Independent Prognostic Predictor Research Articles

Tissue Cadherin 17 (CDH17): An Important Prognostic Determinant of Colorectal Cancer Using Digital Image Analysis

ABSTRACTBackgroundColorectal cancer (CRC) is a commonly diagnosed malignancy with significant mortality rates worldwide. The identification of robust prognostic biomarkers for prediction of survival outcomes and recurrence can aid disease management and improve patients' quality of living.AimThis study aimed to investigate the prognostic value of cadherin 17 (CDH17) tissue expression in CRC patients by utilizing a standardized automated immunohistochemistry (IHC) platform integrated with a digitalized scoring system.Methods and ResultsIHC was conducted to assess CDH17 expression on tumor tissues obtained from 150 retrospective CRC cases. A computer‐assisted imaging analysis was performed to quantify CDH17 tissue expression using an IHC scoring algorithm known as the Membrane (M) Score. The relationship between CDH17 M Score and clinicopathological factors such as TNM staging, distant metastasis, and recurrence status was analyzed. The prognostic value of CDH17 M Score was determined by Kaplan–Meier curves and Cox regression analysis for overall survival (OS) and recurrence‐free survival (RFS). Comparison of M Score and pathologist visual scoring was made to assess the validity of software‐derived IHC scoring. CDH17 expression, as measured by M Score, was found to be significantly increased in tumor tissues compared to adjacent normal tissues, and its expression is associated with advanced staging and distant metastasis (normal vs. tumor, p = 0.0011; Stages IV vs. I–III, p < 0.0162; with vs. without metastasis, p = 0.0026; Mann–Whitney U test). Prognostic analysis revealed that high CDH17 M Score was associated with poor OS and RFS (OS, p = 0.0118; RFS, p = 0.0021; log‐rank test). Furthermore, multivariate Cox regression analysis identified that CDH17 M Score was an independent prognostic predictor for OS (HR = 2.296, 95% CI = 1.154–4.968, p = 0.0240) and RFS (HR = 2.489, 95% CI = 1.062–6.494, p = 0.0447).ConclusionIncreased CDH17 M Score was associated with advanced tumor staging and poor survival outcomes using an automated IHC system integrated with a digital image analysis software, highlighting CDH17 could serve as an independent prognostic marker for CRC patients.

Prognostic Effect of the PNI and LSR in Patients with Esophageal Squamous Cell Carcinoma Patients Receiving Radiotherapy.

The prognostic nutritional index (PNI) has been used to assess the immunonutritional status of cancer patients and can predict the prognosis of various solid cancers, and the serum alanine transaminase (ALT)/aspartate transaminase (AST) ratio (LSR) is considered a good predictor of liver injury. A retrospective cohort analysis was conducted to investigate the relationship between the prognosis of esophageal squamous cell carcinoma (ESCC) patients and LSR or PNI, as well as to combine these two indicators (LSR-PNI) for further prognostic analysis in ESCC patients undergoing radiotherapy (RT). In this study, 134 patients with esophageal cancer were retrospectively analyzed. The Chi-square test was utilized to compare count data, and univariate and multivariate Cox proportional hazards models were employed to identify independent risk and prognostic factors. Additionally, the combination of LSR and PNI (LSR-PNI) was analyzed. This study included a cohort of 134 patients, comprising 105 males with a mean age of 70.7 years and 29 females with a mean age of 76.3 years. Pathological examination categorized 41 cases as stage I-II and 93 cases as stage III-IV. The predominant treatment modality administered was intensity-modulated radiotherapy (IMRT) for esophageal cancer. Of these patients, 96 received radiation doses ≤ 54Gy, while 38 were administered doses > 54Gy. Radiation-induced adverse effects were observed in 67 patients, with the remaining 67 showing no such effects. Kaplan-Meier survival analysis revealed that elevated levels of the lymphocyte-to-serum ratio (LSR) and prognostic nutritional index (PNI) were significantly correlated with improved progression-free survival (PFS) and overall survival (OS). The high-LSR group demonstrated longer PFS (14.4 vs. 9.3 months, p = 0.0469) and OS (19.9 vs. 13.7 months, p = 0.0315) compared to the low-LSR group, with respective 3-year survival rates of 18.4% vs. 12.7%. Similarly, patients in the high-PNI group exhibited superior PFS (13.9 vs. 8.9 months, p = 0.0071) and OS (19.0 vs. 13.5 months, p = 0.0002) compared to the low-PNI group, with 3-year survival rates of 19.6% vs. 11.3%. Stratification based on combined LSR and PNI levels categorized patients into low-, intermediate-, and high-risk groups. The low-risk group demonstrated significantly better PFS (17.8 vs. 10.1 vs. 8.2 months) and OS (24.1 vs. 14.3 vs. 12.9 months, p < 0.0001) compared to the intermediate- and high-risk groups, with 3-year survival rates of 24%, 14%, and 10.3%, respectively. Pretreatment LSR and PNI can serve as independent prognostic predictors for patients, with higher values of both being associated with improved progression-free survival and overall survival. Additionally, the combined LSR-PNI score effectively stratifies patients into distinct risk groups, offering a robust tool for predicting outcomes in clinical practice.

A novel hypoxia-induced lncRNA, SZT2-AS1, boosts HCC progression by mediating HIF heterodimerization and histone trimethylation under a hypoxic microenvironment.

Hypoxic microenvironment plays a critical role in solid tumor growth, metastasis and angiogenesis. Hypoxia-inducible factors (HIFs), which are canonical transcription factors in response to hypoxia, are stabilized under hypoxia and coordinate the process of hypoxia-induced gene expression, leading to cancer progression. Increasing evidence has uncovered that long noncoding RNAs (lncRNAs), which are closely associated with cancer, play crucial roles in hypoxia-mediated HCC progression, while the mechanisms are largely unknown. Here, we identified SZT2-AS1 as a novel lncRNA in HCC, which was induced by hypoxia in a HIF-1-dependent manner and promoted HCC growth, metastasis and angiogenesis both in vitro and in vivo. And SZT2-AS1 also mediated the hypoxia-induced HCC progression. Clinical data indicated that SZT2-AS1 level was substantially increased in HCC and closely associated with poor clinical outcomes, acting as an independent prognostic predictor. Mechanistically, SZT2-AS1 recruited HIF-1α and HIF-1β to form the HIF-1 heterodimer, and it was required for the occupancy of HIF-1 to hypoxia response elements (HREs) and HIF target gene transcription. In addition, SZT2-AS1 was required for hypoxia-induced histone trimethylation (H3K4me3 and H3K36me3) at HREs. Through recruiting methyltransferase SMYD2, SZT2-AS1 promoted trimethylation of H3K4 and H3K36 in HCC cells. Taken together, our results uncovered a lncRNA-involved positive feedback mechanism under hypoxia and established the clinical value of SZT2-AS1 in prognosis and as a potential therapeutic target in HCC.

Identification of Molecular Subtypes and Prognostic Traits Based on Chromosomal Instability Phenotype-Related Genes in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) exhibits significant molecular heterogeneity; however, previous studies have not fully explored its classification into distinct molecular subtypes. Here, we identified LUAD-significant chromosomal instability (CIN) phenotype genes (n = 24) using a TCGA-LUAD cohort (n = 592) and evaluated their ability to predict pathologic grade. Unsupervised clustering and principal component analysis revealed that LUAD patients could be classified into CIN phenotype-related subtypes (GroupLow, GroupModerate, and GroupHigh), each exhibiting distinct transcriptomic patterns. Notably, the GroupHigh showed significantly poor overall survival [OS; hazard ratio (HR) = 1.43, p-value < 10-3] and disease-free survival (DFS; HR = 1.27, p-value < 10-3). Univariate and multivariate analysis confirmed that its expression status was an independent prognostic predictor (p-value < 10-3, HR = 2.18, 95% C.I = 1.26-3.76) of the clinical outcomes, outperforming pathologic grade (p-value < 10-3, HR = 1.2, 95% C.I = 1.08-1.33). Moreover, analysis of surfactant metabolism-related genes revealed higher expression in the GroupLow, which was associated with a favorable prognosis. By integrating multiple independent cohorts (n = 779), we validated these findings and confirmed that CIN phenotype gene status serves as a critical prognostic marker in LUAD. Furthermore, genomic profiling showed that the GroupHigh exhibited frequent mutations in key genes such as KEAP1, LYST, SETD2, and TP53, with oncogenes in this group preferentially showing copy number gains. Our study highlights the significance of CIN phenotype gene status as a predictor of LUAD prognosis and its association with transcriptomic and genomic alterations, paving the way for further clinical validation and potential therapeutic interventions.

Prognosis in patients with residual pulmonary hypertension after transcatheter edge-to-edge repair for secondary mitral regurgitation

Abstract Background Pulmonary hypertension (PH) is an independent prognostic predictor in patients with heart failure (HF). Recently, transcatheter edge-to-edge repair (TEER) for secondary mitral regurgitation (MR) has been reported to reduce HF hospitalizations and mortality. Elevated pulmonary artery pressure (PAP) before TEER is associated with a poor prognosis; however, the impact of residual PH after TEER on clinical events has not been investigated. Purpose The purpose of this study is to clarify whether residual PH influences outcomes in patients with HF treated by TEER for secondary MR. Methods We included 63 patients who underwent TEER for severe secondary MR and post-procedural right heart catheterization in our institute from January 2016 to August 2023. Mean PAP after TEER was categorized as increased (&amp;gt;20mmHg) versus not increased (≤20mmHg), and we investigated the clinical outcomes between the two groups. The primary endpoint is a composite outcome of all-cause mortality and HF hospitalization. Results Among 63 patients, the average age was 78 years, and 60.3% were male. All patients had Secondary MR, and 52 patients (82.6%) had ventricular Secondary MR—right heart catheterization after TEER revealed a mean PAP of 21.6±7.7 mmHg, pulmonary vascular resistance (PVR) of 2.7±1.4 wood unit (WU), and pulmonary artery wedge pressure (PAWP) of 12.2±5.9 mmHg. Patients with residual PH had higher composite outcome rates of death from any cause or HF hospitalization compared to those without PH (56.1% vs. 19.5%; hazard ratio: 2.62; 95% confidence interval: 1.1 to 6.9; p=0.03). Multivariate Cox regression analysis showed that residual PH and higher PAWP after TEER were associated with higher mortality (hazard ratio: 1.14; 95% confidence interval: 1.03 to 1.28; p=0.01). Conclusion Our results suggest that patients with residual PH after TEER have a poor prognosis. Residual PH and high PAWP after TEER are associated with mortality.

Quality of muscle in the thigh predicts the prognosis in patients with non-ischemic cardiomyopathy

Abstract Background Skeletal muscle atrophy is an independent prognostic predictor for patients with chronic heart failure, and the concept of sarcopenia has garnered scientific attention. Furthermore, the importance of not only muscle mass but also quality of muscle has been pointed out. And a sarcopenia diagnosis is confirmed by the presence of low quality of muscle. However, there is a lack of consensus on the implications of ectopic fat as a quality of muscle for the prognosis in patients with non-ischemic cardiomyopathy. Purpose We investigated whether intramuscular fat (IMF) in the thigh affects the prognosis in patients with non-ischemic cardiomyopathy. Methods We recruited 250 patients who were diagnosed with non-ischemic cardiomyopathy by cardiac catheterization and echocardiographic date between September 2017 and November 2022. Finally, 223 patients enrolled in this prospective study conducted at a single center. Functional status was evaluated by using cardiopulmonary exercise test at baseline. All patients were measured quantity of the percentage of IMF (%IMF) in the thigh using computed tomography scan. Demographic, laboratory and echocardiographic date were collected from the patients’ medical records. Patients were followed up for up to 3 years. Clinical endpoints were cardiovascular death or unexpected rehospitalization because of cardiac events. Results During the follow-up 58 patients had cardiac events. The %IMF was significantly higher in the group with adverse events than without (4.49 ± 4.21 and 3.06 ± 2.39%, respectively; p = 0.001). Spearman correlation coefficient analysis showed a modest correlation between %IMF and exercise tolerance such as anaerobic threshold (Spearman r = -0.367; p &amp;lt; 0.001) and peak oxygen uptake (Spearman r = -0.382; p &amp;lt; 0.001). Patients were divided into 2 groups according to the median values of %IMF. Kaplan-Meier analysis demonstrated that events were significantly higher in the high %IMF group (log-rank p = 0.008). Furthermore, subgroup with left ventricular ejection fraction ≦ 40% or BMI ≧ 22 had a significantly greater frequency of adverse events in the high %IMF group. However, there was no significant difference in %IMF between the groups when divided into two groups at the mean age of this study. Multivariate Cox regression analysis adjusted for left ventricular ejection fraction, estimated glomerular filtration rate, hemoglobin and body mass index found %IMF as an independent factor of adverse events (hazard ratio 1.088; 95% confidential interval 1.024-1.156; p = 0.007). Conclusions In patients with non-ischemic cardiomyopathy, quality of muscle represented by %IMF in the thigh is an independent factor for predicting adverse cardiac events.

Identification of m6A-related lncRNAs prognostic signature for predicting immunotherapy response in cervical cancer

BackgroundN6-methylandenosine-related long non-coding RNAs (m6A-related lncRNAs) play a crucial role in the cancer progression and immunotherapeutic efficacy. The potential function of m6A-related lncRNAs signature in cervical cancer has not been systematically clarified. MethodsRNA-seq and the clinical data of cervical cancer were extracted from The Cancer Genome Atlas. All of the patients were randomly classified into training and testing cohorts. The m6A-related lncRNAs prognostic model was constructed by LASSO regression using data in the training cohort.The predictive value of the signature was validated in the whole cohort and testing cohort. Cervical cancer patients were divided into low- and high-risk subgroups by the median value of risk scores. Kaplan-Meier analysis, principal-component analysis (PCA), functional enrichment annotation, and nomogram were used for further evaluation. We also examined the immune response and potential drug sensitivity targeting this model. ResultsSeventy-nine prognostic m6A-related lncRNAs were screened. The risk model comprising four m6A-related lncRNAs (AL139035.1, AC015922.2, AC073529.1, AC008124.1) was identified and verified as an independent prognostic predictor of cervical cancer. A nomogram based on age, tumor grade, clinical stage, TNM stage, and four m6A-related lncRNAs risk signatures was generated. It displayed good accuracy and reliability in predicting the overall survival of patients with CC. Based on our risk model, cervical cancer patients with potential immunotherapy benefits from the candidate drugs could be effectively screened. ConclusionThe four m6A-related lncRNAs signature may provide new targets and allow the prediction of immunotherapy response, which can assist developing individualized treatment for cervical cancer.

Serous Ovarian Carcinoma: Detailed Analysis of Clinico-Pathological Characteristics as Prognostic Factors.

Serous ovarian carcinoma (SOC) is the most common subtype of epithelial ovarian cancer, with high-grade (HGSOC) and low-grade (LGSOC) subtypes presenting distinct clinical behaviours. This study aimed to evaluate histopathologic features in SOC, correlating these with prognostic outcomes, and explore the potential clinical implications. We analysed 51 SOC cases for lymphovascular space invasion (LVSI), tumour border configuration (TBC), microvessel density (MVD), tumour budding (TB), the tumour-stroma ratio (TSR), the stromal type, tumour-infiltrating lymphocytes (TILs), and tertiary lymphoid structures (TLSs). A validation cohort of 54 SOC cases from The Cancer Genome Atlas (TCGA) was used for comparison. In the discovery set, significant predictors of aggressive behaviour included LVSI, high MVD, high TB, and low TILs. These findings were validated in the validation set where the absence of TLSs, lower peritumoural TILs, immature stromal type, and low TSR were associated with worse survival outcomes. The stromal type was identified as an independent prognostic predictor in SOC across both datasets. Inter-observer variability analysis demonstrated substantial to almost perfect agreement for these features, ensuring the reproducibility of the findings. The histopathological evaluation of immune and stromal features, such as TILs, TLSs, TB, TSR, and stromal type, provides critical prognostic information for SOC. Incorporating these markers into routine pathological assessments could enhance risk stratification and guide treatment, offering practical utility, particularly in low-resource settings when molecular testing is not feasible.

CISD3 is a prognostic biomarker and therapeutic target in pan-cancer.

Recent studies indicate that CISD3 is crucial in mitochondrial function and tumorigenesis. Using various databases, we systematically analyzed its expression, prognostic value, and immune activity. Our findings show CISD3 is mainly expressed in tumor cells across cancers, with higher mRNA but lower protein levels, degraded post-translationally via the lysosomal pathway. In certain cancers, CISD3 expression is positively correlated with tumor-infiltrating immune cells. Prognostic analysis suggests dual roles as both protective and risk factors, notably an independent prognostic predictor in renal cell carcinoma (RCC). CISD3 copy number variations are linked to homologous recombination defects and tumor-specific neoantigens, negatively correlated with methylation levels. Pathway analysis reveals CISD3 involvement in oncogenic processes, such as proliferation inhibition and epithelial-mesenchymal transition. Protein interactions underline its role in mitochondrial metabolism and redox balance. Experiments confirm low CISD3 expression in cancers, with overexpression reducing proliferation, migration, invasion, and tumor growth in mice. Mechanistic studies indicate CISD3 overexpression disrupts mitochondrial function, increases ROS levels, decreases GSH/GSSG ratios and mitochondrial membrane potential, inhibiting antioxidant activity and promoting cell damage and ferroptosis, thus impeding cancer progression. This study highlights CISD3's potential as a prognostic biomarker and therapeutic target.

Lymphocyte to White Blood Cell Count Ratio an Independent Risk Factor for Heart Failure

Objective: Heart failure affects 1–2% of the population in developed countries. Hemogram biomarkers are cheap, rapid, readily accessible and are known to have prognostic benefit in cardiovascular, infectious and oncologic diseases. Methods: The aim of the current study is to evaluate lymphocyte-to-white-blood-cell ratio (LWR) as a prognostic predictor in patients with heart failure. Patients with heart failure were recruited between January 2000 and July 2001. Exclusion criteria included metastatic malignancy, exposure to chemotherapy, radiotherapy or medications known to affect complete blood count. Results: 338 patients were enrolled, 33 were excluded. Mean age was 70.1 ± 10.8, 225 patients were male (73%) and 80 were female (27%). All patients were divided into three groups according to LWR. Group 1 &lt; 0.2, group 2—0.2 &lt; LWR &lt; 0.35 and group 3 &gt; 0.35. Patients with LWR ratio &lt; 0.2 had the poorest survival while patients in the highest LWR (ratio &gt; 0.35) had the best long-term survival. Conclusions: Patients with congestive heart failure and LWR &lt; 0.2 showed significant increased mortality. LWR was shown as independent prognostic predictor for HF patients compared to other main outcome parameters, including CRP, NYHA, EF and LDL.

A Novel Nutrition-Related Prognostic Biomarker for Predicting Survival in Patients with Colorectal Cancer

Background Colorectal cancer (CRC) is a prevalent global malignancy with substantial morbidity and mortality. Accurate prognostic evaluation is essential in CRC patient management. This study investigates the prognostic significance of red blood cell count (RBC) and Onodera’s prognostic nutritional index (OPNI) in resectable CRC patients. Methods A retrospective analysis of 210 CRC patients undergoing radical resection (January 2015–January 2017) assessed clinical and hematological factors, including RBC, albumin, hemoglobin, and OPNI. A novel comprehensive biomarker, R-OPNI, combining preoperative RBC with OPNI, was introduced. Correlations with patient survival were analyzed, and R-OPNI’s independent prognostic value was assessed through univariate and multivariate Cox models. Predictive ability was compared to other factors using the receiver operating characteristic (ROC) method. Results Higher RBC levels (≥ 3.9 × 1012/L) and elevated OPNI were associated with significantly improved overall survival. Lower R-OPNI scores (0 or 1) indicated notably poorer survival. Multivariate analysis confirmed R-OPNI’s independent prognostic significance (HR: 0.273, 95% CI: 0.098–0.763, p = 0.013). R-OPNI (AUC = 0.732) demonstrated superior predictive value compared to individual prognostic factors. Conclusion R-OPNI emerges as a robust, independent prognostic predictor for resectable CRC patients, emphasizing the importance of assessing preoperative nutritional status.

An immune-related gene pair signature predicts the prognosis and immunotherapeutic response in glioblastoma

BackgroundGlioblastoma (GBM) has the feature of aggressive growth and high rates of recurrence. Immunotherapy was not included in standard therapy for GBM due to lacking the predictive biomarkers. In the present study, we performed an immune-related gene pair (IRGP) signature to predict the prognosis and immunotherapy response of GBM. MethodsA total of 160 GBM patients from TCGA were included. ssGSEA was conducted to evaluate the immune infiltration level. Univariate Cox, LASSO regression analysis, ROC analysis, and Kaplan-Meier survival analysis were applied to construct and evaluate the risk model. Moreover, the association between immune infiltration and the risk score was assessed. Finally, the expression of immune checkpoints between different risk groups was explored. ResultsAccording to the normal/tumor, high-/low-immunity group, we identified 125 differentially expressed immune-related genes. Subsequently, a prognostic model including 22 IRGPs was established. The area under the ROC curve to predict 1, 3, and 5-year was 0.811, 0.958, and 0.99 respectively. According to the optimal cut-off value of the 3-year ROC curve, patients were classified into high- and low-risk groups. The Kaplan-Meier analysis result indicated that patients in the low-risk group have longer survival time. The risk score was an independent prognostic predictor (P < 0.001). Moreover, PDCD1 was positively correlated with the risk score (P < 0.01). We also found that patients with high PDCD1 expression had worse survival. ConclusionsThe IRGP signature was built to predict the prognosis of GBM patients. This signature can serve as a tool to predict the response to immunotherapy in GBM.

Comprehensive analysis of prognostic and immunological role of basement membrane-related genes in soft tissue sarcoma.

Soft tissue sarcoma (STS) represents highly multifarious malignant tumors that often occur in adolescents and have a poor prognosis. The basement membrane, as an ancient cellular matrix, was recently proven to play a vital role in developing abundant tumors. The relationship between basement membrane-related genes and STS remains unknown. Consensus clustering was employed to identify subgroups related to differentially expressed basement membrane-related genes. Cox and least absolute shrinkage and selection operator regression analyses were utilized to construct this novel signature. Then, we established a nomogram and calibration curve, including the risk score and available clinical characteristics. Finally, we carried out functional enrichment analysis and immune microenvironment analysis to investigate enriched pathways and the tumor immune microenvironment related to the novel signature. A prognostic predictive signature consisting of eight basement membrane-related genes was established. Kaplan-Meier survival curves demonstrated that the patients in the high-risk group had a poor prognosis. Independent analysis illustrated that this risk model could be an independent prognostic predictor. We validated the accuracy of our signature in the validation data set. In addition, gene set enrichment analysis and immune microenvironment analysis showed that patients with low-risk scores were enriched in some pathways associated with immunity. Finally, in vitro experiments showed significantly differential expression levels of these signature genes in STS cells and PSAT1 could promote the malignant behavior of STS. The novel signature is a promising prognostic predictor for STS. The present study may improve the prognosis and enhance individualized treatment for STS in the future.

436. IDENTIFICATION OF M6A-RELATED SIGNATURE GENES IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA BY MACHINE LEARNING METHOD

Abstract Background We aimed to construct and validate the esophageal squamous cell carcinoma (ESCC)-related m6A regulators by means of machine leaning. Methods We used ESCC RNA-seq data of 66 pairs of ESCC from West China Hospital of Sichuan University and the transcriptome data extracted from The Cancer Genome Atlas (TCGA)-ESCA database to find out the ESCC-related m6A regulators, during which, two machine learning approaches: RF (Random Forest) and SVM (Support Vector Machine) were employed to construct the model of ESCC-related m6A regulators. Calibration curves, clinical decision curves, and clinical impact curves (CIC) were used to evaluate the predictive ability and best-effort ability of the model. Finally, western blot and immunohistochemistry staining were used to assess the expression of prognostic ESCC-related m6A regulators. Results 2 m6A regulators (YTHDF1 and HNRNPC) were found to be significantly increased in ESCC tissues after screening out through RF machine learning methods from our RNA-seq data and TCGA-ESCA database, respectively, and overlapping the results of the two clusters. A prognostic signature, consisting of YTHDF1 and HNRNPC, was constructed based on our RNA-seq data and validated on TCGA-ESCA database, which can serve as an independent prognostic predictor. Experimental validation including the western and immunohistochemistry staining were further successfully confirmed the results of bioinformatics analysis. Conclusion We constructed prognostic ESCC-related m6A regulators and validated the model in clinical ESCC cohort as well as in ESCC tissues, which provides reasonable evidence and valuable resources for prognostic stratification and the study of potential targets for ESCC. Key words m6A, RNA methylation, esophageal squamous cell carcinoma, machine learning, experimental validation

Impact of Preoperative Osteosarcopenia and Postoperative Administration of Pancrelipase on the Prognosis of Borderline Resectable and Unresectable Locally Advanced Pancreatic Cancer.

This study aimed to identify postoperative recurrence and prognostic factors, including osteosarcopenia for borderline resectable (BR) and unresectable locally advanced (UR-LA) pancreatic cancer and to examine the impact of postoperative pancreatic enzyme replacement therapy (PERT). We retrospectively examined 32 resected patients with BR and UR-LA pancreatic cancer. We investigated independent factors in the disease-free survival and overall survival. The relation of osteosarcopenia with the clinicopathological factors was investigated. Additionally, the association of the administration of a standard dose of pancrelipase, the amount of lipase required for patients with pancreatic exocrine insufficiency, for ≥6months postoperatively with improvement of sarcopenia, osteopenia, and osteosarcopenia and completion rate of adjuvant chemotherapy was investigated. Multivariate analyses identified osteosarcopenia (P = 0.049) and lymph node metastasis (P = 0.01) as independent recurrence predictors, and osteosarcopenia (P = 0.002), maximum tumor diameter ≥40mm (P = 0.006), and no adjuvant therapy (P = 0.01) as independent prognostic predictors. In the osteosarcopenia group, serum CA19-9 levels were higher (P = 0.03). The administration of a standard dose of pancrelipase for ≥6months postoperatively was none in the osteosarcopenia group (0% vs 42.9%, P = 0.01), while significantly improved postoperative sarcopenia (33% vs 0%, P = 0.004), increased number of cycles of adjuvant chemotherapy (n = 6 vs n = 3, P = 0.03), and the completion rate of adjuvant chemotherapy in excluding cases interrupted because of recurrence (86% vs 25%, P = 0.007). Osteosarcopenia was an independent recurrent and prognostic factor in patients after pancreatectomy for locally advanced pancreatic cancer. Appropriate postoperative PERT may contribute to a better prognosis by improving sarcopenia and increasing the completion rate of adjuvant chemotherapy.

Clinical utility of sarcopenia dynamics assessed by psoas muscle volume in patients with colorectal cancer.

Sarcopenia affects the postoperative prognosis of patients with colorectal cancer (CRC). Recently, it has become possible to measure psoas volume from computed tomography images, and an index called psoas volume index (PVI) has been reported. However, it is unclear whether the dynamics of PVI before and after surgery is associated with clinical outcomes after CRC surgery. This study aimed to evaluate the association between pre- and postoperative PVI dynamics and clinical outcomes after CRC surgery. This study analyzed 1115 patients diagnosed with primary CRC and operated on for treatment between January 2014 and December 2017. Sarcopenia was defined as PVI below the lowest tertile in the preoperative assessment for each sex. The overall population was divided into four groups according to the dynamics of sarcopenia from preoperative to postoperative: group 1 (pre-to postoperative sarcopenia), group 2 (preoperative nonsarcopenia to postoperative sarcopenia), group 3 (pre-to postoperative nonsarcopenia), and group 4 (pre-to postoperative nonsarcopenia). Based on pre- and postoperative sarcopenia dynamics, 343 patients (29.7%) were classified into group 1, 105 patients (9.1%) into group 2, 42 patients (3.6%) into group 3, and 665 patients (57.6%) into group 4. Comparison of overall survival (OS) by the Kaplan-Meier method showed that Group 2 tended to have the worst prognosis (p=0.007). Multivariate analysis showed an increased OS risk in Group 2 in sarcopenia dynamics (Hazard ratio: 2.103, 95% CI: 1.202-3.681, p=0.009). Sarcopenia dynamics using PVI is an independent prognostic predictor of OS in patients with CRC.

The association of inflammatory biomarkers with clinical outcomes in diabetic retinopathy participants: data from NHANES 2009–2018

ObjectiveThe aim of this study was to assess the association of neutrophil lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), and system inflammation response index (SIRI) with the all-cause mortality and diabetes-cardiovascular mortality in participants with diabetic retinopathy (DR).MethodsA total of 572 participants with DR from NHANES were included, and divided into survival group (n = 440) and all-cause death group (n = 132). NLR = neutrophil count/lymphocyte count, MLR = monocyte count/lymphocyte count, SIRI = (neutrophil count × monocyte count)/lymphocyte count. We utilized the NHANES Public-Use Linked Mortality File through April 26, 2022, to determine mortality status. Diabetes-cardiovascular death was defined as death resulting from heart disease, cerebrovascular disease, or diabetes mellitus. The Spearson Correlation Analysis, Kaplan-Meier curves, Cox proportional hazards regression models, Restricted cubic spline plots and Decision Curve Analysis were used.ResultsThe all-cause mortality and diabetes-cardiovascular mortality were significantly higher in NLR ≥ 1.516, MLR ≥ 0.309, SIRI ≥ 0.756, and NLR + MLR + SIRI subgroups than NLR < 1.516, MLR < 0.309, SIRI < 0.756 subgroups, and other participants except NLR + MLR + SIRI (all P < 0.05). The HR of NLR, MLR, SIRI, NLR + MLR + SIRI for all-cause mortality were 1.979(1.13–3.468), 1.850(1.279–2.676), 1.821(1.096–3.025), 1.871(1.296–2.703), respectively. The hazard ratio of NLR, MLR, SIRI, NLR + MLR + SIRI for diabetes-cardiovascular mortality were 2.602(1.028–6.591), 2.673(1.483–4.818), 2.001(0.898–4.459), 2.554(1.426–4.575), respectively. In the restricted cubic spline plots, the relationship between NLR, MLR, SIRI and HR of all-cause mortality and diabetes-cardiovascular mortality was overall as “J” shaped. In both age < 60 and age > 60 years participants, the all-cause mortality and diabetes-cardiovascular mortality were significantly higher in NLR ≥ 1.516, MLR ≥ 0.309, SIRI ≥ 0.756, and NLR + MLR + SIRI subgroups than NLR < 1.516, MLR < 0.309, SIRI < 0.756 subgroups, and other participants except NLR + MLR + SIRI (all P < 0.05).ConclusionNLR, MLR, and SIRI may be three independent prognostic predictors for all-cause mortality and diabetes-cardiovascular mortality among individuals with DR. In practical clinical applications, combining NLR, MLR, and SIRI may enhance the prediction of all-cause mortality and diabetes-cardiovascular mortality in DR.

Serum secretoneurin as a promising biomarker for predicting poor prognosis in intracerebral hemorrhage: A prospective cohort study

ObjectiveSecretoneurin may play a brain-protective role. We aim to discover the relationship between serum secretoneurin levels and severity plus neurological outcome after intracerebral hemorrhage (ICH).MethodsIn this prospective cohort study, serum secretoneurin levels were measured in 110 ICH patients and 110 healthy controls. Glasgow Coma Scale (GCS) and hematoma volume were used to assess stroke severity. Poor prognosis was defined as Glasgow Outcome Scale (GOS) scores of 1–3 at 90 days after ICH. A multivariate logistic regression model was constructed to determine independent correlation of serum secretoneurin levels with severity and poor prognosis. Under receiver operating characteristic (ROC) curve, prognostic ability of serum secretoneurin levels was assessed. Restricted cubic spline (RCS) model and subgroups analysis were used for discovering association of serum secretoneurin levels with risk of poor prognosis. Calibration curve and decision curve were evaluated to confirm performance of nomogram.ResultsSerum secretoneurin levels of patients were significantly higher than those of healthy controls. Serum secretoneurin levels of patients were independently correlated with GCS scores and hematoma volume. There were 42 patients with poor prognosis at 90 days following ICH. Serum secretoneurin levels were significantly higher in patients with poor outcome than in those with good outcome. Under the ROC curve, serum secretoneurin levels significantly differentiated poor outcome. Serum secretoneurin levels ≥ 22.8 ng/mL distinguished patients at risk of poor prognosis at 90 days with a sensitivity of 66.2% and a specificity of 81.0%. Besides, serum secretoneurin levels independently predicted a 90-day poor prognosis. Subgroup analysis showed that serum secretoneurin levels had non-significant interactions with other variables. The nomogram, including independent prognostic predictors, showed reliable prognosis capability using calibration curve and decision curve. Area under the curve of the predictive model was significantly higher than those of GCS scores and hematoma volume.ConclusionSerum secretoneurin levels are strongly related to ICH severity and poor prognosis at 90 days after ICH. Thus, serum secretoneurin may be a promising prognostic biomarker in ICH.

Anlotinib destabilizes PAX3-FOXO1 to induce rhabdomyosarcoma cell death via upregulating NEK2

BackgroundRhabdomyosarcoma (RMS) is one of the most common soft tissue sarcomas in children and adolescents, in which PAX3-FOXO1 fusion gene positive patients have very poor prognosis. PAX3-FOXO1 has been identified as an independent prognostic predictor in RMS, with no currently available targeted therapeutic intervention. The novel tyrosine kinase inhibitor anlotinib exhibits a wide range of anticancer effects in multiple types of cancers; however, there have been no relevant studies regarding its application in RMS. Materials and methodsWe investigated the effects of PAX3-FOXO1 on the therapeutic efficacy of anlotinib using the CCK-8 assay, flow cytometry, invasion assay, wound healing assay, western blotting, quantitative polymerase chain reaction(qPCR), and xenograft experiments. RNA-seq and co-immunoprecipitation assays were conducted to determine the specific mechanism by which anlotinib regulates PAX3-FOXO1 expression. ResultsAnlotinib effectively inhibited RMS cell proliferation and promoted apoptosis and G2/M phase arrest while impeding tumor growth in vivo. Downregulation of PAX3-FOXO1 enhances the antitumor effects of anlotinib. Anlotinib upregulates protein kinase NEK2 and increases the degradation of PAX3-FOXO1 via the ubiquitin-proteasome pathway, leading to a reduction in PAX3-FOXO1 protein levels. ConclusionAnlotinib effectively inhibited the malignant progression of RMS and promoted degradation of the fusion protein PAX3-FOXO1. Anlotinib could be a targeted therapeutic approach to treat PAX3-FOXO1 fusion-positive RMS.

PRRX1 silencing is required for metastatic outgrowth in melanoma and is an independent prognostic of reduced survival in patients.

Paired related homeobox 1 (PRRX1) is an inducer of epithelial-to-mesenchymal transition (EMT) in different types of cancer cells. We detected low PRRX1 expression in nevus but increased levels in primary human melanoma and cell lines carrying the BRAFV600E mutation. High expression of PRRX1 correlates with invasiveness and enrichment of genes belonging to the EMT programme. Conversely, we found that loss of PRRX1 in metastatic samples is an independent prognostic predictor of poor survival for melanoma patients. Here, we show that stable depletion of PRRX1 improves the growth of melanoma xenografts and increases the number of distant spontaneous metastases, compared to controls. We provide evidence that loss of PRRX1 counteracts the EMT phenotype, impairing the expression of other EMT-related transcription factors, causing dysregulation of the ERK and signal transducer and activator of transcription 3 (STAT3) signaling pathways, and abrogating the invasive and migratory properties of melanoma cells while triggering the up-regulation of proliferative/melanocytic genes and the expression of the neural-crest-like markers nerve growth factor receptor (NGFR; also known as neurotrophin receptor p75NTR) and neural cell adhesion molecule L1 (L1CAM). Overall, our results indicate that loss of PRRX1 triggers a switch in the invasive programme, and cells de-differentiate towards a neural crest stem cell (NCSC)-like phenotype that accounts for the metastatic aggressiveness.