Biomarker For Overall Survival Research Articles

Clinical usefulness of C-reactive protein-albumin-lymphocyte (CALLY) index as a prognostic biomarker in patients undergoing surgical resection of pancreatic cancer.

The C-reactive protein-albumin-lymphocyte (CALLY) index, which simultaneously evaluates the nutritional, immunological, and inflammatory statuses, is a new prognostic biomarker in patients with various cancers; however, no study has reported the clinical significance of the CALLY index in patients with pancreatic cancer. This study aimed to investigate whether the preoperative CALLY index is a prognostic biomarker in patients undergoing surgical resection of pancreatic cancer. We retrospectively enrolled 461 patients with pancreatic cancer who underwent surgical resection between January 2013 and December 2022. The overall survival (OS) and relapse-free survival (RFS) rates were calculated using the Kaplan-Meier method. Univariate and multivariate analyses were performed using Cox proportional hazards regression models. The optimal cut-off value for the preoperative CALLY index was 1.9. In the low CALLY group, patients were older (p = 0.012), more patients underwent pancreaticoduodenectomy (p = 0.002), the median tumor size was larger (p < 0.001), more patients had pathologically confirmed metastatic lymph nodes (p = 0.015) and worse pathological stage (p = 0.015), and fewer patients received adjuvant chemotherapy (p = 0.003). A low CALLY index was associated with decreased OS (22.1 vs. 37.9months) and RFS (12.4 vs. 16.4months). Univariate and multivariate analyses showed that the preoperative CALLY index was an independent prognostic factor for OS (p < 0.001) and RFS (p = 0.045). The preoperative CALLY index is a prognostic biomarker for both OS and RFS in patients undergoing surgery for pancreatic cancer.

Prognostic significance of CRLF2 in patients with acute lymphoblastic leukemia: a meta-analysis and systematic review.

The association between cytokine receptor-like factor 2 (CRLF2) and clinical outcomes in acute lymphoblastic leukemia (ALL) has been a topic of ongoing debate, with divergent findings. This article intended to investigate the influence of CRLF2 alterations on ALL prognosis. Following the PRISMA 2020 guidelines, this meta-analysis was conducted. Hazard ratio (HR) values and confidence intervals (CIs) were the primary statistical measures used. Data heterogeneity was judged using the chi-square test and I2 statistic. Publication bias was appraised with funnel plots, Begg's test, and Egger's test. 16 studies with 6771 patients were finally screened out. CRLF2 over-expression (CRLF2 OE) was associated with poorer event-free survival (EFS) (HR = 1.70, 95% CI = 1.18-2.44, P = 0.004) and relapse-free survival (RFS) (HR = 1.70, 95% CI = 1.28-2.24, P = 0.000) in pediatric ALL. Patients with CRLF2-deregulation (CRLF2-d), also known as CRLF2 rearrangement, exhibited shorter overall survival (OS) (HR = 2.22, 95% CI = 1.49-3.32, P = 0.000), EFS (HR = 1.93, 95% CI = 1.43-2.60, P = 0.000), and RFS (HR = 2.2, 95% CI = 1.53-3.18, P = 0.000) compared to those without CRLF2-d. Subgroup analysis of multivariate HRs and corresponding CIs indicated that childhood with CRLF2 OE had a shorter RFS (HR = 1.70, 95% CI = 1.28-2.24, P = 0.006), and CRLF2-d was identified as an independent prognostic biomarker for OS (HR = 2.22, 95% CI = 1.49-3.32, P = 0.000), EFS (HR = 1.95, 95% CI = 1.44-2.64, P = 0.000), and RFS (HR = 2.2, 95% CI = 1.53-3.18, P = 0.000) in pediatric ALL patients. Both CRLF2 OE and CRLF2-d are associated with poor prognosis in ALL patients.

ESR Essentials: response assessment criteria in oncologic imaging-practice recommendations by the European Society of Oncologic Imaging.

Assessing the response to oncological treatments is paramount for determining the prognosis and defining the best treatment for each patient. Several biomarkers, including imaging, can be used, but standardization is fundamental for consistency and reliability. Tumor response evaluation criteria have been defined by international groups for application in pharmaceutical clinical trials evaluating new drugs or therapeutic strategies. RECIST 1.1 criteria are exclusively based on unidimensional lesion measurements; changes in tumor size are used as surrogate imaging biomarkers to correlate with patient outcomes. However, increased tumor size does not always reflect tumor progression. The introduction of immunotherapy has led to the development of new criteria (iRECIST, Level of Evidence (LoE) Ib) that consider the possibility that an increase in disease burden is secondary to the immune response instead of progression, with the new concept of Unconfirmed Progressive Disease (a first progression event which must be confirmed on follow-up). Specific criteria were devised for HCC (mRECIST, LoE IV), which measure only enhancing HCC portions to account for changes after local therapy. For GIST treated with imatinib, criteria were developed to account for the possible increase in size reflecting a response rather than a progression by assessing both tumor size and density on CT (Choi, LoE II). This article provides concise and relevant practice recommendations aimed at general radiologists to help choose and apply the most appropriate criteria for assessing response to treatment in different oncologic scenarios. Though these criteria were developed for clinical trials, they may be applied in clinical practice as a guide for day-to-day interpretation. KEY POINTS: Response evaluation criteria, designed for use in clinical trials, might serve as a surrogate biomarker for overall survival. RECIST 1.1 defines measurable and non-measurable disease among which target lesions and non-target lesions are selected at baseline as reference for follow-ups. Some therapies and/or cancers require the use of different criteria, such as iRECIST, mRECIST, and Choi criteria.

Integrative analysis reveals the potential prognostic roles and immunological values of unc-5 netrin receptor A (UNC5A) in glioma

BackgroundUNC5A had been reported to play crucial roles in multiple cancers. However, little was known about the associations among UNC5A and glioma. Therefore, we first combined scRNA-seq, proteomics, as well as bulk RNA-seq in order to investigate UNC5A’s functions in gliomas.MethodsOnline databases provided scRNA-seq, proteomics, as well as bulk RNA-seq data on UNC5A in gliomas. The following procedures were conducted in order: QRT-PCR, Norman chart, gene set enrichment analysis (GSEA), and univariate/multifactor Cox regression analyses. We further explored the associations among UNC5A and tumor immunity.ResultsBy comparing gliomas with normal tissues, the TCGA dataset showed a significantly reduced expression of UNC5A, which was also confirmed by GSE50161, GSE4290, and QRT-PCR findings (p < 0.05). In both the TCGA and CGGA datasets, gliomas patients with low-UNC5A expression would have poorer overall survival (OS) prognoses (p < 0.05). ScRNA-seq analysis by the CancerSEA online website presented that UNC5A had a low expression in various glioma clusters and significantly associated with six functional states. Moreover, UNC5A might be a reliable independent biomarker of OS in gliomas patients (p < 0.05). Based on the results of GSEA, UNC5A might be connected to three significant pathways in gliomas. We also successfully created a Norman chart to assess the OS prognoses of these patients. Additionally, in aspects of tumor immunity, the infiltration levels of immune cells in LGG, the immune cell pathways, tumor immune microenvironment, as well as immune checkpoints in both LGG and GBM were revealed to be significantly influenced by UNC5A (p < 0.05).ConclusionsUNC5A was found to have prognostic and immunological significance in gliomas, offering patients with gliomas new treatment options.

Exploring the Role of Neutrophil-Related Genes in Osteosarcoma via an Integrative Analysis of Single-Cell and Bulk Transcriptome.

The involvement of neutrophil-related genes (NRGs) in patients with osteosarcoma (OS) has not been adequately explored. In this study, we aimed to examine the association between NRGs and the prognosis as well as the tumor microenvironment of OS. The OS data were obtained from the TARGET-OS and GEO database. Initially, we extracted NRGs by intersecting 538 NRGs from single-cell RNA sequencing (scRNA-seq) data between aneuploid and diploid groups, as well as 161 up-regulated differentially expressed genes (DEGs) from the TARGET-OS datasets. Subsequently, we conducted Least Absolute Shrinkage and Selection Operator (Lasso) analyses to identify the hub genes for constructing the NRG-score and NRG-signature. To assess the prognostic value of the NRG signatures in OS, we performed Kaplan-Meier analysis and generated time-dependent receiver operating characteristic (ROC) curves. Gene enrichment analysis (GSEA) and gene set variation analysis (GSVA) were utilized to ascertain the presence of tumor immune microenvironments (TIMEs) and immunomodulators (IMs). Additionally, the KEGG neutrophil signaling pathway was evaluated using ssGSEA. Subsequently, PCR and IHC were conducted to validate the expression of hub genes and transcription factors (TFs) in K7M2-induced OS mice. FCER1G and C3AR1 have been identified as prognostic biomarkers for overall survival. The findings indicate a significantly improved prognosis for OS patients. The effectiveness and precision of the NRG signature in prognosticating OS patients were validated through survival ROC curves and an external validation dataset. The results clearly demonstrate that patients with elevated NRG scores exhibit decreased levels of immunomodulators, stromal score, immune score, ESTIMATE score, and infiltrating immune cell populations. Furthermore, our findings substantiate the potential role of SPI1 as a transcription factor in the regulation of the two central genes involved in osteosarcoma development. Moreover, our analysis unveiled a significant correlation and activation of the KEGG neutrophil signaling pathway with FCER1G and C3AR1. Notably, PCR and IHC demonstrated a significantly higher expression of C3AR1, FCER1G, and SPI1 in Balb/c mice induced with K7M2. Our research emphasizes the significant contribution of neutrophils within the TIME of osteosarcoma. The newly developed NRG signature could serve as a good instrument for evaluating the prognosis and therapeutic approach for OS.

Diffusion weighted MRI and apparent diffusion coefficient as a prognostic biomarker in evaluating chemotherapy-antiangiogenic treated stage IV non-small cell lung cancer: A prospective, single-arm, open-label, clinical trial (BevMar)

PurposeWhen treating Lung Cancer, it is necessary to identify early treatment failure to enable timely therapeutic adjustments. The Aim of this study was to investigate whether changes in tumor diffusion during treatment with chemotherapy and bevacizumab could serve as a predictor of treatment failure. Material and MethodsA prospective single-arm, open-label, clinical trial was conducted between September 2014 and December 2020, enrolling patients with stage IV non-small cell lung cancer (NSCLC). The patients were treated with chemotherapy-antiangiogenic combination. Diffusion weighted magnetic resonance imaging (DW-MRI) was performed at baseline, two, four, and sixteen weeks after initiating treatment. The differences in apparent diffusion coefficient (ADC) values between pre- and post-treatment MRIs were recorded as Delta values (ΔADC). We assessed whether ΔADC could serve as a prognostic biomarker for overall survival (OS), with a five year follow up. Results18 patients were included in the final analysis. Patients with a ΔADC value ≥ -3 demonstrated a significantly longer OS with an HR of 0.12 (95 % CI; 0.03– 0.61; p = 0.003) The median OS in patients with a ΔADC value ≥ -3 was 18 months, (95 % C.I; 7–46) compared to 7 months (95 % C.I; 5–9) in those with a ΔADC value < -3. ConclusionOur findings suggest that early changes in tumor ADC values, may be indicative of a longer OS. Therefore, DW-MRI could serve as an early biomarker for assessing treatment response in patients receiving chemotherapy combined with antiangiogenic therapy.

Prognostic roles of dysregulated METTL3 protein expression in cancers and potential anticancer value by inhibiting METTL3 function

AbstractBackgroundMany studies have demonstrated the relationship between METTL3 protein expression and clinical outcomes in various cancers and elucidated the mechanism by which METTL3 disrupts the behavior of cancer cells. Here, we attempted to define the prognostic value of METTL3 protein in patients with cancer via systematic analysis and explored the potential effect of inhibiting METTL3 using its specific inhibitor.MethodsWe searched PubMed, Embase, and the Web of Science databases for studies that elucidated the prognostic value of METTL3 protein expression in all cancer types and then calculated the pooled hazard ratios with 95% confidence intervals for the overall survival (OS) of all cancer types and subgroups. Data from The Cancer Genome Atlas dataset were used to study METTL3 mRNA expression in cancers. Further, the effects of a METTL3‐specific inhibitor were studied in cancer cells via the colony formation assay, the cell proliferation assay, and apoptosis detection.ResultsMeta‐analysis of the 33 cohorts in 32 studies (3666 patients in total) revealed that higher METTL3 protein expression indicated poor OS in the majority of cancers. Bioinformatics analysis of METTL3 mRNA expression and cancer prognosis did not show the extremely prominent prognostic value of METTL3 mRNA. Nevertheless, the METTL3‐specific inhibitor attenuated cell proliferation and cell cloning formation and promoted apoptosis.ConclusionsMETTL3 protein expression is associated with poor prognosis in most cancer types and could be a biomarker for OS. Further, METTL3 inhibition might be a potential treatment strategy for cancers.

OPTIMIZE-1 primary analysis: Safety, efficacy and biomarker results of a phase 1b/2 study combining CD40 agonist mitazalimab with mFOLFIRINOX in previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC).

4133 Background: With a 5 year overall survival (OS) rate &lt;5%, PDAC is a leading cause of cancer related mortality. Currently available systemic therapies are not curative and new therapeutic options are needed. Mitazalimab is a human CD40 agonistic IgG1antibody that reduces immune suppression, sensitizes the tumor to chemotherapy, and induces long lasting anti-tumor T cell responses. OPTIMIZE-1 (NCT04888312) is a Phase 1b/2, open label, multicenter study assessing mitazalimab's safety and efficacy combined with mFOLFIRINOX (mFFX) in chemotherapy naïve mPDAC patients (pts). Methods: In the first 21 day cycle, mitazalimab was administered on day 1 and 10 and mFFX infusion started on day 8. In subsequent cycles, treatment followed a 14 day cycle with mitazalimab given 2 days after mFFX. The primary endpoint is objective response rate (ORR) compared to 30% ORR for FFX (Conroy, 2011) (80% power; α (1-sided) =0.10). Secondary and exploratory endpoints include Duration of Response (DoR), progression free survival (PFS), OS, safety, PK and PD biomarker assessments. Results: Seventy pts with mPDAC were treated with mFFX + mitazalimab (safety set: 5 at 450 µg/kg and 65 at 900 µg/kg). 57 patients at 900 µg/kg received ≥2 treatment cycles and were efficacy evaluable. The most common grade ≥3 AEs were neutropenia (25.7%), anemia (11.4%), hypokalemia (15.7%) and thrombocytopenia (11.4%), consistent with FFX safety profile. Two pts discontinued treatment due to AEs. Confirmed ORs were observed in 23 pts (40.4%), including 1 complete responder (CR). Median OS, PFS and duration of Response (DoR) were 14.3 months (mo), 7.4 mo and 12.5 mo respectively, with a median follow up of 12.7 mo. 29 pts (51%) remain in the study (32% on treatment, 19% in survival follow up). Efficacy results including correlation with detected KRAS G12 mutations are summarized (Table). Conclusions: Mitazalimab in combination with mFFX is a feasible regimen with a manageable safety profile. The primary endpoint was met; KRAS G12 V and R mutations were associated with better efficacy. Given the promising DoR linked with survival benefit in previously untreated mPDAC, these results merit continued development of mitazalimab in a confirmatory phase 3 study. Clinical trial information: NCT04888312 . [Table: see text]

Abstract B010: Tumor B8T expression stratifies overall survival in high risk muscle invasive urothelial carcinoma

Abstract Background and Objective: Determining novel biomarkers to identify patients that benefit and do not benefit from immune checkpoint inhibitor (ICI) therapy is critical to avoid overtreatment. Circulating tumor DNA (ctDNA) has emerged as a biomarker that associates with overall survival (OS) benefit to ICI in patients with muscle invasive urothelial carcinoma (MIUC). However, few studies have examined whether existing immune based biomarkers stratify OS within the high risk, ctDNA(+) population. Methods: To address this, we interrogated ctDNA and RNA sequencing data from the IMvigor010 dataset of patients with high risk MIUC after cystectomy who were randomized to adjuvant atezolizumab versus observation. We correlated OS with ctDNA positivity and expression of a B cell and CD8 T cell gene signature (B8T). Key Findings: In patients who were ctDNA(+), high tumor expression of a B cell gene signature (BCGS) associated with significantly higher OS when compared with patients with low tumor BCGS, regardless of whether patients were treated with atezolizumab. In ctDNA(+) patients with high tumor expression of both BCGS and CD8 T cell gene signature (CD8TGS), e.g. B8T high/high, atezolizumab did not associate with OS benefit. Conversely, in patients with B8T high/low tumors, receipt of adjuvant atezolizumab associated with significantly increased OS (p &amp;lt; 0.001), and this benefit remained significant in multivariable analyses (p = 0.047). Notably, benefit with atezolizumab occurred in patients with B8T high/low tumors who were either ctDNA(+) (p = 0.057) or ctDNA(-) (p = 0.034). Conclusions and Clinical Implications: While tumor B8T high/high expression is a prognostic biomarker for OS in ctDNA(+) patients with high risk MIUC, these results suggest B8T high/low is a predictive biomarker for benefit from ICI. Moreover, in a small subset of patients who are ctDNA(-), tumor B8T high/low associates with benefit to ICI. This supports the utility of the B8T biomarker as a prognostic identifier in high risk MIUC, its ability to identify patients who will benefit from ICI regardless of ctDNA status, and for the first time ascertains a potential cohort of patients who are ctDNA(-) yet benefit from ICI. Citation Format: Roy Elias, Adam K. Aragaki, Jean H. Hoffman-Censits, Noah M. Hahn, David J. McConkey, Burles A. Johnson III. Tumor B8T expression stratifies overall survival in high risk muscle invasive urothelial carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B010.

494 Evaluating ERK1 2 Phosphorylation as a Predictive Biomarker for Survival in Recurrent Glioblastoma Patients: A REMARK Criteria-guided Analysis of a Clinical Trial Cohort Treated With Intracerebral PD-1 and CTLA-4 Blockade

INTRODUCTION: Glioblastoma patients exhibit variable clinical responses to anti-PD-1 immunotherapy. Our previous work identified ERK1/2 phosphorylation (p-ERK) in pre-treatment tumor samples as a predictive biomarker of overall survival in two independent cohorts of recurrent glioblastoma patients undergoing adjuvant anti-PD-1 therapy (Arrieta et al, Nat Cancer, 2021). This biomarker, however, has not yet been explored with alternative immune checkpoint blockade strategies nor assessed using REMARK criteria. METHODS: Adhering to REMARK criteria for biomarker validation, we investigated p-ERK as a predictor of survival in 24 evaluable recurrent glioblastoma patients from a clinical trial (NCT03233152; Duerinck J, et al, JITC, 2021). Patients underwent intracerebral administration of immune checkpoint inhibitors within a phase I clinical trial, receiving either ipilimumab (10 mg), or a combination of ipilimumab (5 mg) and nivolumab (10 mg), followed by postsurgical intravenous nivolumab (10 mg). We quantified p-ERK+ cell density in tumor regions and conducted a double-blinded statistical analysis of p-ERK’s association with survival outcomes, performed by an independent statistical team. RESULTS: Although analysis of the entire cohort revealed no statistically significant survival difference between patients with high and low p-ERK tumors (p = 0.29), a focused examination of wild-type IDH GBM patients demonstrated a significantly prolonged survival for those with high p-ERK tumors (median survival = 55.6 weeks, 95% CI 33.86-NA) compared to those with low p-ERK tumors (median OS of 30 weeks, 95% CI 16.14-NA; p = 0.036). CONCLUSIONS: Despite the limited sample size, this study highlights the promising predictive potential of p-ERK as a biomarker in a third independent prospective glioblastoma cohort treated with a novel immune checkpoint blockade administration approach, emphasizing the need for further investigation and validation in larger cohorts.

Abstract 7641: Prognostic impact of functional germline mutations in muscle-invasive bladder cancer identified by neural network analysis

Abstract Background: An accurate prognostic algorithm based on germline whole exome sequencing (WES) would complement tumor omics as a non-invasive source of biomarkers for guiding cancer patient therapy. In a previous study, we used WES and RNA-seq data from muscle-invasive bladder cancer (MIBC) and normal host cells to train a survival model, wherein we discovered that mutated germline genes accounted for 90% of feature importance. We have since defined a larger cohort to identify key germline biomarkers of overall survival (OS) that may be scalable for application in the clinic. Methods: 169 patients from The Cancer Genome Atlas (TCGA) with MIBC stages T2-T4 that underwent radical cystectomy (RC) w/o neoadjuvant treatment were eligible. OS at 4 years was the primary clinical endpoint as it is associated with death due to metastatic tumor recurrence. Patients were dichotomized to control survivors who were alive at 4+ years, and cases who died within 4 years but no less than 4 months after RC. 49 qualifying survivors were propensity matched against 49 dead patients by stage, adjuvant treatment, gender, race, and age. The remaining 71 dead patients served as a holdout. Only high (e.g. frameshift) and moderate (e.g. indel) impact germline variants were included. Mutations were weighted for allele frequency (penalize common) and genotype (reward homozygous) before grouping at the gene level. A panel of the 21 most differential genes in stratified patients were selected for neural network training using AIQC. The model forced protective/pathogenic genes to interact and produced individual survival probabilities. Gene importance was determined via permutation. Results: OS was accurately predicted for 98.2% of patients: 1 FN, 2 FP, 37 TN, 119 TP. The top 3 permuted genes (and related pathways) were: SORL1 (Aβ), KIF27 (hedgehog), CUL7 (p53). The most differential gene was CUL7: 31% of survivors mutated vs 2% of dead. Conclusion: Neural network analysis identified the promise of germline genetics as an accurate predictor of survival and tumor recurrence in MIBC patients. Upon validation in an external cohort, these biomarkers could be used to inform adjuvant therapy and complement molecular residual disease alongside circulating tumor (ct)-DNA. Citation Format: Guru P. Sonpavde, Amin H. Nassar, Arvind Ravi, Layne Sadler. Prognostic impact of functional germline mutations in muscle-invasive bladder cancer identified by neural network analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7641.

Abstract 2491: The Oxford Classic can identify HGSOC patients who may benefit from EMT-targeting therapies

Abstract Introduction: Despite development of novel targeted therapies such as PARP inhibitors and anti-angiogenic drugs, there is a clear lack of treatment options for High Grade Serous Ovarian Cancer (HGSOC) patients who are Homologous Recombination Repair proficient (50% of cases) and those with intrinsic resistance to these drugs. In this study we demonstrate the ability of the Oxford Classic (OxC)1,2, a non-genetic classifier, to identify HGSOC patients who may benefit from EMT targeting drugs. Methods: 139 HGSOC diagnostic tumor tissue (Brescia cohort) underwent RNA sequencing. Scottish cohort3 was used for external validation and TCGA, AOCS &amp; OVCAD datasets were used for meta-analysis. Deconvolution of tumor RNAseq data, survival analyses, differential gene expression (DGE) analysis, gene pathway analyses in R and tumor immune profiling using CIBERSORT were performed. Results: Risk stratification of HGSOC using the Oxford Classic Patients with a higher OxC-EMT score had 3.6 times increased risk of death (95%CI: 1.6-8.0; p=2e-03) compared to patients with a lower OxC-EMT score by a multivariable cox regression analysis of Brescia cohort. By Kaplan-Meier survival analyses, a significant difference in overall survival in Brescia cohort (p=9e-06), Scottish cohort (p=2e-03) and a combined set of 1023 cases (p=1e-04), was observed between EMT-low risk patients (OxC-EMT score-0) and EMT-high risk patients (OxC-EMT score&amp;gt;0). Notably, 5-year median survival of EMT-low risk and EMT-high risk group was 50% and 13%, resp. (95%CI: 36.1%-69.3% vs 7.1%-23.5%) in Brescia cohort. Therapeutic options for OxC-EMT-high risk group DGE analysis of EMT-low patients and EMT-very high patients (OxC-EMT score&amp;gt;0.5) identified 404 differentially expressed genes common to the datasets. These included genes related to extracellular matrix organisation (VCAN, TGFβI), epithelial cell proliferation (RUNX2, FABP4, SERPINF1), cell chemotaxis (CCL19, DUSP1), angiogenic factors (VEGFC, CXCL12) and transmembrane kinase signalling pathways (TGFβ1/3, PDGFRα/β, IGFBP4/5/6, Wnt11). Of note, key EMT transcription factors, TWIST1/2, SNAI1/2, ZEB1/2, and stemness marker, ALDH1A3, were 2-7 times overexpressed in EMT-very high group. Furthermore, immune modulators, IL6 and IL10 were significantly upregulated and M2 macrophages were significantly more abundant in EMT-very high patients. Multiplex IHC is currently underway to confirm the abundance of TAMs and CD8-positive TRM in the two risk groups. Conclusions: 1) The Oxford Classic-based EMT is a robust prognostic biomarker of overall survival in HGSOC, that faithfully represents the complex circuitry of pathways which are a hallmark of Epithelial to Mesenchymal Transition. 2) OxC-EMT risk stratification can identify HGSOC patients who may benefit from EMT-targeting therapies. Reference: 1) Hu Z. Cancer Cell 2020 2) Hu Z. Clin Cancer Res 2021 3) Hollis R. Clin Cancer Res 2022 Citation Format: Lena Rai, Antonella Ravaggi, Eliana Bignotti, Robb Hollis, Joel Nulsen, Leticia Campo, Alistair Easton, Mara Artibani, Mike Churchman, Federico Ferrari, Christopher Yau, Charlie Gourley, Franco Odicino, Ahmed Ahmed. The Oxford Classic can identify HGSOC patients who may benefit from EMT-targeting therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2491.

An Integrated Machine Learning Framework Identifies Prognostic Gene Pair Biomarkers Associated with Programmed Cell Death Modalities in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a common and lethal urological malignancy for which there are no effective personalized therapeutic strategies. Programmed cell death (PCD) patterns have emerged as critical determinants of clinical prognosis and immunotherapy responses. However, the actual clinical relevance of PCD processes in ccRCC is still poorly understood. We screened for PCD-related gene pairs through single-sample gene set enrichment analysis (ssGSEA), consensus cluster analysis, and univariate Cox regression analysis. A novel machine learning framework incorporating 12 algorithms and 113 unique combinations were used to develop the cell death-related gene pair score (CDRGPS). Additionally, a radiomic score (Rad_Score) derived from computed tomography (CT) image features was used to classify the CDRGPS status as high or low. Finally, we conclusively verified the function of PRSS23 in ccRCC. The CDRGPS was developed through an integrated machine learning approach that leveraged 113 algorithm combinations. CDRGPS represents an independent prognostic biomarker for overall survival and demonstrated consistent performance between training and external validation cohorts. Moreover, CDRGPS showed better prognostic accuracy compared to seven previously published cell death-related signatures. In addition, patients classified as high-risk by CDRGPS exhibited increased responsiveness to tyrosine kinase inhibitors (TKIs), mammalian Target of Rapamycin (mTOR) inhibitors, and immunotherapy. The Rad_Score demonstrated excellent discrimination for predicting high versus low CDRGPS status, with an area under the curve (AUC) value of 0.813 in the Cancer Imaging Archive (TCIA) database. PRSS23 was identified as a significant factor in the metastasis and immune response of ccRCC, thereby validating experimental in vitro results. CDRGPS is a robust and non-invasive tool that has the potential to improve clinical outcomes and enable personalized medicine in ccRCC patients.

Clinical significance of small nuclear ribonucleoprotein U1 subunit 70 in patients with hepatocellular carcinoma.

Small nuclear ribonucleoprotein U1 subunit 70 (SNRNP70) as one of the components of the U1 small nuclear ribonucleoprotein (snRNP) is rarely reported in cancers. This study aims to estimate the application potential of SNRNP70 in hepatocellular carcinoma (HCC) clinical practice. Based on the TCGA database and cohort of HCC patients, we investigated the expression patterns and prognostic value of SNRNP70 in HCC. Then, the combination of SNRNP70 and alpha-fetoprotein (AFP) in 278 HCC cases was analyzed. Next, western blotting and immunohistochemistry were used to detect the expression of SNRNP70 in nucleus and cytoplasm. Finally, Cell Counting Kit-8 (CCK-8) and scratch wound healing assays were used to detect the effect of SNRNP70 on the proliferation and migration of HCC cells. SNRNP70 was highly expressed in HCC. Its expression was increasingly high during the progression of HCC and was positively related to immune infiltration cells. Higher SNRNP70 expression indicated a poor outcome of HCC patients. In addition, nuclear SNRNP70/AFP combination could be a prognostic biomarker for overall survival and recurrence. Cell experiments confirmed that knockdown of SNRNP70 inhibited the proliferation and migration of HCC cells. SNRNP70 may be a new biomarker for HCC progression and HCC diagnosis as well as prognosis. SNRNP70 combined with serum AFP may indicate the prognosis and recurrence status of HCC patients after operation.

COP9 signalosome complex is a prognostic biomarker and corresponds with immune infiltration in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is among the most common deadly tumors but still lacks specific biomarkers for diagnosis, prognosis, and treatment guidance. The COP9 signalosome (COPS) is an essential regulator of the ubiquitin conjugation pathway upregulated in various cancers. We evaluated the contributions of COPS subunits to HCC tumorigenesis and their utility for prognosis. We comprehensively evaluated the tumor expression pattern and tumorigenic functions of COPS subunits using The Cancer Genome Atlas (TCGA), The Human Protein Atlas and immunohistochemistry. Kaplan-Meier, Cox regression, ROC curve, and nomogram analyses were used to assess the predictive values of COPS subunits for clinical outcome. Expression levels of COPS subunits were significantly upregulated in HCC tissues, which predicted shorter overall survival (OS). Further, Cox regression analysis identified COPS5, COPS7B, and COPS9 as independent prognostic biomarkers for OS. High mutation rates were also found in COPS subunits. Functional network analysis indicated that COPS and neighboring genes regulate 'protein neddylation', 'protein deneddylation', and 'protein ubiquitination'. The COPS PPI included strong interactions with p53, CUL1/2/3/4, and JUN. Moreover, the correlations between COPS subunit expression levels and tumor immune cell infiltration rates were examined using TIMER, TISIDB, ssGSEA, and ESTIMATE packages. COPS subunits expression levels were positively correlated with specific tumor immune cell infiltration rates, immunoregulator expression levels, and microsatellite instability in HCC. Finally, knockout of COPS6 and COPS9 in HCC cells reduced while overexpression enhanced proliferation rate and metastasis capacity. Our study revealed that COPS potential biomarker for unfavorable HCC prognosis and indicators of immune infiltration, tumorigenicity, and metastasis.

SIRT3 Expression Predicts Overall Survival and Neoadjuvant Chemosensitivity in Triple-Negative Breast Cancer.

The Sirtuin (SIRT) family consists of seven evolutionary conserved NAD-dependent deacetylases that play important roles in various cancers, including breast cancer (BC). SIRTs expression has been reported to have prognostic value in BC, but these studies used limited sample size and yielded inconsistent conclusions. This study evaluated the association of SIRT3 and other SIRT family members with survival and neoadjuvant chemotherapy outcomes. BC patients' data was obtained from the TCGA-BRCA, METABRIC and GEO databases, comprising 4336 samples. SIRTs expression and overall survival (OS) were analyzed using Kaplan-Meier analysis and Cox proportional hazards regression. SIRT3 expression levels were compared between pathologic complete response (pCR) and non-pCR groups after neoadjuvant chemotherapy in triple-negative breast cancer (TNBC). Protein-protein interaction networks were constructed using the STRING database. Gene set enrichment analysis (GSEA) was performed to explore potential functions of SIRT3. Through systematic analysis of SIRTs expression and OS of BC using three independent cohorts: TCGA-BRCA, METABRIC and GSE16446, we found that high SIRT3 expression was significantly associated with worse OS in TNBC in the TCGA-BRCA cohort, which was validated in the METABRIC and GSE16446 cohorts. SIRT3 expression was correlated with BC subtypes and American Joint Committee on Cancer (AJCC) T stage, but not with age-at-diagnosis, race, or tumor stage. Moreover, TNBC patients with higher SIRT3 expression had lower pCR rates after neoadjuvant chemotherapy (p = 6.40e-03) and SIRT3 expression was significantly lower in the pCR group than in the non-pCR group in TNBC (p = 4.2e-03). GSEA indicated that SIRT3 was involved in drug-related pathways such as oxidative phosphorylation, metabolism of xenobiotics by cytochrome P450, and drug metabolism. Our study suggests that SIRT3 is a potential biomarker for both OS and neoadjuvant chemosensitivity in TNBC. It may also assist in selecting suitable candidates and treatment options for TNBC patients.

Molecular characteristics and multivariate survival analysis of 43 patients with locally advanced or metastatic esophageal squamous cell carcinoma.

Esophageal cancer (EC) is an aggressive malignant tumor with poor prognosis and high incidence. It is the sixth leading cause of cancer-related death in the world, and the 5-year overall survival (OS) rate is only 12-20%. The rapid development of next-generation sequencing (NGS) has provided powerful help for the treatment and management of EC patients. Tumor tissue and blood samples of 43 Chinese patients with nonsurgical esophageal squamous cell carcinoma (ESCC) were sequenced using a 425 gene-panel. Genomic profiling was explored and and the Cox proportional hazards model was used to analyze the correlations between gene or signaling pathway alterations and prognosis. In this study, the most common mutated genes were TP53 (90.5%), CCND1 (45.2%), FGF19 (38.1%), NOTCH1 (26.2%), PI3KCA (21.4%) and CDKN2A (19%). Among these mutations, PI3KCA and NOTCH1 showed mutual exclusion to some extent. In the univariate model, mutations in NOTCH1, CBLB and TSC2 genes and tumor mutation burden (TMB) ≥7 were independent biomarkers of OS. NOTCH1 (P=0.007, HR =2.87), CBLB (P=0.011, HR =4.68) and TSC2 (P=0.024, HR =3.7) were significantly associated with poorer OS, and patients with TMB ≥7 had longer OS (P=0.151, HR =0.31). In addition, patients who carried alteration in NOTCH signaling pathway had reduced OS (P=0.014, HR =2.54). NOTCH1, CBLB and TSC2 alterations were found to be potential indicators of poor prognosis in patients with ESCC. TMB was also positively correlated with the OS of ESCC patients, providing valuable insights for their treatment strategies.

Perioperative Platelet Count Ratio Predicts Long-Term Survival after Left Pancreatectomy and Splenectomy for Pancreatic Adenocarcinoma.

The value of platelet characteristics as a prognostic factor in patients with pancreatic adenocarcinoma (PDAC) remains unclear. We assessed the prognostic ability of post-splenectomy thrombocytosis in patients who underwent left pancreatectomy for PDAC. Perioperative platelet count ratio (PPR), defined as the ratio between the maximum platelet count during the first five days following surgery and the preoperative level, was assessed in relation to long-term outcomes in patients who underwent left pancreatectomy for PDAC between November 2008 and October 2022. A comparative cohort of 245 patients who underwent pancreaticoduodenectomy for PDAC was also evaluated. The median PPR among 106 patients who underwent left pancreatectomy was 1.4 (IQR1.1, 1.8). Forty-six had a PPR ≥ 1.5 (median 1.9, IQR1.7, 2.4) and 60 had a PPR < 1.5 (median 1.2, IQR1.0, 1.3). Patients with a PPR ≥ 1.5 had increased median overall survival (OS) compared to patients with a PPR < 1.5 (40 months vs. 20 months, p < 0.001). In multivariate analysis, PPR < 1.5 remained a strong predictor of worse OS (HR 2.24, p = 0.008). Among patients who underwent pancreaticoduodenectomy, the median PPR was 1.1 (IQR1.0, 1.3), which was significantly lower compared to patients who underwent left pancreatectomy (p > 0.001) and did not predict OS. PPR is a biomarker for OS after left pancreatectomy for PDAC. Further studies are warranted to consolidate these findings.

Prognostic and predictive analyses of circulating plasma biomarkers in men with metastatic castration resistant prostate cancer treated with docetaxel/prednisone with or without bevacizumab.

CALGB 90401 (Alliance) was a phase III trial of 1050 patients with metastatic castration-resistant prostate cancer (mCRPC) comparing docetaxel, prednisone, bevacizumab (DP+B) versus DP alone. While this trial did not show an improvement in overall survival (OS), there were improved intermediate outcomes suggesting that subsets of men may derive benefit from this combination. The purpose of this analysis was to identify prognostic and predictive biomarkers associated with OS and progression-free survival (PFS) benefit from DP+B. Baseline EDTA plasma samples from 650 consenting patients were analyzed for 24 biomarkers. The proportional hazards model was utilized to test for the prognostic and predictive importance of the biomarkers for OS. The statistically significant biomarkers of OS were further investigated for prognostic and predictive importance for other secondary outcomes. 15 markers [ICAM-1, VEGF-R3, TIMP-1, TSP-2, Ang-2, Her-3, Osteopontin (OPN), PlGF, VCAM-1, HGF, VEGF, Chromogranin A, IL-6, VEGF-R1, BMP-9] were prognostic of OS, while 9 markers (ICAM-1, VEGF-R3, Her-3, TIMP-1, Ang-2, OPN, PlGF, HGF, and VEGF) were also prognostic of PFS. All markers were statistically significant in univariate analyses after adjustment for multiplicity (FDR < 0.1). In multivariable analyses of OS adjusting for risk score, seven markers had FDR < 0.1, including ICAM-1, VEGF-R3, TIMP-1, Ang-2, VEGF, TSP-2 and HGF. In unadjusted analysis, OPN was predictive of PFS improvement with DP+B, in both univariate and multivariable analysis. However, none of the biomarkers tested were predictive of clinical outcomes after adjusting for multiple comparisons. Multiple biomarkers were identified in CALGB 90401 as prognostic of clinical outcomes but not predictive of OS. While OPN may have promise as a potential biomarker for anti-angiogenic therapies, further mechanistic and clinical studies are needed to determine the underlying biology and potential clinical application.

Preoperative IL-8 levels as prognostic indicators of overall survival: an extended follow-up in a prospective cohort with colorectal liver metastases

IntroductionCRC with liver metastases is a major contributor to cancer-related mortality. Despite advancements in liver resection techniques, patient survival remains a concern due to high recurrence rates. This study seeks to uncover prognostic biomarkers that predict overall survival in patients undergoing curative hepatic resection for CRC liver metastases.MethodsProspectively collected serum samples from a cohort of 49 patients who received curative hepatic resection for CRC liver metastases were studied. The patients are part of a cohort, previously analyzed for perioperative complications (see methods). Various preoperative serum markers, clinical characteristics, and factors were analyzed. Univariate and multivariate Cox regression analyses were conducted to determine associations between these variables and disease-free survival as well as overall survival.ResultsFor disease-free survival, univariate analysis highlighted the correlation between poor outcomes and advanced primary tumor stage, high ASA score, and synchronous liver metastases. Multivariate analysis identified nodal-positive primary tumors and synchronous metastases as independent risk factors for disease-free survival. Regarding overall survival, univariate analysis demonstrated significant links between poor survival and high preoperative IL-8 levels, elevated neutrophil–lymphocyte ratio (NLR), and presence of metastases in other organs. Multivariate analysis confirmed preoperative IL-8 and having three or more liver metastases as independent risk factors for overall survival. The impact of IL-8 on survival was particularly noteworthy, surpassing the influence of established clinical factors.ConclusionThis study establishes preoperative IL-8 levels as a potential prognostic biomarker for overall survival in patients undergoing curative liver resection for CRC liver metastases. This study underscores the importance of incorporating IL-8 and other biomarkers into clinical decision-making, facilitating improved patient stratification and tailored treatment approaches. Further research and validation studies are needed to solidify the clinical utility of IL-8 as a prognostic marker.