Ezetimibe, Niemann-Pick C1 like 1 inhibitor, modulates hepatic phospholipid metabolism to alleviate fat accumulation.

Background: Ezetimibe, which lowers cholesterol by blocking the intestinal cholesterol transporter Niemann-Pick C1 like 1, is reported to reduce hepatic steatosis in humans and animals. Here, we demonstrate the changes in hepatic metabolites and lipids and explain the underlying mechanism of ezetimibe in hepatic steatosis. Methods: We fed Otsuka Long-Evans Tokushima Fatty (OLETF) rats a high-fat diet (60 kcal % fat) with or vehicle (control) or ezetimibe (10 mg kg-1) via stomach gavage for 12 weeks and performed comprehensive metabolomic and lipidomic profiling of liver tissue. We used rat liver tissues, HepG2 hepatoma cell lines, and siRNA to explore the underlying mechanism. Results: In OLETF rats on a high-fat diet, ezetimibe showed improvements in metabolic parameters and reduction in hepatic fat accumulation. The comprehensive metabolomic and lipidomic profiling revealed significant changes in phospholipids, particularly phosphatidylcholines (PC), and alterations in the fatty acyl-chain composition in hepatic PCs. Further analyses involving gene expression and triglyceride assessments in rat liver tissues, HepG2 hepatoma cell lines, and siRNA experiments unveiled that ezetimibe's mechanism involves the upregulation of key phospholipid biosynthesis genes, CTP:phosphocholine cytidylyltransferase alpha and phosphatidylethanolamine N-methyl-transferase, and the phospholipid remodeling gene lysophosphatidylcholine acyltransferase 3. Conclusion: This study demonstrate that ezetimibe improves metabolic parameters and reduces hepatic fat accumulation by influencing the composition and levels of phospholipids, specifically phosphatidylcholines, and by upregulating genes related to phospholipid biosynthesis and remodeling. These findings provide valuable insights into the molecular pathways through which ezetimibe mitigates hepatic fat accumulation, emphasizing the role of phospholipid metabolism.

Unraveling the diagnostic odyssey: stimulator of interferon gene-associated vasculopathy with onset in infancy in a 30-year-old female.

Stimulator of interferon gene (STING)-associated vasculopathy with onset in infancy (SAVI) is an extremely rare autoinflammatory disease. We present the case of a female Korean patient with early-onset interstitial lung disease who was initially suspected to have systemic lupus erythematosus (SLE) but was ultimately diagnosed with SAVI. The patient exhibited signs of interstitial lung disease and cutaneous manifestations before the age of 1 year and continued to have recurrent fever accompanied by pulmonary infiltrates. Based on positive findings for antibodies associated with SLE, such as antinuclear antibodies and anti-double-stranded DNA, the pulmonary involvement was considered a manifestation of SLE. Another significant symptom was recurrent skin ulceration, which led to partial spontaneous amputation of most of the toes due to inflammation. Given the early onset of interstitial lung disease, severe skin ulcers, and symptoms resembling SLE, autoinflammatory syndrome, especially SAVI was suspected. Following confirmation by genetic testing at age 29 years, the patient was started on tofacitinib, a Janus kinase inhibitor. Despite the prolonged use of multiple immunosuppressive therapies, the patient's lung condition continued to worsen, ultimately requiring lung transplantation. This observational report highlights the importance of considering SAVI as a potential diagnosis when manifestations of interstitial lung disease are observed during infancy. Early proactive treatment is crucial for lung involvement, as this can have long-term effects on patient's prognosis.

Comparison of Outcomes in Bowel Resections by Gynecologic Oncologists Versus General Surgeons During Maximal Cytoreductive Surgery for Advanced Ovarian Cancer: Gynecologic Oncology Research Investigators Collaboration Study (GORILLA-3006).

BACKGROUND: This report describes the oncologic outcomes for patients with advanced ovarian cancer who had bowel surgery performed by gynecologic oncologists (GOs) and compares the outcomes with those for bowel surgery performed by general surgeons (GSs) during maximal cytoreductive surgery. METHODS: Patients from six academic institutions who had FIGO stage III or IV ovarian cancer and underwent any bowel surgeries during maximal cytoreductive surgery were eligible for the study. The patients were divided into two groups according to whether bowel surgery was performed by a GO or a GS. In both groups, the GOs were mainly involved in extra bowel debulking procedures. Perioperative and survival outcomes were compared between the two groups. RESULTS: The 761 patients in this study included 113 patients who underwent bowel surgery by a GO and 648 who had bowel surgery by a GS. No discernible differences were observed in age, American Society of Anesthesiology (ASA) score, FIGO stage, histologic type, timing of cytoreductive surgery (primary or interval debulking surgery), or complications between the two groups. The GO group exhibited a shorter operation time than the GS group. Kaplan-Meier analysis showed no survival differences between the two groups. In the Cox analysis, non-serous cell types and gross residual diseases were associated with adverse effects on overall survival. However, performance of bowel surgery by a GO did not have an impact on survival. CONCLUSION: Performance of bowel surgery by a GO during maximal cytoreductive surgery is both feasible and safe. These results should be reflected in the training system for GOs regarding bowel surgery, and further research is needed to confirm that GOs can play a more leading role in performing extra-uterine procedures.

Tailoring Mechanical Reliability in Transparent ZnO-Zincone Thin-Film Electrodes with Organic Interlayer Interfaces and Thickness.

To address the inherent brittleness of conventional transparent conductive oxides, researchers have focused on enhancing their flexibility. This is achieved by incorporating organic films to construct organic-inorganic hybrid layer-by-layer nanostructures, where the interlayer thickness and interface play pivotal roles in determining the properties. These factors are contingent on the type of material, processing conditions, and specific application requirements, making it essential to select the appropriate conditions. In this study, ZnO-zincone nanolaminate thin films were fabricated using atomic layer deposition and molecular layer deposition in various structural configurations. Transmission electron microscopy, X-ray diffraction, and scanning electron microscopy were used to conduct a thorough analysis of the thin-film growth and structural transformations resulting from the deposition conditions. Furthermore, the influence of structural differences at the interfaces on the mechanical properties of the films was investigated by employing both tensile and compression-bending fatigue tests. This comprehensive examination reveals noteworthy variations in the mechanical responses of the films. Thin films characterized by internal porosity and an intermixed amorphous structure demonstrated enhanced compressive toughness, whereas rigid organic layers improved flexibility. These findings offer valuable insights into the development of flexible, transparent multilayer films.

Effects of subcutaneous drain on wound dehiscence and infection in gynecological midline laparotomy: Secondary analysis of a Korean Gynecologic Oncology Group study (KGOG 4001).

OBJECTIVE: To identify the effects of subcutaneous drain insertion on wound dehiscence and infection in patients who underwent gynecological midline laparotomy. METHODS: This analysis identified the secondary endpoints of the KGOG 4001 study, a prospective, multicenter, non-blind, randomized controlled trial. Patients scheduled to undergo midline laparotomy for gynecological diseases and, with body mass index<35 kg/m2, were randomized (1:1) to treatment (with subcutaneous drain) and control (without subcutaneous drain) groups from February 2021 to December 2021. We compared the incidence rate of wound dehiscence 4 weeks post-surgery and the cumulative incidence rate of wound dehiscence and infection up to 4 weeks post-surgery between the two groups. RESULTS: Of 174 patients randomized to the treatment (n = 84) and control (n = 90) groups, 12 were excluded owing to loss to follow-up; finally, 162 patients (treatment, n = 79; control, n = 83) were included in intention-to-treat analysis. The frequency of cancer surgery (79.7 % vs. 77.1 %, p = 0.683), mean surgery time (227.7 vs. 226.7 min, p = 0.960), and mean wound length (24.2 vs. 24.3 cm, p = 0.933) were comparable between two groups. No significant differences were observed in the incidence rate of wound dehiscence 4 weeks post-surgery (1.3 % vs. 2.4 %, p > 0.999), cumulative incidence rate of wound dehiscence (8.9 % vs. 6.0 %, p = 0.491), and cumulative incidence rate of wound infection (1.3 % vs. 0.0 %, p = 0.488) up to 4 weeks post-surgery between the two groups. CONCLUSION: Subcutaneous drain insertion is not associated with a significant improvement in the incidence of wound dehiscence and infection in patients who undergo gynecological midline laparotomy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04643197.

High-throughput viable circulating tumor cell isolation using tapered-slit membrane filter-based chipsets in the differential diagnosis of ovarian tumors.

OBJECTIVE: To evaluate the diagnostic performance of circulating tumor cells (CTCs) using tapered-slit membrane filter (TSF)-based chipsets for the differential diagnosis of adnexal tumors. METHODS: A total of 230 women with indeterminate adnexal tumors were prospectively enrolled. The sensitivity, specificity, and accuracy of the CTC-detecting chipsets were analyzed according to postoperative pathological results and compared with those of cancer antigen (CA)-125 and imaging tests. RESULTS: Eighty-one (40.3%) benign tumors, 31 (15.4%) borderline tumors, and 89 (44.3%) ovarian cancers were pathologically confirmed. The sensitivity, specificity, and accuracy of CTC-detecting chipsets (75.3%, 58.0%, and 67.1%) for differentiating ovarian cancer from benign tumors were similar to CA-125 (78.7%, 53.1%, and 66.5%), but lower than CT/MRI (94.2%, 77.9%, and 86.5%). "CTC or CA125" showed increased sensitivity (91.0%) and "CTC and CA-125" revealed increased specificity (77.8%), comparable to CT/MRI. CTC detection rates in stage I/II and stage III/IV ovarian cancers were 69.6% and 81.4%, respectively. The sensitivity to detect high-grade serous (HGS) cancer from benign tumors (84.6%) was higher than that to detect non-HGS cancers (68.0%). CONCLUSION: Although the diagnostic performance of the TSF platform to differentiate between ovarian cancer and benign tumors did not yield significant results, the combination of CTC and CA-125 showed promising potential in the diagnostic accuracy of ovarian cancer.

The Wiser Strategy of Using Beta-Agonists in Asthma: Mechanisms and Rationales.

Concerns regarding the safety of beta-2 agonists have led to revisions of the major asthma guidelines to better address these issues. Although these updates allow for a combination of previous and current strategies, they may confuse clinical practitioners. Beta-2 agonists are vital for alleviating asthma symptoms by relaxing smooth muscles; however, they also pose significant risks by inducing pro-inflammatory mediators both in vitro and in vivo. In addition to the risks of overuse and symptom masking, the use of beta-agonists alone at therapeutic doses can worsen airway inflammation and enhance virus-induced inflammation during asthma exacerbation. Inhaled corticosteroids (ICS) can effectively prevent these adverse effects. With new insights into the mechanisms of these adverse events, reserving short-acting beta-agonists for acute symptom relief during exacerbations and only for those who are already on ICS or oral steroids represents a careful approach to using beta-agonists with least adverse effects in patients with asthma. However, a major drawback of this approach is the potential non-compliance with ICS, leading to beta-agonist use without the necessary counteraction by ICS. An optimal strategy, both during and outside exacerbations, would integrate beta-agonists into an anti-inflammatory regimen that includes ICS, ideally combined with the same inhaler to ensure their concurrent use where finances allow. This would maintain the beneficial effects of beta-agonists, such as bronchodilation, while preventing the adverse effects from the induction of inflammatory mediators. This method is aligned with diverse clinical settings, maximizes the safe use of beta-agonists, and supports a comprehensive guideline-compliant management strategy.

Congenital central hypoventilation syndrome in korea: 20 years of clinical observation and evaluation of the ventilation strategy in a single center.

Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder characterized by hypoventilation due to impaired breathing control by the central nervous system and other symptoms of autonomic dysfunction. Mutations in paired-like homeobox 2 B (PHOX2B) are responsible for most cases of CCHS. Patients with CCHS have various phenotypes and severities, making the diagnosis difficult. This study aimed to present a comprehensive single-center experience of patients with CCHS, including key clinical features, treatment strategies, and outcomes. A retrospective chart review was performed for patients diagnosed with CCHS between January 2001 and July 2023 at Seoul National University Children's Hospital. Finally, we selected 24 patients and collected their demographic data, genotypes, ventilation methods, and clinical features related to autonomic dysfunction. The relationship between the clinical manifestations and genotypes was also examined. All patients used home ventilators, and tracheostomy was performed in 87.5% of patients. Fifteen (62.5%) patients had constipation and nine (37.5%) were diagnosed with Hirschsprung disease. Arrhythmia, endocrine dysfunction, and subclinical hypothyroidism were present in nine (37.5%), six patients (25.0%), and two patients (16.7%), respectively. A significant number of patients exhibited neurodevelopmental delays (19 patients, 79.2%). There was a correlation between the phenotype and genotype of PHOX2B in patients with CCHS. (r = 0.71, p < 0.001).   Conclusion: There was a positive correlation between paired-like homeobox 2 B mutations (especially the number of GCN repeats in the polyalanine repeat mutations sequence) and clinical manifestations. This study also demonstrated how initial treatment for hypoventilation affects neurodevelopmental outcomes in patients with CCHS. What is Known: • Congenital central hypoventilation syndrome is a rare genetic disorder characterized by hypoventilation and dysfunction of autonomic nervous system. • The disease-defining gene of CCHS is PHOX2B gene - most of the cases have heterozygous PARMs and the number of GCN triplets varies among the patients(20/24 - 20/33). What is New: • We have noted in the Korean patients with CCHS that there is a correlation between genotype (number of GCN repeats) and severity of phenotype. • National support for rare diseases allowed for a prompter diagnosis of patients with CCHS in Korean population.

Complications and Reinterventions of Reverse Total Shoulder Arthroplasty in a Korean Population: 14-Year Experience in Reverse Shoulder Arthroplasty.

Background: There are few reports on the revision or reintervention of reverse total shoulder arthroplasty (RTSA) in South Korea. The purpose of this study was to evaluate the true incidence of complications and reintervention of RTSA and clinical and radiological outcomes based on our 14-year experience in RTSA in a Korean population. Methods: Between March 2008 and June 2022, 412 consecutive cases of RTSA were performed in 388 patients with an average age of 74.4 years at our institute. Excluding 23 patients lost to follow-up, 365 patients (373 shoulders including 8 bilateral cases) who underwent primary RTSA with more than 6 months of follow-up were enrolled in this study. We evaluated those who had complications or reintervention including revision RTSA for failed RTSA. Patient charts were reviewed, and clinical outcomes including clinical scores, complications, and reintervention and radiologic outcomes were evaluated at the last follow-up. Results: Among the 373 shoulders that underwent primary RTSA, complications were found in 50 patients (13.94%, 10 men and 40 women with a mean age of 75.9 ± 6.7 years [range, 51-87 years]). The causes of complications were as follows: 13 acromion, coracoid, or scapular spine fractures, 10 loosening (glenoid: 5, humeral stem: 5), 5 infections, 4 periprosthetic fractures, 2 instability, 2 neurologic complications, and 14 miscellaneous complications. Twenty patients (5.63%, 4 men and 16 women with a mean age of 74.2 ± 8.2 years [range, 51-87 years]) underwent reintervention. The interval to the first reintervention was 27.8 ± 23.1 months (range, 0.1-78 months). The causes of reintervention (20 cases) were 8 loosening (glenoid: 4, humeral stem: 4), 5 infections, 5 fractures, and 2 instability. Among them, 15 component revisions (4.02%) were performed. At the last follow-up, American Shoulder and Elbow Surgeons, University of California at Los Angeles, and Simple Shoulder Test scores were improved from 25.4, 12.4, and 1.6 preoperatively to 40.4, 16.2, and 3.2, respectively. Forward flexion (48° to 87°), abduction (52° to 79°), external rotation (18° to 22°), and internal rotation (buttock to L2) were improved. Conclusions: After primary RTSA in a Korean population, the complication, reintervention, and revision rates were 13.94%, 5.63%, and 4.02%, respectively. Careful evaluation of the complications and adequate treatments should be performed.

Identification of plastic-degrading bacteria in the human gut.

Environmental pollution caused by the excessive use of plastics has resulted in the inflow of microplastics into the human body. However, the effects of microplastics on the human gut microbiota still need to be better understood. To determine whether plastic-degrading bacteria exist in the human gut, we collected the feces of six human individuals, did enrichment cultures and screened for bacterial species with a low-density polyethylene (LDPE) or polypropylene (PP)-degrading activity using a micro-spray method. We successfully isolated four bacterial species with an LDPE-degrading activity and three with a PP-degrading activity. Notably, all bacterial species identified with an LDPE or PP-degrading activity were opportunistic pathogens. We analyzed the microbial degradation of the LDPE or PP surface using scanning electron microscopy and confirmed that each bacterial species caused the physical changes. Chemical structural changes were further investigated using X-ray photoelectron spectroscopy and Fourier-transform-infrared spectroscopy, confirming the oxidation of the LDPE or PP surface with the formation of carbonyl groups (C=O), ester groups (CO), and hydroxyl groups (-OH) by each bacterial species. Finally, high temperature gel permeation chromatography (HT-GPC) analysis showed that these bacterial species performed to a limited extent depolymerization. These results indicate that, as a single species, these opportunistic pathogens in the human gut have a complete set of enzymes and other components required to initiate the oxidation of the carbon chains of LDPE or PP and to degrade them. Furthermore, these findings suggest that these bacterial species can potentially biodegrade and metabolize microplastics in the human gut.

Lymphadenectomy in clinically early epithelial ovarian cancer and survival analysis (LILAC): a Gynecologic Oncology Research Investigators Collaboration (GORILLA-3002) retrospective study.

OBJECTIVE: This study aimed to evaluate the therapeutic role of lymphadenectomy in patients surgically treated for clinically early-stage epithelial ovarian cancer (EOC). METHODS: This retrospective, multicenter study included patients with clinically early-stage EOC based on preoperative abdominal-pelvic computed tomography or magnetic resonance imaging findings between 2007 and 2021. Oncologic outcomes and perioperative complications were compared between the lymphadenectomy and non-lymphadenectomy groups. Independent prognostic factors were determined using Cox regression analysis. Disease-free survival (DFS) was the primary outcome. Overall survival (OS) and perioperative outcomes were the secondary outcomes. RESULTS: In total, 586 patients (lymphadenectomy group, n=453 [77.3%]; non-lymphadenectomy groups, n=133 [22.7%]) were eligible. After surgical staging, upstaging was identified based on the presence of lymph node metastasis in 14 (3.1%) of 453 patients. No significant difference was found in the 5-year DFS (88.9% vs. 83.4%, p=0.203) and 5-year OS (97.2% vs. 97.7%, p=0.895) between the two groups. Using multivariable analysis, lymphadenectomy was not significantly associated with DFS or OS. However, using subgroup analysis, the lymphadenectomy group with serous histology had higher 5-year DFS rates than did the non-lymphadenectomy group (86.5% vs. 74.4%, p=0.048; adjusted hazard ratio=0.281; 95% confidence interval=0.107-0.735; p=0.010). The lymphadenectomy group had longer operating time (p<0.001), higher estimated blood loss (p<0.001), and higher perioperative complication rate (p=0.004) than did the non-lymphadenectomy group. CONCLUSION: In patients with clinically early-stage EOC with serous histology, lymphadenectomy was associated with survival benefits. Considering its potential harm, lymphadenectomy should be performed according to histologic subtype and subsequent chemotherapy in patients with clinically early-stage EOC. TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0007309.

Healthcare service use and medical outcomes of tracheostomy-dependent children: a nationwide study.

BACKGROUND: Despite the rising trend of tracheostomies in children, there is a lack of comprehensive resources for families to navigate the challenges of living with a tracheostomy, emphasising the need for evidence-based support in understanding postoperative care and long-term adjustments. This study aimed to examine the pattern of using healthcare services and nationwide medical outcomes in children who underwent a tracheotomy before the age of 2 years. METHODS: This retrospective study used the National Health Insurance System database from 2008 to 2016 and included all children codified with tracheotomy procedure codes before their second birthday. Healthcare utilisation, such as medical costs, number of hospital visits, home healthcare nursing and medical diagnoses on readmission, in the first 2 years after tracheotomy was evaluated. Multivariable logistic regression analysis was used to determine the factors affecting mortality. RESULTS: In total, 813 patients were included in this study. Their use of healthcare services and the accompanying expenses were higher than the national medians for similar age groups; however, both metrics decreased in the second year. The major causes of admission within 2 years of surgery were respiratory and neurological diseases. The mortality rate within 2 years was 37.8%. Higher risks of mortality were associated with having two or more complex chronic conditions. Use of home healthcare nursing services was associated with a lower mortality risk. CONCLUSION: Paediatric patients with more complex chronic conditions tended to have higher mortality rates within 2 years after surgery. However, receiving home healthcare nursing was significantly associated with a reduced risk of death. Many causes of hospitalisation may be preventable with education and supportive care. Therefore, further research for establishing an integrated care system for these patients and their caregivers is required.

Effect of air temperature on serum 25-hydroxyvitamin D concentrations: A single institutional large-scale study in Korea.

Vitamin D deficiency is a worldwide health issue especially in women. Serum vitamin D concentrations vary depending on the weather. However, the ideal vitamin D supplementation strategy related to weather remains uncertain. We aimed to investigate the relationship between climate factors and serum 25-hydroxy vitamin D [25(OH)D] concentrations. This study included 11,272 women aged 20-79 who visited a health promotion center for annual checkups between January 2013 and December 2015. We reviewed medical records and collected daily meteorological data. We analyzed the association between serum 25(OH)D concentration and climate factors using simple and multiple regression models and then predicted serum 25(OH)D concentration using multiple fractional polynomial models. The median age of the participants was 51 years (20-79 years), and the mean serum 25(OH)D level was 17.4 ± 8.6 ng/mL. The serum 25(OH)D concentration was lower in young women than in older women. The proportions of women with adequate 25(OH)D levels were 14.9% and 47.0% in the age groups 20-29 and 70-79, respectively. The maximum level of predicted log 25(OH)D was found in September, and the minimum was found in January. In multiple regression analysis, age and monthly mean temperature were associated with 25(OH)D concentrations. Serum 25(OH)D level was predicted using the following formula: log (25(OH)D) = 2.144 + 0.009 × age + 0.018 × ((temperature + 12.4)/10)2 (P < 0.001, adjusted R2 = 0.091). Serum 25(OH)D concentrations changed according to air temperature. An adequate strategy for vitamin D supplementation, based on air temperature, is necessary to maintain healthy serum 25(OH)D levels.

Comparison of survival outcome of open, total laparoscopic, and laparoscopy-assisted radical vaginal hysterectomy for stage IB2 cervical cancer patients: A multicenter retrospective study.

The aim of this study was to compare survival outcomes of 3 different radical hysterectomy (RH) types, namely total abdominal radical hysterectomy (TARH), total laparoscopic radical hysterectomy (TLRH), and laparoscopy-assisted radical vaginal hysterectomy (LARVH), in patients with FIGO stage IB2 cervical cancer. We retrospectively identified a cohort of patients who underwent RH for cervical cancer between 2010 and 2017. Patients with stage IB2 cervical cancer were included and were classified into TARH, TLRH, and LARVH treatment groups. Survival outcomes were estimated by the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazards models were fit to estimate the independent association of RH technique with outcome. 194 patients were included in this study: 79 patients in the TARH group, 55 in the TLRH group, and 60 in the LARVH group. No significant differences were found in clinicopathological characteristics between the 3 RH groups. On comparing survival outcomes with TARH, both TLRH and LARVH showed no significant difference in terms of 5-year overall survival (TARH vs TLRH, P = .121 and TARH vs LARVH, P = .436). Conversely, compared to the TARH group, 5-year progression-free survival (PFS) was significantly worse in the TLRH group (P = .034) but not in the LARVH group (P = .288). Multivariate analysis showed that TLRH surgical approach (hazard ratio, 3.232; 95% confidence interval, 1.238-8.438; P = .017) was an independent prognostic factor for PFS in patients with IB2 cervical cancer. Our study suggests that in patients with FIGO stage IB2 cervical cancer, among the minimally invasive RH approaches, TLRH and LARVH, only TLRH approach was associated with worse PFS when compared with the TARH approach.

The evolving value assessment of cancer therapies: Results from a modified Delphi study.

The move toward early detection and treatment of cancer presents challenges for value assessment using traditional endpoints. Current cancer management rarely considers the full economic and societal benefits of therapies. Our study used a modified Delphi process to develop principles for defining and assessing value of cancer therapies that aligns with the current trajectory of oncology research and reflects broader notions of value. 24 experts participated in consensus-building activities across 5 months (16 took part in structured interactions, including a survey, plenary sessions, interviews, and off-line discussions, while 8 participated in interviews). Discussion focused on: 1) which oncology-relevant endpoints should be used for assessing treatments for early-stage cancer and access decisions for early-stage treatments, and 2) the importance of additional value components and how these can be integrated in value assessments. The expert group reached consensus on 4 principles in relation to the first area (consider oncology-relevant endpoints other than overall survival; build evidence for endpoints that provide earlier indication of efficacy; develop evidence for the next generation of predictive measures; use managed entry agreements supported by ongoing evidence collection to address decision-maker evidence needs) and 3 principles in relation to the second (routinely use patient reported outcomes in value assessments; assess broad economic impact of new medicines; consider other value aspects of relevance to patients and society).

Anticancer Effects of BRD4 Inhibitor in Epithelial Ovarian Cancer.

Efforts have been made to develop bromodomain inhibitors as cancer treatments. Sub-pathways, particularly in ovarian cancer, affected by bromodomain-containing protein (BRD) remain unclear. This study verified the antitumor effects of a new drug that can overcome OPT-0139-chemoresistance to treat ovarian cancer. A mouse xenograft model of human ovarian cancer cells, SKOV3 and OVCAR3, was used in this study. Cell viability and proliferation were assessed using MTT and ATP assays. Cell cycle arrest and apoptosis were determined using flow cytometry. BRD4 and c-Myc expression and apoptosis-related molecules were detected using RT-PCR and real-time PCR and Western blot. We confirmed the OPT-0139 effect and mechanism of action in epithelial ovarian cancer. OPT-0139 significantly reduced cell viability and proliferation and induced apoptosis and cell cycle arrest. In the mouse xenograft model, significant changes in tumor growth, volume, weight, and BRD4-related gene expression were observed, suggesting the antitumor effects of BRD4 inhibitors. Combination therapy with cisplatin promoted apoptosis and suppressed tumor growth in vitro and in vivo. Our results suggest OPT-0139, a BRD4 inhibitor, as a promising anticancer drug for the treatment of ovarian cancer by inhibiting cell proliferation, decreasing cell viability, arresting cell cycle, and inducing apoptosis.

Evaluation of prognostic potential of ß-catenin and L1CAM expression according to endometrial cancer risk group.

OBJECTIVE: We investigate the prognostic role of ß-catenin and L1 neuronal cell-adhesion molecule (L1CAM) according to risk groups in endometrial carcinomas (EC). METHODS: A total of 335 EC patients were classified according to the Proactive Molecular Risk Classifier for Endometrial Cancer. We evaluated the expression of ß-catenin and L1CAM using immunohistochemistry, and their association with clinicopathological characteristics and survival. RESULTS: The expressions of ß-catenin and L1CAM were observed in 10.4% of all patients, respectively, and showed mutually exclusive pattern. While ß-catenin expression was associated with endometrioid histology (p = 0.035) and low tumor grade (p = 0.045), L1CAM expression was associated with non-endometrioid histology (p < 0.001), high tumor grade (p < 0.001), lymphovascular space invasion (p = 0.006), and advanced International Federation of Gynecology and Obstetrics (FIGO) stage (p = 0.001). ß-catenin expression was most frequent in the no specific molecular (NSMP) group (26/35, 74.3%), followed by the DNA polymerase-ε-mutated (POLE-mut) (6/35, 17.1%), and mismatch repair-deficiency (dMMR) (3/35, 8.6%). L1CAM expression was most frequent in the p53-abnormal group (22/35, 62.9%), followed by the NSMP (6/35, 17.1%), dMMR (4/35, 11.4%), and POLE-mut (3/35, 8.6%). Although both markers did not show statistical significance in multivariate analysis for both progression-free survival (PFS) and overall survival in entire cohort, ß-catenin positivity was identified as the sole factor associated with worse PFS in the high-intermediate risk subgroup (p = 0.001). CONCLUSION: The expression of nuclear ß-catenin may serve as a potential biomarker for predicting recurrence and guiding therapeutic strategies in high-intermediate risk EC patients.