Poor Relapse-free Survival Research Articles

Prognostic Significance of Innovative Inflammation-nutrition Biomarker Score in Patients With Colorectal Cancer.

A new index, inflammation-nutrition biomarker score (INS), based on host factors, including lymphocyte to C-reactive protein ratio, C-reactive protein to albumin ratio, advanced lung cancer inflammation index, and nutritional risk index, correlated with post-operative survival time independent of the tumor, node, metastasis (TNM) stage, in a cohort of patients with various types of malignancies. Therefore, this study aimed to evaluate the prognostic value of INS in patients with colorectal cancer who underwent curative resection. We retrospectively evaluated 476 consecutive patients who underwent curative surgery for stage I-III colorectal cancer. Based on the INS definition, 240, 132, 57, 23, and 24 patients had a score of 0, 1, 2, 3, and 4, respectively. Patients with INS of 0 and 1 were classified into the low-INS group, and those with INS of 2, 3, and 4 were classified into the high-INS group. The relapse-free and overall survival rates were significantly worse in the high-INS group than in the low-INS group. Furthermore, multivariate analysis of the prognostic factors indicated that INS is an independent prognostic factor for poor relapse-free and overall survival. The combined evaluation of INS and TNM stages may allow for more accurate prognostication.

Impact of postoperative infectious complications on long-term prognosis after esophagectomy.

Postoperative complications have been reported to be a risk factor for worse oncologic outcomes in patients with esophageal cancer. However, the impact of postoperative complications on prognosis after esophagectomy remains controversial. We aimed to investigate the factors that influence the prognosis of postoperative complications in patients who underwent oncological esophagectomy, focusing on chronic obstructive pulmonary disease (COPD). In total, 254 consecutive patients who underwent esophagectomy for esophageal cancer between 2009 and 2021 were eligible. We examined the association between postoperative complications and long-term outcomes. Focusing on infectious complications (IC: a combination of postoperative pneumonia and anastomotic leakage), overall survival (OS) and relapse-free survival (RFS) rates were significantly worse in patients with IC than those without (p<0.01, and <0.01, respectively), whereas the presence of other complications demonstrated no survival impact. No clinicopathological variables have changed the influence of IC on long-term outcomes. Meanwhile, patients with postoperative pneumonia exhibited significantly lower OS and RFS rates compared to those without in non-COPD group, however, the presence of postoperative pneumonia demonstrated no prognostic impact in COPD group. Also, interaction analysis revealed that the effect of postoperative pneumonia on poor RFS differed based on the presence of COPD (p for interaction=0.09). IC influenced the long-term outcomes in patients with esophageal cancer, however no clinicopathological variables have changed the effect of the presence of IC on prognosis. Meanwhile, the effect of postoperative pneumonia on poor survival differed based on the presence of COPD.

The tumor suppressor SALL2 opposes chemotherapeutic resistance in breast cancer.

Chemotherapy continues to be the primary treatment for certain types of breast cancer. However, despite an initial positive response to chemotherapeutic agents, the development of resistance is inevitable. The exact molecular mechanisms underlying this phenomenon remain unclear. In this research, a significant downregulation of SALL2 expression was observed in chemo-resistant breast cancer, which was attributed to promoter methylation. Decreased SALL2 expression correlated significantly with poorer relapse-free survival in chemotherapy-treated patients with breast cancer. Functionally, SALL2 silencing induced a stem cell-like phenotype in breast cancer cells, fostering resistance to cisplatin both in vitro and in vivo. This resistance was mediated, at least in part, through the transcriptional regulation of BTG2, a negative regulator of stemness, achieved by direct binding to its promoter regions. These findings underscore the critical role of SALL2 in modulating cisplatin response and propose SALL2 as a potential prognostic biomarker for chemotherapy response in breast cancer.

Growth differentiation factor 15 (GDF15) predicts relapse free and overall survival in unresected locally advanced non-small cell lung cancer treated with chemoradiotherapy

IntroductionGrowth differentiation factor 15 (GDF15) is a cytokine of the TGFβ family. Here, we analyzed GDF15 levels in patients with locally advanced non-small cell lung cancer (LA-NSCLC) who participated in OCOG-ALMERA (NCT02115464), a phase II randomized clinical trial, that investigated metformin in combination with standard of care concurrent chemoradiotherapy (cCRT). OCOG-ALMERA was not able to demonstrate benefit in the metformin arm. Therefore, biomarker studies are needed to better define stratification parameters for future trials.MethodsPatients were randomized to treatment with platinum-based chemotherapy and concurrent chest radiotherapy (60–66 Gy), with or without metformin (2000 mg/d). The trial collected tumor volume parameters, survival outcomes, and patient blood plasma at baseline, during (weeks 1 and 6) and 6 months after cCRT. Plasma GDF15 levels were assayed with the ELISA method. Statistical analyses explored associations between GDF15, survival outcomes, and radiotherapy tumor volumes.ResultsBaseline plasma levels of GDF15 were elevated in study patients, they increased during cCRT (p < 0.001), and the addition of metformin was associated with a further increase (week 6, p = 0.033). Baseline GDF15 levels correlated with the radiotherapy gross target volume (GTV, p < 0.01), while week 1 of radiotherapy levels correlated with radiotherapy planned target volume (PTV, p < 0.006). In multivariate analysis, baseline plasma GDF15 was prognostic for poor relapse-free (RFS) and overall survival (OS) (p = 0.005 and p = 0.002, respectively).ConclusionsGDF15 is a plasma marker that responds to the treatment of unresected LA-NSCLC with cCRT and metformin. GDF15 levels correspond with tumor volume and increased GDF15 levels predict for poor RFS and OS. These results require validation in larger clinical trial datasets.

A Pan-Cancer Analysis of GAPDH as a Common Biomarker for Various Cancers

Background: The present study aimed to investigate the expression level of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and explore its prognostic value across 24 different human cancers. This investigation was conducted using comprehensive bioinformatics and in vitro approaches that involved multiple layers of analysis. Methods: GAPDH expression and methylation levels were assessed via bioinformatics tools and validated using cell lines through RNA sequencing and targeted bisulfite sequencing analyses. The potential prognostic significance of GAPDH was evaluated through the use of a Kaplan–Meier plotter. Additionally, cBioPortal was employed to investigate genetic alterations associated with this gene. Pathway analysis was conducted using DAVID. Furthermore, a correlation analysis between GAPDH expression and CD8+ T immune cells was performed using TIMER and CDT. Lastly, a gene-drug interaction network analysis was conducted using Cytoscape to examine the relationship between GAPDH and drugs. Results: The GAPDH was found commonly up-regulated in 24 types of human cancers and its up-regulation was significantly correlated with the poor relapse-free survival (RFS) and overall survival (OS) of BLCA, CESC, HNSC, KIRP, LIHC, and LUAD. This implies that GAPDH plays a significant role in the development of these cancers. The GAPDH up-regulation was also noticed to be associated with the different clinicopathological features of BLCA, CESC, HNSC, KIRP, LIHC, and LUAD patients. Pathway analysis has shown GAPDH involvement in different diverse pathways. Furthermore, notable correlations were observed between the expression of GAPDH and its promoter methylation level, genetic alterations, as well as the level of CD8+ T immune cells. Moreover, we identified significant regulatory drugs targeting GAPDH that have the potential to modulate its expression and potentially prevent conditions such as BLCA, CESC, HNSC, KIRP, LIHC, and LUAD. Conclusion: Based on our findings, GAPDH emerged as a promising diagnostic and prognostic biomarker for BLCA, CESC, HNSC, KIRP, LIHC, and LUAD.

Prognostic Significance of Albumin-Globulin Ratio in Urachal Carcinoma

Introduction: Although albumin-globulin ratio (AGR) has been used in the prognostic assessment of multiple solid malignancies, so far no research has confirmed the prognostic significance of AGR as a biomarker for urachal carcinoma. We analyzed the relationship between AGR and prognosis in urachal carcinoma, aiming to identify a promising prognostic biomarker for urachal carcinoma. Methods: We reviewed the clinical data of 25 patients diagnosed with urachal carcinoma in the Xiangya Hospital, Central South University, from January 2008 to October 2021. The best cut-off value of preoperative AGR was determined according to the receiver operator characteristic curve. The Kaplan-Meier curve was used to analyze the effect of preoperative AGR on the overall survival (OS) and relapse-free survival (RFS) of patients. Cox proportional hazards model was used to analyze prognostic factors including preoperative AGR. Results: The best cut-off value of preoperative AGR in urachal carcinoma patients is 1.45. Low preoperative AGR is significantly associated with worse OS and RFS. Univariate analysis and multivariate analysis indicated that low preoperative AGR is an independent and reliable factor to predict poor prognosis, OS, and RFS in urachal carcinoma patients. Conclusion: Urachal carcinoma patients with low preoperative AGR have worse prognosis, and preoperative AGR is a valuable prognostic indicator for urachal carcinoma research.

A Pan-Cancer Analysis of GAPDH as a Common Biomarker for Various Cancers

Objective: To investigate the expression levels of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and explore its prognostic value across 24 different human cancers. This investigation was conducted using comprehensive bioinformatics and in vitro approaches, incorporating multiple layers of analysis. Methods: GAPDH expression and methylation levels were assessed using bioinformatics tools and validated in cell lines through RNA-seq and targeted bisulfite-seq analyses. The potential prognostic significance of GAPDH was evaluated using the KM plotter. Additionally, cBioPortal was employed to investigate genetic alterations associated with this gene. Pathway analysis was conducted using DAVID. Furthermore, a correlation analysis between GAPDH expression and CD8+ T immune cells was performed using TIMER and CDT. Finally, a gene-drug interaction network analysis was conducted using Cytoscape to examine the relationship between GAPDH and various drugs. Results: GAPDH was found to be commonly upregulated in 24 types of human cancers, with its upregulation significantly correlated with poor relapse-free survival (RFS) and overall survival (OS) in BLCA, CESC, HNSC, KIRP, LIHC, and LUAD. This suggests that GAPDH plays a significant role in the development of these cancers. GAPDH upregulation was also associated with various clinicopathological features in patients with BLCA, CESC, HNSC, KIRP, LIHC, and LUAD. Pathway analysis revealed GAPDH’s involvement in diverse pathways. Additionally, notable correlations were observed between GAPDH expression and its promoter methylation level, genetic alterations, and CD8+ T immune cell levels. Moreover, several regulatory drugs targeting GAPDH were identified, with the potential to modulate its expression and potentially prevent conditions such as BLCA, CESC, HNSC, KIRP, LIHC, and LUAD. Conclusion: Based on our findings, GAPDH emerges as a promising diagnostic and prognostic biomarker for BLCA, CESC, HNSC, KIRP, LIHC, and LUAD.

Elucidating the Intricate Roles of Gut and Breast Microbiomes in Breast Cancer Metastasis to the Bone.

Breast cancer is the most predominant and heterogeneous cancer in women. Moreover, breast cancer has a high prevalence to metastasize to distant organs, such as the brain, lungs, and bones. Patients with breast cancer metastasis to the bones have poor overall and relapse-free survival. Moreover, treatment using chemotherapy and immunotherapy is ineffective in preventing or reducing cancer metastasis. Microorganisms residing in the gut and breast, termed as the resident microbiome, have a significant influence on the formation and progression of breast cancer. Recent studies have identified some microorganisms that induce breast cancer metastasis to the bone. These organisms utilize multiple mechanisms, including induction of epithelial-mesenchymal transition, steroid hormone metabolism, immune modification, bone remodeling, and secretion of microbial products that alter tumor microenvironment, and enhance propensity of breast cancer cells to metastasize. However, their involvement makes these microorganisms suitable as novel therapeutic targets. Thus, studies are underway to prevent and reduce breast cancer metastasis to distant organs, including the bone, using chemotherapeutic or immunotherapeutic drugs, along with probiotics, antibiotics or fecal microbiota transplantation. The present review describes association of gut and breast microbiomes with bone metastases. We have elaborated on the mechanisms utilized by breast and gut microbiomes that induce breast cancer metastasis, especially to the bone. The review also highlights the current treatment options that may target both the microbiomes for preventing or reducing breast cancer metastases. Finally, we have specified the necessity of maintaining a diverse gut microbiome to prevent dysbiosis, which otherwise may induce breast carcinogenesis and metastasis especially to the bone. The review may facilitate more detailed investigations of the causal associations between these microbiomes and bone metastases. Moreover, the potential treatment options described in the review may promote discussions and research on the modes to improve survival of patients with breast cancer by targeting the gut and breast microbiomes.

SLC14A1 and TGF-β signaling: a feedback loop driving EMT and colorectal cancer metachronous liver metastasis

BackgroundColorectal cancer (CRC) metachronous liver metastasis is a significant clinical challenge, largely attributable to the late detection and the intricate molecular mechanisms that remain poorly understood. This study aims to elucidate the role of Solute Carrier Family 14 Member 1 (SLC14A1) in the pathogenesis and progression of CRC metachronous liver metastasis.MethodsWe conducted a comprehensive analysis of CRC patient data from The Cancer Genome Atlas and GSE40967 databases, focusing on the differential expression of genes associated with non-metachronous liver metastasis and metachronous liver metastasis. Functional assays, both in vitro and in vivo, were performed to assess the biological impact of SLC14A1 modulation in CRC cells. Gene set enrichment analysis, molecular assays and immunohistochemical analyses on clinical specimens were employed to unravel the underlying mechanisms through which SLC14A1 exerts its effects.ResultsSLC14A1 was identified as a differentially expressed gene, with its overexpression significantly correlating with poor relapse-free and overall survival. Mechanistically, elevated SLC14A1 levels enhanced CRC cell invasiveness and migratory abilities, corroborated by upregulated TGF-β/Smad signaling and Epithelial-Mesenchymal Transition. SLC14A1 interacted with TβRII and stabilized TβRII protein, impeding its Smurf1-mediated K48-linked ubiquitination and degradation, amplifying TGF-β/Smad signaling. Furthermore, TGF-β1 reciprocally elevated SLC14A1 mRNA expression, with Snail identified as a transcriptional regulator, binding downstream of SLC14A1’s transcription start site, establishing a positive feedback loop. Clinically, SLC14A1, phosphorylated Smad2, and Snail were markedly upregulated in CRC patients with metachronous liver metastasis, underscoring their potential as prognostic markers.ConclusionsOur findings unveil SLC14A1 as a critical regulator in CRC metachronous liver metastasis, providing novel insights into the molecular crosstalk between SLC14A1 and TGF-β/Smad signaling. These discoveries not only enhance our understanding of CRC metachronous liver metastasis pathogenesis, but also highlight SLC14A1 as a promising target for therapeutic intervention and predictive marker.

Comprehensive pan-cancer analysis of the C2ORF40 expression: Infiltration associations and prognostic implications.

In recent years, C2ORF40 has been identified as a tumor suppressor gene with multiple functions, including roles in cell proliferation, migration, and senescence. To explore the role of the C2ORF40 gene in different tumors, we used multiple databases for analysis. Compared to adjacent normal tissues, C2ORF40 is downregulated in a variety of malignant tumors, including tumors such as breast cancer, colorectal cancer, bladder cancer, hepatocellular carcinoma and prostate cancer. Notably, low expression of the gene is significantly associated with poor overall survival and relapse-free survival rates. In specific cancers including colon cancer and prostate cancer, the expression of C2ORF40 is correlated with the infiltration of CAFs. C2ORF40 is also involved in biological processes such as cell apoptosis and regulation of protein stability. In conclusion, C2ORF40 can hold promise as a prognostic marker for pan-cancer analysis.

Unsupervised Clustering Analysis of Regimen and HLA Characteristics in Pediatric Umbilical Cord Blood Transplantation

HLA matching is a critical factor in allogeneic unrelated hematopoietic cell transplantation (HCT) because of its impact on post-transplantation survival and quality of life. Umbilical cord blood transplantation (UCBT) offers unique advantages, but determining the optimal approach to graft selection and immunosuppression remains challenging. Unsupervised clustering, a machine learning technique, has potential for analyzing transplantation outcomes, but its application in investigating leukemia outcomes has been limited. This study aimed to identify optimal combinations of HLA/ killer immunoglobulin receptor (KIR) donor-patient pairing, conditioning, and immunosuppressive regimens in pediatric patients with acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML) undergoing UCBT. Outcome data for single, unmanipulated UCBT in pediatric AML (n = 708) and ALL (n = 1034) patients from the Eurocord/EBMT registry were analyzed using unsupervised clustering. Resulting clusters were used to inform post hoc competing risks and Kaplan-Meier analyses. In AML, single HLA-C mismatches with other loci fully matched (7/8) were associated with poorer relapse-free survival (RFS) (P = .039), but a second mismatch at any other locus counteracted this effect. In ALL, total body irradiation (TBI) effectively prevented relapse mortality (P = .007). KIR/HLA-C match status affected RFS in AML (P = .039) but not in ALL (P = .8). Administration of antithymocyte globulin (ATG) substantially increased relapse, with no relapses occurring in the 85 patients who did not receive ATG. Our unsupervised clustering analyses generate several key statistical and mechanistic hypotheses regarding the relationships between HLA matching, conditioning regimens, immunosuppressive therapies, and transplantation outcomes in pediatric AML and ALL patients. HLA-C and KIR combinations significantly impact RFS in pediatric AML but not in ALL. ATG use in fully matched pediatric patients is associated with late-stage relapse. TBI regimens appear to be beneficial in ALL, with efficacy largely independent of histocompatibility variables. These findings reflect the distinct genetic and biological profiles of AML and ALL.

Risks and Outcomes of Early Dose Reduction in Adjuvant CAPOX Therapy for Colorectal Cancer.

Adjuvant capecitabine and oxaliplatin (CAPOX) therapy is standard strategy for colorectal cancer with risk of recurrence. Early dose reduction (EDR) of CAPOX therapy is commonly used in real-world practice. However, there is limited evidence regarding the effectiveness of CAPOX for patients who had EDR. Therefore, this study aimed to clarify the risks of EDR and its effect on long-term outcomes and body composition factors. Patients who received CAPOX therapy after radical surgery for colorectal cancer between June 2013 and December 2021 were included. EDR was defined as dose reduction within four courses of CAPOX therapy. Body composition factors were measured for 1 year following surgery to determine the EDR effects. Eighty-four patients were included; 35 (42%) of them had EDR. The multivariate analysis revealed that underweight [odds ratio (OR)=4.95, 95% confidence interval (CI)=1.13-21.7, p=0.03] was a risk factor for EDR. Relapse-free survival (RFS) was significantly better in the non-EDR group (p=0.01). The 5-year RFS rates for the non-EDR and EDR groups were 88.7% and 65.4%, respectively. The multivariate analysis revealed that age >65 years [hazard ratio (HR)=3.97; 95% CI=1.16-13.62, p=0.03] and EDR (HR=7.62; 95% CI=1.71-33.91, p=0.005) were associated with poorer RFS. The 1-year body composition analysis revealed decreases in all factors in the EDR group. Preoperative underweight status was associated with EDR, which resulted in decreased RFS and body composition factors when compared with the non-EDR group. Therefore, avoiding EDR and early nutritional intervention after EDR may improve outcomes.

Immunohistochemistry of p53 surrogates TP53 mutation as an accurate predictor for early-relapse of surgically resected stage I-III lung adenocarcinoma

IntroductionTP53 is a strong tumor suppressor gene; its deactivation contributes to carcinogenesis and influences clinical outcomes. However, the prognostic influence of p53 deactivation on early relapse in patients with surgically resected non–small cell lung cancer remains unclear. Materials and methodsA cohort of 170 patients with primary stage I through III lung adenocarcinoma (LADC) and lung squamous cell carcinoma who underwent complete resection at Tokyo Medical and Dental University was screened for TP53 mutations using panel testing, and association studies between TP53 mutations and clinical data, including histology and postoperative recurrence, were performed. The association between TP53 mutations and postoperative recurrence was validated using data from 604 patients with MSK-IMPACT from The Cancer Genome Atlas. Additional immunohistochemistry for p53 was performed on some subsets of the Tokyo Medical and Dental University population. ResultsMutations in TP53 were recurrently observed (35.9%; 61 out of 170) in the Tokyo Medical and Dental University cohort. In the histology-stratified analysis, patients with LADC histology showed TP53 mutations that were associated with poor relapse-free survival (log-rank test; P = .020), whereas patients with lung squamous cell carcinoma histology showed TP53 mutations that were not (P = .99). The poor prognosis of TP53 mutation-positive LADCs was validated in The Cancer Genome Atlas-LADC cohort (log-rank test; P = .0065). Additional immunohistochemistry for p53 in patients with LADC histology in the Tokyo Medical and Dental University cohort showed a significant correlation between TP53 mutations and abnormal IHC pattern of p53 (Cramer's correlation coefficient V = 0.67). ConclusionsTP53 mutation is a potential marker for worse prognosis in surgically resected LADC; immunohistochemistry for p53 could be a surrogate method to identify patients with LADC with a worse prognosis.

CASTOR1 phosphorylation as a predictor of survival in male patients with KRAS-mutated lung adenocarcinoma.

e20015 Background: Lung cancer, a leading global cause of cancer-related mortality, necessitates enhanced prognostic markers for improved treatment outcomes. This study focuses on the predictive value of phosphorylated cytosolic arginine sensor for mTORC1 subunit 1 at S14 (pCASTOR1) in lung adenocarcinoma (LUAD) patients, specifically in males with KRAS mutations. Methods: This retrospective study, approved by University of Pittsburgh IRB, utilized formaline-fixed paraffin embedded primary tissues from two independent cohorts of patients who underwent thoracic surgical procedures at the University of Pittsburgh Medical Center (UPMC) from 2002 to 2011. Comprehensive clinical, demographical and pathological information was obtained from UPMC Cancer Registry, with cases lacking incomplete information excluded from analysis. Study endpoints included overall survival (OS) and relapse-free survival (RFS). An antibody targeting pCASTOR1 was employed to analyze LUAD tumor and adjacent non-tumor lung tissues from both cohorts. A pathologist, blinded to patient information and survival outcomes, conducted scoring in 5% increments. Scores were categorized as low or high pCASTOR1 based on second or third quartile. Correlations between pCASTOR1 scores and OS/RFS were examined, stratifying by clinical, pathological, demographic, or genotype data. Univariate OS and RFS analyses were conducted using the Kaplan-Meier method and log-rank test, while multivariate survival significance was assessed via Cox regression analysis. Additionally, unpaired T-tests were utilized to compare pCASTOR1 levels between non-tumor and tumor cells. A significance threshold of p &lt; 0.05 was applied for all analyses. Results: Tumor cells exhibited significantly elevated pCASTOR1 scores compared to non-tumor cells in both cohorts (P &lt; 0.05). High pCASTOR1 scores predicted poor OS (HR = 3.3, P = 0.0008) and RFS (HR = 3.0, P = 0.0035) in male patients with KRAS mutations in Cohort 1. pCASTOR1 remained an independent predictor for OS (HR = 4.1, P = 0.0047) and RFS (HR = 3.5, P = 0.0342) after controlling for other factors. Cohort 2, comprised solely of smokers with incomplete genotype information, validated these findings, with high pCASTOR1 scores correlating with worse OS (HR = 4.8, P = 0.0363). Notably, in early-stage LUAD, elevated pCASTOR1 scores were associated with significantly worse OS (HR = 3.3, P = 0.0176) and RFS (HR = 3.1, P = 0.0277) in male patients with KRAS mutations in Cohort 1, and worse OS (HR = 5.0, P = 0.0069) and RFS (HR = 5.0, P = 0.0069) in Cohort 2, akin to late-stage patients. Conclusions: Elevated pCASTOR1 score serves as a robust biomarker predicting poor OS and RFS in male LUAD patients with KRAS mutations, offering potential clinical utility in optimizing treatment strategies for this subgroup.

Efficacy and biomarker analysis of carboplatin plus taxanes neoadjuvant chemotherapy in triple-negative breast cancer: A prospective multicenter cohort study.

e12619 Background: The efficacy and survival data of carboplatin plus taxane (anthracycline-free) neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) was lack of a large-sample study. The predictive biomarker of efficacy based on cell-free DNA (cfDNA) whole-methylome sequencing (WMS) has not been reported yet. Methods: The prospective multi-center cohort study was conducted in four hospitals of Chinabetween 2016 and 2023. Stage II-III TNBC patients were enrolled to receive NAC of carboplatin (AUC 5) every 3 weeks or carboplatin (AUC 4) every 2 weeks plus taxane(standard dose) for 4-6 cycles. Primary study endpoint were pathological complete response (pCR) and relapse-free survival (RFS). Plasma samples were prospectively collected at baseline (T1) and after NAC(T2). Chromosomal aneuploidy of featured fragments (CAFF),fragment size index (FSI) and methylation density score (MD) of cfDNA were detected with WMS. Results: A total of 267 patients were included in the study. The median age was 49 years, 156 patients (58.4%) were stage III disease. 147 patients (55.1%) received the triweekly NAC. 263 patients underwent breast surgery after NAC and 106 patients (40.3%) achieved pCR. The pCR were similar in biweekly or triweekly groups (39.8% vs 40.7%, P=0.89). The 3-year RFS and overall survival (OS) were 77.9%, 87.6%, respectively. Patients who achieved pCR had a significant better RFS (95.5%) and OS (97.7%) than those non-pCR (76.6%, P&lt;0.001; 81.2%, P&lt;0.001). A total of 66 patients with 120 plasma samples (64 samples at T1, 56 samples at T2) were included in WMS analysis. Patients with CAFF, FSI or MD positive at T1 had a higher tumor burden (stage III or cN2-3, all P values &lt;0.05). The proportion of patients with FSI negative at T2 was significantly higher in pCR group compared to non-pCR(86.2% vs 59.3%, P=0.034). There is a similar tendency in patients with CAFF negative. Patients with MD positive at T1 was significantly associated with poor RFS compared to MD negative (HR = 7.36, 95% CI: 0.93-58.75, Log-rank P=0.028). A linear SVM model based on FSI, CAFF, combining with immune cell (effector memory CD8 T cells, immature B cells) and clinical features was developed to predict pCR, with AUC = 0.90 for training dataset and AUC = 0.86 for testing data. Conclusions: Our large-sample study further confirmed that carboplatin plus taxanes (anthracycline-free) NAC in TNBC is an effective option with clinical applicability. Biomarkers based on cfDNA WMS may offer some predictive and prognostic value which needed to be further investigated.

Increased FGF2 expression promotes immune cell infiltration and correlates with an unfavorable prognosis in thyroid cancer

To delve into the expression and functions of FGF2 in patient with thyroid cancer (THCA), we conducted a systematic analysis of the association of FGF2 with immune cell infiltration, and prognosis in THCA patients. The transcription and protein levels, methylation, and biological properties of FGF2 were examined, along with its correlation with prognosis and immune cell infiltration in THCA patients using online databases UALCAN, Human Protein Atlas, Kaplan-Meier Plotter, DNMIVD, cBioPortal, GEPIA, Metascape, Linkedomics and TIMER. Clinical samples were collected for Western blot analyses. FGF2 was substantially overexpressed in the tumor group and shown correlations with age, tumor histology, nodal metastasis, and cancer stages. Moreover, higher expression of FGF2 (HR = 3.42, 95 % CI:1.57-7.44, p = 0.00099) was greatly correlated with poorer relapse-free survival in THCA patients, particularly in female patients. FGF2 methylation level was increased in the tumor group (p = 1.29E-6), and higher methylation levels of FGF2 were positively correlated with the poorer progression-free interval in THCA patients (p = 0.015). FGF2 mutations were markedly associated with shorter disease-free survival, with a mutation rate of 6 % among the total 498 THCA patients. FGF2 functions were potentially related to cell adhesion, cytokine-cytokine receptor interaction and angiogenesis. FGF2 expression showed positive correlations with the infiltration of B cells (Cor = 0.569, p = 1.04e-42), CD4+ T cells (Cor = 0.555, p = 9.43e-41), macrophages (Cor = 0.438, p = 2.94e-42), neutrophils (Cor = 0.578, p = 9.354e-45), and dendritic cells (Cor = 0.591, p = 5.00e-47). FGF2 is a potential prognostic marker in THCA patients, with its functions possibly related to cell adhesion, interaction of the cytokine-cytokine receptor, angiogenesis, and the promotion of multiple immune cell infiltration.

Value of the HOTAIR expression assay in predicting therapy target in hepatocellular carcinoma: A meta-analysis and bioinformatics analysis.

Several studies show that the long non-coding RNA HOX transcript antisense RNA (HOTAIR) was upregulated in human cancer, which was associated with several clinical features and may have the potential to be prognostic markers. However, the significance of HOTAIR in hepatocellular carcinoma remains unclear. We performed a meta-analysis and bioanalysis to further investigate the association between HOTAIR and hepatocellular carcinoma. Eligible literature was systematically retrieved from PubMed, Embase, and Web of Science databases. The pooled hazard ratios with 95% confidence intervals were used to evaluate to the effect. Raw data on HOTAIR expression were obtained from The Cancer Genome Atlas data portals. All bioinformatics analyses were performed using R software (version 4.3.1). We identified eight studies in this meta-analysis with a total of 399 patients. High-level HOTAIR expression was found to be significantly related to advanced tumor node metastasis stage, distant metastasis, poor tumor differentiation, and patients with hepatitis. Correspondingly, HOTAIR was also associated with poor overall survival and relapse-free survival. Subsequently, in bioanalysis, HOTAIR expression was higher in hepatocellular carcinoma as well as poor overall survival. High HOTAIR expression was strongly correlated with tumor node metastasis stage. Kyoto Encyclopedia of Genes and Genomes analysis revealed that the differentially expressed genes related to HOTAIR may be involved in the cancer-associated signaling pathway. HOTAIR may be a potential biomarker for HCC prediction and is expected to become a new choice for clinical HCC prediction..

FGFR2-triggered autophagy and activation of Nrf-2 reduce breast cancer cell response to anti-ER drugs

BackgroundGenetic abnormalities in the FGFR signalling occur in 40% of breast cancer (BCa) patients resistant to anti-ER therapy, which emphasizes the potential of FGFR-targeting strategies. Recent findings indicate that not only mutated FGFR is a driver of tumour progression but co-mutational landscapes and other markers should be also investigated. Autophagy has been recognized as one of the major mechanisms underlying the role of tumour microenvironment in promotion of cancer cell survival, and resistance to anti-ER drugs. The selective autophagy receptor p62/SQSTM1 promotes Nrf-2 activation by Keap1/Nrf-2 complex dissociation. Herein, we have analysed whether the negative effect of FGFR2 on BCa cell response to anti-ER treatment involves the autophagy process and/or p62/Keap1/Nrf-2 axis.MethodsThe activity of autophagy in ER-positive MCF7 and T47D BCa cell lines was determined by analysis of expression level of autophagy markers (p62 and LC3B) and monitoring of autophagosomes’ maturation. Western blot, qPCR and proximity ligation assay were used to determine the Keap1/Nrf-2 interaction and Nrf-2 activation. Analysis of 3D cell growth in Matrigel® was used to assess BCa cell response to applied treatments. In silico gene expression analysis was performed to determine FGFR2/Nrf-2 prognostic value.ResultsWe have found that FGFR2 signalling induced autophagy in AMPKα/ULK1-dependent manner. FGFR2 activity promoted dissociation of Keap1/Nrf-2 complex and activation of Nrf-2. Both, FGFR2-dependent autophagy and activation of Nrf-2 were found to counteract the effect of anti-ER drugs on BCa cell growth. Moreover, in silico analysis showed that high expression of NFE2L2 (gene encoding Nrf-2) combined with high FGFR2 expression was associated with poor relapse-free survival (RFS) of ER+ BCa patients.ConclusionsThis study revealed the unknown role of FGFR2 signalling in activation of autophagy and regulation of the p62/Keap1/Nrf-2 interdependence, which has a negative impact on the response of ER+ BCa cells to anti-ER therapies. The data from in silico analyses suggest that expression of Nrf-2 could act as a marker indicating potential benefits of implementation of anti-FGFR therapy in patients with ER+ BCa, in particular, when used in combination with anti-ER drugs.Graphical

Interleukin-21 receptor signaling promotes metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma by inducing immunosuppressive IgA+ B cells

BackgroundDysregulation of immune surveillance is tightly linked to the development of metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC); however, its underlying mechanisms remain unclear. Herein, we aimed to determine the role of interleukin-21 receptor (IL-21R) in MASH-driven HCC.MethodsThe clinical significance of IL-21R was assessed in human HCC specimens using immunohistochemistry staining. Furthermore, the expression of IL-21R in mice was assessed in the STAM model. Thereafter, two different MASH-driven HCC mouse models were applied between IL-21R-deficient mice and wild type controls to explore the role of IL-21R in MASH-driven HCC. To further elucidate the potential mechanisms by which IL-21R affected MASH-driven HCC, whole transcriptome sequencing, flow cytometry and adoptive lymphocyte transfer were performed. Finally, flow cytometry, enzyme-linked immunosorbent assay, immunofluorescent staining, chromatin immunoprecipitation assay and western blotting were conducted to explore the mechanism by which IL-21R induced IgA+ B cells.ResultsHCC patients with high IL-21R expression exhibited poor relapse-free survival, advanced TNM stage and severe steatosis. Additionally, IL-21R was demonstrated to be upregulated in mouse liver tumors. Particularly, ablation of IL-21R impeded MASH-driven hepatocarcinogenesis with dramatically reduction of lipid accumulation. Moreover, cytotoxic CD8+ T lymphocyte activation was enhanced in the absence of IL-21R due to the reduction of immunosuppressive IgA+ B cells. Mechanistically, the IL-21R-STAT1-c-Jun/c-Fos regulatory axis was activated in MASH-driven HCC and thus promoted the transcription of Igha, resulting in the induction of IgA+ B cells.ConclusionsIL-21R plays a cancer-promoting role by inducing IgA+ B cells in MASH-driven hepatocarcinogenesis. Targeting IL-21R signaling represents a potential therapeutic strategy for cancer therapy.

Abstract PO1-06-07: EMSY enhances cancer stem cell self-renewal and tumorigenesis by reshaping methionine metabolism in triple-negative breast cancer

Abstract PO1-06-07: EMSY enhances cancer stem cell self-renewal and tumorigenesis by reshaping methionine metabolism in triple-negative breast cancer