Marker For Overall Survival Research Articles

Combined Analyses of Circulating Tumor DNA and Immunoscore in Patients With Stage III Colon Cancer: A Post Hoc Analysis of the PRODIGE-GERCOR IDEA-France/HORG-IDEA-Greece Trials

PURPOSE Immunoscore (IS) and circulating tumor DNA (ctDNA) are two emerging technologies in improving prognostication and tailoring adjuvant treatments in patients resected from a stage III colon cancer (CC). Here, we analyzed the prognostic value of the two biomarkers in patients who participated in the randomized phase III IDEA-France and HORG trials. METHODS Plasma samples were collected after surgery and before adjuvant chemotherapy. ctDNA analysis was performed using a clinically validated, personalized, tumor-informed 16-plex protein chain reaction assay. Multivariable analyses for time to recurrence (TTR; patients without recurrence or death due to CC) and overall survival (OS) were performed using ctDNA and IS results, along with other parameters including treatment duration and disease risk group. RESULTS Of the 554 patients with available ctDNA results, 445 were ctDNA-negative (80.3%) and 109 were ctDNA-positive (19.7%); baseline characteristics showed more T4/N2 and venous embolism/lymphatic invasion/perineural invasion+ in ctDNA-positive patients. With a median follow-up of 6.7 years, the 2-year TTR rate was 43.5% (95% CI, 34.1 to 52.6) for ctDNA-positive patients and 88.1% (95% CI, 84.7 to 90.8) for ctDNA-negative patients ( P < .0001). ctDNA was confirmed as an independent prognostic marker for both TTR (adjusted hazard ratio [adjHR], 5.21 [95% CI, 3.59 to 7.58]; P < .001) and OS (adjHR, 4.84 [95% CI, 3.40 to 6.89]; P < .001). ctDNA remained the most significant prognostic factor irrespective of disease stage, treatment duration, and IS results. IS was not prognostic in ctDNA-positive patients but remained a significant prognostic tool for ctDNA-negative patients. CONCLUSION In this combined analysis of two adjuvant trials dedicated to patients with stage III CC after surgery, ctDNA was detectable in 19.7% of the patients and was confirmed as a major independent prognostic biomarker. IS seems to bring additional prognostic information in the 80.3% of patients who are ctDNA-negative.

A real-world prospective analysis of the relationship between nanoliposomal irinotecan and fluorouracil with folinic acid and neutropenia in patients with pancreatic cancer (NAPOLEON-2 study, NN-2401).

762 Background: Nanoliposomal irinotecan and fluorouracil with folinic acid (NFF) is a standard regimen after gemcitabine-based chemotherapy (CTx) for unresectable or recurrent pancreatic cancer (urPC) patients. Neutropenia caused by systemic CTx has been reported to be a prognostic marker in several cancers, however, the relationship between neutropenia and efficacy of NFF in urPC patients is unknown. Therefore, we initiated a prospective observational study to investigate whether neutropenia can be a prognostic marker in the real-world (NN-2401), followed by a retrospective one (NN-2301). Methods: We collected the data of urPC patients treated with NFF who had received at least one previous CTx in 17 hospitals in Japan from June 2021 to October 2023. The primary endpoint was overall survival (OS). Secondary endpoints included the progression-free survival (PFS) and overall response rate (ORR). To analyze them, we divided urPC patients into three groups by the grade of the most severe neutropenia during NFF (Cutoff A, grade 0 vs 1-4; Cutoff B, grade 0-1 vs 2-4; Cutoff C, grade 0-2 vs 3-4). Besides that, we compared OS among the following three groups receiving NFF ≥4 cycles in Cutoff C; one showed neutropenia with NFF reduction after the 4th cycle (Cutoff C High-Late), another showed neutropenia with NFF reduction in the 2nd or 3rd cycle (Cutoff C High-Early), and the other did grade 0-2 neutropenia (Cutoff C Low). Results: Among the 150 patients, the number of patients with the most severe neutropenia of grade 0, 1, 2, 3, or 4 was 79, 7, 23, 34, and 7, respectively. The median OS of severe neutropenia group in Cutoff A, B, or C was 9.8, 9.8, and 10.6 months, respectively. Both OS and PFS were significantly better in all severe neutropenia groups; hazard ratio [HR] of OS for Cutoff A, B, or C was 0.58, 0.54, and 0.60, respectively; HR of PFS was 0.61, 0.56, and 0.56, respectively. Only Cutoff C showed a significant difference with an odds ratio of 3.06 (95% confidence interval [CI], 1.06-8.80; p=0.04) in ORR. Multivariate Cox regression analysis showed significant difference of OS in all Cutoffs; adjusted HR was 0.58 for Cutoff A, 0.53 for Cutoff B, and 0.52 for Cutoff C. Logistic regression analysis showed a significant difference in ORR of Cutoff C with an odds ratio of 4.02 (95%CI, 1.29-12.6; p=0.02). In addition, the numbers of patients were 73, 14, and 19 in Cutoff C Low, High-Late, and High-Early, respectively. The median OS of Cutoff C High-Late was significantly better than that of Cutoff C High-Early or Cutoff C Low (15.0 vs 10.4 or 9.1 months, p<0.05). Conclusions: In NFF treatment, neutropenia showed the usefulness as a prognostic marker for both OS and PFS, and also a predictive one for tumor response in urPC patients. The results are similar to our previous data, so we conclude that neutropenia can be a useful biomarker of NFF. Clinical trial information: UMIN000043939 .

Preclinical analysis and clinical validation to identify biomarkers for trifluridine/tipiracil (FTD/TPI) efficacy with or without bevacizumab in patients with metastatic colorectal cancer.

230 Background: We previously identified candidate biomarkers for FTD/TPI efficacy through preclinical and translational studies in patients with metastatic colorectal cancer (mCRC). Recent studies reported that FTD/TPI plus bevacizumab (BEV) improved survival compared to FTD/TPI alone. This study evaluated the clinical significance of these biomarkers in patients with refractory mCRC receiving either FTD/TPI plus BEV or FTD/TPI alone. Methods: Candidate biomarkers were selected based on our transcriptomic and cell biological analyses. We validated these biomarkers in mCRC patients treated with FTD/TPI plus BEV (cohort A) or FTD/TPI alone (cohort B). Blood samples were collected at baseline (BL), before the second cycle (2nd), and progressive disease (PD), with serum biomarker levels measured using ELISA. Change patterns were classified as ‘increased’ or ‘decreased’ from BL. To address the unbalanced distribution of baseline characteristics between cohorts, propensity score matching (PSM) was performed. Results: A total of 112 patients were included, with 34 in each cohort after PSM. Cohort A showed significantly longer overall survival (OS) (14.4 vs 6.2 months, HR 0.53, 95%CI: 0.30-0.93) and higher disease control (DC) (58.8 vs 34.4%, P=0.047) compared to cohort B. In univariate analysis, increased IL-8 or AREG at 2nd and increased IFI16 at PD were associated with poorer clinical outcomes. Grade ≥3 neutropenia (NEU) was linked to better survival in both cohorts. Multivariable analysis identified decreased AREG and Grade ≥3 NEU as better markers for progression-free survival and OS. OS was significantly longer in cohort A compared to B (12.8 vs 5.8 months, HR 0.43, 95%CI: 0.21-0.89) when IL-8 increased at 2nd. Cohort A also had longer OS compared to cohort B when EREG (12.8 vs 6.2 months, HR0.27, 95%CI: 0.11-0,65) or AREG (14.2 vs 9.7 months, HR 0.40, 95%CI: 0.17-0.95) decreased at 2nd. There was no significant interaction between the regimen and biomarkers (IL-8, EREG, and AREG) for OS. Conclusions: Our data suggest that AREG may serve as a prognostic marker for FTD/TPI efficacy. Changes in IL-8, EREG and AREG potentially contribute to the extended survival benefit of combining BEV with FTD/TPI.

Apoptosis antagonizing transcription factor expression and its validation as a potential diagnostic and prognostic biomarker in oral squamous cell carcinoma

BackgroundOral squamous cell carcinoma (OSCC) is characterized by a high degree of malignancy and poor prognosis. This study aimed to investigate the expression of apoptosis antagonizing transcription factor (AATF) in OSCC, examine its correlation with clinicopathological features, assess its prognostic implications, and explore its potential role in OSCC progression.MethodsExpression profiles and clinical data of OSCC patients were obtained from The Cancer Genome Atlas (TCGA). Immunohistochemical analysis on tissue microarrays was performed to assess AATF expression in OSCC. Functional enrichment analyses were conducted to identify potential signaling pathways and biological functions associated with AATF. Logistic regression analyses were employed to evaluate the relationship between AATF expression and clinicopathological features. Immune cell infiltration was assessed using single-sample gene set enrichment analysis (ssGSEA). The prognostic value of AATF was determined using Kaplan-Meier and Cox regression analyses. A nomogram was developed to predict overall survival (OS) rates at one, three-, and five years post-cancer diagnosis. Validation of AATF expression was performed using quantitative real-time PCR (qRT-PCR)ResultsAATF was significantly overexpressed in OSCC, and high AATF expression correlated with adverse clinicopathological features, including histologic grade and lymph node metastasis. Functional enrichment analysis revealed several enriched pathways, including epidermis development, immunoglobulin complex, antigen binding and IL-17 signaling pathway. Notably, AATF overexpression was negatively correlated with the infiltration levels of mast cells, interdigitating dendritic cells and Th 17 cells. High AATF expression significantly predicted poorer overall survival (OS) and disease-specific survival (DSS). Multivariate Cox analysis confirmed AATF as an independent negative prognostic marker of OS. Validation via qRT-PCR confirmed the overexpression of AATF in OSCC tissues.ConclusionElevated expression of AATF in OSCC correlates with adverse clinicopathological features and negatively impacts immune cell infiltration. High AATF levels serve as an independent marker of poor OS and DSS. These findings support AATF as a valuable prognostic biomarker and a potential therapeutic target in OSCC, warranting further investigation.

Baseline PSMA PET/CT parameters predict overall survival and treatment response in metastatic castration-resistant prostate cancer patients.

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with varying survival outcomes. This study investigated whether baseline PSMA PET/CT parameters are associated with survival and treatment response. Sixty mCRPC patients underwent [18F]PSMA-1007 PET/CT before treatment with androgen receptor-targeted agents (ARTAs) or chemotherapy. Intensity-based parameters, volumetric parameters, metastatic sites and DmaxVox (distance between the two outermost voxels) from baseline PSMA PET/CT were collected, as well as age, Gleason score and laboratory parameters. Cox regression analysis evaluated their prognostic value for overall survival (OS). Additionally, a preliminary lesion-level analysis was done (n = 241 lesions) with lesion location and twelve radiomic features selected from previous literature. Logistic regression evaluated their association with PSMA PET/CT-based lesion progression after 3-4 months of treatment. Total tumour volume (PSMA-TV) (HR = 1.41 per doubling [1.17-1.70]), total lesion uptake (TL-PSMA) (HR = 1.40 per doubling [1.16-1.69]) and DmaxVox (HR = 1.31 per 10 cm increase [1.07-1.62]) were prognostic for OS, each independent of baseline PSA level (HR = 0.82 per doubling [0.68-0.98]), haemoglobin level (HR = 0.68 per mmol/L increase [0.49-0.95]) and line of treatment. On lesion-level, location (prostate vs bone OR = 0.23 [0.06-0.83]) and SUVmean (OR = 1.72 per doubling [1.08-2.75]) were independent prognostic markers for lesion progression, morphological and texture-based radiomic features were not. Baseline PSMA PET/CT scans have prognostic value in mCRPC patients and can potentially aid in treatment decision-making. DmaxVox can serve as a simpler alternative to PSMA-TV when automated segmentation software is not available. When combined with PSMA-TV, lower PSA levels indicated worse OS, which may be a marker of tumour dedifferentiation. Further research is needed to validate these models in larger patient cohorts. Question mCRPC is a highly heterogeneous disease, requiring good prognostic markers. Findings PSMA-TV was the best independent prognostic marker for OS; maximum distance between lesions (DmaxVox) can be used as a simpler alternative. Clinical relevance Baseline PSMA PET/CT parameters representing tumour burden were independently associated with OS in mCRPC patients, providing prognosticinsights for clinical decision-making. Although PSMA-TV was the best prognostic marker, DmaxVox can serve as an easier to obtain alternative.

Prognostic impact of immunophenotypic variation in subcapsular sinus endothelium of sentinel lymph nodes in invasive breast carcinoma

Introduction Several studies demonstrated the de novo-formation of lymphatic vessels in tumor-draining lymph nodes (LN), partly preceding lymphatic metastases. This “lymphovascular niche” supposedly facilitates survival of metastatic tumor cells. This study aims at evaluating the previously observed immunophenotypic variations of subcapsular endothelial cells (SEC) in a larger cohort by software-assisted image analysis. Methods Suitable cases with sentinel-LN (SLN) of invasive breast cancer were identified in the Institute of Pathology, corresponding data was extracted. LN of 231 patients were stained for HE, D2-40, CD31 and Prox1. QuPath software was used for assessing the immunohistochemical stained area of endothelial cells of the subcapsular sinus. The Cutoff Finder web application was used for identification of the best cutoff for continuous parameters according to overall survival (OS). Collected data was statistically evaluated for available data. Results A larger area of CD31-positive SEC was significantly associated with worse OS (p=0.001), as was a higher proportion of D2-40-stained subcapsular sinus (p=0.045). Larger area of D2-40-/CD31-/Prox1-positive SEC and higher proportion of D2-40 stained subcapsular sinus were independent marker for worse OS in multivariate analysis in the whole cohort, for D2-40- and CD31-positive SECs as well as higher proportion of D2-40-stained sinus including nodal-negative status, respectively. Conclusion QuPath-assisted evaluation of immunophenotypic variation in subcapsular sinus endothelium in SLN essentially confirmed and extended our previous findings. Larger positive area of D2-40 and CD31-positive SECs emerged as a strong independent negative prognostic factor, even before evident nodal metastasis. The potential function of alterations in D2-40-/CD31-expression in SECs has yet to be elucidated.

CYP24A1 DNA Methylation in Colorectal Cancer as Potential Prognostic and Predictive Markers.

The DNA methylation of CYP24A1 can regulate its gene expression and may play a role in the occurrence and progression of colorectal cancer (CRC). However, the association between CYP24A1 DNA methylation and the prognosis of CRC patients has not yet been reported. In this study, differential methylation analysis was conducted in both blood and tissue cohorts, and differential expression analysis was performed in the tissue cohort with in vitro validation. GO and KEGG enrichment analyses were performed on CYP24A1-related genes. A correlation between CYP24A1 promoter methylation and its gene expression was explored. Kaplan-Meier survival and Cox regression analyses were performed to investigate the impact of CYP24A1 DNA methylation on the prognosis of CRC patients. Prognostic risk scores were constructed for survival prediction. Immune infiltration analysis was also conducted. Our results showed that the hypermethylation of cg02712555 in tumor tissues (hazard ratio, 0.48; 95% confidence interval, 0.24-0.94; p = 0.032) and CpG site 41 in peripheral leukocytes (HR, 0.35; 95%CI, 0.14-0.84; p = 0.019) were both associated with decreased overall mortality in CRC patients. Prognostic risk scores showed robust predictive capabilities of these two CpG loci for the prognosis of CRC patients. CYP24A1 hypermethylation was positively correlated with infiltration levels of activated CD4 + T cells, activated CD8 + T cells, activated B cells, activated dendritic cells, and macrophages. Taken together, our findings indicate that the methylation levels of specific CpG sites within the CYP24A1 promoter region in blood leukocytes and tumors are potential prognostic and predictive markers for overall survival in CRC patients.

Evaluation of circ_0002232 and circ-vimentin gene expressions as valuable biomarkers in acute myeloid leukemia patients.

Acute myeloid leukemia (AML) is a remarkably complex malignancy; with considerable genetic, epigenetic, and phenotypic heterogenicity. Circ-RNAs are a novel class of non-coding RNA. They may influence leukemia development and offer exciting possibilities for targeted AML diagnosis and therapy. This study aimed to detect circ_0002232 and circ-VIM expression levels in AML patients and their relation to the clinicopathological characteristics and disease outcome to assess the prognostic potential of both circ-RNAs and achieve a new target therapy for the disease. Circ_0002232 and circ-VIM gene expressions were measured in 60 AML patients and 30 controls using qRT-PCR. Circ_0002232 was significantly downregulated in our patients compared to controls (P value < 0.001). On the other hand, circ-VIM was notably upregulated in our patients (P value = 0.005). Using ROC curve, circ_0002232 and circ-VIM biomarkers could distinguish AML patients from controls with AUC 0.847, 0.683 and P value < 0.0001, = 0.004 respectively. Patients with downregulated circ_0002232 were significantly younger than upregulated patients (p value = 0.003). In addition, downregulated circ_0002232 was significantly associated with decreased hemoglobin level and increased overall survival (OS). Regarding high circ-VIM expression in AML patients, it was significantly correlated with lacking complete remission and leukocytosis. Circ_0002232 and circ-VIM could be valuable diagnostic biomarkers to differentiate AML patients from healthy controls in clinical use. Circ-VIM expression may influence AML prognosis. Further research is needed to validate the clinical utility of circ_0002232 as a prognostic marker for OS in AML patients.

Neoadjuvant immunotherapy in melanoma: pathological response as a surrogate endpoint?

This review evaluates by analyzing recent studies whether pathological complete response (pCR) can be used as a reliable surrogate marker for overall survival (OS) in melanoma treated with neoadjuvant immunotherapy. Trials like Neo-Combi, Neo-Trio and COMBI-Neo show that pCR is crucial for long-term success in targeted therapy for melanoma, while studies like OpACIN-neo and SWOG S1801 demonstrate that immunotherapy can provide durable benefits even with partial responses. Findings from NADINA and the INMC analysis highlight that immunotherapy achieves higher pathologic response rates and improved survival outcomes, offering broader benefits compared to the pCR-dependent outcomes of targeted therapy. pCR serves as a critical prognostic biomarker across cancer types, with strong validation in breast cancer where it predicts long-term survival, particularly in aggressive subtypes like triple-negative and HER2-positive breast cancer. In melanoma, pCR is gaining prominence as a surrogate marker in neoadjuvant therapies, with its predictive value varying between targeted treatments - where achieving pCR is essential - and immunotherapies, which provide durable survival benefits even with partial responses. Despite its potential, the role of pCR as a universally reliable surrogate endpoint in melanoma requires further validation through cancer-specific studies to ensure accurate treatment guidance and personalized care.

Prognostic role of systemic inflammation response index (SIRI) in patients with pancreatic cancer: a meta-analysis.

The significance of the systemic inflammation response index (SIRI) in predicting the prognosis of patients with pancreatic cancer (PC) has been extensively explored; however, findings remain controversial. As such, this meta-analysis was performed to more precisely determine the utility of the SIRI in predicting PC prognosis. A comprehensive literature search of the PubMed, Web of Science, Embase, and Cochrane Library databases for relevant studies, published up to June 25, 2024, was performed. The primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS), respectively. The prognostic utility of the SIRI in predicting PC prognosis was estimated by calculating pooled hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Seven studies comprising 1160 patients were included in the present meta-analysis. Pooled findings revealed that elevated SIRI was as a prominent prognostic marker of OS (HR 2.40 [95% CI 1.88-3.05]; p<0.001) and PFS (HR 1.95 [95% CI 1.19-3.21]; p=0.008) in patients diagnosed with PC. According to subgroup analysis, the SIRI remained an outstanding prognostic marker for OS, irrespective of region, sample size, study center, study design, TNM stage, cancer type, cut-off value, treatment, or survival analysis type (all p<0.05). Moreover, based on subgroup analysis, the SIRI demonstrated significant utility in predicting PFS, irrespective of region and threshold value (p<0.05). Results of the present meta-analysis revealed that an increased SIRI significantly predicted OS and PFS in patients diagnosed with PC. Considering its cost-effectiveness and availability, the SIRI may be a promising biomarker for predicting prognosis in patients with PC.

Bioinformatics insights into the role of GFPT1 in breast invasive carcinoma: implications for tumor prognosis, immune modulation, and therapeutic applications.

Metabolic reprogramming is a hallmark of cancer, including alterations in the hexosamine biosynthesis pathway (HBP). Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is the key regulatory enzyme in the HBP; however, its role in invasive breast carcinoma remains underexplored. This study utilized integrated data from The Cancer Genome Atlas (TCGA) to assess GFPT1 expression in breast cancer (BRCA) patients. Functional enrichment and mutational landscape analyses were performed, along with chemosensitivity predictions. In vitro experiments were conducted by silencing GFPT1 in malignant breast epithelial cells to evaluate changes in proliferation, migration, and apoptosis. Elevated GFPT1 expression was linked to advanced-stage breast cancer and identified as an independent prognostic marker for overall survival (OS). High GFPT1 levels were associated with increased cytoplasmic translation, activation of oncogenic pathways, and infiltration of M2 macrophages. The GFPT1-High group also showed a higher mutational burden, with frequent TP53 mutations. Chemosensitivity analysis revealed increased IC50 values for chemotherapy drugs in this group. GFPT1 silencing led to reduced cell proliferation and migration, along with enhanced apoptosis. These findings indicate that GFPT1 is a novel prognostic biomarker and a predictive indicator of chemotherapy response in invasive breast carcinoma. GFPT1 influences mRNA translation, cell cycle regulation, and M2 macrophage infiltration, thereby promoting cancer cell proliferation and metastasis.

Prognostic factors in localized pancreatic ductal adenocarcinoma after neoadjuvant therapy and resection: a systematic review and Meta-Analysis.

Prognostic markers for overall survival (OS) in resected pancreatic ductal adenocarcinoma (PDAC) are well-established but remain unclear following neoadjuvant therapy (NAT). This systematic review and meta-analysis aimed to determine factors associated with OS following NAT in resected PDAC. The PubMed, Embase, Scopus, Web of Science, and Cochrane CENTRAL databases were systematically searched from inception till May 2024. Studies that reported univariable and multivariable hazard ratios (HRs) were included if patients underwent NAT and resection for localized PDAC. Study quality assessment was performed using the Newcastle-Ottawa scale. Meta-analysis was performed using generic inverse-variance random-effects models. Among 2,208 unique articles identified by the search, 92 were included in the meta-analysis. Eighty-five of these were of 'good' and 7 of 'poor' quality. The NAT regimen was described in 84 studies, of which 62 included patients treated with FOLFIRINOX (FFX). Margin status, nodal disease, AJCC T-stage, and normalization of CA19-9 after NAT were prognostic for OS, while age, sex, perineural invasion, baseline tumor size, and baseline CA19-9 were not. The test for subgroup differences between ypN-substages was not significant in the multivariable model. Neoadjuvant FFX was associated with better survival than other regimens. This meta-analysis identified margin status, nodal disease, AJCC T-stage, and normalization of CA19-9 after NAT as prognostic factors for OS in patients with resected localized PDAC following NAT.

Quantitative and Morphology-Based Deep Convolutional Neural Network Approaches for Osteosarcoma Survival Prediction in the Neoadjuvant and Metastatic Settings.

Necrosis quantification in the neoadjuvant setting using pathology slide review is the most important validated prognostic marker in conventional osteosarcoma. Herein, we explored three deep-learning strategies on histology samples to predict outcome for osteosarcoma in the neoadjuvant setting. Our study relies on a training cohort from New York University (NYU; New York, NY) and an external cohort from Charles University (Prague, Czechia). We trained and validated the performance of a supervised approach that integrates neural network predictions of necrosis/tumor content and compared predicted overall survival (OS) using Kaplan-Meier curves. Furthermore, we explored morphology-based supervised and self-supervised approaches to determine whether intrinsic histomorphologic features could serve as a potential marker for OS in the neoadjuvant setting. Excellent correlation between the trained network and pathologists was obtained for the quantification of necrosis content (R2 = 0.899; r = 0.949; P < 0.0001). OS prediction cutoffs were consistent between pathologists and the neural network (22% and 30% of necrosis, respectively). The morphology-based supervised approach predicted OS; P = 0.0028, HR = 2.43 (1.10-5.38). The self-supervised approach corroborated the findings with clusters enriched in necrosis, fibroblastic stroma, and osteoblastic morphology associating with better OS [log-2 hazard ratio (lg2 HR); -2.366; -1.164; -1.175; 95% confidence interval, (-2.996 to -0.514)]. Viable/partially viable tumor and fat necrosis were associated with worse OS [lg2 HR; 1.287; 0.822; 0.828; 95% confidence interval, (0.38-1.974)]. Neural networks can be used to automatically estimate the necrosis to tumor ratio, a quantitative metric predictive of survival. Furthermore, we identified alternate histomorphologic biomarkers specific to the necrotic and tumor regions, which could serve as predictors.

Abstract PR017: A T-cell signature in circulating cell-free DNA at time of diagnosis predicts response to checkpoint inhibition

Abstract Immune checkpoint inhibitors (ICI) are increasingly used as first line of treatment in a range of cancer types, owing to their efficacy and advantageous toxicological profile. Currently, PD-L1 expression and tumor mutation burden (TMB) are the most common biomarkers to select patients for ICI treatment, yet response to ICI remains highly variable between patients, necessitating more accurate early predictors of treatment response. Circulating cell-free DNA (cfDNA) originates from dying cells throughout the body, each molecule carrying unique epigenetic features of its cell-type of origin. Most studies on cfDNA focus on tumor-derived fragments for diagnostics or minimal residual disease detection. However, variations in the contribution of immune cells and other stromal cell populations could provide important clues to classify a tumor with respect to treatment. To address this, we collected tumor and adjacent normal tissue as well as cfDNA from the blood of 33 patients enrolled in the LUD2015-005 trial in which ICI were administered to patients with non-resectable esophageal adenocarcinoma (EAC) for four weeks, before adding standard-of-care chemotherapy (ICI+CTX). For each patient, we took samples at diagnosis, before ICI+CTX, during and at the end of treatment. Tissue and cfDNA samples were sequenced using TET-Assisted Pyridine-borane Sequencing (TAPS), a method recently developed in Oxford which provides genome-wide high-depth, base- resolution DNA methylation and mutation information from low-input samples. We then selected a representative set of high-purity tumor tissue samples and combined them with whole- genome TAPS data from 9 healthy blood cell types and 5 gastrointestinal tissues to generate a GI-specific atlas of cell-type specific methylation. This atlas allows us to accurately quantify the contribution of tumor and 14 healthy cell types to the cfDNA collected from each patient at each timepoint. Strikingly, the presence of T-cell derived cfDNA at time of diagnosis (tDNA) is a strong positive predictive marker of overall survival (p=0.0024). In contrast, the fraction of tumor-resident T-cells, estimated by either bulk tissue TAPS or RNA sequencing, correlated only weakly with treatment response in this cohort, indicating that T-cell activity is more accurately captured by tDNA. Furthermore, we find that patients with a combination of high TMB and high tDNA have an 80% 2-year survival probability, as opposed to below 25% for others, suggesting that tDNA is derived from T-cells actively engaging tumor cells with high neoantigen load. In summary, we demonstrate that T-cell turnover, as reflected in differential methylation in a set of marker regions spanning only 24kb, is a promising biomarker of treatment response, especially when combined with neoantigen load: in the presented cohort, all but one long-term survivors (alive at last follow up &amp;gt; 3 years after diagnosis) were tDNA positive with high TMB. This demonstrates the power of cfDNA composition analysis for risk stratification in ICI treatment. Citation Format: Phil Xie, Zohar Etzioni, Chun-Xiao Song, Richard P Owen, Mark R Middleton, Xin Lu, Benjamin Schuster-Boeckler. A T-cell signature in circulating cell-free DNA at time of diagnosis predicts response to checkpoint inhibition [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr PR017.

CTNI-13. 18-FET-PET ENHANCED DIAGNOSIS OF PSEUDOPROGRESSION IN GLIOBLASTOMA IS AN INDEPENDENT PROGNOSTIC FACTOR FOR OVERALL SURVIVAL

Abstract INTRODUCTION Detecting pseudoprogression (PSP) in glioblastoma during first-line treatment remains challenging and has significant clinical implications for patient management. The detection of PSP has been shown feasible using FET-PET. The prognostic impact of FET-PET diagnosed PSP on overall survival is still uncertain, as retrospective studies provide limited insights due to the substantial differences in the distribution of prognostic factors between tumor progression (TP) and PSP groups. This study aims to address these uncertainties by leveraging advanced analysis techniques. METHODS Patients with newly diagnosed glioblastoma (WHO 2021) who underwent chemoradiation and contrast-enhanced MRI suspected for TP and subsequent FET-PET scan at Essen University Hospital were retrospectively evaluated. The modified Response Assessment in Neuro-Oncology (RANO) criteria were used to diagnose PSP. FET-PET analysis included mean (TBRmean) and maximum tumor-to-brain ratios (TBRmax). The two groups (TP/PSP) were balanced using a propensity score analysis including age at diagnosis, extent of resection, Karnofsky-Performance-Status Scale (KPS) and MGMT methylation status. Overall survival was predicted using Kaplan-Meier and multivariate analysis as well as conventional FET-PET parameters, PET/MRI volumetry, and FET/MRI-derived radiomics. An independent cohort was used for validation. RESULTS Out of the 165 patients analysed in this study, 38 were diagnosed with PSP. Following balancing analysis, our study cohort consisted of 40 patients (20 TP/20 PSP). Patients with PSP had a significantly longer mean overall survival (mOS) compared to those with TP (mOS TP 20.24 months; mOS PSP 33.25 months; p=0.0023). The multivariate Cox-Regression analysis confirmed PSP as a significant prognostic marker for overall survival (p=0.0153). Confirmation of these results on an independent validation cohort is pending and will be presented at the meeting. CONCLUSION This study shows that PSP is an independent prognostic factor for overall survival in newly diagnosed glioblastoma patients.

Establishment of potential lncRNA-related hub genes involved competitive endogenous RNA in lung adenocarcinoma

Long non-coding RNAs (lncRNAs) have a notable role in the diagnosis and prognosis of cancer. However, the associations between lncRNA-related hub genes (LRHGs) expression and the corresponding outcomes have not been fully understood in lung adenocarcinoma (LUAD). Here, a total of 71 patients diagnosed with LUAD and 60 healthy volunteers at The First Affiliated Hospital of Huzhou University from April, 2023 to December, 2023 were enrolled in the present study. A LRHGs model was established using least absolute shrinkage and selection operator analyses of The Cancer Genome Atlas-LUAD datasets. The underlying mechanisms of the LRHGs were investigated via Gene Set Enrichment Analysis and Gene Set Variation Analysis. Additionally, the diagnostic role of serum HOXD cluster antisense RNA 2 (HOXD-AS2) was assessed by receiver operating characteristic (ROC) curve analysis. Lastly, TCGA-LUAD samples were divided into high- and low-HOXD-AS2 expression groups based on the median expression. The associations between HOXD-AS2 expression and miR-4538 as well as Calmodulin-Dependent Protein Kinase Type II subunit Beta (CAMK2B) levels were conducted through Pearson correlation analysis. A comprehensive analysis identified 141 differentially expressed lncRNAs between 539 LUAD tissues and 59 normal samples. A prognostic marker for overall survival was established by constructing a predictive signature consisting of 9 LRHGs. Subsequently, 474 LUAD samples were categorized into a high or low-risk group based on the median of the risk score. An independent prognostic model was constructed to confirm the validity of this categorization. Further comparisons of the clinicopathological features and LRHG-related pathways were performed between the two groups. Examinations of LRHG expression in two LUAD clusters and of the association between LRHG expression and immune infiltration were also conducted. HOXD-AS2 expression was shown to be elevated in LUAD tissues compared with matched normal tissues, and the serum HOXD-AS2 level was also notably increased in LUAD samples compared with healthy controls. The results of the ROC analysis indicated that the sensitivity and specificity of HOXD-AS2 were higher than that of cytokeratin-19 fragment (CYFRA21-1), which is a serum marker for LUAD. Pearson analyses indicated that miR-4538 level was negatively associated with HOXD-AS2 expression, but CAMK2B level showed positive correlation in LUAD. The results of the present study therefore indicated that the constructed LRHG model, particularly HOXD-AS2, could independently diagnose and predict the prognosis of LUAD, which suggested the underlying mechanism of the HOXD-AS2/miR-4538/CAMK2B, and might offer efficient strategies for LUAD treatment.

Ten Hypermethylated lncRNA Genes Are Specifically Involved in the Initiation, Progression, and Lymphatic and Peritoneal Metastasis of Epithelial Ovarian Cancer.

Our work aimed to evaluate and differentiate the role of ten lncRNA genes (GAS5, HAND2-AS1, KCNK15-AS1, MAGI2-AS3, MEG3, SEMA3B-AS1, SNHG6, SSTR5-AS1, ZEB1-AS1, and ZNF667-AS1) in the development and progression of epithelial ovarian cancer (EOC). A representative set of clinical samples was used: 140 primary tumors from patients without and with metastases and 59 peritoneal metastases. Using MS-qPCR, we demonstrated an increase in methylation levels of all ten lncRNA genes in tumors compared to normal tissues (p < 0.001). Using RT-qPCR, we showed downregulation and an inverse relationship between methylation and expression levels for ten lncRNAs (rs < -0.5). We further identified lncRNA genes that were specifically hypermethylated in tumors from patients with metastases to lymph nodes (HAND2-AS1), peritoneum (KCNK15-AS1, MEG3, and SEMA3B-AS1), and greater omentum (MEG3, SEMA3B-AS1, and ZNF667-AS1). The same four lncRNA genes involved in peritoneal spread were associated with clinical stage and tumor extent (p < 0.001). Interestingly, we found a reversion from increase to decrease in the hypermethylation level of five metastasis-related lncRNA genes (MEG3, SEMA3B-AS1, SSTR5-AS1, ZEB1-AS1, and ZNF667-AS1) in 59 peritoneal metastases. This reversion may be associated with partial epithelial-mesenchymal transition (EMT) in metastatic cells, as indicated by a decrease in the level of the EMT marker, CDH1 mRNA (p < 0.01). Furthermore, novel mRNA targets and regulated miRNAs were predicted for a number of the studied lncRNAs using the NCBI GEO datasets and analyzed by RT-qPCR and transfection of SKOV3 and OVCAR3 cells. In addition, hypermethylation of SEMA3B-AS1, SSTR5-AS1, and ZNF667-AS1 genes was proposed as a marker for overall survival in patients with EOC.

Use of albumin and CRP related immuno-nutritional markers for prediction of locoregional response to treatment in unresectable hepatocellular carcinoma

Objective:We analysed the relationship between albumin and CRP related inflammation markers (Controlling nutritional status(Conut)score, lymphocyte albumin factor(LA), albumin-bilirubin score (ALBI), highly sensitive modified Glasgow prognostic score (Hs-mGPS), Glasgow prognostic score(GPS)) and locoregional treatment response in HCC. Materials and methods:Among 180 HCC patients, 63 patients who underwent locoregional therapy were included in this study. Albumin and CRP related immuno-nutrition scores were calculated by recording routine laboratory tests between the fourth and eighth week after treatment. The predictive and prognostic value of these markers for overall survival(OS) and disease free survival after treatment(DFS) were analysed. Results:The mean age was 63 years (min-max:26-87) and 59 (93.7%) of the patients were male. The mean follow up period was 25 months and 53 patients were deceased (84.1%). mOS: 18.56 months (min-max: 13.13-23.99); mDFS: 7 months (min-max: 3.63-10.37) after locoregional treatment. Cut-off values of prognostic markers were determined by Roc analysis. Statistically significant correlation was found between age(p=0.019), Conut(p=0.001), GPS(p=0.028), Hs-mGPS(p=0.012), LA(p=0.017) and ALBI(p=0.002) and mOS. The relationship between Conut(p=0.002), GPS(p

CT-Defined Coronary Artery Calcification as a Prognostic Marker for Overall Survival in Lung Cancer: A Systematic Review and Meta-analysis

Rationale and ObjectivesCoronary artery calcification (CAC) can be quantified by computed tomography (CT). It is an important predictive and prognostic imaging marker for cardiovascular disease. The prognostic role for CAC in oncological patients is provided in preliminary studies, especially in lung cancer patients. The aim of the present study was to establish the effect of CAC score on overall survival (OS) in lung cancer patients based on the published literature Materials and MethodsLiterature databases were screened for papers analyzing the association between CAC and overall survival in lung cancer patients up to June 2024. The primary endpoint of the present systematic review was the OS. Overall, 7 studies were suitable for the analysis and were included. ResultsThe included studies comprised 2292 patients. The pooled hazard ratio for the association between CAC score and OS was HR=1.42 (95% CI=(1.19; 1.69), p<0.0001) in the univariable analysis and HR=1.56 (95% CI=(1.25; 1.94), p<0.0001) in the multivariable analysis. The pooled odds ratio for the association between CAC score and major cardiovascular events was OR=1.97 (95% CI=(1.24; 3.13)], p=0.004. ConclusionCT-defined CAC has a meaningful impact on overall survival and prediction of major cardiovascular events in lung cancer patients undergoing curative treatment. The sole presence of CAC on staging CT should be reported as an important prognostic marker in these patients.

Fibrinogen to pre-albumin ratio is an independent prognostic index for patients with pancreatic ductal adenocarcinoma after radical resection

BackgroundThis study aims to elucidate the significance of the preoperative fibrinogen to pre-albumin ratio (FPR) in predicting the prognosis of pancreatic ductal adenocarcinoma (PDAC), a correlation not extensively explored previously.MethodsA cohort of 563 patients diagnosed with PDAC and subjected to radical surgical resection was examined. We meticulously documented a range of inflammatory markers, clinical-pathological features, and oncological outcomes. The prognostic value of preoperative FPR was assessed using Kaplan–Meier survival analysis and Cox proportional hazards regression modeling. Furthermore, the predictive accuracy of FPR was evaluated through time-dependent receiver operating characteristic (ROC) curves and decision curve analyses (DCA).ResultsThe determined optimal threshold for FPR was 14.77, which facilitated the stratification of patients into groups with low and high FPR levels. Notably, patients in the high FPR cohort exhibited significantly reduced recurrence-free survival (RFS) and overall survival (OS) rates compared to their low FPR counterparts. Multivariate Cox regression analysis underscored FPR as an independent prognostic indicator for both RFS and OS. In comparison to the neutrophil-to-lymphocyte ratio (NLR), FPR demonstrated superior prognostic accuracy and clinical utility.ConclusionThe preoperative fibrinogen to pre-albumin ratio serves as an independent prognostic marker for RFS and OS among PDAC patients undergoing radical resection. Our findings suggest that FPR could be a valuable addition to the current prognostic models, potentially guiding therapeutic decision-making and patient management strategies in PDAC.