the National Cancer Center, Korea, between January 2021 and September 2023. ctDNA was analyzed using an NGS panel including 46 genes, and variant allele frequencies (VAFs) were determined. Followup samples were analyzed using the NGS panel or droplet digital PCR (ddPCR) when probes were available. Clinical status was compared with ctDNA results, and survival was analyzed using a time-dependent Cox model. Results: Mutations were identified in 13 out of 14 patients (92.8%) with stage II/III cancer and in all nine patients (100%) with stage IV cancer. Mutations were detected in KRAS (N = 15, 65%), APC (N = 8, 35%), TP53 (N = 7, 30%), PIK3CA (N = 5, 22%), and RET (N = 4, 17%). A 1% increase in KRAS and TP53 VAFs was associated with 48% and 32% increased mortality risk, respectively. Changes in VAF correlated well with clinical findings. Conclusions The detection of and an increase in KRAS and TP53 VAFs were associated with poor prognosis. ddPCR-based ctDNA monitoring results were comparable to those obtained with the NGS panel. ctDNA monitoring during treatment is clinically informative in managing colorectal cancer.

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.