Prognostic Power Research Articles

Ceruloplasmin, Catalase and Creatinine Concentrations Are Independently Associated with All-Cause Mortality in Patients with Advanced Heart Failure.

The role of oxidative/antioxidative system imbalances in advanced heart failure (HF) has not been fully investigated. The aim of this study was to identify factors associated with one-year mortality in patients with advanced HF, with particular emphasis on oxidative/antioxidative balance parameters. We analyzed 85 heart transplant candidates who were hospitalized at our institution for right heart catheterization. Ten milliliters of coronary sinus blood was collected to measure oxidative/antioxidative markers. The median age was 58 (50-62) years, and 90.6% of them were male. The one-year mortality rate was 40%. Multivariable logistic regression analysis revealed that ceruloplasmin (OR = 1.342 [1.019-1.770], p = 0.0363; per unit decrease), catalase (OR = 1.053 [1.014-1.093], p = 0.0076; per unit decrease), and creatinine (OR = 1.071 [1.002-1.144], p = 0.0422; per unit increase) were independently associated with one-year mortality. Ceruloplasmin, catalase, and creatinine had areas under the curve of 0.9296 [0.8738-0.9855], 0.9666 [0.9360-0.9971], and 0.7682 [0.6607-0.8756], respectively. Lower ceruloplasmin and catalase in the coronary sinus, as well as higher creatinine in peripheral blood, are independently associated with one-year mortality in patients with advanced HF. Catalase and ceruloplasmin have excellent prognostic power, and creatinine has acceptable prognostic power, allowing the distinction of one-year survivors from nonsurvivors.

Development and validation of a machine learning model to predict prognosis in liver failure patients treated with non-bioartificial liver support system.

The prognosis of liver failure treated with non-bioartificial liver support systems is poor. Detecting its risk factors and developing relevant prognostic models still represent the top priority to lower its death risk. All 215 patients with liver failure treated with non-bioartificial liver support system were retrospectively analyzed. Potential prognostic factors were investigated, and the Nomogram and the Random Survival Forests (RSF) models were constructed, respectively. Notably, we evaluated the performance of models and calculated the risk scores to divide patients into low-risk and high-risk groups. In the training set, multifactorial Cox regression analysis showed that etiology, hepatic encephalopathy, total bilirubin, serum alkaline phosphatase, platelets, and MELD score were independent factors of short-term prognosis. The RSF model (AUC: 0.863, 0.792) performed better in prediction than the Nomogram model (AUC: 0.816, 0.756) and MELD (AUC: 0.658, 0.700) in the training and validation groups. On top of that, patients in the low-risk group had a significantly better prognosis than those in the high-risk group. We constructed the RSF model with etiology, hepatic encephalopathy, total bilirubin, serum alkaline phosphatase, platelets, and MELD score, which showed better prognostic power than the Nomogram model and MELD score and could help physicians make optimal treatment decisions.

PIK3CA mutation-driven immune signature as a prognostic marker for evaluating the tumor immune microenvironment and therapeutic response in breast cancer

PurposeGene mutations drive tumor immune microenvironment (TIME) heterogeneity, in turn affecting prognosis and immunotherapy efficacy. PIK3CA is the most frequently mutated gene in breast cancer (BC), yet its relevance to BC prognosis remains controversial. Herein, we sought to determine the impact of PIK3CA mutation-driven immune genes (PDIGs) on BC prognosis in relation to TIME heterogeneity.MethodsPIK3CA mutation characteristics were compared and verified between the TCGA-BRCA dataset and a patient cohort from our hospital. PIK3CA mutation-driven differentially expressed genes were identified for consensus clustering and weighted gene co-expression network analysis to select the modules most relevant to the immune subtype. Thereafter, the two were intersected to obtain PDIGs. Univariate Cox, LASSO, and multivariate Cox regression analyses were sequentially performed on PDIGs to obtain a PIK3CA mutation-driven immune signature (PDIS), which was then validated using the Gene Expression Omnibus (GEO) database. Differences in functional enrichment, mutation landscape, immune infiltration, checkpoint gene expression, and drug response were compared between different risk groups.ResultsPIK3CA mutation frequencies in the TCGA and validation cohorts were 34.49% and 40.83%, respectively. PIK3CA mutants were significantly associated with ER, PR, and molecular BC subtypes in our hospital cohort. The PDIS allowed for effective risk stratification and exhibited prognostic power in TCGA and GEO sets. The low-risk patients exhibited greater immune infiltration, higher expression of common immune checkpoint factors, and lower scores for tumor immune dysfunction and exclusion.ConclusionThe PDIS can be used as an effective prognostic model for predicting immunotherapy response to guide clinical decision-making.

Enhancing prognostic power in multiple myeloma using a plasma cell signature derived from single-cell RNA sequencing

Multiple myeloma (MM) is a heterogenous plasma cell malignancy, for which the established prognostic models exhibit limitations in capturing the full spectrum of outcome variability. Leveraging single-cell RNA-sequencing data, we developed a novel plasma cell gene signature. We evaluated and validated the associations of the resulting plasma cell malignancy (PBM) score with disease state, progression and clinical outcomes using data from five independent myeloma studies consisting of 2115 samples (1978 MM, 65 monoclonal gammopathy of undetermined significance, 35 smoldering MM, and 37 healthy controls). Overall, a higher PBM score was significantly associated with a more advanced stage within the spectrum of plasma cell dyscrasias (all p < 0.05) and a shorter overall survival in MM (hazard ratio, HR = 1.72; p < 0.001). Notably, the prognostic effect of the PBM score was independent of the International Staging System (ISS) and Revised ISS (R-ISS). The downstream analysis further linked higher PBM scores with the presence of cytogenetic abnormalities, TP53 mutations, and compositional changes in the myeloma tumor immune microenvironment. Our integrated analyses suggest the PBM score may provide an opportunity for refining risk stratification and guide decisions on therapeutic approaches to MM.

Texture analysis of 18F-FDG PET/CT and CECT: Prediction of refractoriness of Hodgkin lymphoma with mediastinal bulk involvement.

To recognize patients at high risk of refractory disease, the identification of novel prognostic parameters improving stratification of newly diagnosed Hodgkin Lymphoma (HL) is still needed. This study investigates the potential value of metabolic and texture features, extracted from baseline 18F-FDG Positron Emission Tomography/Computed Tomography (PET) and Contrast-Enhanced Computed Tomography scan (CECT), together with clinical data, in predicting first-line therapy refractoriness (R) of classical HL (cHL) with mediastinal bulk involvement. We reviewed 69 cHL patients who underwent staging PET and CECT. Lesion segmentation and texture parameter extraction were performed using the freeware software LIFEx 6.3. The prognostic significance of clinical and imaging features was evaluated in relation to the development of refractory disease. Receiver operating characteristic curve, Cox proportional hazard regression and Kaplan-Meier analyses were performed to examine the potential independent predictors and to evaluate their prognostic value. Among clinical characteristics, only stage according to the German Hodgkin Group (GHSG) classification system significantly differed between R and not-R. Among CECT variables, only parameters derived from second order matrices (gray-level co-occurrence matrix (GLCM) and gray-level run length matrix (GLRLM) demonstrated significant prognostic power. Among PET variables, SUVmean, several variables derived from first (histograms, shape), and second order analyses (GLCM, GLRLM, NGLDM) exhibited significant predictive power. Such variables obtained accuracies greater than 70% at receiver operating characteristic analysis and their PFS curves resulted statistically significant in predicting refractoriness. At multivariate analysis, only HISTO_EntropyPET extracted from PET (HISTO_EntropyPET ) and GHSG stage resulted as significant independent predictors. Their combination identified 4 patient groups with significantly different PFS curves, with worst prognosis in patients with higher HISTO_EntropyPET values, regardless of the stage. Imaging radiomics may provide a reference for prognostic evaluation of patients with mediastinal bulky cHL. The best prognostic value in the prediction of R versus not-R disease was reached by combining HISTO_EntropyPET with GHSG stage.

Systemic Immune-Inflammation Index and Systemic Inflammatory Response Index as Predictors of Mortality in ST-Elevation Myocardial Infarction.

(1) Background: The systemic inflammatory response index (SIRI; neutrophil count × monocyte/lymphocyte count), and the systemic immune-inflammation index (SII; platelet count × neutrophil count/lymphocyte count) are recently proposed biomarkers to assess the immune and inflammatory status. However, data on SIRI and SII are still relatively lacking and do not definitively and exhaustively define their role as predictors of an adverse prognosis in acute myocardial infarction (AMI). The aim of the present study was to evaluate SII and SIRI determinants as well as to assess SIRI and SII prognostic power in ST-elevation myocardial infarction (STEMI). (2) Methods: A total of 105 STEMI patients (74 males, 70 ± 11 years) were studied (median follow-up 54 ± 25 months, 24 deaths). (3) Results: The main determinants of SIRI and SII were creatinine and brain natriuretic peptide (BNP) (multivariate regression). Patients with higher SIRI (>75th percentile, 4.9) and SII (>75th percentile, 1257.5) had lower survival rates than those in the low SIRI/SII group (Kaplan-Meier analysis). Univariate Cox regression revealed that high SIRI and SII were associated with mortality (HR: 2.6, 95% CI: 1.1-5.8, p < 0.05; 2.2, 1-4.9, p ≤ 0.05, respectively); however, these associations lost their significance after multivariate adjustment. (4) Conclusions: SIRI and SII association with mortality was significantly affected by confounding factors in our population, especially creatinine and BNP, which are associated with both the inflammatory indices and the outcome.

A novel peroxisome-related gene signature predicts clinical prognosis and is associated with immune microenvironment in low-grade glioma.

Low-grade glioma (LGG), a common primary tumor, mainly originates from astrocytes and oligodendrocytes. Increasing evidence has shown that peroxisomes function in the regulation of tumorigenesis and development of cancer. However, the prognostic value of peroxisome-related genes (PRGs) in LGG has not been reported. Therefore, it is necessary to construct a prognostic risk model for LGG patients based on the expression profiles of peroxisome-related genes. Our study mainly concentrated on developing a peroxisome-related gene signature for overall survival (OS) prediction in LGG patients. First, according to these peroxisome-related genes, all LGG patients from The Cancer Genome Atlas (TCGA) database could be divided into two subtypes. Univariate Cox regression analysis was used to find prognostic peroxisome-related genes in TCGA_LGG dataset, and least absolute shrinkage and selection operator Cox regression analysis was employed to establish a 14-gene signature. The risk score based on the signature was positively associated with unfavorable prognosis. Then, multivariate Cox regression incorporating additional clinical characteristics showed that the 14-gene signature was an independent predictor of LGG. Time-dependent ROC curves revealed good performance of this prognostic signature in LGG patients. The performance about predicting OS of LGG was validated using the GSE107850 dataset derived from the Gene Expression Omnibus (GEO) database. Furethermore, we constructed a nomogram model based on the gene signature and age, which showed a better prognostic power. Gene ontology (GO) and Kyoto Encylopedia of Genes and Genomes (KEGG) analyses showed that neuroactive ligand-receptor interaction and phagosome were enriched and that the immune status was decreased in the high-risk group. Finally, cell counting kit-8 (CCK8) were used to detect cell proliferation of U251 and A172 cells. Inhibition of ATAD1 (ATPase family AAA domain-containing 1) and ACBD5 (Acyl-CoA binding-domain-containing-5) expression led to significant inhibition of U251 and A172 cell proliferation. Flow cytometry detection showed that ATAD1 and ACBD5 could induce apoptosis of U251 and A172 cells. Therefore, through bioinformatics methods and cell experiments, our study developed a new peroxisome-related gene signature that migh t help improve personalized OS prediction in LGG patients.

Prognostic Power of Foot Mobility in Identifying the Risk of Musculoskeletal Injuries: A Cross-Sectional Study of Male Volleyball Players at Different Competitive Levels.

(1) Background: The arch structure and mobility of the foot are considered injury risk factors in volleyball. However, there are limited studies presenting differences in injury prevalence and the risk of lower limb injuries in relation to the competitive level in male volleyball. Therefore, the main aim of the current study was to evaluate foot mobility (through navicular drop test) as an injury risk factor in volleyball players from different competitive levels. (2) Methods: The reliability and usefulness of navicular drop testing were initially assessed in test-retest procedures (based on a sample of eight participants and 16 feet measurements), with primary analyses conducted using foot measurements of the twelve top-level volleyball players (24 feet) and eighteen academic-level volleyball players (36 feet). The modified navicular drop test was conducted, and the feet were classified based on arch height, and injury prevalence was retrospectively assessed with a previously validated questionnaire. Chi-squared tests, receiver operating curves, and logistic regression were used as statistical methods. The navicular drop test was verified as a reliable tool by intraclass correlation coefficient (ICC) (3.1) analysis. (3) Results: There were no significant differences in injury prevalence between academic- and top-level volleyball players, though there was a significant relationship between pronated foot and injury risk independent of competitive level. Generally, for both groups, thresholds above 10 mm of the navicular drop were predictors of lower limb injuries. The risk of injury if the foot was pronated ranged from 70% (academic level) to over 90% (top-level players). However, no statistically significant effect of competitive level on the chance of injury was observed. (4) Conclusions: Our study found a high prevalence of foot injuries independently of competitive level. There was a relationship between pronation of the foot and the risk of injury. However, the risk of lower limb injury was higher in pronated top-level players. Also, a navicular drop greater than 10 mm was an excellent predictor of injuries at both competitive levels.

The six-minute step test can predict COPD exacerbations: a 36-month follow-up study

The six-minute step test (6MST) has been shown to be effective in assessing exercise capacity in individuals with COPD regardless of severity and, despite its easy execution, accessibility and validity, information on the prognostic power of this test remains uncertain. The aim of this study is to investigate whether the 6MST can predict the occurrence of exacerbations in patients with COPD. This is a prospective cohort study with a 36-month follow-up in patients with COPD. All patients completed a clinical assessment, followed by pulmonary function testing and a 6MST. The 6MST was performed on a 20 cm high step; heart rate, blood pressure, oxygen saturation, BORG dyspnea and fatigue were collected. Sixty-four patients were included in the study, the majority being elderly men. Performance on the 6MST demonstrated lower performance compared to normative values proposed in the literature, indicating a reduced functional capacity. Kaplan Meier analysis revealed that ≤ 59 steps climbed during the 6MST was a strong predictor of COPD exacerbation over a 36-month follow-up. We have identified a minimal threshold number of steps (≤ 59) obtained through the 6MST may be able predict the risk of exacerbations in patients with COPD.

Comparison of Three Different Disseminated Intravascular Coagulation (DIC) Criteria and Diagnostic and Prognostic Value of Antithrombin Investigation in Patients with Confirmed Sepsis-Induced Coagulopathy (SIC).

A new scoring system termed sepsis-induced coagulopathy (SIC) has been proposed to diagnose early sepsis-induced disseminated intravascular coagulation (DIC). This study performed DIC-related analyses in patients with confirmed SIC. Data from the intensive care unit (ICU) departments of the three hospitals between 2020 and 2022 were retrospectively analyzed. Finally, 125 patients with confirmed SIC were enrolled in the study. The diagnostic value of three widely used DIC criteria was assessed in patients with newly diagnosed SIC. In addition, the diagnostic and prognostic value of antithrombin (AT) was analyzed in patients with SIC. The Japanese Association for Acute Medicine DIC criteria (JAAM) exhibited the highest DIC diagnostic rate, while the mortality risk of SIC patients demonstrated a proportional increase with higher International Society on Thrombosis and Haemostasis (ISTH) and Chinese DIC scoring system (CDSS) scores. Low AT activity (<70%) in septic patients upon SIC diagnosis predicted a very high 28-day mortality rate, almost twice as high as in the normal AT activity (≥70%) group. A decreasing tendency in AT activity after clinical interventions was correlated with increased mortality. The area under the ROC curve (AU-ROC) of AT in DIC diagnosis was statistically significant when CDSS and ISTH were used as diagnostic criteria, but not JAAM. Each of the three DIC diagnostic criteria showed diagnostic and prognostic advantages for SIC. AT could be an independent prognostic indicator for SIC but demonstrated a relatively limited DIC diagnostic value. Adding AT to the SIC scoring system may increase its prognostic power.

Low FHL1 expression indicates a good prognosis and drug sensitivity in ovarian cancer.

Chemotherapy resistance is the main reason for the poor prognosis of ovarian cancer (OC). FHL1 is an important tumour regulator, but its relationship with the prognosis, drug resistance, and tumour microenvironment of OC is unknown. Immunohistochemistry was used to determine FHL1 expression in OC. Kaplan‒Meier plotter was used for survival analysis. The value of gene expression in predicting drug resistance was estimated using the area under the curve (AUC). Bivariate correlation was used to determine the coexpression of two genes. Functional cluster and pathway enrichment were used to uncover hidden signalling pathways. The relationship between gene levels and the tumour microenvironment was visualised through the ggstatsplot and pheatmap packages. The mRNA and protein levels of FHL1 were downregulated in 426 and 100 OC tissues, respectively. Low FHL1 expression was correlated with good progression-free survival (PFS), postprogression survival, and overall survival (OS) in 1815 OC patients,and was further confirmed to be associated with good OS by immunohistochemistry in 152 OC tissues. Furthermore, FHL1 was downregulated in drug-sensitive tissues, while its high expression predicted drug resistance (AUC > 0.65). Mechanistically, FHL1 was coexpressed with FLNC, CAV1, PPP1R12B, and FLNA at the mRNA and protein levels in 558 and 174 OC tissues, respectively, and their expression was downregulated in OC. Additionally, very strong coexpression of FHL1 with the four genes was identified in at least 23 different tumours. Low expression of the four genes was associated with good PFS, and the combination of FHL1 with the four genes provided better prognostic power. Meanwhile, the expression of all five genes was strongly and positively associated with the abundance of macrophages. Low FHL1 expression acts as a favourable factor in OC, probably via positive coexpression with FLNC, CAV1, PPP1R12B, and FLNA.

Abstract A086: Retrospective study on postoperative adjuvant radiotherapy in primary malignant angiosarcoma of the breast patients following mastectomy or breast-conserving surgery using SEER database

Abstract Primary Angiosarcoma of the breast (PAOB) is one of the rarest types of breast tumors, representing less than 0.2% of all breast tumors. These tumors are also associated with a poor prognosis. Mastectomy or breast-conserving surgery (BCS) are considered the best therapeutic techniques in patients with (PAOB). However, there is a debate about the need for postoperative radiotherapy (RT). PAOB is a rare tumor, therefore best management techniques are based only on expert opinion and clinical experience, which are scarce. The aim of this paper is to study the effectiveness of postoperative radiotherapy (RT) for PAOB over a long period. Patients with primary angiosarcoma of the breast (PAOB), who underwent a mastectomy and breast-conserving surgery (BCS), were identified through the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2020. Descriptive analyses were conducted to evaluate the clinical characteristics of patients with PAOB.Age, ethnicity, year of diagnosis, grade, tumor extent, lymph node (LN) metastasis and Postoperative radiotherapy (RT) were incorporated.Cancer-specific survival (CSS) was calculated using the Kaplan Meier and compared using the log rank test. Univariate and multivariate Cox proportional hazards regressions were performed to evaluate the prognostic power of factors on (CSS). A total of 542 women with primary angiosarcoma of the breast (PAOB) were included in this study. Most women (82.8%) underwent mastectomy, while (17.2%) underwent breast conserving surgery (BCS). Postoperative radiotherapy (RT) was performed on 102 women (18.8%), with 27 (29.0%) in the BCS group and 75 (16.7%) in the mastectomy group.Postoperative radiotherapy (RT) was more likely to be performed in women with adverse risk factors, such as a larger tumor size in the mastectomy group and a higher tumor grade in both groups.Lymph node (LN) metastasis was rarely found in PAOB, only 11 patients had positive lymph node (LN) metastasis. Among those, 9 patients underwent mastectomy, and 2 patients underwent BCS. Additionally, lymph node involvement increased the chance of postoperative RT in the mastectomy group. In both groups, the need for postoperative radiotherapy (RT) increased as the tumor size became more than (3cm).However, this pattern was less obvious in the BCS group.In multivariate analysis, there weren’t any significant prognostic factors impact on Cancer-specific survival (CSS) in the mastectomy group, also, postoperative radiotherapy RT had no impact (P = 0.656).In the BCS group,age, tumor size and lymph node (LN) metastasis were significant predictive factors on Cancer-specific survival (CSS),meanwhile postoperative radiotherapy (RT) had no effect on (CSS) (P = 0.152). PAOB patients with more adverse prognostic factors received postoperative radiotherapy (RT).There was no statistically significant difference in CSS between radiotherapy (RT) group and non-(RT) group,regardless of whether the procedure is a mastectomy or a breast-conserving surgery (BCS).Further trials are needed to reach more accurate evaluations. Citation Format: Ramez M. Odat, Ismail A. Ibrahim, Mohamed Ahmed Ali, Sara A. Haddadin, Bashar M. Al Zoubi, Mohamed Nezar Abohalawa, Alexander Leeper. Retrospective study on postoperative adjuvant radiotherapy in primary malignant angiosarcoma of the breast patients following mastectomy or breast-conserving surgery using SEER database [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A086.

CRP kinetics to predict long-term efficacy of first-line immune-checkpoint inhibition combination therapies in metastatic renal cell carcinoma: An updated multicenter real-world experience applying different CRP kinetics definitions.

405 Background: Although biomarkers predicting therapy response in 1st line metastatic renal carcinoma (mRCC) therapy remain to be defined, C-reactive protein (CRP) kinetics have recently been associated with immunotherapy (IO) response. To assess the predictive and prognostic power of two contemporary CRP kinetics definitions in a large, real-world 1st line mRCC cohort. Methods: mRCC patients treated with IO-based 1st line therapy within 5 years were retrospectively included in this multi-center study. According to Fukuda et al., patients were defined as ‘CRP flare-responder’, ’CRP responder’ and ‘non-CRP responder’; according to Ishihara et al., as ‘normal’, ‘normalized’ and ‘non-normalized’ based on their early CRP kinetics. Patient and tumor characteristics were compared, and treatment outcome was measured by overall (OS) and progression-free survival (PFS), including multivariable Cox regression analyses. Results: Out of 316 mRCC patients, 227 (72%) were assigned to CRP groups according to Fukuda. Both CRP flare- (HR [Hazard ratio]: 0.59) and CRP responders (HR: 0.52) had a longer PFS, but not OS, than non-CRP responders. According to Ishihara, 276 (87%) patients were assigned to the respective groups, and both normal and normalized patients had a significantly longer PFS and OS, compared to non-normalized group. Conclusions: Different early CRP kinetics may predict therapy response in 1st line mRCC therapy in a large real-world cohort. However, further research regarding the optimal timing and frequency of measurement is needed.

Establishment and verification of the first prognostic nomograms in locally advanced thyroid cancer based on the analysis of clinical and follow-up information on 2396 patients

Background and objectivesThe purpose of this research was to develop and validate the first prognostic nomograms for 3-, 5-, and 10-year cancer-specific survival (CSS) and overall survival (OS) in patients diagnosed with locally advanced thyroid cancer (LATC) by evaluating independent predictors of prognosis in a population of LATC patients. MethodsDemographics, clinicopathologic characteristics, treatment, and follow-up of 2396 LATC patients in the surveillance, epidemiology, and end results database from 2004 to 2015 were retrospectively analyzed and compared with patients with LATC according to staging. We randomized all LATC patients into training and validation groups in a 7:3 ratio. Cox regression analyses helped us to derive independent prognostic factors for LATC patients. According to these results, we established and validated the first prognostic nomograms and risk stratification. ResultsIn our research, the clinical information of LATC patients was compared and significant differences were found in the relevant variables including CSS and OS (P < 0.05), with CSS of 82.0 % and 49.0 %, and OS of 70.6 % and 40.0 %, respectively. Cox regression analyses showed that age at diagnosis, tumor diameter, presence of DM, extrathyroidal extension sites, histological type, thyroidectomy scope, radiotherapy status, and chronological sequence of radiotherapy and surgery were observably correlated with CSS in LATC patients, and in addition to the above factors, gender, marital status, and chemotherapy status were also observably correlated with OS in LATC patients. The prognostic predictive power of the above factors is visualized by the Kaplan-Meier survival curve. The concordance index of nomograms for CSS and OS were 0.933, 0.925, and 0.926 (CSS), 0.918, 0.909, and 0.906 (OS), respectively, and the time-dependent receiver operating characteristic curve, area under curve, calibration curve and decision curve analysis curve indicate that the nomograms have good discriminatory ability, accuracy and clinical applicability in both the training and validation groups. ConclusionsIn these findings, we drawed a conclusion that there were significant differences in clinical information between patients with T4a and T4b LATC, and we established and validated the first prognostic nomograms and risk stratification of CSS and OS for LATC patients at 3, 5, and 10 years, which will help clinicians to individualize their postoperative treatment and individualized follow-up.

Ferroptosis heterogeneity within the tumor microenvironment revealed a genetic blueprint of breast cancer.

The tumor microenvironment (TME) significantly influences disease progression through immune infiltration, while ferroptosis, a recently discovered cell death mechanism, plays a crucial role in tumor suppression. However, its role in breast cancer is not clear. In this study, we analyzed bulk RNA and single-cell RNA sequencing data from 1217 samples, including 1104 breast cancer patients and 113 controls, to identify ferroptosis-related genes (FRGs) and construct a prognostic model. Using univariate cox regression, LASSO regression, and multivariate cox regression analysis, we discovered 21 FRGs and 3 TME-related immune cell types with prognostic value. Dimensionality reduction clustering and visualization were performed using the UMAP method, while the immune infiltration process was calculated with the TIP online tool. We employed GSEA enrichment analysis, WGCNA clustering analysis, and correlation analysis to examine functional differences, and the mutation analysis of the best and worst prognosis groups was conducted using the maftools package. Our findings revealed that knocking down the expression of the hub gene SLC39A7 significantly impacted cancer cell apoptosis and combining ferroptosis and TME scores yielded high prognostic power. Epithelial cells and B cells exhibited higher ferroptosis scores, which were independently associated with immune checkpoint blockade (ICB) response and ICB gene expression. This study provides a foundation for further exploration of the relationship between ferroptosis and ICB response in breast cancer. In conclusion, we developed a prognostic model based on ferroptosis and infiltrated immune cells that effectively stratified breast cancer patients and demonstrated the role of SLC39A7 in breast cancer pathogenesis through the regulation of apoptosis.

Multiomics characterization of pyroptosis in the tumor microenvironment and therapeutic relevance in metastatic melanoma

BackgroundPyroptosis, mediated by gasdermins with the release of multiple inflammatory cytokines, has emerged as playing an important role in targeted therapy and immunotherapy due to its effectiveness at inhibiting tumor growth. Melanoma is one of the most commonly used models for immunotherapy development, though an inadequate immune response can occur. Moreover, the development of pyroptosis-related therapy and combinations with other therapeutic strategies is limited due to insufficient understanding of the role of pyroptosis in the context of different tumor immune microenvironments (TMEs).MethodsHere, we present a computational model (pyroptosis-related gene score, PScore) to assess the pyroptosis status. We applied PScore to 1388 melanoma samples in our in-house cohort and eight other publicly available independent cohorts and then calculated its prognostic power of and potential as a predictive marker of immunotherapy efficacy. Furthermore, we performed association analysis for PScore and the characteristics of the TME by using bulk, single-cell, and spatial transcriptomics and assessed the association of PScore with mutation status, which contributes to targeted therapy.ResultsPyroptosis-related genes (PRGs) showed distinct expression patterns and prognostic predictive ability in melanoma. Most PRGs were associated with better survival in metastatic melanoma. Our PScore model based on genes associated with prognosis exhibits robust performance in survival prediction in multiple metastatic melanoma cohorts. We also found PScore to be associated with BRAF mutation and correlate positively with multiple molecular signatures, such as KRAS signaling and the IFN gamma response pathway. Based on our data, melanoma with an immune-enriched TME had a higher PScore than melanoma with an immune-depleted or fibrotic TME. Additionally, monocytes had the highest PScore and malignant cells and fibroblasts the lowest PScore based on single-cell and spatial transcriptome analyses. Finally, a higher PScore was associated with better therapeutic efficacy of immune checkpoint blockade, suggesting the potential of pyroptosis to serve as a marker of immunotherapy response.ConclusionsCollectively, our findings indicate that pyroptosis is a prognostic factor and is associated with the immune response in metastatic melanoma, as based on multiomics data. Our results provide a theoretical basis for drug combination and reveal potential immunotherapy response markers.

Prognostic Significance of Glycolysis-Related Genes in Lung Squamous Cell Carcinoma.

Lung squamous cell carcinoma (LUSC) is one of the most common malignancies. There is growing evidence that glycolysis-related genes play a critical role in tumor development, maintenance, and therapeutic response by altering tumor metabolism and thereby influencing the tumor immune microenvironment. However, the overall impact of glycolysis-related genes on the prognostic significance, tumor microenvironment characteristics, and treatment outcome of patients with LUSC has not been fully elucidated. We used The Cancer Genome Atlas (TCGA) dataset to screen glycolysis-related genes with prognostic effects in LUSC and constructed signature and nomogram models using Lasso and Cox regression, respectively. In addition, we analyzed the immune infiltration and tumor mutation load of the genes in the models. We finally obtained a total of glycolysis-associated DEGs. The signature model and nomogram model had good prognostic power for LUSC. Gene expression in the models was highly correlated with multiple immune cells in LUSC. Through this analysis, we have identified and validated for the first time that glycolysis-related genes are highly associated with the development of LUSC. In addition, we constructed the signature model and nomogram model for clinical decision-making.

The value of right ventricular to pulmonary arterial coupling in the critically ill: a National Echocardiography Database of Australia (NEDA) substudy.

Right ventricular (RV) function is tightly coupled to afterload, yet echocardiographic indices of RV function are frequently assessed in isolation. Normalizing RV function for afterload (RV-PA coupling) using a simplified ratio of tricuspid annular plane systolic excursion (TAPSE)/ tricuspid regurgitant velocity (TRV) could help to identify RV decompensation and improve risk stratification in critically ill patients. This is the first study to explore the distribution of TAPSE/TRV ratio and its prognostic relevance in a large general critical care cohort. We undertook retrospective analysis of echocardiographic, clinical, and mortality data of intensive care unit (ICU) patients between January 2012 and May 2017. A total of 1077 patients were included and stratified into tertile groups based on TAPSE/TRV ratio: low (< 5.9mm.(m/s)-1), middle (≥ 5.9-8.02mm.(m/s)-1), and high (≥ 8.03mm.(m/s)-1). The distribution of the TAPSE/TRV ratio across ventricular function subtypes of normal, isolated left ventricular (LV), isolated RV, and biventricular dysfunction was explored. The overall prognostic relevance of the TAPSE/TRV ratio was tested, including distribution across septic, cardiovascular, respiratory, and neurological subgroups. Higher proportions of ventricular dysfunctions were seen in low TAPSE/TRV tertiles. TAPSE/TRV ratio is impacted by LV systolic function but to a lesser extent than RV dysfunction or biventricular dysfunction. There was a strong inverse relationship between TAPSE/TRV ratio and survival. After multivariate analysis, higher TAPSE/TRV ratios (indicating better RV-PA coupling) were independently associated with lower risk of death in ICU (HR 0.927 [0.872-0.985], p < 0.05). Kaplan-Meier analysis demonstrated higher overall survival in middle and high tertiles compared to low tertiles (log rank p < 0.0001). The prognostic relevance of TAPSE/TRV ratio was strongest in respiratory and sepsis subgroups. Patients with TAPSE/TRV < 5.9mm(m/s)-1 had a significantly worse prognosis than those with higher TAPSE/TRV ratios. The TAPSE/TRV ratio has prognostic relevance in critically ill patients. The prognostic power may be stronger in respiratory and septic subgroups. Larger prospective studies are needed to investigate the role of TAPSE/TRV in pre-specified subgroups including its role in clinical decision-making.

Abstract A092: Exploiting the neural-like properties of a new pancreatic cancer morpho-biotype for the development of a combinatorial treatment targeting tumor heterogeneity

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers in which high intra-tumor heterogeneity and plasticity makes PDAC poorly responsive to available treatments. Coupling transcriptional profiling with laser capture microdissection of groups of cancer cells defined by distinct histological patterns, we were able to describe three PDAC “morpho-biotypes”. Such morpho-biotypes represent the combined morphological, molecular and functional properties of PDAC cells that coexist, in various proportions, in nearly all patients analyzed. Compared to single cells, our approach, that integrates morphological and spatial features, was able to clearly identify a novel morpho-biotype, primed toward a neural-like lineage differentiation. Only combining the expression of those genes able to discriminate all three morpho-biotypes, we achieved high prognostic power, underscoring the relevance of the co-existence of different cancer populations for clinical assessment. We therefore hypothesize that only combinatorial therapies, that target all the different biotypes simultaneously, can result in an effective cancer treatment. We identified an antiepileptic drug to be the best candidate to interfere with the neuronal-like program we unexpectedly found enriched in one of the PDAC morpho-biotypes. Using this drug with other oncogenic inhibitors specific for the other morpho-biotypes we obtained a complete stop of the tumor progression in a mouse model of xenografted human tumor fragments that maintained tumor heterogeneity. A similar neural progenitor-like signature was recently found enriched in single cell data form neo-adjuvant treated patients. This founding indirectly suggests that the new morpho-biotype we described in treatment-naïve patients could be responsible for the failure of the available treatments. This study not only contributes to our understanding of the effects of the combinatorial treatment, but also provides valuable molecular data for development of improved treatment schemes and histological maps that can guide pathologists’ diagnosis. Citation Format: Giuseppe R. Diaferia, Pierluigi Di Chiaro, Francesca Fiumani, Lucia Nacci, Alessandro Zerbi, Paola Spaggiari, Iros Barozzi, Gioacchino Natoli. Exploiting the neural-like properties of a new pancreatic cancer morpho-biotype for the development of a combinatorial treatment targeting tumor heterogeneity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A092.

Exploring the relationship between metabolism and immune microenvironment in osteosarcoma based on metabolic pathways

BackgroundMetabolic remodeling and changes in tumor immune microenvironment (TIME) in osteosarcoma are important factors affecting prognosis and treatment. However, the relationship between metabolism and TIME needs to be further explored.MethodsRNA-Seq data and clinical information of 84 patients with osteosarcoma from the TARGET database and an independent cohort from the GEO database were included in this study. The activity of seven metabolic super-pathways and immune infiltration levels were inferred in osteosarcoma patients. Metabolism-related genes (MRGs) were identified and different metabolic clusters and MRG-related gene clusters were identified using unsupervised clustering. Then the TIME differences between the different clusters were compared. In addition, an MRGs-based risk model was constructed and the role of a key risk gene, ST3GAL4, in osteosarcoma cells was explored using molecular biological experiments.ResultsThis study revealed four key metabolic pathways in osteosarcoma, with vitamin and cofactor metabolism being the most relevant to prognosis and to TIME. Two metabolic pathway-related clusters (C1 and C2) were identified, with some differences in immune activating cell infiltration between the two clusters, and C2 was more likely to respond to two chemotherapeutic agents than C1. Three MRG-related gene clusters (GC1-3) were also identified, with significant differences in prognosis among the three clusters. GC2 and GC3 had higher immune cell infiltration than GC1. GC3 is most likely to respond to immune checkpoint blockade and to three commonly used clinical drugs. A metabolism-related risk model was developed and validated. The risk model has strong prognostic predictive power and the low-risk group has a higher level of immune infiltration than the high-risk group. Knockdown of ST3GAL4 significantly inhibited proliferation, migration, invasion and glycolysis of osteosarcoma cells and inhibited the M2 polarization of macrophages.ConclusionThe metabolism of vitamins and cofactors is an important prognostic regulator of TIME in osteosarcoma, MRG-related gene clusters can well reflect changes in osteosarcoma TIME and predict chemotherapy and immunotherapy response. The metabolism-related risk model may serve as a useful prognostic predictor. ST3GAL4 plays a critical role in the progression, glycolysis, and TIME of osteosarcoma cells.