Renal cell carcinoma (RCC) presents significant clinical challenges, highlighting the importance of understanding its molecular mechanisms. While store-operated Ca2+ entry (SOCE) is known to play an essential role in tumorigenesis and metastasis, its specific implications across various RCC subtypes remain underexplored.This study analyzed SOCE-related mRNA profiles from the KIRC and KIRP projects in The Cancer Genome Atlas (TCGA) database, focusing on differential gene expression and overall survival outcomes. Functional studies in clear cell RCC (Caki-1) and papillary RCC cell lines (pRCC, Caki-2) revealed increased expression of Orai1 and Orai3, along with STIM1, exhibited in both subtypes, with decreased STIM2 and increased Orai2 expression in pRCC. Notably, Orai3 expression had a gender-specific impact on survival, particularly in females with pRCC, where it inversely correlated with STIM2 expression. Functional assays showed Orai3 dominance in Caki-2 and Orai1 in Caki-1. Interestingly, 2-APB inhibited SOCE in Caki-1 but enhanced it in Caki-2, suggesting Orai3 as the primary SOCE channel in pRCC. Knockdown of Orai1 and Orai3 reduced cell migration and proliferation via regulating focal adhesion kinase (FAK) and Cyclin D1 in both cell lines. These findings highlight the critical roles of Orai1 and Orai3 in RCC metastasis, with Orai3 linked to poorer prognosis in females with pRCC. This study offers valuable insights into RCC diagnostics and potential therapeutic strategies targeting ORAI channels and STIM proteins.

Donepezil, an acetylcholinesterase inhibitor, is widely used for managing the symptoms of Alzheimer’s disease (AD), yet its clinical response varies widely among individuals. This study aims to investigate the influence of CYP2D6 genetic variants on donepezil concentration, treatment response, and adverse effects in Korean patients with AD dementia. We conducted a longitudinal study involving 76 patients receiving either 5 mg or 10 mg of donepezil. Genetic testing identified 9 CYP2D6 alleles, categorizing patients by metabolizing abilities. Blood sampling for plasma concentrations of donepezil were performed at steady-state. Mini-Mental State Examination (MMSE) were conducted at 12, 24 and 36 months after the initiation of treatment. Adverse events were collected throughout the study period.Donepezil plasma concentrations differed significantly among metabolizer statuses (mean 56.8 ± 27.1 ng/ml in normal metabolizers vs. 69.6 ± 30.1 ng/ml in intermediate metabolizers, p = 0.042), but these differences did not affect cognitive function over three years as assessed by MMSE. Additionally, there was no significant correlation between donepezil plasma concentration and adverse events. Our study is the first to elucidate the associations between CYP2D6 genotype and the concentration, clinical response or adverse events of donepezil in Korean patients with AD dementia. Larger studies are necessary to fully understand the impact of CYP2D6 genetic variants on therapeutic outcomes with donepezil.

Purpose: This study aimed to explore the effects of both the presence and size of posterior subependymal germinal matrix hemorrhage (PS-GMH), considered a mild form of hemorrhage, on the neurodevelopmental outcomes of extremely preterm infants. Methods: A retrospective analysis was conducted on 221 extremely preterm infants, assessing their initial and term-equivalent age (TEA) cranial ultrasound (cUS) examinations from 2016 to 2021. Infants were classified based on the presence and size (small/large) of PS-GMH. Neurodevelopmental outcomes at corrected ages of 18-24 months were analyzed in 135 infants. Results: PS-GMH was identified in 86.9% (192/221) of the infants, with 13.5% (26/192) exhibiting large PS-GMH. Among the 135 infants who were followed up, those with PS-GMH were found to have younger gestational ages (P<0.001) and a higher incidence of maternal chorioamnionitis (P=0.016) than those without PS-GMH. Significant differences were observed in the incidence of grade II intraventricular hemorrhage (IVH) on initial cUS (P=0.003) and ventriculomegaly at TEA cUS (P=0.026) across the groups with no PS-GMH, small PS-GMH, and large PS-GMH. The large PS-GMH group exhibited a higher occurrence of grade II IVH than the small PS-GMH group (P=0.006). However, ventriculomegaly incidence did not significantly vary with PS-GMH status. Neurodevelopmental outcomes were also not significantly different across PS-GMH statuses. The adjusted odds ratios for any neurodevelopmental impairment, compared to the no PS-GMH group, were 1.70 (95% confidence interval [CI], 0.40 to 7.26; P=0.471) for all PS-GMH, 1.61 (95% CI, 0.37 to 6.93; P=0.526) for small PS-GMH, and 3.84 (95% CI, 0.62 to 24.00; P=0.150) for large PS-GMH. Conclusion PS-GMH was frequently observed in extremely preterm infants; however, it did not independently predict adverse neurodevelopmental outcomes.

Purpose: Pediatric papillary thyroid cancer (PTC) is recommended to perform aggressive surgery to reduce the risk of recurrence.This study was designed to evaluate the concurrent association between multifocality, bilaterality, and the risk of recurrence in pediatric PTC. Materials and Methods: This retrospective cohort study included pediatric patients (age <19 years) who underwent total thyroidectomy for PTC between 1996 and 2014 in a single tertiary center. Clinicopathological parameters were analyzed to evaluate the prevalence of multifocality, bilaterality, recurrence, and their association. Results: We analyzed 58 pediatric patients with PTC. There was no factor related to the presence of multifocality or bilaterality in multivariate analysis. Also, in univariate analysis, multifocality and bilaterality were not independent risk factors of each other’s presentation (p=0.061 and p=0.061, respectively). Recurrence was observed in 19 (32.8%) patients. In multivariate analysis of recurrence, clear cell subtype, multifocality, and gross extrathyroidal extension (ETE) were independent risk factors (p=0.027, p=0.035, and p=0.038, respectively). Most recurrences (68.4%) happened during the first 4 years of follow-up after the initial thyroidectomy. Conclusion Multifocality and bilaterality were not independent risk factors of each other’s presentation; however, multifocality was the risk factor for recurrence in pediatric PTC. For pediatric PTC, close monitoring for recurrence within the initial 4 years is recommended, particularly in patients with clear cell subtype, multifocality, and gross ETE.

Purpose: Recent development in perioperative treatment of resectable non–small cell lung cancer (NSCLC) have changed the landscape of early lung cancer management. The ADAURA trial has demonstrated the efficacy of adjuvant osimertinib treatment in resectable NSCLC patients; however, studies are required to show which subgroup of patients are at a high risk of relapse and require adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment. This study evaluated risk factors for postoperative relapse among patients who underwent complete resection. Materials and Methods: Data were obtained from the Korean Association for Lung Cancer Registry (KALC-R), a database created using a retrospective sampling survey by the Korean Central Cancer Registry (KCCR) and the Lung Cancer Registration Committee. Results: A total of 3,176 patients who underwent curative resection was evaluated. The mean observation time was approximately 35.4 months. Among stage I to IIIA NSCLC patients, the EGFR-mutant subgroup included 867 patients, and 75.2%, 11.2%, and 11.8% were classified as stage I, stage II, and stage III, respectively. Within the EGFR-mutant subgroup, 44 (5.1%) and 121 (14.0%) patients showed early and late recurrence, respectively. Multivariate analysis on association with postoperative relapse among the EGFR-mutant subgroup showed that age, pathologic N and TNM stages, pleural invasion status, and surgery type were independent significant factors. Conclusion Among the population that underwent complete resection for early NSCLC with EGFR mutation, patients with advanced stage, pleural invasion, or limited resection are more likely to show postoperative relapse.

Purpose: In Korea, the Act on Hospice and Palliative Care and Decisions on Life-Sustaining Treatment (LST) was implemented on February 4, 2018. We aimed to investigate relevant factors and clinical changes associated with LST decisions after law enforcement. Materials and Methods: This single-center retrospective study included patients who completed LST documents using legal forms at Asan Medical Center from February 5, 2018, to June 30, 2020. Results: 5,896 patients completed LST documents, of which 2,704 (45.8%) signed the documents in person, while family members of 3,192 (54%) wrote the documents on behalf of the patients. Comparing first year and following year of implementation of the act, the self-documentation rate increased (43.9% to 47.2%, p=0.014). Moreover, the number of LST decisions made during or after intensive care unit admission decreased (37.8% vs. 35.2%, p=0.045), and the completion rate of LST documents during chemotherapy increased (6.6% vs. 8.9%, p=0.001). In multivariate analysis, age < 65 (odds ratio [OR], 1.724; 95% confidence interval [CI], 1.538 to 1.933; p < 0.001), unmarried status (OR, 1.309; 95% CI, 1.097 to 1.561; p=0.003), palliative care consultation (OR, 1.538; 95% CI, 1.340 to 1.765; p < 0.001), malignancy (OR, 1.864; 95% CI, 1.628 to 2.133; p < 0.001), and changes in timing on the first year versus following year (OR, 1.124; 95% CI, 1.003 to 1.260; p=0.045) were related to a higher self-documentation rate. Conclusion Age < 65 years, unmarried status, malignancy, and referral to a palliative care team were associated with patients making LST decisions themselves. Furthermore, the subject and timing of LST decisions have changed with the LST act.

Background/Aims: We investigated the clinical practice patterns of Korean endoscopists for the endoscopic resection of colorectal polyps. Methods: From September to November 2021, an online survey was conducted regarding the preferred resection methods for colorectal polyps, and responses were compared with the international guidelines. Results: Among 246 respondents, those with <4 years, 4–9 years, and ≥10 years of experiencein colonoscopy practices accounted for 25.6%, 34.1%, and 40.2% of endoscopists, respectively. The most preferred resection methods for non-pedunculated lesions were cold forceps polypectomy for ≤3 mm lesions (81.7%), cold snare polypectomy for 4–5 mm (61.0%) and 6–9 mm (43.5%) lesions, hot endoscopic mucosal resection (EMR) for 10–19 mm lesions (72.0%), precut EMR for 20–25 mm lesions (22.0%), and endoscopic submucosal dissection (ESD) for ≥26 mm lesions (29.3%). Hot EMR was favored for pedunculated lesions with a head size <20 mm and stalk size <10 mm (75.6%) and for those with a head size ≥20 mm or stalk size ≥10 mm (58.5%). For suspected superficial and deep submucosal lesions measuring 10–19 mm and ≥20 mm, ESD (26.0% and 38.6%) and surgery (36.6% and 46.3%) were preferred, respectively. The adherence rate to the guidelines ranged from 11.2% to 96.9%, depending on the size, shape, and histology of the lesions. Conclusions Adherence to the guidelines for endoscopic resection techniques varied depend-ing on the characteristics of colorectal polyps. Thus, an individualized approach is required to increase adherence to the guidelines.

Background/Aims: We investigated the incidences of overall and site-specific malignancies and chemopreventive effects of statin, metformin, and aspirin in patients with ulcerative colitis. Methods: We collected data using the Health Insurance Review and Assessment claims database from January 2007 to April 2020. Results: The overall malignancy risk among the 35,189 ulcerative colitis patients was similar to that of the general population (standardized incidence ratio, 0.94; 95% confidence interval, 0.88–1.00). In male patients, standardized incidence ratios were high for thyroid cancer and low for stomach cancer, colorectal cancer, liver cancer, and lung cancer. Concurrently, standard incidence ratios were high for liver cancer and central nervous system cancer in female patients. While 122 cases of colorectal cancer occurred in the study patients, the standardized incidence ratio was 0.83 (95% confidence interval, 0.69–0.99). Treatment for ulcerative colitis was not associated with an increased adjusted hazard ratio, while comorbidities increased it for all malignancies. Treatment for ulcerative colitis was associated with an increased adjusted hazard ratio, while comorbidities did not increase it for colorectal cancer. After adjusting for age, sex, comorbidities, and ulcerative colitis treatment, statins showed a dose-dependent chemopreventive effect for all malignancies (P=0.002), while metformin and aspirin did not show any. Conclusions In ulcerative colitis patients, standardized incidence ratios for all malignancies and colorectal cancer did not increase. Adjusted hazard ratios for all malignancies increased with comorbidities and those for colorectal cancer with ulcerative colitis treatment. Statins have a dose-dependent chemopreventive effect for all malignancies.

Purpose: This study evaluated the postoperative quality of life (QoL) after various types of gastrectomy for gastric cancer. Materials and Methods: A multicenter prospective observational study was conducted in Korea using the Korean Quality of Life in Stomach Cancer Patients Study (KOQUSS)-40, a new QoL assessment tool focusing on postgastrectomy syndrome. Overall, 496 patients with gastric cancer were enrolled, and QoL was assessed at 5 time points: preoperatively and at 1, 3, 6, and 12 months after surgery. Results: Distal gastrectomy (DG) and pylorus-preserving gastrectomy (PPG) showed significantly better outcomes than total gastrectomy (TG) and proximal gastrectomy (PG) with regard to total score, indigestion, and dysphagia. DG, PPG, and TG also showed significantly better outcomes than PG in terms of dumping syndrome and worry about cancer. Postoperative QoL did not differ significantly according to anastomosis type in DG, except for Billroth I anastomosis, which achieved better bowel habit change scores than the others. No domains differed significantly when comparing double tract reconstruction and esophagogastrostomy after PG. The total QoL score correlated significantly with postoperative body weight loss (more than 10%) and extent of resection (P<0.05 for both).Reflux as assessed by KOQUSS-40 did not correlate significantly with reflux observed on gastroscopy 1 year postoperatively (P=0.064). Conclusions Our prospective observation using KOQUSS-40 revealed that DG and PPG lead to better QoL than TG and PG. Further study is needed to compare postoperative QoL according to anastomosis type in DG and PG.

Clonorchiasis is a parasitic disease caused by Clonorchis sinensis, a trematode that inhabits the intrahepatic bile ducts of humans and mammals. C. sinensis is one of common foodborne trematodes, prevalent in East Asia including Korea. The International Agency for Research on Cancer reclassified C. sinensis as the Group 1 biological carcinogen of human cholangiocarcinoma (CCA). Evidence supporting the carcinogenicity of C. sinensis includes epidemiological studies showing increased prevalence and odds ratio (OR) of CCA in clonorchiasis patients, the development of CCA in experimental animals, and molecular studies. Approximately 10% of CCA in Korea are believed to be solely caused by clonorchiasis, with an OR of 4.7 for CCA risk among clonorchiasis patients. All hamsters exposed to both of C. sinensis and N-nitrosodimethylamine (NDMA) developed CCA while those exposed to either C. sinensis or NDMA alone did not. In vitro studies using cell models investigated carcinogenetic changes of the intracellular molecules and genes following stimulation with a soluble extract of C. sinensis. The in vitro stimulated cells showed a significant shift to G2/M phage, produced oncogenic molecules, changed expression of oncogenes, increased cell proliferation and suppressed apoptosis. Additionally, the gap-junction proteins between cells, such as connexin (Cx) 43, Cx 26, and Cx 32, were changed significantly, disrupting intercellular homeostasis. These findings suggest that C. sinensis and nitrogen compounds synergistically stimulate the cholangiocytes to become neoplastic. C. sinensis is a biological carcinogen of human CCA, and the World Health Organization guidelines enlist food-borne trematodes as one of target neglected tropical diseases to be eliminated by 2030. The present article reviews and updates perspectives on clonorchiasis, focusing on carcinogenesis.