Univariate Cox Regression Analysis Research Articles

Investigation and validation of neurotransmitter receptor-related biomarkers for forecasting clinical outcomes and immunotherapeutic efficacy in breast cancer

PurposeThe prognostic role of neurotransmitters and their receptors in breast cancer (BC) has not been fully investigated. The aim of this study was to construct a survival model for the prognosis of BC patients based on neurotransmitter receptor-related genes (NRRGs). MethodsBC-related differentially expressed genes (DEGs) were screened and intersected with NRRGs. GO, KEGG and PPI analyses were performed. Univariate Cox, Least Absolute Shrinkage and Selection Operator (LASSO) and multivariate Cox regression analyses were used to construct prognostic models for biomarker expression levels. The model was validated using an external validation set. The receiver operating characteristic curves (ROC) for diagnostic value prediction and clinicopathologic characteristic nomogram were constructed. qRT-PCR was used for further in vitro validation experiments. ResultsForty-five overlapping genes were obtained by intersecting BC-related DEGs with 172 NRRGs. Univariate Cox, LASSO and multivariate Cox regression analyses were used to construct prognostic models for the expression levels of biomarkers including DLG3, SLC1A1, PSCA and PRKCZ. The feasibility of the model was validated by the GEO validation set. ROC curves were established for diagnostic value prediction. Patients in the high-risk group had a worse prognosis, higher TMB score, higher probability of gene mutation, and higher immune cell infiltration. RiskScore, M, N and Age were strongly correlated with survival. The mRNA expression levels of DLG3, PSCA and PRKCZ in the BC group were significantly higher than those in the control group. ConclusionRisk prediction model based on DLG3, SLC1A1, PSCA and PRKCZ, which are closely related to BC prognosis, was successfully constructed.

The Treatment of Primary Lymphoepithelioma-Like Carcinoma in the Head and Neck and Nasopharyngeal Carcinoma.

An uncommon cancer, lymphoepithelioma-like carcinoma (LELC) resembles undifferentiated nasopharyngeal carcinoma (NPC) histologically. The aim is mainly to introduce the diagnosis and treatment of LELC and compare it with NPC in our descriptive study. A total of 278 patients with NPC and 157 patients with head and neck LELC had their medical records examined in this study. The propensity score matching (PSM) approach was employed to attain a 1:1 match between the LELC and NPC groups. Kaplan-Meier analysis was performed for overall survival (OS) of LELC and NPC. To determine their predictive values for OS, univariate and multivariate Cox regression analyses with significant survival differences (p < 0.05) were carried out. Similar to NPC, 107 (68.2%) LELC cases had Epstein-Barr virus (EBV) infection. LELC of the parotid glands was present in nearly 46.5% of patients with head and neck LELC. Most patients were treated with surgery with neck dissection. After PSM, LELC had similar 5-year OS rates to NPC (81.6% vs. 79.0%). LELC was less prone to distant metastasis compared to NPC. Age, T stage, N stage, and distant metastases were found to be substantially correlated with the outcome of LELC, according to the multivariate Cox regression analysis (p < 0.05). EBV infection in the head and neck has been associated with LELC and NPC. When compared to NPC, LELC is more likely to arise in the salivary glands and has a lower incidence of distant metastasis. Surgery with neck dissection is the primary treatment for LELC.

Associations of retinal microvascular density and fractal dimension with glaucoma: a prospective study from UK Biobank

ObjectiveTo explore the association between retinal microvascular parameters and glaucoma. DesignProspective study. SubjectsThe UK Biobank subjects with fundus images and without a history of glaucoma. MethodsWe employed the Retina-based Microvascular Health Assessment System (RMHAS) to utilize the noninvasive nature of fundus photography and quantify retinal microvascular parameters including retinal vascular skeleton density (VSD) and fractal dimension (FD). We also utilized propensity score matching (PSM) to pair individuals with glaucoma and healthy controls (HC). PSM was implemented via a logistic regression model with a caliper of 0.1 and a matching ratio of 1:4 sans replacements. We conducted univariable Cox regression analyses to study the association between retinal microvascular parameters and incident glaucoma, in both continuous and quartile forms. Main outcome measureVSD, FD, and glaucoma. ResultsIn a study of 41,632 participants without prior glaucoma, 482 cases of glaucoma were recorded during a median follow-up of 11.0 years. In the Cox proportional hazards regression model post-PSM, we found that incident glaucoma has significant negative associations with arteriolar VSD (HR = 0.24, 95% CI 0.11–0.52, P < 0.001), venular VSD (HR = 0.34, 95% CI 0.15–0.74, P = 0.007), arteriolar FD (HR = 0.24, 95% CI 0.10–0.60, P = 0.002) and venular FD (HR = 0.31, 95% CI 0.12–0.85, P = 0.022). Subgroup analysis using covariates revealed that individuals aged 60 and above, non-smokers, moderate alcohol consumers, and those with hypertension and myopia exhibited P values below 0.05 consistently pre- and post-matching, differing from other subgroups within this covariate. ConclusionOur study found that reduced retinal VSD and lower FD are linked to elevated glaucoma risk.

Construction and Validation of a Prognostic Prediction Model for Gastric Mucinous Adenocarcinoma Based on the SEER Database

This study focused on the development and validation of a prognostic model to predict overall survival (OS) in patients with gastric mucinous adenocarcinoma (GMA), utilizing data from the SEER database. A cohort of 537 GMA patients was analyzed to identify factors affecting survival, using both univariate and multivariate Cox regression analyses on demographic and clinicopathological variables. The analysis led to the creation of a nomogram model. Findings revealed that TNM staging and the administration of radiotherapy or chemotherapy were significant factors impacting survival outcomes. Specifically, patients at stages T4, N3, and M1 faced a notably higher mortality risk, while those who received radiotherapy and chemotherapy experienced a significant reduction in mortality risk. The model's performance, as indicated by C-indices of 0.73 in the training set and 0.66 in the validation set, suggests robust predictive capability. The area under the curve (AUC) analysis confirmed high accuracy in predicting 1-year, 3-year, and 5-year survival rates, and calibration curves displayed strong agreement between predicted and actual outcomes. Decision curve analysis (DCA) demonstrated that the model exhibited significant clinical utility across various thresholds. Overall, this study presents a reliable prognostic tool for individualized risk stratification and clinical treatment in GMA patients. Future work should focus on enhancing the model by incorporating molecular biological data to increase its predictive accuracy and applicability.

A Novel Liver Metastasis Score for Patients Undergoing Surgical Resection of Gastroenteropancreatic Neuroendocrine Tumors: A Multi-institutional Study.

Liver metastasis impacts survival in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs); however, current guidelines lack consensus on post-resection surveillance and adjuvant therapy. A comprehensive risk stratification tool is needed to guide personalized management. We aimed to develop and validate a predictive model for liver metastasis risk after surgical resection of GEP-NETs that incorporates pathological factors and adjuvant therapy. Patients with GEP-NETs who underwent surgical resection with curative intent at three major Chinese hospitals (2010-2022) were identified. Univariable and multivariable Cox regression analysis identified independent risk factors of liver metastasis. The liver metastasis score (LMS) was developed using weighted risk factors and validated by tenfold cross-validation. Among the 724 patients included in the analytic cohort, liver metastasis occurred in 66 patients (9.1%) at a median of 36 months; patients with liver metastasis had a worse 5-year overall survival (no liver metastasis 63.6% vs. liver metastasis 95.8%; p<0.001). Independent predictors were Ki-67 index (hazard ratio [HR] 10.36 for Ki-67 3-20%, HR 18.30 for Ki-67 >20%, vs. <3%), vascular invasion (HR 5.03), lymph node metastases (HR 2.24), and lack of adjuvant therapy (HR 3.03). The LMS demonstrated excellent discrimination (C-index 0.888) and stratified patients into low, intermediate, and high-risk relative to 5-year risk of liver metastasis: 2.9%, 20.8%, and 49.7%, respectively (p<0.001). The novel LMS effectively predicted the risk of liver metastasis after surgical resection of GEP-NETs. This validated model can help guide personalized surveillance and adjuvant treatment strategies, potentially improving outcomes for high-risk patients.

Construction of a combined prognostic model for pancreatic ductal adenocarcinoma based on deep learning and digital pathology images

BackgroundDeep learning has made significant advancements in the field of digital pathology, and the integration of multiple models has further improved accuracy. In this study, we aimed to construct a combined prognostic model using deep learning-extracted features from digital pathology images of pancreatic ductal adenocarcinoma (PDAC) alongside clinical predictive indicators and to explore its prognostic value.MethodsA retrospective analysis was conducted on 142 postoperative pathologically confirmed PDAC cases. These cases were divided into training (n = 114) and testing sets (n = 28) at an 8:2 ratio. Tumor whole-slide imaging features were extracted and screened to construct a pathological risk model based on a pre-trained deep learning model. Clinical and pathological data from the training set were used to select independent predictive factors for PDAC and establish a clinical risk model using LASSO, univariate, and multivariate Cox regression analyses. Based on the pathological and clinical risk models, a combined model was developed. The Harrell concordance index (C-index) was computed to assess the predictive performance of each model for PDAC survival prognosis.ResultsFor the training and testing sets, the C-index values for the clinical risk model were 0.76 and 0.75, respectively; for the pathological risk model, they were 0.82 and 0.73, respectively; and for the combined model, they were 0.86 and 0.77, respectively. The combined model exhibited appropriate calibration at 1-, 3-, and 5-year time points, as well as a superior area under the curve of the receiver operating characteristic curve and clinical net benefit compared to the single models.ConclusionsIntegrating the pathological and clinical risk models may provide a higher predictive value for survival prognosis.

Identification and validation of a prognostic model based on immune-related genes in ovarian carcinoma.

A novel valuable prognostic model has been developed on the basis of immune-related genes (IRGs), which could be used to estimate overall survival (OS) in ovarian cancer (OC) patients in The Cancer Genome Atlas (TCGA) dataset and the International Cancer Genome Consortium (ICGC) dataset. This prognostic model was engineered by employing LASSO regression in training cohort (TCGA dataset). The corresponding growth predictive values of this model for individualized survival was evaluated using survival analysis, receiver operating characteristic curve (ROC curve), and risk curve analysis. Combined with clinical characteristics, a model risk score nomogram for OS was well built. Thereafter, depended on the model risk score, patients were divided into high and low risk subgroups. The survival difference between these subgroups was measured using Kaplan-Meier survival method. In addition, correlations containing pathway enrichment, treatment, immune cell infiltration and the prognostic model were also analyzed. We established the ovarian cancer cell line W038 for this study and identified the performances of GBP1P1 knockdown on a series of activities including cellular proliferation, apoptosis, migration, and invasion of W038 cells in vitro. We constructed a 25-genes prognostic model (TNFAIP8L3, PI3, TMEM181, GBP1P1 (LOC400759), STX18, KIF26B, MRPS11, CACNA1C, PACSIN3, GMPR, MANF, PYGB, SNRPA1, ST7L, ZBP1, BMPR1B-DT, STAC2, LINC02585, LYPD6, NSG1, ACOT13, FAM120B, LEFTY1, SULT1A2, FZD3). The areas under the curves (AUC) of 1, 2 and 3 years were 0.806, 0.773 and 0.762, in the TCGA cohort, respectively. Besides, the effectiveness of the model was verified using ICGC testing data. Univariate and multivariate Cox regression analysis exposes the risk score as an independent prognosis predictor for OS both in the TCGA and ICGC cohort. In summary, we utilized comprehensive bioinformatics analysis to build an effective prognostic gene model for OC patients. These bioinformatic results suggested that GBP1P1 could act as a novel biomarker for OC. GBP1P1 knockdown substantially inhibited the proliferation, migration, and invasion of W038 cells in vitro, and increased the percentage of apoptotic W038 cells. The analyses of genetic status of patients with 25-genes model might improve the ability to predict the prognosis of patients with OC and help to select patients suit able to therapies. Immune-related gene GBP1P1 might serve as prognostic biomarker for OC.

Relationship between changes in nutritional status during treatment and overall survival of newly diagnosed nasopharyngeal carcinoma patients

PurposeThis study investigates the relationship between changes in nutritional status during treatment and overall survival in NPC patients. MethodUsing a prospective cohort design, the electronic health records of newly diagnosed NPC patients from a medical center in Taiwan (from January 1, 2018, to March 31, 2024) were analyzed. A total of 73 newly diagnosed NPC patients were tracked; nutritional indicators such as body mass index (BMI), prealbumin levels, and Patient-Generated Subjective Global Assessment (PG-SGA) scores were recorded at four time points: one week before treatment, the first week of treatment, and four and eight weeks after treatment began. ResultsThe study found that most patients experienced a decrease in BMI (B = −0.62, p < .001) and prealbumin levels (B = −0.79, p = .015) during treatment, although BMI remained in the overweight range and prealbumin stayed within normal levels. PG-SGA scores increased (B = 1.01, p < .001), indicating a shift from low to moderate nutritional risk. Univariate Cox regression analysis showed that the Charlson Comorbidity Index (HR = 1.86, 95% CI: 1.38–2.51), NPC stage (HR = 15.67, 95% CI: 2.07–118.61), treatment method (HR = 2.96, 95% CI: 1.45–6.04), prealbumin (HR = 2.95, 95% CI: 1.46–5.99), and PG-SGA score trajectories (HR = 2.85, 95% CI: 1.27–6.40) were associated with overall survival. However, multivariate analysis revealed that the survival of NPC patients was only associated with CCI and NPC stage. ConclusionsThe study underscores the importance of monitoring nutritional status changes during treatment, particularly prealbumin and PG-SGA trajectories.

Integrated multi-level omics profiling of disulfidptosis identifis SPAG4 as an innovative immunotherapeutic target in glioblastoma.

To investigate the association between disulfidptosis-related genes (DFRGs) and patient prognosis, while concurrently identifying potential therapeutic targets in glioblastoma (GBM). We retrieved RNA sequencing data and clinical characteristics of GBM patients from the TCGA database. We found there was a total of 6 distinct clusters in GBM, which was identified by the t-SNE and UMAP dimension reduction analysis. Prognostically significant genes in GBM were identified using the limma package, coupled with univariate Cox regression analysis. Machine learning algorithms were then applied to identify central genes. The CIBERSORT algorithm was utilized to assess the immunological landscape across different GBM subtypes. In vitro and in vivo experiments were conducted to investigate the role of SPAG4 in regulating the proliferation, invasion of GBM, and its effects within the immune microenvironment. 23 genes, termed DFRGs, were successfully identified, demonstrating substantial potential for establishing a prognostic model for GBM. Single cell analysis revealed a significant correlation between DFRGs and the progression of GBM. Utilizing individual risk scores derived from this model enabled the stratification of patients into two distinct risk groups, revealing significant variations in immune infiltration patterns and responses to immunotherapy. Utilizing the random survival forests algorithm, SPAG4 was identified as the gene with the highest prognostic significance within our model. In vitro studies have elucidated SPAG4's significant role in GBM pathogenesis, potentially through the regulation of fatty acid metabolism pathways. Our in vivo investigations using a subcutaneous xenograft model have confirmed SPAG4's influence on tumor growth and its capacity to modulate the immune microenvironment. Advanced research hints that SPAG4 might achieve immune evasion by increasing CD47 expression, consequently reducing phagocytosis. These findings highlight SPAG4 as a potential GBM therapeutic target and emphasize the complexity of the immune microenvironment in GBM progression.

Predictive value of early-stage postoperative albumin-bilirubin grade on the overall survival of hepatocellular carcinoma patients undergoing resection.

The albumin-bilirubin (ALBI) and ΔALBI grades have attracted substantial attention for their ability to predict the overall survival (OS) of patients with hepatocellular carcinoma (HCC). This retrospective study aimed to evaluate the predictive value of the ALBI grade at different time points for the OS of patients with HCC who underwent surgical resection. The clinical data of patients with HCC who underwent radical resection in our hospital were collected and analyzed. The survival rate was analyzed using the Kaplan-Meier method and log-rank test. The risk factors influencing OS were identified via univariate and multivariate Cox regression analyses. A total of 104 patients with HCC were included in this study. The 1-, 3-, and 5-year OS rates of these patients were 91.3%, 64.0%, and 60.2%, respectively. The OS rates were significantly higher in patients with early-stage postoperative ALBI grade 2 than in those with grade 3 (P < 0.001); however, the preoperative ALBI grade, later-stage postoperative ALBI grade, ΔALBI grade (early stage), or ΔALBI grade (later stage) did not affect the OS rate. Furthermore, resection of ≥3 Couinaud liver segments [hazard ratio (HR) = 4.74; 95% confidence interval (CI), 2.32-9.67; P < 0.001], occurrence of postoperative complications (HR = 2.95; 95% CI, 1.38-6.31; P = 0.005), and early-stage postoperative ALBI grade 3 (HR = 2.50; 95% CI, 1.18-5.31; P = 0.02) were identified as independent risk factors for the OS of patients with HCC. Early-stage postoperative ALBI grade can be used to predict the OS of patients with HCC who have undergone radical hepatectomy. Early-stage postoperative ALBI grade 3, resection of ≥3 Couinaud liver segments, and occurrence of postoperative complications are independent risk factors affecting the OS of these patients.

Development of a prognostic model for early-stage gastric cancer-related DNA methylation-driven genes and analysis of immune landscape.

This study aimed to develop a prognostic model based on DNA methylation-driven genes for patients with early-stage gastric cancer and to examine immune infiltration and function across varying risk levels. We analyzed data from stage I/II gastric cancer patients in The Cancer Genome Atlas which included clinical details, mRNA expression profiles, and level 3 DNA methylation array data. Using the empirical Bayes method of the limma package, we identified differentially expressed genes (DEGs), and the MethylMix package facilitated the identification of DNA methylation-driven genes (DMGs). Univariate Cox regression and LASSO (least absolute shrinkage and selector operation) analyses were utilized to pinpoint critical genes. A risk score prediction model was formulated using two genes that demonstrated the most significant hazard ratios (HRs). Model performance was evaluated within the initial cohort and verified in the GSE84437 cohort; a nomogram was also constructed based on these genes. We further examined 50 methylation sites associated with three CpG islands in C1orf35 and 14 methylation sites linked to one CpG island in FAAH. The CIBERSORT package was employed to identify immune cell clusters in the prediction model. A total of 176 DNA methylation-driven genes were refined down to a four-gene signature (ZC3H12A was hypermethylated; GATA3, C1orf35, and FAAH were hypomethylated), which exhibited a significant correlation with overall survival (OS), as evidenced by p-values below 0.05 following univariate Cox regression and LASSO analysis. Specifically, for the risk score prediction model, C1orf35, which had the highest hazard ratio (HR = 2.035, p = 0.028), and FAAH, with the lowest hazard ratio (HR = 0.656, p = 0.012), were selected. The Kaplan-Meier analysis demonstrated distinct survival outcomes between the high-risk and low-risk score groups. The model's predictive accuracy was confirmed with an area under the curve (AUC) of 0.611 for 3-year survival and 0.564 for 5-year survival. Notably, the hypomethylation of the three CpG islands in C1orf35 and the single CpG island in FAAH was significantly different in stage I/II gastric cancer patients compared to normal tissues. Additionally, the high-risk score group showed a notable association with resting CD4 memory T cells. Promoter hypomethylation of C1orf35 and FAAH in early-stage gastric cancer underscores their potential as biomarkers for accurate diagnosis and treatment. The developed predictive model employing genes affected by DNA methylation serves as a crucial independent prognostic factor in early-stage gastric cancer.

Chest Wall Hydatid Disease: Surgical management and risk Factors for Recurrence and Mortality

Background Hydatidosis of the thoracic wall differs from other hydatid localizations in its pathophysiology, diagnostic, and therapeutic management. It is a little-studied entity. The objectives of our work were to describe its surgical management and to analyze the factors that may influence recurrence and mortality. Methods A retrospective, descriptive, longitudinal, and multicenter study on four university hospital surgical centers of Tunis, from January 1995 to December 2022 including operated hydatid cysts of the thoracic wall. Overall survival (OS) and cumulative recurrence rates were calculated. Univariate and multivariable Cox regression analyses were performed to identify recurrence and mortality risk factors. Results Forty-nine patients were included. The mean age was 41 ± 17 years [8-76]. The main presenting sign was thoracic parietal swelling (n=22). Chest ultrasound and CT scan showed multivesicular formation in 17 and 33 cases, respectively. Muscle involvement was in the intercostal (n=4), paravertebral (n=13), and pectoralis major (n=3) muscles. Bone involvement was vertebral (n=11), costal (n=12), costo-vertebral (n=21) and sternal (n=2). A posterolateral thoracotomy was performed (n=20). Surgical excision at various levels of the chest wall with spinal stabilization (n=15) was performed. Sixty-three percent of the patients received antiparasitic medical treatment. Recurrence occurred in 37% of cases. Four patients died from hydatidosis-related complications. Factors could be independently associated with recurrence such as male gender, and vertebral involvement. The presence of a visceral hydatid cyst located at a distance from the parietal lesion at the time of diagnosis and the occurrence of postoperative infectious complications could increase mortality. Conclusions Chest wall hydatidosis represents a rare medical condition where surgery remains the preferred treatment modality. However, it carries a substantial burden of morbidity and mortality, influenced by various factors. Further large-scale studies are necessary to gain a deeper understanding of these factors and to optimize management strategies accordingly.

Comprehensive Analysis of Prognostic Alternative Splicing Signatures in Tumor Immune Infiltration in Bladder Cancer.

Bladder cancer exhibits substantial heterogeneity encompassing genetic expressions and histological features. This heterogeneity is predominantly attributed to alternative splicing (AS) and AS-regulated splicing factors (SFs), which, in turn, influence bladder cancer development, progression, and response to treatment. This study aimed to explore the immune landscape of aberrant AS in bladder cancer and establish the prognostic signatures for survival prediction. Bladder cancer-related RNA-Seq, transcriptome, and corresponding clinical information were downloaded from The Cancer Genome Atlas (TCGA). Gene set enrichment analysis (GSEA) was used to identify significantly enriched pathways of cancer-related AS events. The underlying interactions among differentially expressed genes (DEGs) and cancer-related AS events were assessed by a protein-protein interaction network. Univariate and multivariate Cox regression analyses were performed to identify crucial prognostic DEGs that co-occurred with cancer-related AS events (DEGAS) for overall survival. The area under the curve (AUC) of receiver operating characteristic (ROC) curves was used to assess the efficiency of the prognostic signatures. The CIBERSORT algorithm was used to explore the abundance of immune infiltrating cells. A total of 3755 cancer-related AS events and 3110 DEGs in bladder cancer were identified. Among them, 379 DEGs co-occurred with cancer-related AS events (DEGAS), of which 102 DEGAS were associated with 14 dysregulated SFs. GSEA and KEGG analysis showed that cancer-related AS events were predominantly enriched in pathways related to immunity, tumorigenesis, and treatment difficulties of bladder cancer. Multivariate Cox regression analysis identified 8 DEGAS (CABP1, KCNN2, TNFRSF13B, PCDH7, SNRPA1, APOLD1, CX3CL1, and DENND5A) significantly associated with OS, and they were further integrated into the prediction model with good AUCs at 3-year, 5-year and 7-year ROC curves (all>0.7). Immune infiltration analysis revealed the significant enrichment of three immune cell types (B cells naïve, dendritic cells resting, and dendritic cell activated) in high-risk bladder cancer patients. This study not only unveiled comprehensive prognostic signatures of AS events in bladder cancer but also established a robust prognostic model based on survival-related DEGAS. These aberrant AS events, dysregulated SFs, and the identified 8 DEGAS may have significant clinical potential as therapeutic targets for bladder cancer.

A multidimensional analysis of the impact of obesity on immune checkpoint inhibitor therapy efficacy

BackgroundObesity is a well-known risk factor for developing malignant tumors and promoting tumor cell growth and spread. However, recent studies have shown that obese cancer patients, who typically have a worse prognosis than nonobese cancer patients, show a significant improvement in survival after receiving immune checkpoint inhibitor (ICI) therapy. This phenomenon is known as the “obesity paradox”. However, this phenomenon is influenced by tumor type and sex. Therefore, this study aimed to explore the impact of obesity on immunotherapy efficacy from multiple perspectives, aiming to verify this paradox and provide new scientific evidence on the effect of obesity on ICI efficacy.MethodsThis retrospective study evaluated the data of patients who received ICI therapy between June 2019 and August 2023. Automatic segmentation of skeletal muscle, subcutaneous fat, and visceral fat was performed using Slice-O-Matic software, and the corresponding skeletal muscle index (SMI), subcutaneous fat index (SFI) and visceral fat index (VFI) were calculated. The neutrophil-to-lymphocyte ratio (NLR) was determined by dividing the neutrophil count by the lymphocyte count. Univariate and multivariate Cox regression analyses were used to evaluate the correlation between body mass index (BMI), body composition parameters, and the NLR with overall survival (OS) and progression-free survival (PFS) in obese patients receiving ICI therapy.ResultsWe analyzed 219 patients with a median age of 60 years (IQR 53–69 years; 155 men and 64 women). Obese patients, particularly those with visceral fat accumulation, exhibited extended OS after ICI therapy (log­rank P = 0.027). Cox multivariate analysis revealed that the NLR (HR = 1.036; 95% CI: 0.996 to 1.078; P = 0.002) was independently associated with OS. Patients with a high NLR had worse OS than those with a low NLR.ConclusionsThis study corroborates the veracity of the "obesity paradox" under specific conditions and identifies NLR as an independent prognostic factor, with elevated NLR indicative of a poor prognosis.

Extracellular Vesicles May Predict Response to Atezolizumab Plus Bevacizumab in Patients with Advanced Hepatocellular Carcinoma.

Treatment with atezolizumab and bevacizumab has been approved as one of the standards of care for patients with advanced hepatocellular carcinoma (HCC). The median overall survival (OS) upon available treatments still remains below 2 years, urgently suggesting better stratification tools to identify ideal candidates for this treatment and potentially allowing personalized approaches. In this study, we evaluated the potential role of extracellular vesicles (EVs) as a novel biomarker in patients receiving atezolizumab and bevacizumab for HCC. We characterized EVs in 212 longitudinal serum samples from an observational cohort of 53 individuals with advanced HCC, who started therapy with atezolizumab plus bevacizumab at our center between January 2020 and March 2022. In our cohort, the overall efficacy of atezolizumab and bevacizumab was comparable to previously published phase III data. We detected significantly smaller EVs in treatment responders, while enlarged EVs were associated with significantly decreased efficacy of atezolizumab and bevacizumab in terms of OS. A decrease in vesicle size during immunotherapy was related to a longer progression-free survival (PFS). A univariate Cox regression analysis including various clinicopathological parameters (e.g., tumor stage, markers of inflammation, organ dysfunction, or tumor markers) revealed vesicle size as an independent prognostic marker in HCC patients receiving atezolizumab and bevacizumab. Moreover, higher vesicle concentrations and lower zeta potentials were identified as a positive prognostic factor throughout treatment. Distinct EV characteristics such as vesicle size, concentration, and zeta potential represent promising novel biomarkers in patients with advanced HCC receiving atezolizumab and bevacizumab, potentially helping to identify optimal candidates for checkpoint inhibitor-based treatments.

The very long-term risk of stroke after acute coronary syndrome and geographic differences. The ABC-10* study on heart disease

Abstract Background Little is known about the very long-term risk of stroke among acute coronary syndrome (ACS) survivors. Methods In this prospective study, we enrolled 535 ACS patients admitted to hospitals in three Italian provinces, discharged alive and followed for 24 years or death. The patient's residency was classified into three urban and three nearby rural areas. Results All patients completed the follow-up (6142 Perso-years). 85 (16%) patients suffered an acute stroke. Patients median age was 67 years, 70% were male, and 318 patients were residing in rural areas. Patients who had a stroke and those who had not shared most of the demographic and clinical characteristics. The incidence rate of overall stroke was 14/1000 person-year. Cox analyses showed older age (HR 3.13;95%CI 2.31-4.26), male gender (HR 1.88;95%CI 1.20-2.95), baseline diabetes (HR 2.25 95%CI 1.37-3.69), heart failure (HR 2.69;95%CI 1.71-4.24), and higher albumin/creatinine ratio (HR 1.75;95%CI 1.33-2.30) were all associated with an increased risk of stroke. while higher baseline eGFR, reperfusion, statin and beta-blockers treatment during follow-up were associated with a decreased risk; HR (0.55 (95%CI 0.42-0.72), 0.45(95%CI 0.29-0.71), 0.21(95%CI 0.13-0.34), and 0.37(95%CI 0.23-0.57), respectively). In the multivariate analysis, only older age (HR1.55;95%CI 1.08-2.21; p=0.02) was an independent predictor of stroke while statin treatment was independently associated with a lower risk (HR 0.35;95% CI 0.21-0.58; p&amp;lt;0.0001). However, all these variables did not predict the risk of stroke in competing risk regression analysis where death was treated as the competing event. A sub-analysis of the 43 patients who had a fatal stroke (FS) revealed 7/1000 person-year FS IR. The Cox regression and competing risk analyses of predictors of FS showed similar results. Interestingly, we observed an association between geographic areas of residence and the long-term FS risk as the risk increased going from rural to urban (HR 2.08;95%CI 1.14-3.80; p=0.02) areas and from north to middle and south provinces (HR 1.47;95%CI 1.00-2.15; p=0.04) in the univariate Cox regression analysis. Results kept true using multivariate Cox and Competing risk regression models. Conclusion This analysis reveals the significant urban-rural difference in the very long–term risk of fatal stroke among unselected ACS patients which highlights the importance of implementing a preventive policy based on area-specific knowledge.

Implantable loop recorders in children and adolescents with Brugada syndrome: the YoungBruLoop study

Abstract Background Young (&amp;lt;18 years of age) patients with Brugada syndrome (BrS) are often underrepresented in BrS studies and their management, especially related to syncopal episodes, remains unclear. Purpose To describe the arrhythmia prevalence and clinical implication derived from continuous rhythm monitoring by implantable loop recorder (ILR) among patients younger than 18 years of age, and to assess the etiology behind syncope of undetermined origin. Methods A total of 147 BrS patients with ILR were enrolled in 12 international centers and divided into pediatric (age &amp;lt;12 years; n=77, 52%) and adolescents (age 13 to 18 years; n=70, 48%). Results Mean age was 11.3 years (36.1% females, 21.1% spontaneous type I ECG). Forty-six patients (31.2%) underwent ILR implant due to syncope. Over a median follow-up of 3.6 years, an arrhythmic event was recorded in 22.4% of patients and in the vast majority of cases it was of non-ventricular origin (44% atrial, 47% bradyarrhythmias). Predictors of arrhythmias at univariate Cox Regression analysis were spontaneous type I ECG (HR 2.1 - 95%C.I. 1.1-4.1), history of syncope (HR 3.1 - 95%CI 1.5-6.3) and age &amp;gt;12 years (HR 2.0 - 95%C.I. 1.0-3.3). Ventricular arrhythmias occurred in 4 patients, all with spontaneous BrS, and were related to fever in half of cases. In patients with recurrent syncope, the prevalence of truly arrhythmic syncope was 17.8%, and it was due to brady-, atrial- and ventricular arrhythmias in 40%, 20% and 40% of cases, respectively. Conclusions Continuous rhythm monitoring with ILRs in BrS pediatric patients detects a broad range of heart rhythm disturbances including life-threatening arrhythmias. Ventricular arrhythmias occur predominantly in patients with spontaneous type I ECG and in half of cases are fever-related. Despite the young age, brady- and atrial arrhythmias are overall frequent and represent the cause of arrhythmic syncope in 60% of patients. Young BrS patients with syncope of undetermined origin may benefit from ILR implant.

Incidence and predictors of 2-year mortality following percutaneous left atrial appendage occlusion in the EWOLUTION tria

Abstract Background and aims Sufficient survival time following left atrial appendage occlusion (LAAO) is essential for ensuring the efficacy and cost-effectiveness of this strategy for stroke prevention. Understanding prognostic factors for early mortality after LAAO could optimize patient selection. In the current study we perform an in-depth analysis of 2-year mortality after LAAO, focusing particularly on potential predictors. Methods The EWOLUTION registry is a real-world cohort comprising 1020 patients that underwent LAAO. Endpoint definitions were prespecified and death was categorized as cardiovascular, non-cardiovascular, or of unknown origin. Mortality rates were calculated from Kaplan-Meier estimates. Patient characteristics and event rates were compared between deceased and alive patients by unpaired T-tests or Chi-squared test, as appropriate. Baseline characteristics significantly associated with death in univariate Cox regression analysis were incorporated into the multivariate analysis. All multivariate predictors were included in a risk model. Results 2-year mortality rate was 16.4% (CI: 14.0-18.7%), with 50% of patients dying from a noncardiovascular cause. Deceased patients had more comorbities and more often had a major bleeding after LAAO (20.6% vs 3.3%, p&amp;lt;0.001). Multivariate baseline predictors of 2-year mortality included age (HR 1.05, CI: 1.03-1.08, per year increase), heart failure (HR 1.73, CI: 1.24-2.41), vascular disease(HR 1.47, CI: 1.05-2.05), valvular disease (HR 1.63 CI: 1.15-2.33), abnormal liver function (HR 1.80 CI: 1.02-3.17) and abnormal renal function (HR 1.58, CI: 1.10-2.27). Mortality rate exhibited a gradual rise as the number of risk factors increased, reaching 46.1% in patients presenting with five or six risk factors. Conclusion One in six patients died within 2 years after LAAO. We were able to identify six independent predictors of mortality. When combined, this model showed a gradual increase in mortality rate with a growing number of risk factors, which may guide appropriate patient selection for LAAO.

Long-term prognosis in patients undergoing atrial fibrillation ablation

Abstract Aims The aim of the analysis was to assess the risk of atrial fibrillation (AF) recurrence in the long-term observation of contemporary patients undergoing pulmonary vein isolation (PVI), who did not have recurrence during the first year after catheter ablation. Methods Retrospective analysis has been performed. Inclusion criteria: (1) the patients undergoing their first PVI in years 2017–2022, (2) the electroanatomical system, contact force catheters and lesion indexes (Ablation Index or Lesion Size Index) were used, (3) no recurrences were observed during the first 12 months of follow-up, and (4) follow-up longer than 12 months was available. Demographic, clinical and echocardiographic data were collected. Follow-up was based on ambulatory visits with ECG/holter monitoring or implanted device interrogation, when available. Results A total of 247 patients were included. The median follow-up was 22 months (interquartile range, 16–31 months). After 24 months, ablation efficacy was 84%, and after 36 months, it was 72%. In the univariate Cox regression analysis, age, previous electrical cardioversion, glomerular filtration rate (eGFR) and the presence of coronary artery disease were linked to AF-free survival. Interestingly, nonparoxysmal AF, left atrial (LA) dimension, heart failure, hypertension or diabetes were not linked to the risk of long-term recurrences. In multivariate Cox regression analysis, presence of coronary artery disease and previous electrical cardioversion were independently linked to the risk of long-term recurrence. In 127 (51.4%) patients, information about the presence of low voltage areas (LVA) was available, and in 21 (16.5%) patients in this group, the presence of LVA was found. Survival of patients with LVA was strikingly worse than that of those without (Figure 1), log-rank test p &amp;lt;0.0001. Conclusions Patients who had no recurrences within one year after PVI, still have substantial risk of recurrence in the next 2 years. That concerns specially the patients who had LVA in the electroanatomical mapping.

Health-related quality of life and prognosis in cardiac sarcoidosis

Abstract Background Cardiac sarcoidosis (CS) is characterized by inflammatory myocardial disease, often leading to conduction disturbances, ventricular tachycardias, and heart failure. While factors like initial symptoms, LVEF, and troponin levels are known prognostic indicators, the impact of CS on health-related quality of life (HRQoL) is not well-understood. Additionally, limited data exists on the predictive value of FDG-PET in CS. Purpose This study aimed to assess HRQoL in CS patients and investigate its prognostic relevance concerning cardiac events. Methods Patients diagnosed with CS completed the RAND-36 general health-related questionnaire, covering eight dimensions. Clinical data were obtained from the Finnish myocardial inflammatory diseases registry. Follow-up data on cardiac events, including life-threatening ventricular tachyarrhythmias (VT/VF), heart transplant, left ventricular assist device (LVAD) implantation, pericardial tamponade, or death, were collected over 36 months. Results Of the 240 CS patients surveyed, 179 (75%) were female, with a median age of 56 [IQR 48 – 64]. CS patients reported significantly lower RAND-36 scores across all dimensions compared to the general Finnish population. Over the 3-year follow-up, 38 (16%) patients experienced cardiac-related adverse events, including VT/VF (26 cases), deaths (8 cases), heart transplants (2 cases), LVAD implantation (1 case), and pericardial tamponade (1 case). We divided CS patients into those without adverse event (N=202) and with adverse events (N=38). Interestingly, in four dimensions of PF 70.0 [50.0-90.0] vs 60.0 [33.8-80.0], p=0.019, RP 50.0 [0.0-100.0] vs 0.00 [0-56.3], p=0.002, MH 76.0 [59.0-88.0] vs 66.0 [51.0-84.0], p=0.036, and SF 75.0 [50-100] vs 62.5 [37.5-78.1], p=0.037 were significantly lower scores in the event group. Univariate Cox regression analysis (Table 1) revealed that physical functioning (PF) and role-physical (RP) dimensions, along with certain clinical factors, such as younger age, higher NYHA classification, elevated proBNP levels, lower hemoglobin levels, and the main manifestation of the disease as ventricular tachyarrhythmia, independently predicted adverse cardiac events. In the multivariate analysis, lower role-physical scores and younger age remained independent prognostic factors for adverse cardiac events. Conclusions Patients with CS demonstrated lower HRQoL compared to the general Finnish population. This study enhances our understanding of prognosis in CS and underscores the predictive value of HRQoL in identifying future adverse cardiac events, highlighting its relevance in the clinical management of these patients.