Univariate Survival Analysis Research Articles

High expression of tetraspanin CD63 predicts poor prognosis in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) has one of the poorest cancer prognosis rates; there is an urgent need to develop new drug therapies and biomarkers. CD63, a tetraspanin protein and well-known exosomal marker, is implicated in cancer progression; however, the significance of CD63 expression in ESCC remains unclear. Herein, we report the significance of CD63 expression by analyzing ESCC patient samples and ESCC cell lines. ESCC patient samples (n=86) were evaluated for CD63 expression by immunostaining; univariate and multivariate analysis using Cox proportional hazards were used to evaluate CD63 expression and clinicopathological features as prognostic factors for survival. For in vitro analysis, CD63 knockdown was performed in human ESCC cell lines (TE2 and TE15) using siRNA, and changes in proliferative potential. The gene expression change were also analyzed by microarray and gene set enrichment analysis. Overall survival was significantly worse in the CD63 high group (P=0.031, log-rank test). Five-year overall survival univariate analysis identified positive lymph nodes, pStage 3 or higher, and CD63 high expression as poor prognostic factors, while multivariate analysis showed that CD63 high expression was an independent poor prognostic factor (P=0.009, HR 2.56, 95%CI 1.269-5.167). CD63 knockdown in ESCC cell lines resulted in a phenotype of decreased proliferative potential. CD63 knockdown increased the expression of genes involved in cell adhesion and suppressed the expression of genes involved in granule secretion. CD63 also shown to affect nuclear import, protein complex localization, and ERBB-signaling pathways. In conclusion, CD63 affects gene expression in ESCC, and high tissue expression of CD63 predicts poor prognosis in ESCC patients.

Revisiting ABC Transporters and Their Clinical Significance in Glioblastoma.

Background: The multiple drug-resistant phenomenon has long since plagued the effectiveness of various chemotherapies used in the treatment of patients with glioblastoma (GBM), which is still incurable to this day. ATP-binding cassette (ABC) transporters function as drug transporters and have been touted to be the main culprits in developing resistance to xenobiotic drugs in GBM. Methods: This review systematically analyzed the efficacy of ABC transporters against various anticancer drugs from 16 studies identified from five databases (PubMed, Medline, Embase, Scopus, and ScienceDirect). Results: Inhibition of ABC transporters, especially ABCB1, improved drug efficacies. Staple GBM phenotypes, such as GBM stem cells and increased activation of the PI3K/Akt/NF-κB pathway, have been implicated in the expression of several ABC transporters. Using the datasets in The Cancer Genome Atlas and Gene Expression Omnibus, we found upregulated ABC transporters that either negatively impacted survival in univariate analyses (ABCA1, ABCA13, ABCB9, ABCD4) or were independent negative prognosis factors for patients with GBM (ABCA13, ABCB9). Our multivariate analysis further demonstrated three ABC transporters, ABCA13 (Hazard Ratio (HR) = 1.31, p = 0.017), ABCB9 (HR = 1.26, p = 0.03), and ABCB5 (HR = 0.77, p = 0.016), with the administration of alkylating agents (HR = 0.41, p < 0.001), were independent negative prognosis factors for patients with GBM. Conclusions: These findings reinforce the important role played by ABC transporters, particularly by ABCA13, ABCB9, and ABCB1, which could be potential targets that warrant further evaluations for alternate strategies to augment the effects of existing alkylating agents and xenobiotic drugs.

Ferroptosis Transcriptional Regulation and Prognostic Impact in Medulloblastoma Subtypes Revealed by RNA-Seq.

Medulloblastoma (MB) is the most common malignant brain tumor in children, typically arising during infancy and childhood. Despite multimodal therapies achieving a response rate of 70% in children older than 3 years, treatment remains challenging. Ferroptosis, a form of regulated cell death, can be induced in medulloblastoma cells in vitro using erastin or RSL3. Using two independent medulloblastoma RNA-sequencing cohorts (MB-PBTA and MTAB-10767), we investigated the expression of ferroptosis-related molecules through multiple approaches, including Weighted Gene Co-Expression Network Analysis (WGCNA), molecular subtype stratification, protein-protein interaction (PPI) networks, and univariable and multivariable overall survival analyses. A prognostic expression score was computed based on a cross-validated ferroptosis signature. In training and validation cohorts, the regulation of the ferroptosis transcriptional program distinguished the four molecular subtypes of medulloblastoma. WGCNA identified nine gene modules in the MB tumor transcriptome; five correlated with molecular subtypes, implicating pathways related to oxidative stress, hypoxia, and trans-synaptic signaling. One module, associated with disease recurrence, included epigenetic regulators and nucleosome organizers. Univariable survival analyses identified a 45-gene ferroptosis prognostic signature associated with nutrient sensing, cysteine and methionine metabolism, and trans-sulfuration within a one-carbon metabolism. The top ten unfavorable ferroptosis genes included CCT3, SNX5, SQOR, G3BP1, CARS1, SLC39A14, FAM98A, FXR1, TFAP2C, and ATF4. Patients with a high ferroptosis score showed a worse prognosis, particularly in the G3 and SHH subtypes. The PPI network highlighted IL6 and CBS as unfavorable hub genes. In a multivariable overall survival model, which included gender, age, and the molecular subtype classification, the ferroptosis expression score was validated as an independent adverse prognostic marker (hazard ratio: 5.8; p-value = 1.04 × 10-9). This study demonstrates that the regulation of the ferroptosis transcriptional program is linked to medulloblastoma molecular subtypes and patient prognosis. A cross-validated ferroptosis signature was identified in two independent RNA-sequencing cohorts, and the ferroptosis score was confirmed as an independent and adverse prognostic factor in medulloblastoma.

Tumor-infiltrating plasma cells are a prognostic factor in penile squamous cell carcinoma.

Penile cancer (PeCa) is a rare disease with poor prognosis in the metastatic stage. Neither effective adjuvant nor palliative therapeutic options are available. Research efforts in this field have so far failed to establish robust predictors of survival. To identify prognostic targets in PeCa, the current project focused on characterizing the tumor microenvironment (TME). A study cohort of 93 men with PeCa was used for the construction of a tissue microarray and immunohistochemical staining for CD3, CD4, CD8, CD20, CD56, CD138, FoxP3, and PD-L1. The quantity and spatial distribution of tumor-infiltrating immune cells were analyzed using digital image analysis. PD-L1 staining of tumor and immune cells was manually scored (combined positivity score (CPS)). T cells, T helper cells, cytotoxic T cells (CTLs), and regulatory T cells were detected in > 90% of PeCa and B cells in 88%, plasma cells in 85%, and NK cells in 23%. Approximately 50% of the PeCa samples were PD-L1 positive. In the univariate survival analysis, high PD-L1 CPS, plasma cells, CTLs, and B cells were significantly associated with favorable overall survival (OS), and the latter two with adverse recurrence-free survival. In multivariate analysis, plasma cells remained a significant factor for favorable OS (p = 0.04). In this study, the immune cells in the TME, especially plasma cells, were favorably associated with patient survival compared to other established prognostic factors in PeCa. Contemporarily, plasma cells have been discussed in the light of contributing to responses to modern immunotherapies. The results of this study support this notion.

The immune-related gene CD5 is a prognostic biomarker associated with the tumor microenvironment of breast cancer.

The occurrence and progression of breast cancer (BCa) are complex processes involving multiple factors and multiple steps. The tumor microenvironment (TME) plays an important role in this process, but the functions of immune components and stromal components in the TME require further elucidation. In this study, we obtained the RNA-seq data of 1086 patients from The Cancer Genome Atlas (TCGA) database. We calculated the proportions of tumor-infiltrating immune cells (TICs) and immune and stromal components using the CIBERSORT and ESTIMATE methods, and we screened differentially expressedgenes (DEGs). Univariate Cox regression analysis of overall survival was performed on the DEGs, and a protein-protein interaction network of their protein products was generated. Finally, the hub gene CD5 was obtained. High CD5 expression was found to be associated with longer survival than low expression. Gene set enrichment analysis showed that DEGs upregulated in the high-CD5 expression group were mainly enriched in tumor- and immune-related pathways, while those upregulated in the low-expression group were enriched in protein export and lipid synthesis. TIC analysis showed that CD5 expression was positively correlated with the infiltration of CD8+ T cells, activated memory CD4+ T cells, gamma delta T cells, and M1 macrophages and negatively correlated with the infiltration of M2 macrophages. CD5 can increase anticancer immune cell infiltration and reduce M2 macrophage infiltration. These results suggest that CD5 is likely a potential prognostic biomarker and therapeutic target, providing novel insights into the treatment and prognostic assessment of BCa.

Analysis of the effect of inflatable mediastinoscopy esophagectomy and minimally invasive Mckeown esophagectomy combined with thoracoscopy and laparoscopy in the treatment of early esophageal cancer

Objective: To explore the operioperative and long-term outcomes of inflatable mediastinoscopic resection of esophageal carcinoma (IVMTE) and minimally invasive Mckeown resection of esophageal carcinoma (MIME) in early esophageal cancer. Methods: This is a retrospective cohort study. A retrospectively analysis was conducted on 176 patients with cT1N0M0 esophageal cancer who underwent IVMTE or MIME at the Department of Thoracic Surgery, Anhui Provincial Hospital Affiliated with Anhui Medical University from April 2017 to April 2019. There were 128 males and 48 females, aged (66.4±7.7) years (range: 45 to 87 years). General data, perioperative outcomes, pathological data of the tumors, and complications were recorded. Independent sample t-test, χ² test, and Wilcoxon rank-sum test was used to compare the data between the two groups. Propensity score matching was performed with gender, age, tumor location, differentiation degree, pT stage, pN stage, American Society of Anesthesiologists (ASA) classification, smoking history, and alcohol history were considered as covariates. The IVMTE group and MIME group were matched in a 1∶2 ratio using nearest neighbor match method with a caliper value of 0.02. Kaplan-Meier method was used to plot survival curves, with Log-rank test for univariate survival analysis. The Cox proportional hazards model was applied to analyze prognostic factors for overall survival, and subgroup stratification analysis was performed for pT stage. Results: After matching, the MIME group consisted of 54 cases, and the IVMTE group consisted of 27 cases. There were no statistically significant differences between the two groups in terms of gender, age, smoking history, alcohol history, ASA classification, tumor location, and other factors. The IVMTE group had shorter surgery time (M(IQR), 220 (45) minutes vs. 245 (56) minutes, Z=2.950, P=0.003) and less intraoperative blood loss (100 (50) ml vs. 125 (100) ml, Z=2.193, P=0.028) compared to the MIME group. There were no differences between the two groups in the number and quantity of lymph node stations dissected, and the IVMTE group was not at a disadvantage in terms of the number of lymph nodes dissected around the recurrent laryngeal nerve (all P>0.05). The 1-, 3-, and 5-year overall survival (OS) rates and recurrence-free survival (RFS) rates were not significantly different between the two groups (all P>0.05). Subgroup analysis showed no significant difference in OS and RFS rates between the pT1 and pT2 subgroups (all P>0.05). Multivariate Cox regression analysis suggested that ASA classification (HR=2.516, 95%CI: 1.126 to 5.624, P=0.025), pN stage (HR=2.485, 95%CI: 0.984 to 6.274, P=0.046), and whether adjuvant therapy was given postoperatively (HR=2.915, 95%CI: 1.304 to 6.515, P=0.009) were independent risk factors affecting 5-year OS rate. For 5-year RFS, pT stage (HR=0.403, 95%CI: 0.194 to 0.838, P=0.011), pN stage (HR=5.219, 95%CI: 2.401 to 11.346, P<0.01), and whether adjuvant therapy was given postoperatively (HR=5.644, 95%CI: 2.691 to 11.838, P<0.01) were independent risk factors, while the surgical approach was not an independent risk factor affecting patient prognosis. Conclusion: The short-term and long-term effect of IVMTE in the treatment of early esophageal cancer is good, and it can achieve effects comparable to MIME.

Associations of serum and tissue TIMP1 with host response and survival in colorectal cancer

Tissue inhibitor of matrix metalloproteinase 1 (TIMP1) is a multifaceted, cytokine-like bioactive molecule whose levels are elevated in a wide range of inflammatory diseases and are associated with prognosis. Additionally, TIMP1 may play a role in driving systemic inflammation. TIMP1 immunohistochemistry and TIMP1 serum concentrations were analyzed in a cohort of 776 colorectal cancer patients. TIMP1 histoscore by cell type (tumor cell, other) was quantified using digital image analysis. Serum TIMP1 levels were evaluated for correlations with tumor TIMP1 expression, and their associations with tumor characteristics, inflammation, and prognosis were investigated. High serum TIMP1 concentrations associated with shorter overall survival (multivariable HR 1.85, 95% CI 1.30–2.65). Serum TIMP1 levels positively correlated with markers of systemic inflammation and tumor necrosis percentage but not with TIMP1 expression in tumor tissue. High TIMP1 intensity in tumor stroma associated with longer cancer-specific and overall survival in univariable analysis but not in multivariable models. T cell densities in tumor tissue positively correlated with tumor stromal TIMP1 expression and negatively with tumor epithelial TIMP1 expression. Serum TIMP1 levels show promise as a prognostic marker for colorectal cancer and correlate with systemic inflammatory markers, but do not correlate with TIMP1 expression in tumor tissue.

Association Between Artificial Liver Support System and Prognosis in Hepatitis B Virus-Related Acute-on-Chronic Liver Failure.

The artificial liver support system (ALSS) has been recruited as an available method for patients with acute-on-chronic liver failure (ACLF), but its impact on the outcome of ACLF remains controversial. This study aimed to investigate the association between ALSS treatment and short-term prognosis of hepatitis B-related ACLF (HBV-ACLF). This was a retrospective observational cohort study, and data were obtained from the Center of Infectious Diseases, West China Hospital of Sichuan University, between Mar 2015 and December 2021. The primary outcome was 28-day transplant-free mortality and the secondary outcomes were 60- and 90-day transplant-free mortality. Patients were divided into standard medical therapy (SMT) and ALSS groups. Kaplan-Meier survival analysis curves show the 28-day, 60-day and 90-day transplant-free mortality. Based on the feature selection result of univariate logistic, univariate Cox and Boruta algorithm, the univariate and multivariate logistic and COX regression models were used to investigate the association of ALSS with 28-day, 60-day and 90-day outcomes in patients with HBV-ACLF. Subgroup analyses were conducted to test the robustness of the results. A total of 589hBV-ACLF patients were enrolled in this study (median age, 48.00 years [IQR,44.00-55.00 years]; 70 [11.9%] female). The 28-day, 60-day and 90-day transplant-free mortality rates were 25.6%, 35.8% and 38.9%, respectively. In the univariate and Kaplan-Meier survival analysis, ALSS could significantly reduce 28-day, 60-day and 90-day transplant-free mortality compared to SMT. Furthermore, an in-depth analysis of our study revealed that the therapeutic benefits of the ALSS were observed exclusively within the end-stage (PT-INR ≥ 2.5) subgroup of HBV-ACLF patients. Compared to SMT, ALSS demonstrated efficacy primarily in enhancing the short- term prognosis of end-stage HBV-ACLF patients, rather than across the entire spectrum of HBV-ACLF patients.

Protein expression of CD44 in patients with meningioma tumors: association with clinicopathological parameters and survival

ObjectiveMeningiomas are a molecularly ill-defined heterogeneous group of indolent intracranial tumors. Though, WHO grade 1 tumors are histologically benign, sometimes they transform into malignant and may be recurrent which remains always challenging to clinicians. Therefore, the current study sought to discover the clinical relevance of CD44 in meningioma patients.MethodProtein expression of CD44 was investigated using immunohistochemistry in a total of 70 meningioma patients. Immunoscore performed using modified H-score, CD44 expression correlated with clinicopathological parameters and progression-free survival (PFS) and overall survival (OS). Univariate and multivariate survival analysis was analyzed. The data was evaluated using SPSS statistical software and P-value ≤ 0.05 was considered as significant.ResultsThe membranous and cytoplasmic protein expression of CD44 was noted in meningioma tumors. Based on H-score, the weak (0–190 score) and strong (191–300 score) immunoreactivity was observed in 62.9% and 37.1% of patients, respectively. A statistically significant positive correlation was found between strong CD44 expression and WHO grade 2/3 tumors (χ2 = 33.551, r = + 0.692, P = 0.0001), and with the presence of brain invasion (χ2 = 19.521, r = + 0.528, P = 0.001). In Kaplan–Meier univariate survival analysis for PFS and OS, apart from WHO grade of tumors (PFS; log-rank = 12.309, P = 0.0001, OS; log-rank = 17.830, P = 0.0001) and brain invasion status (PFS; log-rank = 11.941, P = 0.001, OS; log-rank = 13.554, P = 0.0001) CD44 expression (PFS; log-rank = 14.942, P = 0.0001, OS; log-rank = 20.986, P = 0.0001) remained significant prognostic factor for PFS and OS. In multivariate survival analysis, at step 1, only CD44 remained independent prognosticator for PFS (HR = 11.014, 95% CI = 2.256–23.602, P = 0.001) and OS (HR = 8.553, 95% CI = 2.831–25.847, P = 0.0001). In relation to treatment offered, patients with strong CD44 expression and if treated with surgery followed by adjuvant radiotherapy showed a high incidence of death (log-rank = 13.402, P = 0.0001) as compared to patients treated with surgery only. Receiver operating characteristic (ROC) curves also confirmed a good efficacy of CD44 as a prognosticator for disease outcome (PFS; P = 0.0001, OS; P = 0001).ConclusionOur overall findings addressed that a study of CD44 protein expression would be beneficiated to meningioma patients from unnecessary overtreatment and drug-induced toxicity. Also, CD44 could be one of the promising biomarkers that might differentiate high-risk meningioma patients for better treatment management.

Supracricoid Partial Laryngectomy Versus Radiation Therapy for cT3N0M0 Glottic SCC: Outcomes in Candidates for Total Laryngectomy Responding Well to Induction Chemotherapy.

To evaluate whether supracricoid partial laryngectomy (SCPL) may be a viable alternative to radiation therapy (RT) for patients with glottic cT3N0M0 squamous cell carcinoma (SCC) who are surgical candidates for total laryngectomy (TL) and respond well to platinum-based induction chemotherapy. Retrospective case series review of 18 consecutive patients with cT3N0M0 glottic SCC, initially considered surgical candidates only for TL who showed a good response to platinum-based induction chemotherapy, managed at a French university teaching institution with either SCPL (n = 9) or RT (n = 9). The main endpoints were 10-year local control and laryngeal preservation. The secondary endpoints were 10-year survival, causes of death analysis, and univariate analysis of local control and survival. The 10-year actuarial local control, laryngeal preservation, survival rates were 77.8%, 88.9%, and 66.7% after SCPL, respectively, and 72.9%, 87.5%, and 33.3%, after RT without significant statistical differences. In univariate analysis none of the clinical variables under analysis were related to local control and survival. Our data suggest that SCPL may warrant further consideration as a treatment option for glottic cT3N0M0 SCC patients who respond well to platinum-based induction chemotherapy. However, additional prospective research is warranted given the retrospective, nonrandomized nature of the presented case series.

Whole slide imaging of tumour microenvironment in classical Hodgkin’s lymphoma: development of a clinical prediction model based on programmed death-ligand 1 and tumorous Reed-Sternberg cells

AimsThe prognostic impact of programmed death-ligand 1 (PD-L1) cells in classic Hodgkin lymphoma (cHL) tumour microenvironment remains undefined.MethodsModel development via Transparent Reporting of a multivariable prediction model for Individual Prognosis...

Low Expression of FAM96B is Associated with Poor Prognosis in Hepatocellular Carcinoma.

Recently, studies on FAM96B functions mainly focused on its role in maintaining the normal physiological function of cells. However, the clinical implications of FAM96B in hepatocellular carcinoma (HCC) are still unclear. FAM96B mRNA expression was detected in human HCC tissues and the matched nontumorous tissues by quantitative real-time reverse transcription (qRT-PCR) and then validated in The Cancer Genome Atlas (TCGA) database. Immunohistochemistry assay (IHC) was performed on all 137 cases of HCC samples to examine the protein level of FAM96B. Subsequently, the associations between FAM96B expression and clinicopathological parameters and prognosis were further analyzed. The mRNA level of FAM96B was found to be significantly lower in HCC tissues compared to non-tumorous tissues, as observed in both the local hospital and TCGA database.Immunohistochemistry assay analysis revealed a decrease in FAM96B expression in 78 out of 137 cases, which was significantly associated with larger tumor size, higher Barcelona clinic liver cancer or Child stage, and early distant metastasis. Patients with low FAM96B levels tended to have an unfavorable disease-free and overall survival. Moreover, FAM96B was identified as an independent predictor of patient prognosis in both univariate and multivariate survival analyses. Mechanistically, FAM96B was found to inhibit cancer progression by inducing apoptosis in liver cancer cells and inhibiting their growth. Our findings provide the first evidence suggesting the involvement of FAM96B in the progression of HCC. Additionally, FAM96B could potentially serve as a marker for tumor recurrence and prognosis in HCC patients.

Long-term Outcomes of Persistent Postoperative Opioid Use: A Retrospective Cohort Study.

To determine the association between PPOU and the long-term risk of OUD and opioid overdose. PPOU is a commonly used outcome in the surgical literature; its incidence and risk factors have been well described. However, its association to long term outcomes, including OUD and opioid overdose, is unknown. A retrospective cohort study utilizing the Veterans Health Administration corporate data warehouse. Patients undergoing any surgery between January 1, 2008 and December 31, 2018 were included and followed until December 31, 2020. Univariate and multivariate survival analysis were used to determine the association between PPOU and OUD and overdose. Sensitivity analyses were conducted to determine the impact of different definitions of persistent opioid use and the effect of preoperative opioid use. A total of 344,745 patients undergoing surgery were included and followed for a median of 6.18 years (IQR 3.53-9.12). PPOU was associated with an increased hazard of developing both OUD (HR = 1.88, CI: 1.81-1.95, P < 0.001) and overdose (HR = 1.83, CI: 1.72-1.94, P < 0.001). This association remained consistent after adjustment for comorbidities and across all sensitivity analyses. Surgical patients who develop PPOU are at increased risk of both OUD and overdose as compared to surgical patients who do not develop persistent use.

Prognostic effect of immunohistochemically determined molecular subtypes in gastric cancer

IntroductionGastric cancer is the fifth most common cancer worldwide and the fourth most common cause of cancer-related death. Two molecular subtyping classifications were recently introduced: The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) classifications.MethodsWe classified a cohort of 283 gastric cancer patients undergoing surgery at Helsinki University Hospital between 2000 and 2009. We constructed a tumour tissue microarray immunostained for the following markers: microsatellite instability (MSI) markers MSH2, MSH6, MLH1, and PMS2; p53; E-cadherin; and EBERISH.ResultsIn the univariate survival analysis for disease-specific survival, the Epstein–Barr virus (EBV) -positive subtype exhibited the worst prognosis with a hazard ratio (HR) of 2.49 (95% confidence interval [CI] 1.19–5.25, p = 0.016) compared with the most benign subtype, chromosomal instability (CIN). Using TCGA’s classification, the genetically stable (GS) and MSI subtypes exhibited a worse survival compared with CIN (HR 1.73 [95% CI 1.15–2.60], p = 0.009 and HR 1.74 [95% CI 1.06–2.84], p = 0.027, respectively). Using the ACRG classification, the p53 aberrant subtype exhibited the best prognosis, whereas wild-type p53, MSI, and the epithelial–mesenchymal transition (EMT) subtypes exhibited poorer prognoses (EMT: HR 1.90 [95% CI 1.30–2.77], p < 0.001) when compared with aberrant p53.ConclusionsImmunohistochemical analysis can identify prognostically different molecular subtypes of gastric cancer. The method is inexpensive and fast, yet reveals significant information for clinical decision-making. However, our study did not find that either molecular subtyping performed better than the other classification. Thus, further development of the most optimal grouping of different molecular subtypes is still needed.

ITGB4 is a prognostic biomarker and correlated with lung adenocarcinoma brain metastasis.

The aim of this study is to explore the prognostic value and immune signature of ITGB4 expression in lung adenocarcinoma (LUAD) brain metastasis. We comprehensively screened genes associated with LUAD brain metastasis by integrating datasets from the GEO database and TMT-based quantitative proteomics profiles. Univariable survival and Multivariate Cox analysis was used to compare several clinical characteristics with survival, and a risk model was constructed. The biological functions were explored via GO and KEGG analysis. Gene set enrichment analysis (GSEA) was performed using the TCGA dataset. In addition, we use TIMER to explore the collection of ITGB4 Expression and Immune Infiltration Level in LUAD. The ability of ITGB4 to regulate tumor metastasis was further assessed by migration, invasion assay and Western-blot in H1975-BrM4 cells. We found that ITGB4 was the only gene with high clinical diagnostic and prognostic value in LUAD. Enrichment analysis indicated that ITGB4 is associated with brain metastasis, infiltration of immune cells, and the response to immunotherapy. ITGB4 expression can effectively predict the outcomes of patients with LUAD who are receiving anti-PD-1 therapy. ITGB4 knockdown inhibited the invasion, migration of H1975-BrM4 brain metastasis cells, as well as epithelial-mesenchymal transition (EMT) abilities. The heightened expression of ITGB4 protein was shown to promote EMT and enhance the metastatic potential. ITGB4 promotes the progression in H1975-BrM4 cells via MEK/ERK signaling pathway. Our findings indicate that the expression of ITGB4 is linked to the occurrence of brain metastasis and infiltration of immune cells, suggesting that ITGB4 might be a clinical treatment target for LUAD.

Impact of natremia on metastatic non small cell lung cancer patients receiving immune checkpoint inhibitors

Hyponatremia has been established as a prognostic indicator of survival in metastatic non-small cell lung cancer (mNSCLC). Conversely, the influence of normal sodium levels remains unexplored. This study aims to investigate the impact of natremia in mNSCLC patients undergoing treatment with immune checkpoint inhibitors (ICIs). Clinical and biochemical data of patients treated with ICIs for mNSCLC were obtained. Availability of baseline sodium values was a study inclusion criterion. Patients were categorized into two groups based on the cut off sodium value, determined using the receiver operating characteristic curve. Subsequently, the influence of sodium levels on response rate (RR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) was analyzed. PFS and OS were assessed via the Kaplan–Meier method. Univariate and multivariate Cox regression analyses were conducted to evaluate prognostic factors for PFS and OS. The analysis included 88 patients, of whom 73.1% were men, with a median age of 71 years (range, 47–91). A comparison between patients with baseline natremia ≥ 140 mEq/L (n = 43) and those with < 140 mEq/L (n = 45) revealed PFS durations of 7.0 vs. 2.1 months (p < .01) and OS durations of 15.6 vs. 6.8 months, respectively (p = .02). In the univariate survival analysis, pre-ICI serum sodium ≥ 140 mEq/L (p = .01) was associated with improved PFS, while factors associated with OS included brain metastasis (p = .05) and pre-ICI serum sodium ≥ 140 mEq/L (p = .02). In the multivariate analysis, pre-ICI serum sodium ≥ 140 mEq/L maintained a statistically significant association with OS (p = .04)..This study represents the first investigation into the impact of normonatremia in mNSCLC. Our findings suggest that serum sodium levels < 140 mEq/L at baseline and initial assessment are independently associated with poorer PFS and OS in mNSCLC patients undergoing first-line treatment with ICIs.

Predictors of poor treatment outcomes among drug-resistant tuberculosis patients in Hunan province, China

BackgroundDrug-resistant tuberculosis (DR-TB) is a significant public health concern, often resulting in poor treatment outcomes. This study aims to identify predictors of poor treatment outcomes among patients with DR-TB in Hunan Province, China. MethodsA retrospective cohort study was conducted in Hunan Province using data collected between 2013 and 2018 among patients with DR-TB treatment. Univariable and multivariable parametric survival analyses were performed using a shared frailty survival model with a Weibull distribution and Gamma frailty to identify determinants of poor treatment outcomes. Adjusted hazard ratios (AHR) with a 95 % confidence interval (CI) were calculated for the best-fitted model. The goodness of fit for the model was assessed using the Cox-Snell residual test. ResultsA total of 1384 bacteriologically confirmed DR-TB patients were included in the analysis. Of these, 9.97 % (95 % CI: 8.05–11.67 %) experienced poor treatment outcomes. The hazard of poor treatment outcomes was significantly higher among patients with a history of previous TB treatment compared to those with new TB (AHR = 1.82, 95 % CI: 1.27–2.61). Additionally, each one-day delay in diagnosis was associated with a slightly increased hazard of poor treatment outcomes (AHR = 1.00034, 95 % CI:1.000041–1.00064). Patients who received medication supervision and consistent treatment follow-up (i.e., systematic management) had a significantly lower hazard of poor treatment outcomes than those without systematic management (AHR = 0.08, 95 % CI: 0.05–0.14). ConclusionA substantial proportion of DR-TB patients in Hunan Province experience poor treatment outcomes, with prior TB treatment and delays in diagnosis being key predictors. Early diagnosis and systematic management, including medication supervision and consistent follow-up, significantly reduce the risk of poor treatment outcomes. Focused interventions for previously treated TB cases are crucial to improving treatment outcomes and mitigating the risk of long-term physical sequelae among DR-TB survivors.

Predictive value of direct bilirubin and total bile acid in lung adenocarcinoma patients treated with EGFR-TKIs

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have been the standard treatment for patients with sensitizing EGFR mutation. However, almost all patients eventually acquire resistance to EGFR-TKIs. Therefore, easily available parameters to estimate the outcome of lung adenocarcinoma patients treated with EGFR-TKIs are in urgent need. Lung adenocarcinoma patients harbored EGFR sensitive mutant and received EGFR-TKIs as first-line or second-line treatment were recruited in the study. X-tile software were utilized to determine the optimal cut-off value of Alkaline phosphatase (ALP), direct bilirubin (DB), total bile acid (TBA), and high-density lipoprotein-cholesterol (HDL-C). The prognostic value of ALP, DB, TBA, and HDL-C for Progression-free survival (PFS) in patients were evaluated by the Kaplan-Meier curve. We applied univariate and multivariate survival analysis to identify the independent predictor for PFS in patients with EGFR-mutant advanced lung adenocarcinoma and received EGFR-TKIs. A total of 131 lung adenocarcinoma patients with a median age of 58 years old were included in the final analysis. Patients with elevated level of DB and HDL-C showed a longer PFS, while high level of ALP and TBA indicated shorter PFS in response to EGFR-TKI treatment. The multivariate survival analyses revealed a significant association of prolonged PFS with increased DB, and decreased TBA. In conclusion, these findings suggest that DB and TBA were significant independent predictors of PFS in EGFR-TKI-treated patients with advanced lung adenocarcinoma.

Role of volumetric tumor enhancement on CT in predicting overall survival in patients with unresectable pancreatic ductal adenocarcinoma

PurposeTo assess the utility of volumetric tumor enhancement on CT to predict tumor treatment response and the overall survival (OS) of patients with PDAC undergoing FOLFIRINOX-based systemic chemotherapy. Additionally, we aim to explore the performance of a novel model that incorporates relevant volumetric CT-derived parameters to the established RECIST 1.1 in predicting both treatment response and OS. Material and methodsIn this retrospective single-institution study, 127 patients with PDAC who received FOLFIRINOX neoadjuvant chemotherapy between December 2012 and November 2021 were included. Manual volumetric segmentation of the single largest tumor was performed on portal venous phase images. Total and enhancing tumor volumes were calculated. Response by RECIST 1.1 was compared to response by tumor volume and enhancing tumor volume on follow-up CT. ResultsThere was no association between overall survival and RECIST 1.1 (p-value = 0.284), volumetric RECIST (p-value = 0.402), and other volumetric CT variables, except for a percentage reduction in enhancing tumor volume (p-value = 0.043). Using univariate survival analysis for categorical thresholds defined by CART, the percentage change in enhancing tumor volume was associated with OS (p-value = 0.018). There was also a significant association between baseline enhancing tumor volume and OS (p-value <0.0001). Using these two categories, we defined a multivariable model associated with OS (p-value <0.0001). ConclusionPercentage reduction in enhancing tumor volume was related to OS in non-surgical PDAC patients treated with FOLFIRINOX chemotherapy and could potentially be incorporated into patient survival prediction models.

Risk Factors for Chronic Kidney Disease in Adult Patients with Congenital Heart Disease and Its Relationship with Cardiovascular Mortality.

Background: Patients with congenital heart disease (CHD) show risk factors for chronic kidney disease (CKD) and it is well known that CKD has a large negative impact on survival. Methods: Observational and prospective cohort study. Adult CHD patients and controls were matched for age and sex. Results: A total of 657 CHD adult patients (cases) and 1954 controls were studied. Median age in CHD patients was 30 (17-62) years and 373 (57%) were male. The prevalence of CKD (Glomerular filtration rate (GFR) < 60 mL/min/1.73 m2) was 0.2% and 4.5% in the control and CHD groups, respectively. Binary logistic regression analysis determined as risk factors for CKD in CHD patients: age [1.54 (1.04-1.28), p = 0.009], dyslipidemia [19.8 (1.35-301.1), p = 0.031], low iron concentration [0.96 (0.96-0.93), p = 0.048], cyanosis [25.7 (1.60-411.8), p = 0.022], and Down syndrome [46.8 (8.09-2710), p = 0.003]. During a follow-up time of 6.8 (1.2-10.5) years, cardiovascular mortality occurred in 31 patients with CHD showing, through the Kaplan-Meier test, a worse outcome among patients with CKD (p < 0.05) as was also seen in the univariate Cox regression survival analysis. However, after adjusting for other variables, this significance was lost, with age remaining as the unique independent prognostic factor. Conclusions: The prevalence of CKD was much higher in patients with CHD than in the control group; age, cyanosis, and Down syndrome were the predictors of a higher risk of CKD among CHD patients. Although CKD was associated with worse survival in CHD patients, only age was identified as an independent prognostic factor for cardiovascular mortality.