Longitudinal Comparative Analysis of Circulating Tumor DNA and Matched Tumor Tissue DNA in Patients with Metastatic Colorectal Cancer Receiving Palliative First-Line Systemic Anti-Cancer Therapy.

Purpose: This study aimed to compare tumor tissue DNA (ttDNA) and circulating tumor DNA (ctDNA) to explore the clinical applicability of ctDNA and to better understand clonal evolution in patients with metastatic colorectal cancer undergoing palliative first-line systemic therapy. Materials and Methods: We performed targeted sequencing analysis of 88 cancer-associated genes using germline DNA, ctDNA at baseline (baseline-ctDNA), and ctDNA at progressive disease (PD-ctDNA). The results were compared with ttDNA data. Results: Among 208 consecutively enrolled patients, we selected 84 (41 males; median age 59, range 35 to 90) with all four sample types available. A total of 202 driver mutations were found in 34 genes. ttDNA exhibited the highest mutation frequency (n=232), followed by baseline-ctDNA (n=155) and PD-ctDNA (n=117). Sequencing ctDNA alongside ttDNA revealed additional mutations in 40 patients (47.6%). PD-ctDNA detected 13 novel mutations in 10 patients (11.9%) compared to ttDNA and baseline-ctDNA. Notably, 7 mutations in 5 patients (6.0%) were missense or nonsense mutations in APC, TP53, SMAD4, and CDH1 genes. In baseline-ctDNA, higher maximal variant allele frequency (VAF) values (p=0.010) and higher VAF values of APC (p=0.012), TP53 (p=0.012), and KRAS (p=0.005) mutations were significantly associated with worse overall survival. Conclusion: While ttDNA remains more sensitive than ctDNA, our ctDNA platform demonstrated validity and potential value when ttDNA was unavailable. Post-treatment analysis of PD-ctDNA unveiled new pathogenic mutations, signifying cancer's clonal evolution. Additionally, baseline-ctDNA's VAF values were prognostic after treatment.

Exploration of neuroanatomical characteristics to differentiate prodromal Alzheimer's disease from cognitively unimpaired amyloid-positive individuals.

Differentiating clinical stages based solely on positive findings from amyloid PET is challenging. We aimed to investigate the neuroanatomical characteristics at the whole-brain level that differentiate prodromal Alzheimer's disease (AD) from cognitively unimpaired amyloid-positive individuals (CU A+) in relation to amyloid deposition and regional atrophy. We included 45 CU A+ participants and 135 participants with amyloid-positive prodromal AD matched 1:3 by age, sex, and education. All participants underwent 18F-florbetaben positron emission tomography and 3D structural T1-weighted magnetic resonance imaging. We compared the standardized uptake value ratios (SUVRs) and volumes in 80 regions of interest (ROIs) between CU A+ and prodromal AD groups using independent t-tests, and employed the least absolute selection and shrinkage operator (LASSO) logistic regression model to identify ROIs associated with prodromal AD in relation to amyloid deposition, regional atrophy, and their interaction. After applying False Discovery Rate correction at < 0.1, there were no differences in global and regional SUVR between CU A+ and prodromal AD groups. Regional volume differences between the two groups were observed in the amygdala, hippocampus, entorhinal cortex, insula, parahippocampal gyrus, and inferior temporal and parietal cortices. LASSO logistic regression model showed significant associations between prodromal AD and atrophy in the entorhinal cortex, inferior parietal cortex, both amygdalae, and left hippocampus. The mean SUVR in the right superior parietal cortex (beta coefficient = 0.0172) and its interaction with the regional volume (0.0672) were also selected in the LASSO model. The mean SUVR in the right superior parietal cortex was associated with an increased likelihood of prodromal AD (Odds ratio [OR] 1.602, p = 0.014), particularly in participants with lower regional volume (OR 3.389, p < 0.001). Only regional volume differences, not amyloid deposition, were observed between CU A+ and prodromal AD. The reduced volume in the superior parietal cortex may play a significant role in the progression to prodromal AD through its interaction with amyloid deposition in that region.

Sirolimus-coated Eustachian tube balloon dilatation for treating Eustachian tube dysfunction in a rat model.

Eustachian tube balloon dilatation (ETBD) has shown promising results in the treatment of ET dysfunction (ETD); however, recurrent symptoms after ETBD frequently occur in patients with refractory ETD. The excessive pressure of balloon catheter during ETBD may induce the tissue hyperplasia and fibrotic changes around the injured mucosa. Sirolimus (SRL), an antiproliferative agent, inhibits tissue proliferation. An SRL-coated balloon catheter was fabricated using an ultrasonic spray coating technique with a coating solution composed of SRL, purified shellac, and vitamin E. This study aimed to investigate effectiveness of ETBD with a SRL-coated balloon catheter to prevent tissue proliferation in the rat ET after ETBD. In 21 Sprague-Dawley rats, the left ET was randomly divided into the control (drug-free ETBD; n = 9) and the SRL (n = 9) groups. All rats were sacrificed for histological examination immediately after and at 1 and 4 weeks after ETBD. Three rats were used to represent the normal ET. The SRL-coated ETBD significantly suppressed tissue proliferation caused by mechanical injuries compared with the control group. ETBD with SRL-coated balloon catheter was effective and safe to maintain ET luminal patency without tissue proliferation at the site of mechanical injuries for 4 weeks in a rat ET model.

Time-lapse imaging of morula compaction for selecting high-quality blastocysts: a retrospective cohort study.

PURPOSE: Before blastocyst development, embryos undergo morphological and metabolic changes crucial for their subsequent growth. This study aimed to investigate the relationship between morula compaction and blastocyst formation and the subsequent chromosomal status of the embryos. METHODS: This retrospective cohort study evaluated embryo development (n = 371) using time-lapse imaging; 94 blastocysts underwent preimplantation genetic testing for aneuploidy (PGT-A). RESULTS: The embryos were classified as fully (Group 1, n = 194) or partially (Group 2, n = 177) compacted. Group 1 had significantly higher proportions of good- and average-quality blastocysts than Group 2 (21.6% vs. 3.4%, p = 0.001; 47.9% vs. 26.6%, p = 0.001, respectively). The time from the morula stage to the beginning and completion of compaction and blastocyst formation was significantly shorter in Group 1 than in Group 2 (78.6 vs. 82.4 h, p = 0.001; 87.0 vs. 92.2 h, p = 0.001; 100.2 vs. 103.7 h, p = 0.017, respectively). Group 1 embryos had larger surface areas than Group 2 embryos at various time points following blastocyst formation. Group 1 blastocysts had significantly higher average expansion rates than Group 2 blastocysts (653.6 vs. 499.2 µm2/h, p = 0.001). PGT-A revealed a higher proportion of euploid embryos in Group 1 than in Group 2 (47.2% vs. 36.6%, p = 0.303). CONCLUSION: Time-lapse microscopy uncovered a positive relationship between compaction and blastocyst quality and its association with embryo ploidy. Hence, compaction evaluation should be prioritized before blastocyst selection for transfer or cryopreservation.

Repeated photodynamic therapy using a chlorin e6-embedded device to prolong the therapeutic effects on obesity.

OBJECTIVE: This study aimed to investigate the efficacy and safety of repeated photodynamic therapy (PDT) with a chlorin e6 (Ce6)-embedded intragastric satiety-inducing device (ISD) to maintain therapeutic effects of obesity in a juvenile pig. METHODS: The Ce6-embedded ISD was fabricated with a dipping method. Twelve pigs were divided into four groups of three and were administered control, single, biweekly, or weekly PDT, respectively. The therapeutic effects were assessed by comparing the results of phototoxicity, endoscopy, fluoroscopy, hormone and weight changes, and histological examination. RESULTS: The percentage of total body weight gain was significantly suppressed in PDT-treated pigs compared with control pigs (all p < 0.001). This suppression persisted in the repeated PDT groups, but percentage of total body weight gain gradually increased when PDT was stopped. Ghrelin levels in the PDT-treated groups were significantly lower and leptin levels were significantly higher than those in the control group (all p < 0.05). Inflammatory cell infiltration, collagen, TUNEL, and anti-ghrelin-positive deposition in the weekly group were significantly higher than those in the control, single, and biweekly groups (all p < 0.01). CONCLUSIONS: Repeated and periodic PDT was technically feasible and safe and successfully maintained the therapeutic effects against obesity while eliminating the indwelling time and reducing ISD-related complications in pigs.

Uncovering risk factors for adverse events and infections in rheumatoid arthritis and rheumatoid arthritis with interstitial lung disease under treatment with biologics or targeted synthetic DMARDs: insights from the KOBIO Registry.

OBJECTIVES: This study aimed to identify the risk factors associated with overall adverse events (AEs) and infections in patients with rheumatoid arthritis (RA) and comorbid interstitial lung disease (ILD), receiving biologic or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs), using data from the Korean College of Rheumatology Biologics registry. METHODS: We analysed data from a cohort of 2,266 adult patients with RA who received b/tsDMARDs, including 169 patients with comorbid ILD. We identified the risk factors for overall AEs and infections in both the all RA group and the subgroup of patients with RA-ILD and investigated the impact of infections on mortality in patients with RA-ILD. RESULTS: Among all patients with RA, 45.7% withdrew b/tsDMARDs, whereas among those with RA-ILD, a higher proportion of 57.4% withdrew their treatment regimen. The main reason for withdrawing b/tsDMARDs in the RA-ILD group was AEs, with infections accounting for the largest proportion of reported AEs. In multivariable analysis of the risk factors for overall AEs and infections in the RA-ILD group, older age was identified as a risk factor for overall AEs (odds ratio [OR], 3.01; p=0.014), and only a current smoking status was identified as a risk factor for infections (OR, 2.11; p=0.035). CONCLUSIONS: Patients with RA-ILD exhibited a higher rate of b/tsDMARDs withdrawal due to overall AEs and infections than those with RA without ILD. In the RA-ILD group, older age was identified as a risk factor for overall AEs, whereas a current smoking status was identified as a risk factor for infections.

Risk of cardiovascular disease with high-dose versus low-dose use of non-steroidal anti-inflammatory drugs in ankylosing spondylitis.

OBJECTIVE: To investigate the risk of cardiovascular disease (CVD) associated with increasing dose of a non-steroidal anti-inflammatory drug (NSAID) in patients with ankylosing spondylitis (AS). METHODS: Using the Korean National Health Insurance database, patients newly diagnosed with AS without prior CVD between 2010 and 2018 were included in this nationwide cohort study. The primary outcome was CVD, a composite outcome of ischaemic heart disease, stroke or congestive heart failure. Exposure to NSAIDs was evaluated using a time-varying approach. The dose of NSAIDs was considered in each exposure period. Cox proportional hazard regression was used to investigate the risk of CVD associated with NSAID use. RESULTS: Of the 19 775 patients (mean age, 36 years; 75% were male), 19 706 received NSAID treatment. During follow-up period of 98 290 person-years, 1663 cases of CVD occurred including 1157 cases of ischaemic heart disease, 301 cases of stroke and 613 cases of congestive heart failure. Increasing dose of NSAIDs was associated with incident CVD after adjusting for confounders (adjusted HR (aHR) 1.10; 95% CI 1.08 to 1.13). Specifically, increasing dose of NSAIDs was associated with incident ischaemic heart disease (aHR 1.08; 95% CI 1.05 to 1.11), stroke (aHR 1.09; 95% CI 1.04 to 1.15) and congestive heart failure (aHR 1.12; 95% CI 1.08 to 1.16). The association between NSAID dose and higher CVD risk was consistent in different subgroups. CONCLUSION: In a real-world AS cohort, higher dose of NSAID treatment was associated with a higher risk of CVD, including ischaemic heart disease, stroke and congestive heart failure.

Novel self-expandable stent-based endobiliary radiofrequency ablation for unresectable malignant biliary obstruction.

BACKGROUND AND AIMS: Endobiliary radiofrequency ablation (RFA) is an emerging endoscopic palliative adjunctive therapy used for the local treatment of unresectable malignant biliary obstruction (MBO). However, irregular ablation ranges caused by insufficient electrode-to-bile duct contact pose a significant obstacle. The aim was to investigate the feasibility of a self-expandable stent (SES)-based electrode with a customized RFA generator in the porcine liver and common bile duct (CBD). METHODS: A SES-RFA system with polarity-switching was developed to perform endobiliary RFA. The ablation ranges of 20 ablation protocols were evaluated to validate the feasibility of the newly developed RFA system in the porcine liver. Nine of the 20 ablation protocols were selected for evaluation in the porcine CBD with cholangiography, endoscopy, and histological and immunohistochemical analysis. RESULTS: The SES-RFA system with polarity-switching was successfully constructed and demonstrated high accuracy and reproducibility. The ablation area was clearly identified between the two SESs. The ablation ranges and degree of mucosal damage including TUNEL- and HSP70-positive depositions increased proportionally with ablation protocols in the porcine liver and CBD (all P < .05). Ablation length and depth linearly increased with ablation protocols from 8.74 ± 0.25 to 31.25 ± 0.67 mm and 1.61 ± 0.09 to 11.94 ± 0.44 mm, respectively. CONCLUSIONS: The SES-RFA system with polarity-switching between electrodes provided an even circumferential area of ablation and enhanced ablation depth between the electrodes. This novel endobiliary RFA system is a promising modality for local ablation in patients with unresectable MBO.

3D-printed versatile biliary stents with nanoengineered surface for anti-hyperplasia and antibiofilm formation.

Biliary strictures are characterized by the narrowing of the bile duct lumen, usually caused by surgical biliary injury, cancer, inflammation, and scarring from gallstones. Endoscopic stent placement is a well-established method for the management of biliary strictures. However, maintaining optimal mechanical properties of stents and designing surfaces that can prevent stent-induced tissue hyperplasia and biofilm formation are challenges in the fabrication of biodegradable biliary stents (BBSs) for customized treatment. This study proposes a novel approach to fabricating functionalized polymer BBSs with nanoengineered surfaces using 3D printing. The 3D printed stents, fabricated from bioactive silica poly(ε-carprolactone) (PCL) via a sol-gel method, exhibited tunable mechanical properties suitable for supporting the bile duct while ensuring biocompatibility. Furthermore, a nanoengineered surface layer was successfully created on a sirolimus (SRL)-coated functionalized PCL (fPCL) stent using Zn ion sputtering-based plasma immersion ion implantation (S-PIII) treatment to enhance the performance of the stent. The nanoengineered surface of the SRL-coated fPCL stent effectively reduced bacterial responses and remarkably inhibited fibroblast proliferation and initial burst release of SRL in vitro systems. The physicochemical properties and biological behaviors, including in vitro biocompatibility and in vivo therapeutic efficacy in the rabbit bile duct, of the Zn-SRL@fPCL stent demonstrated its potential as a versatile platform for clinical applications in bile duct tissue engineering.

COVID-19 (SARS-CoV-2) mRNA vaccination does not affect basal sex hormone levels (follicle-stimulating hormone, luteinizing hormone, estradiol) in reproductive-age women.

Objective: People vaccinated with the coronavirus disease 2019 (COVID-19) (severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2]) mRNA vaccine have reported experiencing various adverse effects. For instance, reproductive-age women have presented with complaints of abnormal uterine bleeding or menstrual cycle changes. We speculated that differences in basal sex hormone levels before and after vaccination may be present in women who experienced irregular bleeding or menstrual cycle changes; thus, this study aimed to investigate the differences in basal sex hormone levels of women before and after two doses of SARS-CoV-2 mRNA vaccination. Methods: This retrospective study included patients who received SARS-CoV-2 mRNA vaccines between January 2021 and February 2022 at a single center. In an outpatient setting, patients were queried regarding their menstrual cycle, the date of SARS-CoV-2 mRNA vaccination, vaccination type, and vaccination side effects. Differences in basal hormone levels (menstrual cycle days 2-3, follicle-stimulating hormone [FSH], luteinizing hormone [LH], and estradiol) before and after vaccination were compared. Results: Among the 326 patients, patients with no laboratory records of the hormones were excluded. The median time interval between SARS-CoV-2 mRNA vaccination and the laboratory test day was 79 days (interquartile range, 44 to 127). A comparative analysis of these hormones before and after vaccination revealed no significant differences. Subgroup analyses based on age and reported adverse events also found no statistically significant differences. Conclusion: This study showed no significant differences in basal hormone levels (FSH, LH, and estradiol) before and after SARS-CoV-2 mRNA vaccination.

Sex differences in associated factors for age-related hearing loss.

The prevalence and age of onset of hearing loss differ according to sex. This study aimed to identify associated factors for age-related hearing loss (ARHL) and determine whether there are differences between males and females regarding associated factors for ARHL. This cross-sectional study used data from adults who underwent medical examinations including hearing tests from 2011 to 2021. A total of 2,349 individuals were included. The study conducted sex-specific analyses using both univariate and multiple regression. Univariate analysis employed logistic regression, while multiple regression involved variable selection through the augmented backward elimination method. Separate multiple logistic regression analyses were conducted for each sex. In the univariate analysis, among males, age, underweight, alcohol consumption, weight, and height exhibited statistical significance. Among females, age, hypertension, diabetes, dyslipidemia, obesity, sarcopenia, weight, height, age at menarche, and duration of hormone exposure were found to be significant factors. However, in the multiple logistic regression model for males, underweight, and smoking emerged as significant, while in females, age, weight, obesity, and age at menarche retained their significance. We found that there are different associated factors for ARHL in each sex. Assessment and counseling for smoking, obstetric history, underweight, and obesity may be beneficial in managing patients with ARHL.

Efficacy of an assistive guide tube for improved endoscopic access to gastrointestinal lesions: an in vivo study in a porcine model.

BACKGROUND/AIMS: Guide tube-assisted endoscopy for procedures that require repeated endoscopic access is safer and more effective than conventional endoscopy. However, its effectiveness has not been confirmed in animal studies. We assessed the usefulness of guide tube-assisted endoscopic procedures in an in vivo porcine model. METHODS: Five different guide tube-assisted endoscopic procedures were performed by experienced endoscopists on a pig weighing 32 kg. To evaluate the efficacy of these procedures, we compared the endoscopic approach time when a guide tube was used to that when it was not. Additional endoscopic procedures using a guide tube were performed, including multiple foreign body extractions, multiple polypectomies, and multiple submucosal dissections. To evaluate safety, we compared the insertion force into the proximal esophagus between the guide tube and conventional overtube methods. RESULTS: Using the endoscopic approach with a guide tube required a shorter average approach time to reach the three target lesions than when using the endoscopic approach without a guide tube (p<0.001). Compared to the conventional overtube method, the guide tube method produced a lower average resistance during insertion into the upper esophagus (p<0.001). CONCLUSION: Guide tube-assisted endoscopic procedures are effective and safe for repeated endoscopic access in an in vivo porcine model.

Beauvericin, produced by Fusarium oxysporum inhibits bisphenol A-induced proliferation of human breast cancer cell line by regulating ERα/p38 pathway.

Beauvericin (BEA) is a cyclic depsipeptide secondary metabolite of Fusarium species. It causes chemical hazards in food products and exists in an environment containing soil and various food types. On the other hand, the purified BEA has various biological activities and is regarded as a potential candidate for pharmaceutical research. This study was performed to assess the anti-proliferation activity of BEA against human breast cancer cells by regulating the estrogen receptor-alpha (ERα)/p38 pathway. TA and BA assays verified that BEA is a completed ER antagonist. Additionally, BEA suppressed cell proliferation in the anti-proliferation assay involving ER-positive human breast cancer cells co-treated with BPA and BEA. In respect to an anti-proliferation activity, the BPA-induced phosphorylation of p38 protein was inhibited in the presence of BEA. These results suggested that BEA exerts inhibitory potentials on endocrine disrupting effect and possibly acts as a natural therapeutic material for human estrogen hormonal health.

Patient preference, efficacy, and compliance with zoledronic acid for glucocorticoid-induced osteoporosis in patients with autoimmune diseases.

PURPOSE: We evaluated the preference, patient satisfaction, and efficacy of zoledronic acid compared with oral bisphosphonates (BPs) for glucocorticoid-induced osteoporosis (GIOP) in patients with autoimmune diseases. METHODS: We enrolled 50 patients with new fractures or osteoporosis detected on follow-up bone densitometry after at least 1 year of oral BP use among patients diagnosed with GIOP during treatment for autoimmune diseases. After 1 year of zoledronic acid treatment, patients completed a survey for preference and satisfaction assessment. Treatment efficacy was analysed by comparing bone mineral density changes and fractures with those in a control group of patients who continued oral BP use. RESULTS: Age, sex, treatment duration, and medication history did not differ significantly between the two groups. Among the participants, 86.7% preferred and were more satisfied with intravenous zoledronic acid than with oral BPs, primarily because of the convenience of its administration interval. Only two patients (4%) reported infusion-related adverse events with zoledronic acid. Furthermore, no significant differences were observed in the annualized percentage change in the bone mineral density of the lumbar spine, femur neck, and hip between patients receiving zoledronic acid and those receiving oral BPs. The occurrence of new fractures was consistent across both groups, with two cases in each, showing no significant differences. CONCLUSION: Patients showed a preference for and greater satisfaction with zoledronic acid, and its efficacy in treating osteoporosis was comparable to that of oral BPs. Therefore, zoledronic acid is a suitable treatment option for GIOP in patients with autoimmune diseases.

Preoperative Hindfoot Alignment and Outcomes After High Tibial Osteotomy for Varus Knee Osteoarthritis: We Walk on Our Heel, Not Our Ankle.

UPDATE: This article was updated on May 15, 2024 because of previous errors, which were discovered after the preliminary version of the article was posted online. On page 898, in the section entitled "Materials and Methods," the sentence that had read "The WBL ratio of the knee joint was defined as the point where the GA or MA passed through the width of the tibia and intersected a line from the center of the femoral head to the center of the calcaneus (for the GA) or talus (for the MA), with the medial edge defined as 0% and the lateral edge as 100%." now reads "The WBL ratio of the knee joint was defined as the point where the GA or MA passed through the width of the tibia and intersected a line from the center of the femoral head to the lowest point of the calcaneus (for the GA) or the center of the talus (for the MA), with the medial edge defined as 0% and the lateral edge as 100%." Likewise, in the legend for Figure 3 on page 899, the sentence that had read "Depiction of the ground mechanical axis (GA), defined as the line (represented by the solid red line) from the center of the femoral head to the ground reaction point at the center of the calcaneus, passing lateral to the traditional mechanical axis (MA; represented by the dashed red line)." now reads "Depiction of the ground mechanical axis (GA), defined as the line (represented by the solid red line) from the center of the femoral head to the ground reaction point at the lowest point of the calcaneus, passing lateral to the traditional mechanical axis (MA; represented by the dashed red line)." Finally, on page 903, "HKA" was changed to "HKA angle" in Table III. BACKGROUND: The hip-to-calcaneus axis, previously known as the ground mechanical axis (GA), ideally passes through the center of the knee joint in the native knee. The aim of this study was to elucidate, with use of hip-to-calcaneus radiographs, changes in knee and hindfoot alignment and changes in outcomes following high tibial osteotomy (HTO). METHODS: We reviewed the records for 128 patients who underwent HTO between 2018 and 2020. Patients were stratified into 2 groups, a hindfoot valgus group (n = 94) and a hindfoot varus group (n = 34), on the basis of their preoperative hindfoot alignment. The hindfoot alignment was evaluated with use of the hindfoot alignment angle (HAA). To evaluate lower-limb alignment, full-length standing posteroanterior hip-to-calcaneus radiographs were utilized to measure 4 radiographic parameters preoperatively and 2 years postoperatively: the hip-knee-ankle (HKA) angle, hip-knee-calcaneus (HKC) angle, and the weight-bearing line (WBL) ratios of the mechanical axis (MA) and GA. RESULTS: The mean HAA improved significantly from 5.1° valgus preoperatively to 1.9° valgus postoperatively in the hindfoot valgus group (p < 0.001). In contrast, in the hindfoot varus group, the HAA showed no meaningful improvement in the coronal alignment of the hindfoot following HTO (p = 0.236). The postoperative mean HKC angle in the hindfoot varus group was 2° more varus than that in the hindfoot valgus group (1.0° versus 3.0°; p = 0.001), and the GA in the hindfoot varus group passed across the knee 8.0% more medially than that in the hindfoot valgus group (55% versus 63% from the most medial to the most lateral part of the tibial plateau). The hindfoot varus group had worse postoperative clinical outcomes than the hindfoot valgus group in terms of the mean Knee injury and Osteoarthritis Outcome Score for pain and American Orthopaedic Foot & Ankle Society Ankle-Hindfoot Score. CONCLUSIONS: Although our findings did not provide sufficient evidence to establish clinically relevant differences between the groups, they indicated that the group with a preoperative fixed hindfoot varus deformity had a higher rate of undercorrection and worse clinical outcomes, especially pain, following HTO. Therefore, modification of the procedure to shift the GA more laterally may be required for these patients. LEVEL OF EVIDENCE: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Sex-dependent different clinicopathological characterization of Epstein-Barr virus-associated gastric carcinoma: a large-scale study.

BACKGROUND: Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) has been reported to account for approximately 5-16% of all GCs with good prognosis compared to EBV-negative GC. We evaluated the clinicopathological characteristics of EBVaGC including survival rate in South Korea. METHODS: A total of 4,587 patients with GC who underwent EBV in situ hybridization (EBV-ISH) were prospectively enrolled at the Seoul National University Bundang Hospital from 2003 to 2021. Age, sex, smoking status, cancer type and stage, tumor size and location, histological type, molecular features and survival information were analyzed. RESULTS: A total of 456 patients with GC (9.9%) were positive for EBV. The EBVaGC group displayed a higher proportion of males (P < 0.001), a predominant presence in the proximal stomach (P < 0.001), a higher proportion of undifferentiated cancer (P < 0.001), and a lower cancer stage (P = 0.004) than the EBV-negative group. Cox multivariate analyses revealed age (hazard ratio [HR] = 1.025, P < 0.001), tumor size (HR = 1.109, P < 0.001), and cancer stage (stage2 HR = 4.761, P < 0.001; stage3 HR = 13.286, P < 0.001; stage4 HR = 42.528, P < 0.001) as significant risk factors for GC-specific mortality, whereas EBV positivity was inversely correlated (HR = 0.620, P = 0.022). Furthermore, the EBVaGC group displayed statistically significant survival advantages over the EBV-negative cancer group in terms of both overall (P = 0.021) and GC-specific survival (P = 0.007) on the Kaplan-Meier survival curve. However, this effect was evident only in males. CONCLUSIONS: EBVaGC patients showed better prognoses despite their association with proximal location and poorly differentiated histology in male, probably due to the difference in immunity between males and females.

Localized Photodynamic Therapy Using a Chlorin e6-Embedded Silicone-Covered Self-Expandable Metallic Stent as a Palliative Treatment for Malignant Esophageal Strictures.

Localized photodynamic therapy (PDT) uses a polymeric-photosensitizer (PS)-embedded, covered self-expandable metallic stent (SEMS). PDT is minimally invasive and a noteworthy potential alternative for treating esophageal strictures, where surgery is not a viable option. However, preclinical evidence is insufficient, and optimized irradiation energy dose ranges for localized PDT are unclear. Herein, we validated the irradiation energy doses of the SEMS (embedded in a PS using chlorin e6 [Ce6] and covered in silicone) and PDT-induced tissue changes in a rat esophagus. Cytotoxicity and phototoxicity in the Ce6-embedded SEMS piece with laser irradiation were significantly higher than that of the silicone-covered SEMS with or without laser and the Ce6-embedded silicone-covered SEMS without laser groups (all p < 0.001). Moreover, surface morphology, atomic changes, and homogeneous coverage of the Ce6-embedded silicone-covered membrane were confirmed. The ablation range of the porcine liver was proportionally increased with the irradiation dose (all p < 0.001). The ablation region was identified at different irradiation energy doses of 50, 100, 200, and 400 J/cm2. The in vivo study in the rat esophagus comprised a control group and 100, 200, and 400 J/cm2 energy-dose groups. Finally, histology and immunohistochemistry (TUNEL and Ki67) confirmed that the optimized Ce6-embedded silicone-covered SEMS with selected irradiation energy doses (200 and 400 J/cm2) effectively damaged the esophageal tissue without ductal perforation. The polymeric PS-embedded silicone-covered SEMS can be easily placed via a minimally invasive approach and represents a promising new approach for the palliative treatment of malignant esophageal strictures.

Risk of cardiovascular disease associated with long-term use of non-steroidal anti-inflammatory drugs in ankylosing spondylitis.

OBJECTIVE: To examine the risk of cardiovascular disease associated with long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) in a large real-world ankylosing spondylitis (AS) cohort. METHODS: This nationwide population-based cohort study used data from the Korean National Health Insurance Database. Patients aged ≥18 years old who were newly diagnosed with AS without prior cardiovascular disease between January 2010 and December 2018 were included in this study. Controls without AS were randomly selected by age, sex, and index year. The primary outcome was cardiovascular disease, a composite outcome of ischemic heart disease, stroke, or congestive heart failure. Long-term use of NSAIDs was defined as use of NSAIDs for >365 cumulative defined daily doses. The association between long-term use of NSAIDs and incident cardiovascular disease was examined in both AS and non-AS populations. RESULTS: Among 19 775 patients with AS and 59 325 matched controls without AS, there were 1,663 and 4,308 incident cases of cardiovascular disease, showing an incidence of 16.9 and 13.8 per 1,000 person-years, respectively. Long-term use of NSAIDs was associated with increased risk of cardiovascular disease in non-AS controls (adjusted hazard ratio [aHR], 1.64; 95% CI, 1.48-1.82). In contrast, long-term use of NSAIDs did not increase the risk of cardiovascular disease in AS patients (aHR, 1.06; 95% CI, 0.94-1.20; adjusted for age, sex, socioeconomic status, body mass index, smoking status, hypertension, diabetes, hyperlipidemia, and tumor necrosis factor inhibitor use). CONCLUSION: Prolonged NSAID treatment in AS patients may not be as harmful as in the general population regarding cardiovascular risk.

Therapeutic strategy using novel RET/YES1 dual-target inhibitor in lung cancer.

Lung cancer represents a significant global health concern and stands as the leading cause of cancer-related mortality worldwide. The identification of specific genomic alterations such as EGFR and KRAS in lung cancer has paved the way for the development of targeted therapies. While targeted therapies for lung cancer exhibiting EGFR, MET and ALK mutations have been well-established, the options for RET mutations remain limited. Importantly, RET mutations have been found to be mutually exclusive from other genomic mutations and to be related with high incidences of brain metastasis. Given these facts, it is imperative to explore the development of RET-targeting therapies and to elucidate the mechanisms underlying metastasis in RET-expressing lung cancer cells. In this study, we investigated PLM-101, a novel dual-target inhibitor of RET/YES1, which exhibits notable anti-cancer activities against CCDC6-RET-positive cancer cells and anti-metastatic effects against YES1-positive cancer cells. Our findings shed light on the significance of the YES1-Cortactin-actin remodeling pathway in the metastasis of lung cancer cells, establishing YES1 as a promising target for suppression of metastasis. This paper unveils a novel inhibitor that effectively targets both RET and YES1, thereby demonstrating its potential to impede the growth and metastasis of RET rearrangement lung cancer.

Analysis of Characteristics and Risk Factors of Patients with Single Gastric Cancer and Synchronous Multiple Gastric Cancer among 14,603 Patients.

Background/Aims: Synchronous multiple gastric cancer (SMGC) accounts for approximately 6% to 14% of gastric cancer (GC) cases. This study aimed to identify risk factors for SMGC. Methods: A total of 14,603 patients diagnosed with GC were prospectively enrolled. Data including age, sex, body mass index, smoking, alcohol consumption, family history, p53 expression, microsatellite instability, cancer classification, lymph node metastasis, and treatment were collected. Risk factors were analyzed using logistic regression analysis between a single GC and SMGC. Results: The incidence of SMGC was 4.04%, and that of early GC (EGC) and advanced GC (AGC) was 5.43% and 3.11%, respectively. Patients with SMGC were older (65.33 years vs 61.75 years, p<0.001) and more likely to be male. Lymph node metastasis was found in 27% of patients with SMGC and 32% of patients with single GC. Multivariate analysis showed that SMGC was associated with sex (male odds ratio [OR], 1.669; 95% confidence interval [CI], 1.223 to 2.278; p=0.001), age (≥65 years OR, 1.532; 95% CI, 1.169 to 2.008; p=0.002), and EGC (OR, 1.929; 95% CI, 1.432 to 2.600; p<0.001). Survival rates were affected by Lauren classification, sex, tumor size, cancer type, distant metastasis, and venous invasion but were not related to the number of GCs. However, the survival rate of AGC with SMGC was very high. Conclusions: SMGC had unique characteristics such as male sex, older age, and EGC, and the survival rate of AGC, in which the intestinal type was much more frequent, was very good (Trial registration number: NCT04973631).