NCAPD2 augments the tumorigenesis and progression of human liver cancer via the PI3K­Akt­mTOR signaling pathway.

Non­SMC condensin I complex subunit D2 (NCAPD2) is a newly identified oncogene; however, the specific biological function and molecular mechanism of NCAPD2 in liver cancer progression remain unknown. In the present study, the aberrant expression of NCAPD2 in liver cancer was investigated using public tumor databases, including TNMplot, The Cancer Genome Atlas and the International Cancer Genome Consortium based on bioinformatics analyses, and it was validated using a clinical cohort. It was revealed that NCAPD2 was significantly upregulated in liver cancer tissues compared with in control liver tissues, and NCAPD2 served as an independent prognostic factor and predicted poor prognosis in liver cancer. In addition, the expression of NCAPD2 was positively correlated with the percentage of Ki67+ cells. Finally, single­cell sequencing data, gene­set enrichment analyses and in vitro investigations, including cell proliferation assay, Transwell assay, wound healing assay, cell cycle experiments, cell apoptosis assay and western blotting, were carried out in human liver cancer cell lines to assess the biological mechanisms of NCAPD2 in patients with liver cancer. The results revealed that the upregulation of NCAPD2 enhanced tumor cell proliferation, invasion and cell cycle progression at the G2/M­phase transition, and inhibited apoptosis in liver cancer cells. Furthermore, NCAPD2 overexpression was closely associated with the phosphatidylinositol 3­kinase (PI3K)­Akt­mammalian target of rapamycin (mTOR)/c­Myc signaling pathway and epithelial­mesenchymal transition (EMT) progression in HepG2 and Huh7 cells. In addition, upregulated NCAPD2 was shown to have adverse effects on overall survival and disease­specific survival in liver cancer. In conclusion, the overexpression of NCAPD2 was shown to lead to cell cycle progression at the G2/M­phase transition, activation of the PI3K­Akt­mTOR/c­Myc signaling pathway and EMT progression in human liver cancer cells.

Comparative efficacy of radical prostatectomy and radiotherapy in the treatment of high-risk prostate cancer.

BACKGROUND: Both radical prostatectomy and radiation therapy are effective in controlling the condition of patients with hormone-resistant prostate cancer (HRPCa). However, there is limited research on the prognosis and quality of life of HRPCa patients after different treatment modalities. OBJECTIVE: To explore the efficacy of radical prostatectomy (RP) and radiotherapy (RT), when treating high-risk prostate cancer (HRPCa). METHODS: Overall 103 HRPCa patients were included and were divided into RP group and RT group according to different treatment methods. The propensity score matching method (PSM) was used to balance the baseline data of the two groups and match 34 patients in each group. The prognosis, quality of life, and basic efficacy of patients were compared. RESULTS: After intervention, the disease-free survival rate of the RT group was higher than that of the RP group (79.41% vs. 55.88%, p= 0.038). Quality of life scores between the two treatment methods had no difference before intervention (p> 0.05), but higher in RT group than that of the RP group after intervention (p< 0.05). After treatment, there was no statistically significant difference in total effective rate of treatment between two groups (44.12% vs. 58.82%, p> 0.05), but the disease control rate was significantly higher in RT group (94.12% vs. 76.47%, p= 0.040). CONCLUSION: Radical radiotherapy is effective in the clinical treatment of HRPCa patients, with a higher disease-free survival rate and improved quality of life after treatment, and is worth promoting.

Impact of Catheter Ablation of Electrical Storm on Survival: A Propensity Score-Matched Analysis.

BACKGROUND: Electrical storm (ES) is a life-threatening condition, associated with substantial early and subacute mortality. Catheter ablation (CA) is a well-established therapy for ES. However, data regarding the impact of CA on the short-term and midterm survival of patients admitted for ES remain unclear. OBJECTIVES: This multicenter study aimed to investigate the impact of CA of ES on survival outcomes, while accounting for key patient characteristics associated with treatment selection. METHODS: A propensity score-matching (PSM) analysis was performed on 780 consecutive patients admitted for ES in 4 tertiary centers. PSM (1:1) based on the main characteristics associated with the use of CA or medical therapy alone was performed, resulting in 2 groups of 288 patients. RESULTS: After PSM, patients who underwent CA (n = 288) and those treated with medical therapy alone (n = 288) did not present any significant differences in the main demographic characteristics, ES presentation, and management. Compared with medical therapy alone, CA was associated with a significantly lower rate of ES recurrence at 1 year (5% vs 26%; P < 0.001). Similarly, CA was associated with a higher 1-year (91% vs 81%; P < 0.001) and 3-year (78% vs 71%; P = 0.017) survival after discharge. In subgroup analyses, effect of ablation therapy remained consistent in patients older than 70 years of age (HR: 0.39; 95% CI: 0.24-0.66), with substantial efficacy in patients with a LVEF <35% (HR: 0.39; 95% CI: 0.27-0.59). CONCLUSIONS: In propensity-matched analyses, this large study shows that CA-based management of patients admitted for ES is associated with a reduction in mortality compared with medical treatment, particularly in patients with a low ejection fraction.

Association of hospital volume with survival but not with postoperative mortality in glioblastoma patients in Belgium.

OBJECTIVES: Standard of care treatment for glioblastoma (GBM) involves surgical resection followed by chemoradiotherapy. However, variations in treatment decisions and outcomes exist across hospitals and physicians. In Belgium, where oncological care is dispersed, the impact of hospital volume on GBM outcomes remains unexplored. This nationwide study aims to analyse interhospital variability in 30-day postoperative mortality and 1-/2-year survival for GBM patients. METHODS: Data collected from the Belgian Cancer Registry, identified GBM patients diagnosed between 2016 and 2019. Surgical resection and biopsy cases were identified, and hospital case load was determined. Associations between hospital volume and mortality and survival probabilities were analysed, considering patient characteristics. Statistical analysis included logistic regression for mortality and Cox proportional hazard models for survival. RESULTS: A total of 2269 GBM patients were identified (1665 underwent resection, 662 underwent only biopsy). Thirty-day mortality rates post-resection/post-biopsy were 5.1%/11.9% (target < 3%/<5%). Rates were higher in elderly patients and those with worse WHO-performance scores. No significant difference was found based on hospital case load. Survival probabilities at 1/2 years were 48.6% and 21.3% post-resection; 22.4% and 8.3% post-biopsy. Hazard ratio for all-cause death for low vs. high volume centres was 1.618 in first 0.7 year post-resection (p < 0.0001) and 1.411 in first 0.8 year post-biopsy (p = 0.0046). CONCLUSION: While 30-day postoperative mortality rates were above predefined targets, no association between hospital volume and mortality was found. However, survival probabilities demonstrated benefits from treatment in higher volume centres, particularly in the initial months post-surgery. These variations highlight the need for continuous improvement in neuro-oncological practice and should stimulate reflection on the neuro-oncological care organisation in Belgium.

Multimodal assessment of high-risk human papillomavirus in sinonasal squamous cell carcinoma.

High-risk human papillomavirus (hrHPV) is an emerging risk factor for sinonasal squamous cell carcinoma (SNSCC). The goal of this study was to assess the prevalence of hrHPV and subtype distribution in SNSCC and correlation with patient and clinical characteristics. This retrospective cohort study included 43 cases diagnosed with incident primary SNSCC at the University of Cincinnati Medical Center from 2010 to 2015. The prevalence of hrHPV was interrogated using a multi-assay approach that included p16 immunohistochemistry (IHC), RNA in-situ hybridization (ISH), and hrHPV DNA sequencing. The association of hrHPV with 5-year overall survival (OS) and 2-year disease-free survival (DFS) was assessed. Fourteen cases (32.6 %) were classified as hrHPV positive, based on the a priori definition of having either a positive RNAScope™ ISH test or hrHPV DNA and p16-positive IHC; 9 cases (20.9 %) were positive for all three tests. All cases that arose from an inverted sinonasal papilloma (ex-ISP) were negative for hrHPV. HPV16 was the most common subtype among hrHPV positive cases (58.8 %), followed by HPV18 (17.6 %). No significant association was observed between hrHPV and OS or DFS after adjusting for potential confounding. hrHPV is prevalent in a sizable fraction of SNSCC. Additional studies are needed to better elucidate the relationship with patient survival outcomes and determine the optimal testing modality for prognostication.

The combination of handgrip strength and CONUT predicts overall survival in patients with gastrointestinal cancer: A multicenter cohort study.

BACKGROUND: The controlled nutritional status score (CONUT) and handgrip strength (HGS) were both predictive indexes for the prognosis of cancers. However, the combination of CONUT and HGS for predicting the prognosis of gastrointestinal cancer had not been developed. This study aimed to explore the combination of CONUT and HGS as the potential predictive prognosis in patients with gastric and colorectal cancer. METHODS: A cohort study was conducted with gastric and colorectal cancer patients in multicenter in China. Based on the optimal HGS cutoff value for different sex, the HGS cutoff value was determined. The patients were divided into high and low HGS groups based on their HGS scores. A CONUT score of 4 or less was defined as a low CONUT, whereas scores higher than 4 were defined as high CONUT. The Kaplan-Meier method was used to create survival curves, and the log-rank test was used to compare time-event relationships between groups. A Cox proportional hazard regression model was used to determine independent risk factors for overall survival (OS). RESULTS: A total 2177 gastric and colorectal patients were enrolled in this study, in which 1391 (63.9%) were men (mean [SD] age, 66.11 [11.60] years). Multivariate analysis revealed that patients with high HGS had a lower risk of death than those with low HGS (hazard ratio [HR],0.87; 95% confidence interval [CI], 0.753-1.006, P = 0.06), while high CONUT had a higher risk of death than those with low CONUT (HR, 1.476; 95% CI, 1.227-1.777, P < 0.001). Patients with both low HGS and high CONUT had 1.712 fold increased risk of death (HR, 1.712; 95% CI, 1.364-2.15, P < 0.001). Moreover, cancer type and sex were stratified and found that patients with high CONUT and low HGS had lower survival rate than those with low CONUT and high HGS in both gastric or colorectal cancer, and both male and female. CONCLUSION: A combination of low HGS and high CONUT was associated with poor prognosis in patients with gastrointestinal cancer, which could probably predict the prognosis of gastrointestinal cancer more accurate than HGS or CONUT alone.

Befotertinib for patients with pretreated EGFR T790M mutated locally advanced or metastatic NSCLC: Final overall survival results from a phase 2 trial.

BACKGROUND: In the initial analysis of a pivotal phase 2 single-arm study (NCT03861156), befotertinib (D-0316) showed clinical benefit with a manageable safety profile in pretreated patients with EGFR T790M mutated non-small cell lung cancer (NSCLC), including those with brain metastases. METHODS: Eligible patients received oral befotertinib of 50 mg (cohort A) or 75-100 mg (cohort B) once daily until disease progression, withdrawal of informed consent, or death. The primary endpoint for the initial analysis was objective response rate (ORR) assessed by an independent review committee. OS and safety were secondary endpoints. Herein, we present the final OS and safety data. RESULTS: A total of 176 patients in cohort A and 290 patients in cohort B were finally enrolled. At data cutoff (May 31, 2023), the median duration of follow-up was 47.9 months (95 % CI: 47.1-48.3) in cohort A and 36.7 months (35.9-37.9) in cohort B. The median OS was 23.9 months (95 % CI: 21.1-27.2) in cohort A and 31.5 months (26.8-35.3) in cohort B. The median OS for patients with and without brain metastasis in cohort A was 18.6 months (95 % CI: 14.9-26.3) and 26.4 months (95 % CI: 23.0-29.0), respectively. In cohort B, these data was 23.0 months (95 % CI: 18.6-29.1) and 35.5 months (95 % CI: 29.3-NE), respectively. The safety profile of befotertinib remained consistent with previous data. Grade 3 or higher treatment-emergent adverse events were 38.1 % in the cohort A and 50.3 % in the cohort B, and 22.2 % and 31.7 % were related to the study drug. CONCLUSION: Befotertinib demonstrated a more profound OS benefit compared to other 3rd-generation EGFR TKI, despite that cross trial data comparison should be interpreted with caution. The safety profile was manageable and consistent with previously report data in pretreated patients with confirmed T790M mutation-positive NSCLC.

DN-ODE: Data-driven neural-ODE modeling for breast cancer tumor dynamics and progression-free survivals.

Pharmacokinetic/Pharmacodynamic (PK/PD) modeling is crucial in the development of new drugs. However, traditional population-based PK/PD models encounter challenges when modeling for individual patients. We aim to explore the potential of constructing a pharmacodynamic model for individual breast cancer pharmacodynamics leveraging only limited data from early clinical trial phases. While previous studies on Neural Ordinary Differential Equations (ODEs) suggest promising results in clinical trial practices, they primarily focused on theoretical applications or independent PK/PD modeling. PD modeling from complex and irregular clinical trial data, especially when interacting with PK parameters, is still unclear. To achieve that, we introduce a Data-driven Neural Ordinary Differential Equation (DN-ODE) modeling for breast cancer tumor dynamics and progression-free survival data. To validate this approach, experiments are conducted with early-phase clinical trial data from the Amcenestrant (an oral treatment for breast cancer) dataset (AMEERA 1-2), aiming to predict pharmacodynamics in the later phase (AMEERA 3). DN-ODE model achieves RMSE scores of 8.78 and 0.21 in tumor size and progression-free survival, respectively, with R2 scores over 0.9 for each task. Compared to PK/PD methodologies, DN-ODE is able to predict robust individual tumor dynamics with only limited cycle data. We also introduce Principal Component Analysis visualizations for encoder results, demonstrating the DN-ODE's capability to discern individual distributions and diverse tumor growth patterns. Therefore, DN-ODE facilitates comprehensive drug efficacy assessments, pinpoints potential responders, and aids in trial design.

The Anastomotic Leak Triad: Preoperative Patient Characteristics, Intraoperative Risk Factors, and Postoperative Outcomes.

INTRODUCTION: The aim of the study is to determine perioperative risk factors associated with anastomotic leak (AL) following Minimally Invasive Esophagectomy (MIE), and its association on cancer recurrence and overall survival. METHODS: This retrospective observational study of electronic health record data included patients who underwent MIE for esophageal cancer between September 2013 and July 2023 at a tertiary center. The primary outcome was AL following esophagectomy, while secondary outcomes included time to cancer recurrence and overall survival. Perioperative patient factors were evaluated to determine their associations with both the primary and secondary outcomes. Propensity score matched logistic regression assessed associations between perioperative factors and AL. Kaplan-Meier survival curves compared cancer recurrence and overall survival by AL. RESULTS: A total of 251 consecutive patients with esophageal cancer were included in the analysis; 15 (6%) developed AL. Anemia, hospital complications, hospital length of stay and 30-day readmissions significantly differed from those with and without AL (p = 0.037, < 0.001, < 0.001, and 0.016, respectively). Thirty and 90-day mortality were not statistically affected by presence of AL (p = 0.417, and 0.456, respectively). Logistic regression modeling showed drug history and anemia were significantly associated with AL (p = 0.022 and 0.011, respectively). The presence of AL did not significantly impact cancer recurrence or overall survival (p = 0.439 and 0.301, respectively). CONCLUSION: The etiology of AL is multifactorial. Anastomotic leak is significantly associated with drug history, preoperative anemia, hospital length of stay and 30-day readmissions, but it was not significantly associated with 30- or 90-day mortality, cancer recurrence or overall survival. Patients should be optimized prior to undergoing MIE with special consideration for correcting anemia. Ongoing research is needed to identify more modifiable risk factors to minimize AL development and its associated morbidity.

Tenofovir is associated with a better prognosis than entecavir for hepatitis B virus-related hepatocellular carcinoma.

BACKGROUND AND AIMS: Whether tenofovir or entecavir has different effects on the prevention of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in secondary and tertiary preventive settings is still a matter of debate. This study aimed to compare the long-term prognosis of HCC between tenofovir and entecavir in patients with chronic hepatitis B (CHB). METHODS: CHB patients diagnosed with HCC between November 2008 and December 2018 and treated with either entecavir or tenofovir at a tertiary center in Korea were included. The effect of tenofovir compared to entecavir on the prognosis of HBV-related HCC was assessed using multivariable-adjusted Cox and propensity score (PS)-matched analyses. Various predefined subgroup analyses were conducted. RESULTS: During a median follow-up period of 3.0 years, the mortality rate for entecavir-treated patients (n = 3,469) was 41.2%, while tenofovir-treated patients (n = 3,056) had a mortality rate of 34.6%. Overall survival (OS) was better in the tenofovir group (adjusted hazard ratio [aHR], 0.79; P < .001), which were consistently observed in the PS-matched analysis. The magnitude of the risk difference in OS was more prominent 2 years after the diagnosis of HCC (aHR, 0.50; P < .001) than 2 years before (aHR, 0.88; P = .005), and it was more pronounced in patients with earlier HCC stages. In all subgroups, except for those with shorter life expectancy, such as those with compromised liver function, tenofovir was associated with better OS compared to entecavir. CONCLUSIONS: Among patients with HBV-related HCC, those treated with tenofovir had a better prognosis than those treated with entecavir, particularly among those with prolonged survival.

How to correctly fit an SIR model to data from an SEIR model?

In epidemiology, realistic disease dynamics often require Susceptible-Exposed-Infected-Recovered (SEIR)-like models because they account for incubation periods before individuals become infectious. However, for the sake of analytical tractability, simpler Susceptible-Infected-Recovered (SIR) models are commonly used, despite their lack of biological realism. Bridging these models is crucial for accurately estimating parameters and fitting models to observed data, particularly in population-level studies of infectious diseases. This paper investigates stochastic versions of the SEIR and SIR frameworks and demonstrates that the SEIR model can be effectively approximated by a SIR model with time-dependent infection and recovery rates. The validity of this approximation is supported by the derivation of a large-population Functional Law of Large Numbers (FLLN) limit and a finite-population concentration inequality. To apply this approximation in practice, the paper introduces a parameter inference methodology based on the Dynamic Survival Analysis (DSA) survival analysis framework. This method enables the fitting of the SIR model to data simulated from the more complex SEIR dynamics, as illustrated through simulated experiments.

Whole-exome sequencing of vulvar squamous cell carcinomas reveals an impaired prognosis in patients with TP53 mutations and concurrent CCND1 gains.

Very little information is available on the mutational landscape of vulvar squamous cell carcinoma (VSCC), a disease that mainly affects older women. Studies focusing on the mutational patterns of the currently recognized etiopathogenic types of this tumor [human papillomavirus (HPV)-associated (HPV-A), HPV-independent (HPV-I) with TP53 mutation (HPV-I/TP53mut), and HPV-I with wild-type TP53 (HPV-I/TP53wt]) are particularly rare, and there is almost no information on the prognostic implications of these abnormalities. Whole-exome DNA sequencing of 60 VSCC and matched normal tissues from each patient was performed. HPV detection, immunohistochemistry (IHC) for p16, p53, and mismatch repair proteins were also performed. Ten tumors (16.7%) were classified as HPV-A, 37 (61.7%) as HPV-I/TP53mut, and 13 (21.6%) as HPV-I/TP53wt. TP53 was the most frequently mutated gene (66.7%), followed by FAT1 (28.3%), CDKN2A (25.0%), RNF213 (23.3%), NFE2L2 (20%) and PIK3CA (20%). All the 60 tumors (100%) were DNA mismatch repair proficient. Seventeen tumors (28.3%) showed CCND1 gain. Bivariate analysis, adjusted for FIGO stage, revealed that TP53 mutation, CCND1 gain, and the combination of the two alterations were strongly associated with impaired recurrence-free survival (hazard ratio=4.4, p<0.001) and disease-specific survival (hazard ratio=6.1, p=0.002). Similar results were obtained when p53 IHC status was used instead of TP53 status and when considering only HPV-I VSCC. However, in the latter category, p53 IHC maintained its prognostic impact only in combination with CCND1 gains. All tumors carried at least one potentially actionable genomic alteration. In conclusion, VSCCs with CCND1 gain represent a prognostically adverse category among HPV-I/TP53mut tumors. All patients with VSCCs are potential candidates for targeted therapy.

Effectiveness of the Korean-Patient Placement Criteria for Alcohol Use Disorders: A Prospective Exploratory Study.

OBJECTIVE: Various patient placement criteria (PPC) have been developed to address alcohol use disorder (AUD), which has a high relapse rate and imposes substantial socioeconomic costs. Although research has shown PPC to be an effective tool, evidence supporting the Korean-PPC (K-PPC) is insufficient. This paper investigated whether treatment matching with the K-PPC was effective, based on variables related to AUD. METHODS: In total, 524 participants were evaluated using the 6 dimensions of the K-PPC and levels of care (LoC) were recommended based on the results. Participants whose treatment matched with the recommended LoC were classified into the matched group, and those whose treatment did not match were classified into the mismatched group. Subsequently, treatment was planned according to the determined LoC, and a total of 3 follow-up evaluations were conducted at 1 month, 3 months, and 6 months. RESULTS: There was no significant difference in the follow-up rate between the K-PPC matched group and the mismatched group. Of the variables measured by the 6 dimensions of the K-PPC, alcohol-related variables, depression, insight, and biomedical outcomes showed the most significant results (especially alcohol-related variables) from the baseline evaluation to the 6-month follow-up. In addition, the average adherence to the treatment program in the 6-month period was found to be higher in the matched group than in the mismatched group. CONCLUSION: The K-PPC could be effective for placing patients and providing treatment by matching patient characteristics. Enhancing treatment program retention can also have a positive effect on clinical outcomes.

Novel genetic variants in the NLRP3 inflammasome-related PANX1 and APP genes predict survival of patients with hepatitis B virus-related hepatocellular carcinoma.

BACKGROUND: The nod-like receptor protein 3 (NLRP3) is one of the most characterized inflammasomes involved in the pathogenesis of several cancers, including hepatocellular carcinoma (HCC). However, the effects of genetic variants in the NLRP3 inflammasome-related genes on survival of hepatitis B virus (HBV)-related HCC patients are unclear. METHODS: We performed multivariable Cox proportional hazards regression analysis to evaluate associations between 299 single-nucleotide polymorphisms (SNPs) in 16 NLRP3 inflammasome-related genes and overall survival (OS) of 866 patients with HBV-related HCC. We further performed expression quantitative trait loci (eQTL) analysis using the data from the GTEx project and 1000 Genomes projects, and performed differential expression analysis using the TCGA dataset to explore possible molecular mechanisms underlying the observed associations. RESULTS: We found that two functional SNPs (PANX1 rs3020013 A > G and APP rs9976425 C > T) were significantly associated with HBV-related HCC OS with the adjusted hazard ratio (HR) of 0.83 [95% confidence interval (CI) = 0.73-0.95, P = 0.008], and 1.26 (95% CI = 1.02-1.55, P = 0.033), respectively. Moreover, the eQTL analysis revealed that the rs3020013 G allele was correlated with decreased mRNA expression levels of PANX1 in both normal liver tissues (P = 0.044) and whole blood (P < 0.001) in the GTEx dataset, and PANX1 mRNA expression levels were significantly higher in HCC samples and associated with a poorer survival of HCC patients. However, we did not observe such correlations for APP rs9976425. CONCLUSIONS: These results indicated that SNPs in the NLRP3 inflammasome-related genes may serve as potential biomarkers for HBV-related HCC survival, once replicated by additional larger studies.

Low Absolute Lymphocyte Count Correlates with Lymph Node Metastases and Worse Survival of Patients with Gastric Cancer.

BACKGROUND: Several studies have found that the absolute lymphocyte (ALC) or neutrophil count predicts the survival of patients with solid tumors, and that the neutrophil-to-lymphocyte ratio and the prognostic nutritional index are useful markers of gastric cancer prognosis. However, it remains unclear whether the ALC is prognostic of lymph node (LN) metastasis in patients with gastric cancer. In this study, we aimed to explore the impact of ALC on prognosis and distinctive clinical characteristics in patients with gastric cancer. PATIENTS AND METHODS: The medical records of patients with gastric adenocarcinomas who underwent radical gastrectomy with curative intent at Seoul St. Mary's Hospital and Yeouido St. Mary's Hospital between January 2010 and December 2017 were reviewed. Of these, 4149 patients for whom preoperative white blood cell, neutrophil, and lymphocyte counts were available were enrolled. RESULTS: In all 4149 patients, ALC gradually decreased as the pN stage increased. Those with an ALC of less than 1360 cells/µL were defined as a low-ALC group, and advanced cT and cN stages were the strongest risk factors for LN metastasis in both univariate and multivariate analyses; undifferentiated tumor histology and a low ALC were also significant risk factors. Patients of all stages in the ALC-low group exhibited poorer prognoses. The ALC-low group also exhibited a higher recurrence rate in a greater proportion of LNs. CONCLUSIONS: In patients with gastric cancer, as the preoperative ALC decreases, the incidence of LN metastasis increases. A low ALC is associated with a high recurrence rate, particularly in LNs.

U1 snRNA interactions with deep intronic sequences regulate splicing of multiple exons of spinal muscular atrophy genes.

Introduction: The U1 small nuclear RNA (snRNA) forms ribonucleoprotein particles (RNPs) such as U1 snRNP and U1-TAF15 snRNP. U1 snRNP is one of the most studied RNPs due to its critical role in pre-mRNA splicing in defining the 5' splice site (5'ss) of every exon through direct interactions with sequences at exon/intron junctions. Recent reports support the role of U1 snRNP in all steps of transcription, namely initiation, elongation, and termination. Functions of U1-TAF15 snRNP are less understood, though it associates with the transcription machinery and may modulate pre-mRNA splicing by interacting with the 5'ss and/or 5'ss-like sequences within the pre-mRNA. An anti-U1 antisense oligonucleotide (ASO) that sequesters the 5' end of U1 snRNA inhibits the functions of U1 snRNP, including transcription and splicing. However, it is not known if the inhibition of U1 snRNP influences post-transcriptional regulation of pre-mRNA splicing through deep intronic sequences. Methods: We examined the effect of an anti-U1 ASO that sequesters the 5' end of U1 snRNA on transcription and splicing of all internal exons of the spinal muscular atrophy (SMA) genes, SMN1 and SMN2. Our study was enabled by the employment of a multi-exon-skipping detection assay (MESDA) that discriminates against prematurely terminated transcripts. We employed an SMN2 super minigene to determine if anti-U1 ASO differently affects splicing in the context of truncated introns. Results: We observed substantial skipping of multiple internal exons of SMN1 and SMN2 triggered by anti-U1 treatment. Suggesting a role for U1 snRNP in interacting with deep intronic sequences, early exons of the SMN2 super minigene with truncated introns were resistant to anti-U1 induced skipping. Consistently, overexpression of engineered U1 snRNAs targeting the 5'ss of early SMN1 and SMN2 exons did not prevent exon skipping caused by anti-U1 treatment. Discussion: Our results uncover a unique role of the U1 snRNA-associated RNPs in splicing regulation executed through deep intronic sequences. Findings are significant for developing novel therapies for SMA based on deep intronic targets.

The prognostic role of an optimal machine learning model based on clinical available indicators in HCC patients.

Although methods in diagnosis and therapy of hepatocellular carcinoma (HCC) have made significant progress in the past decades, the overall survival (OS) of liver cancer is still disappointing. Machine learning models have several advantages over traditional cox models in prognostic prediction. This study aimed at designing an optimal panel and constructing an optimal machine learning model in predicting prognosis for HCC. A total of 941 HCC patients with completed survival data and preoperative clinical chemistry and immunology indicators from two medical centers were included. The OCC panel was designed by univariate and multivariate cox regression analysis. Subsequently, cox model and machine-learning models were established and assessed for predicting OS and PFS in discovery cohort and internal validation cohort. The best OCC model was validated in the external validation cohort and analyzed in different subgroups. In discovery, internal and external validation cohort, C-indexes of our optimal OCC model were 0.871 (95% CI, 0.863-0.878), 0.692 (95% CI, 0.667-0.717) and 0.648 (95% CI, 0.630-0.667), respectively; the 2-year AUCs of OCC model were 0.939 (95% CI, 0.920-0.959), 0.738 (95% CI, 0.667-0.809) and 0.725 (95% CI, 0.643-0.808), respectively. For subgroup analysis of HCC patients with HBV, aged less than 65, cirrhosis or resection as first therapy, C-indexes of our optimal OCC model were 0.772 (95% CI, 0.752-0.792), 0.769 (95% CI, 0.750-0.789), 0.855 (95% CI, 0.846-0.864) and 0.760 (95% CI, 0.741-0.778), respectively. In general, the optimal OCC model based on RSF algorithm shows prognostic guidance value in HCC patients undergoing individualized treatment.

Impact of frailty on postoperative outcomes after hepatectomy: A systematic review and meta-analysis.

BACKGROUND: The impact of frailty on postoperative outcomes in patients undergoing hepatectomy is still unclear. AIM: To study the influence of frailty on postoperative outcomes, such as mortality, rate of complications, and length of hospitalization, following hepatectomy. METHODS: PubMed, EMBASE, and Scopus databases were searched for observational studies with adult (≥ 18 years) patients after planned/elective hepatectomy. A random-effects model was used for all analyses, and the results are expressed as weighted mean difference (WMD), relative risk (RR), or hazards ratio (HR) with 95% confidence interval (CI). RESULTS: Analysis of the 13 included studies showed a significant association of frailty with elevated risk of in-hospital mortality (RR = 2.76, 95%CI: 2.10-3.64), mortality at 30 d (RR = 4.60, 95%CI: 1.85-11.40), and mortality at 90 d (RR = 2.52, 95%CI: 1.70-3.75) in the postoperative period. Frail patients had a poorer long-term survival (HR = 2.89, 95%CI: 1.84-4.53) and higher incidence of "any" complications (RR = 1.69, 95%CI: 1.40-2.03) and major (grade III or higher on the Clavien-Dindo scale) complications (RR = 2.69, 95%CI: 1.85-3.92). Frailty was correlated with markedly lengthier hospital stay (WMD = 3.65, 95%CI: 1.45-5.85). CONCLUSION: Frailty correlates with elevated risks of mortality, complications, and prolonged hospitalization, which need to be considered in surgical management. Further research is essential to formulate strategies for improved outcomes in this vulnerable cohort.

Preoperative albumin-bilirubin score predicts short-term outcomes and long-term prognosis in colorectal cancer patients undergoing radical surgery.

BACKGROUND: The albumin-bilirubin (ALBI) score is a serum biochemical indicator of liver function and has been proven to have prognostic value in a variety of cancers. In colorectal cancer (CRC), a high ALBI score tends to be associated with poorer survival. AIM: To investigate the correlation between the preoperative ALBI score and outcomes in CRC patients who underwent radical surgery. METHODS: Patients who underwent radical CRC surgery between January 2011 and January 2020 at a single clinical center were included. The ALBI score was calculated by the formula (log10 bilirubin × 0.66) + (albumin × -0.085), and the cutoff value for grouping patients was -2.8. The short-term outcomes, overall survival (OS), and disease-free survival (DFS) were calculated. RESULTS: A total of 4025 CRC patients who underwent radical surgery were enrolled in this study, and there were 1908 patients in the low ALBI group and 2117 patients in the high ALBI group. Cox regression analysis revealed that age, tumor size, tumor stage, ALBI score, and overall complications were independent risk factors for OS; age, tumor stage, ALBI score, and overall complications were identified as independent risk factors for DFS. CONCLUSION: A high preoperative ALBI score is correlated with adverse short-term outcomes, and the ALBI score is an independent risk factor for OS and DFS in patients with CRC undergoing radical surgery.

Sarcopenia is a prognostic factor in lymphoma patients: a systematic review and meta-analysis.

Findings regarding the relationship between sarcopenia and lymphoma have been inconsistent across studies. This study investigated the association between sarcopenia and lymphoma. We systematically searched the Embase, Science Direct, Cochrane Library, and PubMed databases from inception to 31 March 2024 to identify relevant studies. Two researchers independently extracted and evaluated studies that met inclusion and exclusion criteria. Twenty-six studies with 3659 participants were included. Sarcopenic lymphoma patients had poor overall survival (OS) (HR = 1.88; 95% CI: 1.47-2.41; p < 0.001). The heterogeneity was high (I2=80%). However, the result of the Egger test indicated a significant publication bias (p < 0.001). After employing the trim and fill method to adjust for this bias, the HR of OS became non-significant (p > 0.05). The progression-free survival (PFS) was worse in sarcopenic patients (HR = 1.77; 95% CI: 1.37-2.29; p < 0.001; I2=70%). There was no significant publication bias (p > 0.05). In the subgroup analyses, sarcopenia was a negative predictor of OS in lymphoma patients who undergo hematopoietic cell transplantation (HCT) (HR  = 1.61;95% CI: 1.19-2.18; I2=30%). Male lymphoma patients with sarcopenia had a significantly worse OS (HR = 2.29; 95% CI:1.24-4.24; p = 0.009). Among patients with primary central nervous system lymphoma (PCNSL), those with sarcopenia defined by temporal muscle thickness (TMT) exhibited significantly worse OS (HR = 2.20; 95% CI:1.04-4.65; p = 0.039; I2=68%). Sarcopenia is associated with worse PFS in lymphoma patients. Subgroup analyses indicate that sarcopenia is a negative predictor of OS after HCT, and male lymphoma patients who suffer from sarcopenia have higher mortality. Sarcopenia defined by TMT is also a negative predictor of OS for patients with PCNSL.