TFE3/PI3K/Akt/mTOR Axis in Renal Cell Carcinoma Affects Tumor Microenvironment.

The role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in renal cell carcinoma (RCC) progression, metastasis, and resistance to therapies has not been investigated thoroughly. Transcription factor E3 (TFE3) expression is related to a poorer prognosis and tumor microenvironment in patients with RCC. This study aimed to determine the relationship between TFE3 and the PI3K/Akt pathway. TFE3 down-regulation was achieved by transient transfection of siRNA and shRNA in UOK146 cells. TFE3 overexpression was induced by transient transfection with pcDNA3.1 encoding the constitutively active form of TFE3. The cells were treated with mammalian target of rapamycin (mTOR) and PI3K inhibitors. Western blot was performed to detect TFE3, programmed death-ligand 1, phospho-Akt, and Akt. Phospho-Akt expression increased significantly upon TFE3 down-regulation, and decreased significantly upon up-regulation. When RCC cells were treated with a PI3K inhibitor (LY294002), TFE3 expression increased and phospho-Akt expression decreased. Data from this study indicate that TFE3 plays a role in the PI3K/Akt pathway in RCC. The results of this study suggest that PI3K/Akt inhibitors may aid in the treatment of patients with RCC by affecting the tumor microenvironment.

Timing of fractional flow reserve-guided complete revascularization in patients with ST-segment elevation myocardial infarction with multivessel disease: Rationale and design of the OPTION-STEMI trial.

BACKGROUND: Current guidelines recommend complete revascularization (CR) in hemodynamically stable patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease (MVD). With regard to the timing of percutaneous coronary intervention (PCI) for non-infarct-related artery (non-IRA), recent randomized clinical trials have revealed that immediate CR was non-inferior to staged CR. However, the optimal timing of CR remains uncertain. The OPTION-STEMI trial compared immediate CR and in-hospital staged CR guided by fractional flow reserve (FFR) for intermediate stenosis of the non-IRA. METHODS: The OPTION-STEMI is a multicenter, investigator-initiated, prospective, open-label, non-inferiority randomized clinical trial. The study included patients with at least 1 non-IRA lesion with ≥50% stenosis by visual estimation. Patients fulfilling the inclusion criteria were randomized into 2 groups at a 1:1 ratio: immediate CR (i.e., PCI for the non-IRA performed during primary angioplasty) or in-hospital staged CR. In the in-hospital staged CR group, PCI for non-IRA lesions was performed on another day during the index hospitalization. Non-IRA lesions with 50%-69% stenosis by visual estimation were evaluated by FFR, whereas those with ≥70% stenosis was revascularized without FFR. The primary endpoint was the composite of all-cause death, non-fatal myocardial infarction, and all unplanned revascularization at 1 year after randomization. Enrolment began in December 2019 and was completed in January 2024. The follow-up for the primary endpoint will be completed in January 2025, and primary results will be available in the middle of 2025. CONCLUSIONS: The OPTION-STEMI is a multicenter, non-inferiority, randomized trial that evaluated the timing of in-hospital CR with the aid of FFR in patients with STEMI and MVD. TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov. Unique identifier: NCT04626882; and URL: https://cris.nih.go.kr. Unique identifier: KCT0004457.

The relationship between tumor-infiltrating neutrophils and clinical outcomes in patients with resectable hepatocellular carcinoma.

BACKGROUND: The impact of tumor-infiltrating neutrophils (TINs) on clinical outcomes has been reported in various cancer types, but their role in hepatocellular carcinoma (HCC) has not been fully evaluated. The aim of this study was to investigate the prognostic values for TINs in HCC patients undergoing curative resection. METHODS: We assessed immune markers (CD3, CD4, CD8, CD66b) using immunohistochemistry in 115 patients who underwent curative resection for HCC. We analyzed the prognostic values for tumor-infiltrating immune cells, including neutrophils, and other clinicopathological factors. RESULTS: In the Multivariate Cox analysis of overall survival (OS), alpha-fetoprotein (AFP) ≥ 100 ng/mL (hazard ratio (HR), 2.74, 95% confidence interval (CI), 1.17-6.44; P = 0.021) and Barcelona Clinic Liver Cancer (BCLC) B/C stage (HR, 3.98, 95% CI, 1.68-9.43; P = 0.020) were found to be independent poor prognostic factors in HCC patients undergoing resection. The presence of CD66b+TINs was observed in 66 (57.4%) patients. However, CD66b+TINs were not associated with recurrence-free survival and OS. CONCLUSIONS: Our study identified low CD66b+TINs in resectable HCC, and CD66b+ TINs did not have a significant role for the clinical outcomes of patients undergoing curative resection. The results suggest that TINs may play a role in more advanced stages of HCC.

Transradial Versus Transfemoral Access for Bifurcation Percutaneous Coronary Intervention Using Second-Generation Drug-Eluting Stent.

BACKGROUND: The benefits of transradial access (TRA) over transfemoral access (TFA) for bifurcation percutaneous coronary intervention (PCI) are uncertain because of the limited availability of device selection. This study aimed to compare the procedural differences and the in-hospital and long-term outcomes of TRA and TFA for bifurcation PCI using second-generation drug-eluting stents (DESs). METHODS: Based on data from the Coronary Bifurcation Stenting Registry III, a retrospective registry of 2,648 patients undergoing bifurcation PCI with second-generation DES from 21 centers in South Korea, patients were categorized into the TRA group (n = 1,507) or the TFA group (n = 1,141). After propensity score matching (PSM), procedural differences, in-hospital outcomes, and device-oriented composite outcomes (DOCOs; a composite of cardiac death, target vessel-related myocardial infarction, and target lesion revascularization) were compared between the two groups (772 matched patients each group). RESULTS: Despite well-balanced baseline clinical and lesion characteristics after PSM, the use of the two-stent strategy (14.2% vs. 23.7%, P = 0.001) and the incidence of in-hospital adverse outcomes, primarily driven by access site complications (2.2% vs. 4.4%, P = 0.015), were significantly lower in the TRA group than in the TFA group. At the 5-year follow-up, the incidence of DOCOs was similar between the groups (6.3% vs. 7.1%, P = 0.639). CONCLUSION: The findings suggested that TRA may be safer than TFA for bifurcation PCI using second-generation DESs. Despite differences in treatment strategy, TRA was associated with similar long-term clinical outcomes as those of TFA. Therefore, TRA might be the preferred access for bifurcation PCI using second-generation DES. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03068494.

Automated Pavement Condition Index Assessment with Deep Learning and Image Analysis: An End-to-End Approach.

The degradation of road pavements due to environmental factors is a pressing issue in infrastructure maintenance, necessitating precise identification of pavement distresses. The pavement condition index (PCI) serves as a critical metric for evaluating pavement conditions, essential for effective budget allocation and performance tracking. Traditional manual PCI assessment methods are limited by labor intensity, subjectivity, and susceptibility to human error. Addressing these challenges, this paper presents a novel, end-to-end automated method for PCI calculation, integrating deep learning and image processing technologies. The first stage employs a deep learning algorithm for accurate detection of pavement cracks, followed by the application of a segmentation-based skeleton algorithm in image processing to estimate crack width precisely. This integrated approach enhances the assessment process, providing a more comprehensive evaluation of pavement integrity. The validation results demonstrate a 95% accuracy in crack detection and 90% accuracy in crack width estimation. Leveraging these results, the automated PCI rating is achieved, aligned with standards, showcasing significant improvements in the efficiency and reliability of PCI evaluations. This method offers advancements in pavement maintenance strategies and potential applications in broader road infrastructure management.

Impact of Neoadjuvant Chemotherapy (NAC) on Biomarker Expression in Breast Cancer.

Background and Objectives: This study aimed to explore biomarker change after NAC (neoadjuvant chemotherapy) and to investigate biomarker expression as a prognostic factor in patients with residual disease (RD) after NAC. Materials and Methods: We retrospectively evaluated 104 patients with invasive breast cancer, who underwent NAC and surgery at Pusan National University Hospital from 2015 to July 2022. The expression of the biomarker was assessed, and the overall survival (OS) and disease-free survival (DFS) were investigated. Results: After NAC, 24 patients (23.1%) out of 104 total patients had a pathological complete response (pCR). We found that changes in at least one biomarker were observed in 41 patients (51.2%), among 80 patients with RD. In patients with RD after NAC (n = 80), a subtype change was identified in 20 patients (25.0%). Any kind of change in the HER2 status was present 19 (23.7%) patients. The hormone receptor (HR)+/HER2+ subtype was significantly associated with better disease-free survival (DFS) (HR, 0.13; 95% CI, 0.02-0.99; p = 0.049). No change in p53 was associated with better DFS, and negative-to-positive change in p53 expression after NAC was correlated with worse DFS (p < 0.001). Negative-to-positive change in p53 was an independent, worse DFS factor in the multivariate analysis (HR,18.44; 95% CI, 1.86-182.97; p = 0.013). Conclusions: Biomarker change and subtype change after NAC were not infrequent, which can affect the further treatment strategy after surgery. The expression change of p53 might have a prognostic role. Overall, we suggest that the re-evaluation of biomarkers after NAC can provide a prognostic role and is needed for the best decision to be made on further treatment.

Ginsenosides Decrease ß-Amyloid Production via Potentiating Capacitative Calcium Entry.

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder characterized by extracellular amyloid plaques composed of amyloid ß-peptide (Aß). Studies have indicated that Ca2+ dysregulation is involved in AD pathology. It is reported that decreased capacitative Ca2+ entry (CCE), a refilling mechanism of intracellular Ca2+, resulting in increased Aß production. In contrast, constitutive activation of CCE could decrease Aß production. Panax ginseng Meyer is known to enhance memory and cognitive functions in healthy human subjects. We have previously reported that some ginsenosides decrease Aß levels in cultured primary neurons and AD mouse model brains. However, mechanisms involved in the Aß-lowering effect of ginsenosides remain unclear. In this study, we investigated the relationship between CCE and Aß production by examining the effects of various ginsenosides on CCE levels. Aß-lowering ginsenosides such as Rk1, Rg5, and Rg3 potentiated CCE. In contrast, ginsenosides without Aß-lowering effects (Re and Rb2) failed to potentiate CCE. The potentiating effect of ginsenosides on CCE was inhibited by the presence of 2-aminoethoxydipherryl borate (2APB), an inhibitor of CCE. 2APB alone increased Aß42 production. Furthermore, the presence of 2APB prevented the effects of ginsenosides on Aß42 production. Our results indicate that ginsenosides decrease Aß production via potentiating CCE levels, confirming a close relationship between CCE levels and Aß production. Since CCE levels are closely related to Aß production, modulating CCE could be a novel target for AD therapeutics.

Surgical Outcomes of Extensive Dome-Like Laminoplasty Using En Bloc Resection of C2 Inner Lamina for Patients With Severe Cord Compression Behind C2 Body.

STUDY DESIGN: A retrospective, single-center study. OBJECTIVE: The aim of this study is to evaluate the efficacy and safety of a newly developed extensive dome-like laminoplasty using en bloc resection of the C2 inner lamina in patients with severe cord compression behind the C2 body. SUMMARY OF BACKGROUND DATA: A surgery for severe cord compression behind C2 body is challenging for spinal surgeons. To date, there has been no established solution for severe cord compression behind the C2 body. MATERIALS AND METHODS: Patients with severe cord compression behind the C2 body who underwent posterior surgery consecutively were enrolled. Extensive dome-like laminoplasty that was newly developed was performed to remove en bloc removal of the C2 inner lamina were performed. Preoperative and postoperative canal diameters behind the C2 and mean removed area of the C2 inner lamina were measured using MRI and CT scan. Clinical and radiographic parameters were assessed preoperative and postoperative periods. In addition, perioperative complications were analyzed. RESULTS: A total of 36 patients underwent extensive dome-like laminoplasty and their diagnoses were ossification of the posterior longitudinal ligament (OPLL, 66.7%) and congenital stenosis with spondylosis (33.3%). The mean canal diameter behind the C2 increased from 9.85 (2.28) mm preoperatively to 19.91 (3.93) mm at the last follow-up ( P <0.001). Clinically, neck and arm visual analog scale, Japanese Orthopaedic Association score, and neck disability index significantly improved at postoperative 1 month ( P <0.05), and the scores were maintained until the last follow-up. No meaningful radiographic changes occurred after the surgeries. During the procedures, there were no particular complications, but one patient showed deteriorated myelopathic symptoms and underwent additional C1-C2 decompressive surgery. CONCLUSIONS: After extensive dome-like laminoplasty, surgical outcomes are satisfactory, and complications are rare. This technique may be a viable option for patients with severe cord compression behind the C2 body. LEVEL OF EVIDENCE: Level IV.

Effects of Minimally Invasive Lateral Lumbar Interbody Fusion with Accessory Rod Technique on Rod Fracture in Adult Spinal Deformity Surgery: Analysis of 239 Patients.

STUDY DESIGN: A retrospective study. OBJECTIVES: To analyze factors associated with rod fracture (RF) in adult spinal deformity (ASD), and to assess whether the accessory rod (AR) technique can reduce RF occurrence in deformity correction in the setting of minimally invasive lateral lumbar interbody fusion (LLIF). SUMMARY OF BACKGROUND DATA: Instrumentation failure is the most common reason for revision surgery in ASD. Several RF reduction methods have been introduced. However, there are insufficient studies on postoperative RF after deformity correction using minimally invasive LLIF. METHODS: This study included 239 patients (average age 71.4 y and a minimum 2-year follow up) with ASD who underwent long-segment fusion from T10 to sacrum with sacropelvic fixation. Patients were classified into the non-RF group and the RF group. After logistic regression analysis of the risk factors for RF, subgroup analyses were performed; pedicle subtraction osteotomy (PSO) with 2-rod (P2 group) versus PSO with 2-rod and AR (P4 group), and LLIF with 2-rod (L2 group) versus LLIF with 2-rod and AR (L4 group). RESULTS: RF occurred in 50 patients (21%) at an average of 25 months. RF occurred more frequently in patients who underwent PSO than in those who underwent LLIF (P=0.002), and the use of the AR technique was significantly higher in the non-RF group (P<0.05).Following logistic regression analysis, preoperative PI-LL mismatch, PSO, and the AR technique were associated with RF. In subgroup analyses, RF incidence was 65% (24/37 cases) of P2 group, 8% (4/51 cases) of P4 group, and 21% (22/105 cases) of L2 group. In the L4 group, there was no RF. CONCLUSION: Minimally invasive multilevel LLIF with the AR technique is capable of as much LL correction as conventional PSO and appears to be an effective method for reducing RF.

Ideal length of accessory rod for the prevention of rod fracture after pedicle subtraction osteotomy in adult spinal deformity: short or long?

OBJECTIVE: Pedicle subtraction osteotomy (PSO) is an effective surgical procedure for adult spinal deformity (ASD). However, the complexity of the procedure and its associated complications including rod fracture (RF) remain challenging issues. Among several RF reduction methods, the accessory rod (AR) is an important surgical technique. To date, knowledge about the ideal length and configuration of the AR is limited. This study aimed to assess the influence of the connection levels and configuration of the AR on RF occurrence in patients with ASD who underwent long level constructs and PSO. METHODS: The authors retrospectively selected 57 consecutive patients (mean age 70.6 years) who underwent deformity correction including PSO and the AR technique with a minimum 2-year follow-up. The patients were classified into a non-RF group (n = 49) and an RF group (n = 8). Along with analysis of patient and radiological factors in the 2 groups, comparative studies were performed including configuration of the AR (D shaped vs linear shaped) and the connection levels of AR (long AR [the lower end below S1-2] vs short AR [above L5-S1]). RESULTS: The overall rate of RF incidence was 14% (8/57 cases) at an average of 42.5 months (2 patients with unilateral RF and 6 with bilateral RF). RF occurred most commonly at the L4-5 level, below the lower end of the AR: 6 below the lower end of the AR and 2 at the PSO site. There were no significant differences in patient and radiological factors between the groups. Comparisons between the 2 groups indicated that more RFs occurred when the configuration of the AR was a linear shape (p = 0.016) and when the distal end of the AR was above L5-S1 (p = 0.025). CONCLUSIONS: In this study the authors found that the D-shaped configuration of the AR and lower end of the AR below S1-2 (i.e., long AR) could be preventive methods for reducing RF after deformity correction performed using PSO and the AR technique for ASD. Here, the authors have provided the first comprehensive outline for the AR technique. These findings could establish effective guidelines for spine surgeons.

Corner Osteotomy as the more Advanced Approach to Deformity Correction in Adult Spinal Deformity: A Retrospective Comparative Study Between Two Osteotomy Techniques.

STUDY DESIGN: A retrospective study. OBJECTIVE: To investigate the usefulness of corner osteotomy (CO) in patients with adult spinal deformity (ASD) by comparing with pedicle subtraction osteotomy (PSO) for lordosis correction. SUMMARY OF BACKGROUND DATA: PSO remains a valuable procedure for patients with ASD, but it has a limit to obtaining correction angles exceeding 45° in patients with a large pelvic incidence or with previous spinal fusion surgeries. Theoretically, CO can exceed the limitation of PSO and can achieve a wide range of correction angles. However, no study has analyzed the clinical data and usefulness of CO. METHODS: This study included 115 patients (mean age 71.1 y, mean follow-up period 78.9 mo) with ASD who underwent deformity correction using PSO or CO. Comparative analysis was performed on spinopelvic parameters including segmental angle (SA) around the osteotomy site, and clinical and surgical assessment between the PSO and corner groups. RESULTS: In the corner group, the postoperative SA (35° vs. -39.3°, P=0.004) and the degree of SA correction (34.8° vs. 39.7°, P=0.004) were greater, and a broader range of SA correction was also possible (18-51° vs. 18-61°). Although the operative time was longer in the corner group (316.8 min vs. 342.3 min, P=0.014), the estimated blood loss (EBL) was lower (2841.3 mL vs. 2465.4 mL, P=0.032). There was no difference in major complication rates, but the frequency of rod fracture (RF) was lower in the corner group (36/27 vs. 1/51, P<0.05). CONCLUSION: CO showed a greater SA correction and achieved a broader range of SA correction angles than PSO with no difference in the incidence of major complications. In addition, the EBL and the frequency of RF were lower. Based on these results, we expect that CO can serve as a promising surgical alternative to PSO for spinal deformity correction among patients with ASD.

P2Y12 Inhibitor Monotherapy vs Dual Antiplatelet Therapy After Deployment of a Drug-Eluting Stent: The SHARE Randomized Clinical Trial.

Importance: P2Y12 inhibitor monotherapy after dual antiplatelet therapy (DAPT; a P2Y12 inhibitor plus aspirin) for a brief duration has recently emerged as an attractive alternative for patients undergoing percutaneous coronary intervention (PCI) with a drug-eluting stent. Objective: To investigate whether P2Y12 inhibitor monotherapy after 3 months of DAPT was noninferior to 12 months of DAPT following PCI with a drug-eluting stent. Design, Setting, and Participants: The Short-Term Dual Antiplatelet Therapy After Deployment of Bioabsorbable Polymer Everolimus-Eluting Stent (SHARE) open-label, noninferiority randomized clinical trial was conducted from December 15, 2017, through December 14, 2020. Final 1-year clinical follow-up was completed in January 2022. This study was a multicenter trial that was conducted at 20 hospitals in South Korea. Patients who underwent successful PCI with bioabsorbable polymer everolimus-eluting stents were enrolled. Interventions: Patients were randomly assigned to receive P2Y12 inhibitor monotherapy after 3 months of DAPT (n = 694) or 12 months of DAPT (n = 693). Main Outcomes and Measures: The primary outcome was a net adverse clinical event, a composite of major bleeding (based on Bleeding Academic Research Consortium type 3 or type 5 bleeding) and major adverse cardiac and cerebrovascular events (cardiac death, myocardial infarction, stent thrombosis, stroke, or ischemia-driven target lesion revascularization) between 3 and 12 months after the index PCI. The major secondary outcomes were major adverse cardiac and cerebrovascular events and major bleeding. The noninferiority margin was 3.0%. Results: Of the total 1452 eligible patients, 65 patients were excluded before the 3-month follow-up, and 1387 patients (mean [SD] age, 63.0 [10.7] years; 1055 men [76.1%]) were assigned to P2Y12 inhibitor monotherapy (n = 694) or DAPT (n = 693). Between 3 and 12 months of follow-up, the primary outcome (using Kaplan-Meier estimates) occurred in 9 patients (1.7%) in the P2Y12 inhibitor monotherapy group and in 16 patients (2.6%) in the DAPT group (absolute difference, -0.93 [1-sided 95% CI, -2.64 to 0.77] percentage points; P < .001 for noninferiority). For the major secondary outcomes (using Kaplan-Meier estimates), major adverse cardiac and cerebrovascular events occurred in 8 patients (1.5%) in the P2Y12 inhibitor monotherapy group and in 12 patients (2.0%) in the DAPT group (absolute difference, -0.49 [95% CI, -2.07 to 1.09] percentage points; P = .54). Major bleeding occurred in 1 patient (0.2%) in the P2Y12 inhibitor monotherapy group and in 5 patients (0.8%) in the DAPT group (absolute difference, -0.60 [95% CI, -1.33 to 0.12] percentage points; P = .10). Conclusions and Relevance: In patients with coronary artery disease undergoing PCI with the latest generation of drug-eluting stents, P2Y12 inhibitor monotherapy after 3-month DAPT was not inferior to 12-month DAPT for net adverse clinical events. Considering the study population and lower-than-expected event rates, further research is required in other populations. Trial Registration: ClinicalTrials.gov Identifier: NCT03447379.

Discordance Between Angiographic Assessment and Fractional Flow Reserve or Intravascular Ultrasound in Intermediate Coronary Lesions: A Post-hoc Analysis of the FLAVOUR Trial.

BACKGROUND AND OBJECTIVES: Angiographic assessment of coronary stenosis severity using quantitative coronary angiography (QCA) is often inconsistent with that based on fractional flow reserve (FFR) or intravascular ultrasound (IVUS). We investigated the incidence of discrepancies between QCA and FFR or IVUS, and the outcomes of FFR- and IVUS-guided strategies in discordant coronary lesions. METHODS: This study was a post-hoc analysis of the FLAVOUR study. We used a QCA-derived diameter stenosis (DS) of 60% or greater, the highest tertile, to classify coronary lesions as concordant or discordant with FFR or IVUS criteria for percutaneous coronary intervention (PCI). The patient-oriented composite outcome (POCO) was defined as a composite of death, myocardial infarction, or revascularization at 24 months. RESULTS: The discordance rate between QCA and FFR or IVUS was 30.2% (n=551). The QCA-FFR discordance rate was numerically lower than the QCA-IVUS discordance rate (28.2% vs. 32.4%, p=0.050). In 200 patients with ≥60% DS, PCI was deferred according to negative FFR (n=141) and negative IVUS (n=59) (15.3% vs. 6.5%, p<0.001). The POCO incidence was comparable between the FFR- and IVUS-guided deferral strategies (5.9% vs. 3.4%, p=0.479). Conversely, 351 patients with DS <60% underwent PCI according to positive FFR (n=118) and positive IVUS (n=233) (12.8% vs. 25.9%, p<0.001). FFR- and IVUS-guided PCI did not differ in the incidence of POCO (9.5% vs. 6.5%, p=0.294). CONCLUSIONS: The proportion of QCA-FFR or IVUS discordance was approximately one third for intermediate coronary lesions. FFR- or IVUS-guided strategies for these lesions were comparable with respect to POCO at 24 months. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02673424.