Primary cilia function as critical sensory organelles that mediate multiple signaling pathways, including the Hedgehog (Hh) pathway, which is essential for organ patterning and morphogenesis. Disruptions in Hh signaling have been implicated in supernumerary tooth formation and molar fusion in mutant mice. Cilk1, a highly conserved serine/threonine-protein kinase localized within primary cilia, plays a critical role in ciliary transport. Loss of Cilk1 results in severe ciliopathy phenotypes, including polydactyly, edema, and cleft palate. However, the role of Cilk1 in tooth development remains unexplored. In this study, we investigated the role of Cilk1 in tooth development. Cilk1 was found to be expressed in both the epithelial and mesenchymal compartments of developing molars. Cilk1 deficiency resulted in altered ciliary dynamics, characterized by reduced frequency and increased length, accompanied by downregulation of Hh target genes, such as Ptch1 and Sostdc1, leading to the formation of diastemal supernumerary teeth. Furthermore, in Cilk1^-/-;PCS1-MRCS1^△/△ mice, which exhibit a compounded suppression of Hh signaling, we uncovered a novel phenomenon: diastemal supernumerary teeth can be larger than first molars. Based on these findings, we propose a progressive model linking Hh signaling levels to sequential changes in tooth patterning: initially inducing diastemal supernumerary teeth, then enlarging them, and ultimately leading to molar fusion. This study reveals a previously unrecognized role of Cilk1 in controlling tooth morphology via Hh signaling and highlights how Hh signaling levels shape tooth patterning in a gradient-dependent manner.
Animals ; Hedgehog Proteins/physiology* ; Mice ; Signal Transduction/physiology* ; Tooth, Supernumerary ; Molar ; Cilia/physiology* ; Odontogenesis/physiology* ; Patched-1 Receptor ; Protein Serine-Threonine Kinases/physiology* ; Mice, Knockout ; Adaptor Proteins, Signal Transducing

Purpose: Erectile dysfunction (ED) is considered a microvascular disorder and serves as an indicator for the potential development of cardiovascular disease (CVD). Although left ventricular diastolic dysfunction (LVDD) reflects early myocardial damage caused by microvascular disorders, the association between ED and LVDD remains poorly elucidated. Materials and Methods: A cross-sectional study was conducted on 123 patients with ED. They underwent RigiScan, and conventional echocardiography, and attempted International Index of Erectile Function (IIEF) questionnaire. ED severity was evaluated by measuring changes in the penile base circumference and duration of penile rigidity (≥70%) during erection. The early diastolic velocity of mitral inflow (E) and early diastolic velocity of the mitral annulus (e′) were measured using echocardiography. The patients were grouped based on the presence of CVD. Results: Among 123 patients, 29 had CVD and 94 did not. Patients with CVD exhibited more pronounced ED and more severe LVDD. Associations between increased penile circumference with echocardiographic parameters were more prominent in patients with CVD than in those without CVD (ΔTtop and e′ wave, r=0.508 and r=0.282, respectively, p for interaction=0.033; ΔTbase and E/e′ ratio, r=-0.338 and r=-0.293, respectively, p for interaction <0.001). In the multivariate linear regression, the increase of penile base circumference was an independent risk factor for LVDD (e′, B=0.503; E/e′ ratio, B=-1.416, respectively, p<0.001). Conclusions ED severity correlated well with LV diastolic dysfunction, particularly in the presence of CVD. This study highlighted the potential role of ED assessment as early indicator of CVD development.

Purpose: This subgroup analysis of the Korean subset of patients in the phase 3 LASER301 trial evaluated the efficacy and safety of lazertinib versus gefitinib as first-line therapy for epidermal growth factor receptor mutated (EGFRm) non–small cell lung cancer (NSCLC). Materials and Methods: Patients with locally advanced or metastatic EGFRm NSCLC were randomized 1:1 to lazertinib (240 mg/day) or gefitinib (250 mg/day). The primary endpoint was investigator-assessed progression-free survival (PFS). Results: In total, 172 Korean patients were enrolled (lazertinib, n=87; gefitinib, n=85). Baseline characteristics were balanced between the treatment groups. One-third of patients had brain metastases (BM) at baseline. Median PFS was 20.8 months (95% confidence interval [CI], 16.7 to 26.1) for lazertinib and 9.6 months (95% CI, 8.2 to 12.3) for gefitinib (hazard ratio [HR], 0.41; 95% CI, 0.28 to 0.60). This was supported by PFS analysis based on blinded independent central review. Significant PFS benefit with lazertinib was consistently observed across predefined subgroups, including patients with BM (HR, 0.28; 95% CI, 0.15 to 0.53) and those with L858R mutations (HR, 0.36; 95% CI, 0.20 to 0.63). Lazertinib safety data were consistent with its previously reported safety profile. Common adverse events (AEs) in both groups included rash, pruritus, and diarrhoea. Numerically fewer severe AEs and severe treatment–related AEs occurred with lazertinib than gefitinib. Conclusion Consistent with results for the overall LASER301 population, this analysis showed significant PFS benefit with lazertinib versus gefitinib with comparable safety in Korean patients with untreated EGFRm NSCLC, supporting lazertinib as a new potential treatment option for this patient population.

Background: It is well known that a large number of patients with diabetes also have dyslipidemia, which significantly increases the risk of cardiovascular disease (CVD). This study aimed to evaluate the efficacy and safety of combination drugs consisting of metformin and atorvastatin, widely used as therapeutic agents for diabetes and dyslipidemia. Methods: This randomized, double-blind, placebo-controlled, parallel-group and phase III multicenter study included adults with glycosylated hemoglobin (HbA1c) levels >7.0% and <10.0%, low-density lipoprotein cholesterol (LDL-C) >100 and <250 mg/dL. One hundred eighty-five eligible subjects were randomized to the combination group (metformin+atorvastatin), metformin group (metformin+atorvastatin placebo), and atorvastatin group (atorvastatin+metformin placebo). The primary efficacy endpoints were the percent changes in HbA1c and LDL-C levels from baseline at the end of the treatment. Results: After 16 weeks of treatment compared to baseline, HbA1c showed a significant difference of 0.94% compared to the atorvastatin group in the combination group (0.35% vs. −0.58%, respectively; P<0.0001), whereas the proportion of patients with increased HbA1c was also 62% and 15%, respectively, showing a significant difference (P<0.001). The combination group also showed a significant decrease in LDL-C levels compared to the metformin group (−55.20% vs. −7.69%, P<0.001) without previously unknown adverse drug events. Conclusion The addition of atorvastatin to metformin improved HbA1c and LDL-C levels to a significant extent compared to metformin or atorvastatin alone in diabetes and dyslipidemia patients. This study also suggested metformin’s preventive effect on the glucose-elevating potential of atorvastatin in patients with type 2 diabetes mellitus and dyslipidemia, insufficiently controlled with exercise and diet. Metformin and atorvastatin combination might be an effective treatment in reducing the CVD risk in patients with both diabetes and dyslipidemia because of its lowering effect on LDL-C and glucose.

Purpose: The objective of this study was to evaluate the effect of Polymyxin B hemoperfusion (PMX-HP) on patients with sepsis. Methods: A systematic review and meta-analysis was performed using relevant articles retrieved from 3 databases (PubMed, Cochrane Library, EMBASE). Randomized studies from 1 January 1999 to 28 February 2022 were examined to determine the clinical results of PMX-HP. A meta-analysis was carried out using the random-effects method, meta-regression with clinical variables, and assessment of risk of bias (ROB) tool (Cochrane ROB assessment tool). Mortality was evaluated within 60 days of hospitalization (in-hospital death 28-day, 30-day, and 60-day mortality) and predictors associated with mortality were determined using meta-regression. Results: There were 11 randomized studies with 548 patients included in the meta-analysis. The pooled mortality was 35% (95% CI, 27%-42%, 95% CI 0.53-0.96). Further subgroup analysis was performed according to the duration of PMX-HP. An extension of PMX-HP treatment beyond 2 hours (pooled mortality, 43%; 95% CI, 9%-76%) compared with a 2-hour session (pooled mortality, 33%. 95% CI, 27%-38%) showed an increase in mortality rates. However, this was not statistically significant. Univariate meta-regression showed that patient’s age, the acute physiology and chronic health evaluation score, and the sequential organ failure assessment score did not significantly impact mortality. Conclusion While PMX-HP is valuable in the management of septic shock, treatment duration should be based on careful assessment of the patient's condition, the risks and benefits of prolonged therapy, and the overall treatment strategy including antimicrobial management and source control.

Purpose: Liposarcoma is a mesenchymal neoplasm and comprise 20%–30% of all soft tissue sarcomas, accounting for 1% of all malignancies. This study documented the clinical manifestation and oncological outcomes of dedifferentiated liposarcoma (DDLPS). Materials and Methods: Eleven patients were diagnosed and treated for DDLPS between January 2013 and December 2020. The age, gender, symptom onset, tumor location, magnetic resonance images, surgical margin, and pathologic diagnosis of the identified cohort were reviewed. The time to local recurrence or metastasis, follow-up duration, and the patients’ final status were analyzed. Results: The patients comprised seven male and four female patients with a mean age of 59 years (43–73 years). The tumor location was in the thigh in five, inguinal in two, upper arm in two, forearm in one, and popliteal in one. The average tumor diameter was 12 cm (3.5–27.0 cm). At the time of diagnosis, one patient was American Joint Committee on Cancer stage IB, two were II, four were IIIA, and four were IIIB. Local recurrence occurred in four, and distant metastasis occurred in five. The five-year overall survival of patients with DDLPS was 54.5±17.6%, and four died due to disease progression. Conclusion Primary DDLPS in the extremities is a subtype of liposarcoma with a poorer prognosis than well-differentiated liposarcoma and myxoid liposarcoma.

Purpose: Giant cell tumor (GCT) of the proximal femur is relatively rare, with only a few case series reported thus far. This study aimed to evaluate the clinical outcomes of GCT of the proximal femur treated with intralesional curettage and expand the understanding of their characteristics and treatment considerations. Materials and Methods: Fifteen cases treated with curettage for GCT of the proximal femur between 2007 and 2020 were reviewed. The median follow-up was 46 months (25–150 months). There were 10 males and 5 females with a median age of 26 years (17–71 years). After curettage, the bone defect was filled with either an allograft (7 cases) or bone cement (8 cases). Results: The postoperative complications were local recurrences in three cases (20.0%), including malignant transformation in one case and a femur neck fracture in one case (6.7%) following curettage and strut allograft. Among the 15 cases, 13 (86.7%) retained their native joint at the last follow-up. No patients developed degenerative changes or osteonecrosis. Conclusion The results of proximal femoral GCT with curettage were acceptable despite local recurrences in three cases (20.0%), and femur neck fracture in one case. An appropriate surgical approach and reconstruction according to the extent of the lesion are necessary for successful treatment.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by the deficient activity of α-galactosidase (α-Gal A), affecting multiple organs including kidney. In this study, we aimed to determine the prevalence of FD in patients with chronic kidney disease (CKD) including those on renal replacement therapy in Korea. Methods: This is a national, multicenter, observational study performed between August 24, 2017 and February 28, 2020. Patients with the presence of proteinuria or treated on dialysis were screened by measuring the α-Gal A enzyme activity using either dried blood spot or whole blood, and plasma globotriaosylsphingosine (lyso-GL3) concentration. A GLA gene analysis was performed in patients with low α-Gal A enzyme activity or increased plasma lyso-GL3 concentration. Results: Of 897 screened patients, 405 (45.2%) were male and 279 (31.1%) were on dialysis. The α-Gal A enzyme activity was measured in 891 patients (99.3%), and plasma lyso-GL3 concentration was measured in all patients. Ten patients were eligible for a GLA gene analysis: eight with low α-Gal A enzyme activity and two with increased plasma lyso-GL3 concentration. The GLA mutations were analyzed in nine patients and one patient was found with a pathogenic mutation. Therefore, one patient was identified with FD, giving a prevalence of 0.1% (1 of 897) in this CKD population. Conclusion: Although the prevalence of FD in the CKD population was low (0.1%), screening tests are crucial to detect potential diseases in patients with relatives who can benefit from early treatment.

Background: Mechanical failures of tumor endoprosthesis in the distal femur usually require revision surgery. We investigated if the proximal femur host bone can be salvaged by onlay and overlapping allograft in revision surgeries due to aseptic loosening and stem fractures. Methods: We retrospectively reviewed 18 patients (7 men and 11 women) with osteosarcoma around the knee. The entire cohort was classified into three subgroups (no bone graft: 6, onlay allograft: 7, and overlapping allograft: 5) according to our treatment strategy. Results: The median interval from the initial surgery to the revision was 94.5 months (range, 21–219 months), and the median follow-up period from the revision surgery was 88.0 months (range, 24–179 months). At the last follow-up, 9 of the 18 patients maintained their endoprostheses, and the 5-year prosthesis survival rate was 57.9%. Limb survival was 100%. Five-year prosthesis survival rate was 66.7% in the no bone graft group, 85.7% in the onlay allograft group while 30.0% in the overlapping allograft group. In the no bone graft group and onlay allograft group, 66.7% (4/6) and 57.1% (4/7) maintained their revision prostheses while no prostheses survived in the overlapping allograft group. Recurrent stem loosening was observed in 14.2% (1/7) and 60.0% (3/5) of the onlay allograft and overlapping allograft groups, respectively, despite allograft bone union. The complication rate was 66.7% (12/18) in the entire cohort. The most common type of complication was infection (n = 6), followed by aseptic loosening (n = 4) and mechanical failure (n = 2). Conclusions This study indicates that onlay allograft can be used as a supportive method in revising failed endoprosthesis if the extent of host bone destruction is extensive. However, applying overlapping allograft to secure bone stock showed a high rate of mechanical failures and infection in the long term. Future studies with a larger cohort are necessary to assess the prognostic factors for the higher complication rate in overlapping allograft and the need for overlapping allograft. Surveillance with consideration of the risk of anteromedial osteolysis in allograft and efforts for prevention of periprosthetic infection are essential.

Background/Aims: We aimed to compare the effectiveness and safety of Janus kinase inhibitors (JAKi) vs. biologic disease- modifying antirheumatic drugs (bDMARD) in Korean patients with rheumatoid arthritis (RA) who had an inadequate response to conventional synthetic DMARDs. Methods: A quasi-experimental, multi-center, prospective, non-randomized study was conducted to compare response rates between JAKi and bDMARDs in patients with RA naïve to targeted therapy. An interim analysis was performed to estimate the proportion of patients achieving low disease activity (LDA) based on disease activity score (DAS)–28– erythroid sedimentation rate (ESR) (DAS28-ESR) at 24 weeks after treatment initiation and to evaluate the development of adverse events (AEs). Results: Among 506 patients enrolled from 17 institutions between April 2020 and August 2022, 346 (196 JAKi group and 150 bDMARD group) were included in the analysis. After 24 weeks of treatment, 49.0% of JAKi users and 48.7% of bDMARD users achieved LDA (p = 0.954). DAS28-ESR remission rates were also comparable between JAKi and bDMARD users (30.1% and 31.3%, respectively; p = 0.806). The frequency of AEs reported in the JAKi group was numerically higher than that in the bDMARDs group, but the frequencies of serious and severe AEs were comparable between the groups. Conclusions Our interim findings reveal JAKi have comparable effectiveness and safety to bDMARDs at 24 weeks after treatment initiation.