Predictor Of Poor Overall Survival Research Articles

N4-acetylcytidine-dependent GLMP mRNA stabilization by NAT10 promotes head and neck squamous cell carcinoma metastasis and remodels tumor microenvironment through MAPK/ERK signaling pathway

N4-acetylcytidine (ac4C) is a post-transcriptional RNA modification that regulates in various important biological processes. However, its role in human cancer, especially lymph node metastasis, remains largely unknown. Here, we demonstrated N-Acetyltransferase 10 (NAT10), as the only known “writer” of ac4C mRNA modification, was highly expressed in head and neck squamous cell carcinoma (HNSCC) patients with lymph node metastasis. High NAT10 levels in the lymph nodes of patients with HNSCC patients are a predictor of poor overall survival. Moreover, we found that high expression of NAT10 was positively upregulated by Nuclear Respiratory Factor 1 (NRF1) transcription factor. Gain- and loss-of-function experiments displayed that NAT10 promoted cell metastasis in mice. Mechanistically, NAT10 induced ac4C modification of Glycosylated Lysosomal Membrane Protein (GLMP) and stabilized its mRNA, which triggered the activation of the MAPK/ERK signaling pathway. Finally, the NAT10-specific inhibitor, remodelin, could inhibit HNSCC tumorigenesis in a 4-Nitroquinoline 1-oxide (4NQO)-induced murine tumor model and remodel the tumor microenvironment, including angiogenesis, CD8+ T cells and Treg recruitment. These results demonstrate that NAT10 promotes lymph node metastasis in HNSCC via ac4C-dependent stabilization of the GLMP transcript, providing a potential epitranscriptomic-targeted therapeutic strategy for HNSCC.

Optimization of therapeutic strategies for selective lateral lymph node dissection after neoadjuvant chemoradiotherapy in patients with rectal cancer with clinical suspected lateral lymph node metastasis.

Selective lateral lymph node (LLN) dissection with total mesorectal excision after neoadjuvant chemoradiotherapy (nCRT) is pointed out to reduce lateral compartment recurrence and to improve survival in patients with rectal cancer with LLN metastases. This study aimed to explore the safety, surgical indications, and survival outcomes of LLN dissection after nCRT. This multicenter retrospective study included patients with rectal cancer with clinical evidence of LLN metastases (n = 466) treated across three hospitals in China. Patients who underwent total mesorectal excision and LLN dissection were grouped into nCRT (n = 155) and non-nCRT (n = 291), respectively. Propensity score matching was used to minimize selection bias. After matching, nCRT did not significantly increase the surgery duration, intraoperative blood loss or postoperative complications (P > 0.05). In a multivariate logistic regression analysis, poor/mucinous/signet adenocarcinoma (P = 0.042) and post-nCRT LLN short diameter ≥7 mm (P < 0.001) were independent risk factors for pathological LLN metastasis after nCRT. Overall survival (P < 0.001) and disease-free survival (P < 0.001) were significantly worse in patients with LLN metastasis, which was, however, not an independent risk factor for survival after eliminating confounders. Multivariate prognostic analysis of 40-patient subset with pathological LLN metastasis showed that distant metastasis, metastasis beyond the obturator or internal iliac region, and ≥2 LLN metastasis were independent predictors of poor overall survival. Selective LLN dissection after nCRT is safe and feasible with acceptable perioperative outcomes. Patients with a post-nCRT LLN short diameter ≥7 mm or poor/mucinous/signet adenocarcinoma should receive supplementary LLN dissection after nCRT. However, patients with distant metastasis, metastasis beyond the obturator or internal iliac region, and involvement of ≥2 LLN may not benefit from LLN dissection, and LLN dissection should be carefully considered in such patients.

Feasible living donor liver transplantation for patients on chronic hemodialysis: a multicenter study in East Asian countries.

End-stage liver and kidney disease is an indication for simultaneous liver and kidney transplantation. However, in countries where deceased donor transplantation is not well established, living donor liver transplantation (LDLT) is a realistic option for patients on hemodialysis (HD). We investigated the outcomes of LDLT for patients on HD. We conducted a retrospective multicenter survey of patients on chronic HD who underwent LDLT in East Asian countries. The characteristics of donors and recipients and the short and long-term outcomes were analyzed. Between 2001 and 2021, 45 patients on HD underwent LDLT and 11 of these patients also underwent kidney transplantation (KT). The overall survival rate at 5years of the 34 patients who underwent only LDLT was 44.5%. Multivariate analysis identified a low graft recipient weight ratio (< 1%) (p = 0.048) and long HD duration (≥ 10years) (p = 0.046) as independent predictors of poor overall survival. The major complication was posttransplant bleeding, which occurred in12 patients (35%). It is important to establish the indications for LDLT, taking into consideration graft size and HD duration in candidate patients on HD.

Diffusion heterogeneity and vascular perfusion in tumor and peritumoral areas for prediction of overall survival in patients with high-grade glioma

ObjectiveTo evaluation of diffusion heterogeneity and vascular perfusion in tumor and peritumoral areas for prognostic prediction in high-grade glioma (HGG, WHO III/IV grade). MethodsForty patients with HGG underwent diffusion kurtosis imaging (DKI), intravoxel incoherent motion (IVIM), and arterial spin labeling (ASL) MRI before operation. After normalization, the parameters were divided into diffusion heterogeneity parameters (rD, rMD, rMK, rKr, rKa) and vascular perfusion parameters (rD*, rF, rCBF). Univariate and multivariate Cox regression analyses were used to evaluate associations between overall survival (OS) and the above parameters, clinical factors, and IDH1 status. The Mann-Whitney test was used to evaluate differences in the parameters between different IDH1 states. ResultsIn the univariate Cox regression analysis, OS was significantly associated with tumor resection range, IDH1 status, tumor heterogeneity parameters (rD, rMD, rMK, rKr, rKa), and rCBF in tumor area(all p < 0.05). In addition, rD and rCBF measured in the peritumoral region were also predictors of poor OS (both p < 0.01). Multivariate Cox regression analysis indicated that rMK in the tumor area and rCBF in the peritumoral area (hazard ratio = 7.900 and 5.466, respectively, for each 0.1 increase in the normalized value) were independent predictors of OS. ConclusionThe rMK of tumor area and rCBF of peritumoral area had independent predictive value for OS in patients with HGG. Advances in knowledgeThis study explored useful imaging biomarkers from the diffusion heterogeneity and vascular perfusion of tumor and peritumoral areas in HGG, which is useful to help clinician to make precise therapeutic plans, and predict the prognostic for glioma patients.

FTP7.10 Preoperative C-reactive protein-to-albumin ratio and its ability to predict outcomes of pancreatic cancer resection: a systematic review

Abstract Aim To evaluate the ability of c-reactive protein-to-albumin ratio (CAR) in predicting outcomes in patients undergoing pancreatic cancer resection. Methods We conducted a systematic search of multiple electronic information sources and bibliographic reference lists. We applied a combination of free text and controlled vocabulary search adapted to thesaurus headings, search operators and limits in each of the above databases. Survival outcomes and perioperative morbidity were the evaluated outcome parameters. Results Eight observational studies reporting a total number of 1,056 patients undergoing pancreatic cancer resection were identified. The median cut-off value for CAR was 0.05 (range 0.0003- 0.54). Using multivariate analysis, all the included studies demonstrated that a higher CAR value was an independent and significant predictor of poor overall survival in patients undergoing pancreatic cancer resection. The estimated hazard ratio provided by the included studies ranged from 1.4 to 3.6. There was significant heterogeneity among the included studies; for example use of neoadjuvant or adjuvant chemotherapy, pTNM staging, lymph node metastasis, preoperative Ca19-9 and CEA levels, neutrophil-to-lymphocyte ratio, and modified Glasgow prognostic score. Furthermore, important prognostic characteristics such as tumour site and size, pathological T factor, and vascular involvement were poorly reported. Conclusions Preoperative CAR value seems to be an important prognostic score in predicting survival outcomes in patients undergoing pancreatic cancer resection. However, the current evidence does not allow determination of an optimal cut-off value for CAR considering the heterogeneous reporting of cut-off values by the available studies and lack of knowledge of their sensitivity and specificity. Future research is required.

Expression Patterns of Immune Checkpoints in Breast Cancer Patients

Background: immunotherapy with immune checkpoint inhibitors (ICIs) for solid tumors had significantly improved overall survival (OS). Positive response to PD-1/PD-L1 blockades was observed in the treatment of solid tumors. Breast cancer (BC) patients are no exception. However, the efficacy of immunocheckpoint therapy in BC patients remains poor. A particularly important factor is the lack of studies on the expression patterns of immune checkpoints in BC patients. Methods：This article summarizes the expression of immune checkpoints such as PD-1, PD-L1, STAT1, CTLA-4 in BC, and analyzes the relationship between the expression of these immune checkpoints and OS.Results: It was found that increased expression of PD-1, PD-L1, STAT1, CTLA-4 was associated with poor OS in BC patients. In addition, co-expression of PD-L1 with PD-1, STAT1or CTLA-4 and co-expression of PD-1 with CTLA-4was related to poor OS. We analyzed associations between the proportionate expression of PD-L1 and PD-1, PD-L1 and STAT1, PD-1 and CTLA-4, PD-1 and LAG3, PD-L1 and CTLA-4 in BC patients, there was significance in correlation in both of the BC patients. Conclusions: our results suggest that transcriptome-based co-expression of STAT1 and PD-L1 is a predictor for poor OS in BC patients, which might provide novel insight into designing combinational targeted therapy for BC.

Impact of bone metastasis on the prognosis of non-small cell lung cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis.

This review was implemented to examine the impact of bone metastasis on the prognosis of non-small cell lung cancer patients (NSCLC) treated with immune checkpoint inhibitors (ICIs). A literature search was conducted in the PubMed, CENTRAL, Web of Science, and Embase databases up to 4th September 2022. Multivariable adjusted data were pooled in a random-effects model. 13 studies were included. On a combined analysis of 10 studies, it was noted that bony metastasis was associated with poor overall survival (OS) in NSCLC patients treated with ICIs (HR: 1.55 95% CI 1.24, 1.94 I2 = 69% p = 0.001). Meta-analysis of seven studies showed that bony metastasis was not associated with poor progression-free survival (PFS) in NSCLC patients treated with ICIs (HR: 1.31 95% CI 0.85, 2.01 I2 = 85% p = 0.22). Meta-regression analysis using the moderator's age, male gender, smoking history, squamous histology, and ICI as 1st line therapy for the outcome OS was not statistically significant. The presence of bone metastasis is a predictor of poor OS in NSCLC treated with ICIs. However, PFS does not seem to be influenced by the presence of bone metastasis. Clinicians should prioritize the management of NSCLC patients with bone metastasis and explore the use of combination therapies to achieve optimal results. Further studies taking into account different combination therapies for such patients would strengthen the evidence.

Long-term survival outcomes of salvage [225Ac]Ac-PSMA-617 targeted alpha therapy in patients with PSMA-expressing end-stage metastatic castration-resistant prostate cancer: a real-world study.

Despite the existence of various treatment options, the prognosis for patients with metastatic castration-resistant prostate cancer (mCRPC) remains unfavorable. One potential therapeutic approach is the use of [225Ac]Ac-PSMA-617, a targeted alpha therapy (TAT) that administers alpha-particle radiation specifically to prostate cancer cells expressing PSMA. In this study, we report the long-term survival outcomes of this novel therapy in a series of patients with mCRPC who have exhausted all standard treatment options. The study enrolled patients with mCRPC who had shown resistance to standard lines of therapies, including next-generation anti-androgen therapies and taxane-based chemotherapies. These eligible patients received treatment with [225Ac]Ac-PSMA-617 at 100-150 kBq/kg doses administered every 8 weeks. The primary objective of the study was to assess overall survival (OS), while secondary objectives included evaluating radiological progression-free survival (rPFS), monitoring serum prostate-specific antigen (PSA) levels as a measure of biochemical response, and assessing adverse events using the CTCAE v5.0 grading system. Among the 63 initially enrolled patients, a total of 56 patients who had completed at least two cycles of [225Ac]Ac-PSMA-617 were included in this study. The mean age was 67 years (range, 39-87) and patients received a total of 204 cycles of [225Ac]Ac-PSMA-617 TAT. 91% of patients exhibited any PSA decline, with 67.8% experiencing a decline of 50% or more. The median follow-up was of 22 months (range: 6-59 months). Imaging-based disease progression was observed in 68% of patients, and 66% of patients succumbed to the disease. The median OS was 15 months (95% CI: 10-19). In univariate analysis, factors such as lack of >50% PSA decline (P=0.031), Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher (P=0.048), and radiological progression (rPD) (P<0.001) were found to be predictors of poor OS. However, in multivariate analysis, only rPD emerged as an independent prognostic factor with a hazard ratio (HR) of 8.264 (95% CI: 1.429-16.497, P=0.004). The estimated median rPFS was 9 months (95% CI: 7-15). Moreover, patients who demonstrated any PSA decline had a median rPFS of 10 months compared to only 3 months in patients without any PSA decline (multivariate HR: 6.749; 95% CI: 1.949-23.370; P=0.002). Fatigue was one of the most common treatment-emergent adverse events, with grades 1/2 occurring in 70% of patients and grades 3 or higher in 3.5% of patients. This fatigue was transient and resolved before the next treatment cycle. Additionally, approximately one-third of patients experienced xerostomia (grades 1/2: 32.1%). [225Ac]Ac-PSMA-617 targeted alpha therapy, was found to be well-tolerated with acceptable adverse events and effective in the treatment of patients with end-stage mCRPC.

Preoperative C-Reactive Protein-to-Albumin Ratio and Its Ability to Predict Outcomes of Pancreatic Cancer Resection: A Systematic Review.

To evaluate the ability of the c-reactive protein-to-albumin ratio (CAR) in predicting outcomes in patients undergoing pancreatic cancer resection. A systematic search of electronic information sources and bibliographic reference lists was conducted. Survival outcomes and perioperative morbidity were the evaluated outcome parameters. Eight studies reporting a total of 1056 patients undergoing pancreatic cancer resection were identified. The median cut-off value for CAR was 0.05 (range 0.0003-0.54). Using multivariate analysis, all studies demonstrated that a higher CAR value was an independent and significant predictor of poor overall survival in patients undergoing pancreatic cancer resection. The estimated hazard ratio (HR) ranged from 1.4 to 3.6. Although there was a positive correlation between the reported cut-off values for CAR and HRs for overall survival, it was weak and non-significant (r = 0.36, n = 6, p = 0.480). There was significant between-study heterogeneity. Preoperative CAR value seems to be an important prognostic score in predicting survival outcomes in patients undergoing pancreatic cancer resection. However, the current evidence does not allow the determination of an optimal cut-off value for CAR, considering the heterogeneous reporting of cut-off values by the available studies and the lack of knowledge of their sensitivity and specificity. Future research is required.

TMEM200A is a potential prognostic biomarker and correlated with immune infiltrates in gastric cancer.

Gastric cancer (GC) is one of the most common malignant tumors in the digestive system. Several transmembrane (TMEM) proteins are defined as tumor suppressors or oncogenes. However, the role and underlying mechanism of TMEM200A in GC remain unclear. We analyzed the expression of TMEM200A in GC. Furthermore, the influence of TMEM200A on survival of GC patients was evaluated. The correlations between the clinical information and TMEM200A expression were analyzed using chi-square test and logistic regression. Relevant prognostic factors were identified performing univariate and multivariate analysis. Gene set enrichment analysis (GSEA) was performed based on the TCGA dataset. Finally, we explore the relationship between TMEM200A expression and cancer immune infiltrates using CIBERSORT. TMEM200A was up-regulated in GC tissues than that in adjacent non-tumor tissues based on TCGA database. Meta-analysis and RT-qPCR validated the difference in TMEM200A expression. Kaplan-Meier curves suggested the increased TMEM200A had a poor prognosis in GC patients. The chi-square test and logistic regression analyses showed that the TMEM200A expression correlates significantly with T stage. Multivariate analysis showed that TMEM200A expression might be an important independent predictor of poor overall survival in GC patients. GSEA identified five immune-related signaling pathways and five tumor-related signaling pathways significantly enriched in the high TMEM200A expression phenotype pathway. Finally, we found CD8+ T cells is apparently decreased in high TMEM200A expression group. Conversely, eosinophils is increased in high expression group compared with low expression group. TMEM200A is a potential prognostic biomarker and correlated with immune infiltrates in GC.

When is neoadjuvant chemotherapy indicated in rectal neuroendocrine tumors? An analysis of the National Cancer Database.

e15631 Background: Rectal neuroendocrine tumors (rNET) are rare and challenging to manage. While most patients with small rNET can be definitively treated with local excision, the role of chemotherapy in general and neoadjuvant therapy specifically in managing advanced rNET has not been well established. Therefore, this study aimed to determine which patients with rNET may gain a survival benefit from neoadjuvant chemotherapy. Methods: A retrospective cohort analysis of all patients who underwent surgical resection of rNET in the US National Cancer Database (NCDB) (2004-2019) was performed. First, univariate and multivariate cox regression analyses were performed to determine the independent predictors of poor overall survival (OS) and define the high-risk groups. Afterwards, stratified OS analyses were performed for each high-risk group to assess whether neoadjuvant chemotherapy had a survival benefit in each group. Results: 1837 patients (49.8% female; mean age 56.6 ±12.3 years) underwent radical resection of a rectal neuroendocrine tumor. Tumors &gt; 20 mm in size, clinical T4 tumors, poorly differentiated tumors, and metastatic disease were independent predictors of worse OS and were defined as high risk groups. Neoadjuvant chemotherapy did not have a significant survival benefit in any of the high-risk groups, except for patients with high-grade rNETs where neoadjuvant therapy significantly improved OS to a mean of 30.9 months compared to 15.9 months when neoadjuvant therapy was not given (p = 0.006). Conclusions: Neoadjuvant chemotherapy improved OS of patients with high-grade rNET by 15 months and may be indicated for this group.

Risk factors of early liver metastasis in patients with breast cancer.

e13011 Background: Breast Cancer Liver Metastasis is very common in the clinical treatment of breast cancer. Although great progress has been made in the early diagnosis and treatment of breast cancer, 20% to 30% of patients with early breast cancer will develop tumor metastasis. Relevant studies have found that liver metastasis is an independent predictor of poor overall survival in breast cancer patients compared with bone metastasis and other factors. There is a lack of large-scale clinical research on the risk factors of early liver metastasis of breast cancer across the world. This study aims to explore the possible risk factors of early liver metastasis of breast cancer patients by analyzing the clinical data of 70 breast cancer patients with first liver metastasis. Methods: A retrospective study was conducted on 70 female breast cancer patients with liver metastasis who were diagnosed and treated in the First Affiliated Hospital of Nanjing Medical University from January 2011 to December 2021 and had complete medical records. The main clinical and pathological data of the patients were obtained by reading the medical records, such as age, menstrual status, surgical method, history of non-alcoholic fatty liver disease, T stage of the primary tumor, molecular type, vascular tumor thrombus and pathological type. SPSS 25.0 statistical software was used to analyze the data. Kaplan-Meier Survival curve and log-rank test were used to compare the disease-free survival (DFS) of breast cancer patients with and without non-alcoholic fatty liver Disease, different ER expression, Ki67 expression and histological grade. DFS is the interval between breast cancer surgery and the occurrence of metastases. COX regression model was used to analyze the risk factors of early metastasis of breast cancer. P &lt; 0.05 was considered statistically significant. Results: The median liver metastasis-free time of the 70 breast cancer patients was 34 months (range 4-121 months). High histological grade, non-alcoholic fatty liver disease, negative expression of ER and Ki-67&gt;15% were risk factors for early liver metastasis in patients with breast cancer after operation (χ2 =8.367, P=0.015; χ2 =6.883, P=0.009; χ2 =7.507, P=0.006; χ2 =10.488, P=0.001). Conclusions: In this study, the independent risk factors of early liver metastasis in breast cancer patients are high histological grade, high expression of Ki-67, and combined with alcoholic fatty liver, which is consistent with most studies at home and abroad, and proves that Chinese breast cancer patients have the same risk factors as foreign patients. However, the role of ER, PR and HER-2 expression is unclear, which may be related to the fact that some patients do not receive systemic endocrine and targeted therapy. More samples and multi-center prospective clinical studies are needed to confirm, but it still has certain clinical significance for the prognosis and intervention of breast cancer patients.

Prognostic Value of Post-Operative C-Reactive Protein-Based Inflammatory Biomarkers in Colorectal Cancer Patients: Systematic Review and Meta-Analysis.

Post-operative inflammation in cancer patients can be modulated by drugs and diets, but evidence on its prognostic role, which would be crucial for personalized treatment and surveillance schemes, remains rather limited. We aimed to systematically review and meta-analyse studies on the prognostic value of post-operative C-reactive protein (CRP)-based inflammatory biomarkers among patients with colorectal cancer (CRC) (PROSPERO#: CRD42022293832). PubMed, Web of Science and Cochrane databases were searched until February 2023. Studies reporting associations between post-operative CRP, Glasgow Prognostic Score (GPS) or modified Glasgow Prognostic Score (mGPS) with overall survival (OS), CRC-specific survival (CSS) and recurrence-free survival (RFS) were included. Hazard ratios (HRs) with 95% confidence intervals (CIs) for the predictor-outcome associations were pooled using R-software, version 4.2. Sixteen studies (n = 6079) were included in the meta-analyses. Elevated post-operative CRP was a predictor of poor OS, CSS and RFS compared with low CRP levels [HR (95% CI): 1.72 (1.32-2.25); 1.63 (1.30-2.05); 2.23 (1.44-3.47), respectively]. A unit increase in post-operative GPS predicted poor OS [HR (95% Cl): 1.31 (1.14-1.51)]. Moreover, a unit increase in post-operative mGPS was associated with poor OS and CSS [HR (95% Cl): 1.93 (1.37-2.72); 3.16 (1.48-6.76), respectively]. Post-operative CRP-based inflammatory biomarkers have a significant prognostic role for patients with CRC. Prognostic value of these easy-to-obtain routine measurements thereby seems to outperform most of the much more complex blood- or tissue-based predictors in the current focus of multi-omics-based research. Future studies should validate our findings, establish optimal time for biomarker assessment and determine clinically useful cut-off values of these biomarkers for post-operative risk-stratification and treatment-response monitoring.

Clinical impact of anti-inflammatory microglia and macrophage phenotypes at glioblastoma margins.

Glioblastoma is a devastating brain cancer for which effective treatments are required. Tumour-associated microglia and macrophages promote glioblastoma growth in an immune-suppressed microenvironment. Most recurrences occur at the invasive margin of the surrounding brain, yet the relationships between microglia/macrophage phenotypes, T cells and programmed death-ligand 1 (an immune checkpoint) across human glioblastoma regions are understudied. In this study, we performed a quantitative immunohistochemical analysis of 15 markers of microglia/macrophage phenotypes (including anti-inflammatory markers triggering receptor expressed on myeloid cells 2 and CD163, and the low-affinity-activating receptor CD32a), T cells, natural killer cells and programmed death-ligand 1, in 59 human IDH1-wild-type glioblastoma multi-regional samples (n = 177; 1 sample at tumour core, 2 samples at the margins: the infiltrating zone and leading edge). Assessment was made for the prognostic value of markers; the results were validated in an independent cohort. Microglia/macrophage motility and activation (Iba1, CD68), programmed death-ligand 1 and CD4+ T cells were reduced, and homeostatic microglia (P2RY12) were increased in the invasive margins compared with the tumour core. There were significant positive correlations between microglia/macrophage markers CD68 (phagocytic)/triggering receptor expressed on myeloid cells 2 (anti-inflammatory) and CD8+ T cells in the invasive margins but not in the tumour core (P < 0.01). Programmed death-ligand 1 expression was associated with microglia/macrophage markers (including anti-inflammatory) CD68, CD163, CD32a and triggering receptor expressed on myeloid cells 2, only in the leading edge of glioblastomas (P < 0.01). Similarly, there was a positive correlation between programmed death-ligand 1 expression and CD8+ T-cell infiltration in the leading edge (P < 0.001). There was no relationship between CD64 (a receptor for autoreactive T-cell responses) and CD8+/CD4+ T cells, or between the microglia/macrophage antigen presentation marker HLA-DR and microglial motility (Iba1) in the tumour margins. Natural killer cell infiltration (CD335+) correlated with CD8+ T cells and with CD68/CD163/triggering receptor expressed on myeloid cells 2 anti-inflammatory microglia/macrophages at the leading edge. In an independent large glioblastoma cohort with transcriptomic data, positive correlations between anti-inflammatory microglia/macrophage markers (triggering receptor expressed on myeloid cells 2, CD163 and CD32a) and CD4+/CD8+/programmed death-ligand 1 RNA expression were validated (P < 0.001). Finally, multivariate analysis showed that high triggering receptor expressed on myeloid cells 2, programmed death-ligand 1 and CD32a expression at the leading edge were significantly associated with poorer overall patient survival (hazard ratio = 2.05, 3.42 and 2.11, respectively), independent of clinical variables. In conclusion, anti-inflammatory microglia/macrophages, CD8+ T cells and programmed death-ligand 1 are correlated in the invasive margins of glioblastoma, consistent with immune-suppressive interactions. High triggering receptor expressed on myeloid cells 2, programmed death-ligand 1 and CD32a expression at the human glioblastoma leading edge are predictors of poorer overall survival. Given substantial interest in targeting microglia/macrophages, together with immune checkpoint inhibitors in cancer, these data have major clinical implications.

Methylated SEPT9 assay-based liquid biopsy as a biomarker in molecular targeted agent-treated hepatocellular carcinoma.

The development of molecular targeted agents (MTAs) has changed the treatment strategy for hepatocellular carcinoma (HCC). However, currently, there are no established predictive biomarkers for the treatment efficacy of MTAs. Previously, we developed a novel liquid biopsy test for HCC screening using sensitive methylated DNA testing of septin 9 gene (SEPT9). Here, we hypothesized that SEPT9 could be used as a biomarker for MTA treatment efficacy. We enrolled 157 patients receiving sorafenib or lenvatinib as a first-line therapy and allocated 85 and 72 patients to the training and validation cohorts, respectively. For the methylation assay, DNA was treated with methylation-sensitive restriction enzymes, followed by multiplex droplet digital PCR. Various clinical parameters were compared with clinical outcomes. The multivariate analysis revealed Eastern Cooperative Oncology Group performance status (≥ 1; p = 0.048), alpha-fetoprotein (AFP) (≥ 400ng/mL; p < 0.001), and methylated-septin-9 (m-SEPT9) (≥ 205 copies/mL; p = 0.018) as significant predictors of poor overall survival (OS) in the training cohort. m-SEPT9 was identified as a predictor of poor OS in the validation cohort. We developed a predictive score, called the MTA score, consisting of these three significant OS parameters (two points were added for AFP and one point for each of the other predictors). Patients with MTA scores ≥ 2 showed a significantly poor prognosis compared to those with MTA scores ≤ 1 in both the training and validation cohorts. m-SEPT9 could be a potential predictive biomarker for survival in patients with HCC treated with MTAs.

Targeting BRD3 eradicates nuclear TYRO3-induced colorectal cancer metastasis.

Metastasis is the main cause of death in many cancers including colorectal cancer (CRC); however, the underlying mechanisms responsible for metastatic progression remain largely unknown. We found that nuclear TYRO3 receptor tyrosine kinase is a strong predictor of poor overall survival in patients with CRC. The metastasis-promoting function of nuclear TYRO3 requires its kinase activity and matrix metalloproteinase-2 (MMP-2)-mediated cleavage but is independent of ligand binding. Using proteomic analysis, we identified bromodomain-containing protein 3 (BRD3), an acetyl-lysine reading epigenetic regulator, as one of nuclear TYRO3's substrates. Chromatin immunoprecipitation-sequencing data reveal that TYRO3-phosphorylated BRD3 regulates genes involved in anti-apoptosis and epithelial-mesenchymal transition. Inhibition of MMP-2 or BRD3 activity by selective inhibitors abrogates nuclear TYRO3-induced drug resistance and metastasis in organoid culture and in orthotopic mouse models. These data demonstrate that MMP-2/TYRO3/BRD3 axis promotes the metastasis of CRC, and blocking this signaling cascade is a promising approach to ameliorate CRC malignancy.

Peritoneal metastasis of advanced epithelial ovarian carcinoma treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: A retrospective international multicentric data analysis

IntroductionThe purpose of our study was to evaluate outcome data after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal metastasis originating from advanced epithelial ovarian carcinoma (PMOC). Patients and methodsA retrospective international multi-institutional registry was established through collaborative efforts of participating units affiliated with the Peritoneal Surface Oncology Group. ResultsOne thousand four hundred and ninety-one patients from 11 specialized units underwent CRS and HIPEC that of those 326 (21.9%) upfront surgeries, 504 (33.8%) interval surgery, and 661(44.3%) recurrent cases. Complete Cytoreduction(CC0/1) was achieved in 1213 patients (81.3%). Treatment -related mortality was 0.8%, major operative complications (Grades 3–5) was 25.1%. Factors associated with major operative complications include prior surgical score (PSS for recurrent cases; RC) PSS>2,p = 0.000), PCI(≤15, >15 cut-off level; p ≤ 0.000), completeness of cytoreduction (CC, p=0.000), high CA125 levels (>25 mg/dl), presence of ascites, high CRP (>5 mg/dl) levels and low albumin levels (below to 2.5 mg/dl) (p ≤ 0.05).The median survival was 58 months in upfront surgery(UFS), 60 months in interval surgery(IS), and 42 months in RC. The overall survival for five years was 45% for UFS, 37% for IS, 28% for RC cases. CCscore (p = 0.000), CA125, CRP and albumin levels (p ≤ 0.05) were predictors for progression free survival. PCI(p ≤ 0.000), major postoperative complications (p = 0.004), incomplete CRS(CC2/3)(p < 0.001), prior chemotherapy (hazard ratio [HR], 3–8; p < 0.001) and PSS>2 for RC were independent predictors of poor overall survival. ConclusionThe combined treatment strategy for PMOC may be performed safely with acceptable morbidity and mortality in the specialized units.

MiR-17-5p slows progression of hepatocellular carcinoma by downregulating TGFβR2.

Downregulation of miR-17-5p has been reported in several cancers, but whether and how miR-17-5p is downregulated in hepatocellular carcinoma (HCC) is unknown. Here, we examined whether miR-17-5p is downregulated in HCC and whether that affects expression of its target gene encoding transforming growth factor β receptor 2 (TGFβR). We screened for potential microRNAs (miRNAs) involved in HCC by analyzing published transcriptomes from HCC patients. Expression of miR-17-5p was measured in HCC cell lines and in tissues from HCC patients using quantitative real-time PCR. The in vitro effects of miR-17-5p on HCC cells were assessed by EdU proliferation assay, CCK-8 cell proliferation assay, colony-formation assay, transwell migration/invasion assay, wound healing assay, and flow cytometry. Effects of miR-17-5p were evaluated in vivo using mice with subcutaneous tumors. Effects of the miRNA on the epithelial-mesenchymal transition (EMT) were assessed, while its effects on TGFβR2 expression were analyzed using bioinformatics and a dual luciferase reporter assay. Patients with low miR-17-5p expression showed lower rates of overall and recurrence-free survival than patients with high miR-17-5p expression, and multivariate Cox regression identified low miR-17-5p expression as an independent predictor of poor overall survival in HCC patients. In vitro, miR-17-5p significantly inhibited HCC cell proliferation, migration, invasion, and the EMT, while promoting apoptosis. In vivo, it slowed the development of tumors. These protective effects of miR-17-5p were associated with downregulation of TGFβR2. The miRNA miR-17-5p can negatively regulate the expression of TGFβR2 and inhibit the EMT, thereby slowing tumor growth in HCC, suggesting a potential therapeutic approach against HCC.

Abstract 1306: New therapeutic approach for triple negative breast cancer: soluble TNFα blockade and MUC4 expression as a prognostic biomarker

Abstract Among all breast cancers, triple negative (TNBC) subtype has the worst survival rate. We have demonstrated that the proinflammatory cytokine TNFα induces trastuzumab resistance through Mucin4 (MUC4) upregulation and it is an independent biomarker of poor response to therapy in HER2+ breast cancer. MUC4 is a transmembrane glycoprotein expressed in several tumors and it is involved in metastasis dissemination. Here, we evaluated the role of TNFα and MUC4 in metastasis in TNBC cell lines and we assessed the clinical impact of MUC4 expression in TNBC patients. TNFα blockade was achieved using etanercept (E), which blocks the soluble (sTNFα) and transmembrane isoforms of TNFα, or dominant negative protein INB03 (DN) which only neutralizes sTNFα. BT-549 and MDA-MB-231 TNBC cell lines treated with E or DN exhibit a decrease in MUC4 expression. TNFα blockade decreases the expression of the mesenchymal markers vimentin and snail in both cell lines. To assess the impact of TNFα blockade on tumor cells and its effect on the tumor microenvironment (TME), we collected conditioned media (CM) of MDA-MB-231 and BT-549 cells treated with E or DN which were used to evaluate the invasive capacity of the TNBC cell lines. The invasion of BT-549 was impaired with CM-Eta (p&amp;lt;0.01) and CM-DN (p&amp;lt;0.01), and MDA-MB-231 invasive capacity was reduced only with CM-DN (p&amp;lt;0.01). We evaluated MUC4 participation on invasion in MDA-MB-231 cell line transfected with a siRNA targeting MUC4 with or without DN treatment, and an invasion assay was performed. MUC4 knockdown impaired cell invasion (p=0.0001 vs siRNA control transfected cells). The treatment with DN of the MUC4-silenced cells did not further enhanced the effect, demonstrating that the impairment of the invasion is due to the decrease in MUC4. We determined the presence of TILs by H&amp;E and the expression of MUC4, Ki67, PD-L1 (SP142), androgen receptor (AR) and cytokeratin 5 by immunohistochemistry in a cohort of 55 TNBC patients. MUC4 expression inversely correlated with TILs (p=0.00013). Since TILs are associated with good prognosis, we evaluated the effect of BT-549-CM on T cell migration. CM-DN increased T cell migration compared to control CM (p&amp;lt;0.01). MUC4 expression inversely correlated with Ki67 (p=0.016), PD-L1 (p=0.001) and AR (p=0.047) in our cohort. Moreover, MUC4 proved to be an independent predictor of poor overall survival (p=0.02), and is associated with a higher metastasis risk (p=0.005).In conclusion, TNFα blocking agents decrease MUC4, mesenchymal markers and the invasive capacity of TNBC cells, and in turn increase human T cell migration. MUC4 is an independent biomarker of poor overall survival, it is associated with an increased risk of metastasis and immune desert tumors. We propose TNFα as a new target for the treatment of TNBC, and MUC4 as a predictive marker to guide a combined treatment of TNFα blockers with chemotherapy or immunotherapy. Citation Format: Florencia Mauro, Sofia Bruni, Agustina Dupont, Gloria Inurrigarro, Silvina Figurelli, Sabrina Barchuk, Daniel Lopez Della Vecchia, Rosalia Cordo Russo, Ernesto Gil Deza, María Florencia Mercogliano, Roxana Schillaci. New therapeutic approach for triple negative breast cancer: soluble TNFα blockade and MUC4 expression as a prognostic biomarker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1306.

Low diffusion capacity predicts poor prognosis in extensive stage small cell lung cancer: a single-center analysis of 10 years

BackgroundPoor pulmonary function and chronic obstructive pulmonary disease (COPD) are associated with poorer overall survival (OS) in non-small-cell lung cancer (NSCLC) patients. Few studies have investigated the association between pulmonary function and OS in small-cell lung cancer (SCLC) patients. We compared the clinical characteristics of extensive disease SCLC (ED-SCLC) with or without moderately impaired diffusion capacity for carbon monoxide (DLco) and investigated the factors associated with survival in ED-SCLC patients.MethodsThis retrospective single-center study was performed between January 2011 and December 2020. Of the 307 SCLC patients who received cancer therapy during the study, 142 with ED-SCLC were analyzed. The patients were divided into DLco < 60% group and DLco ≥ 60% groups. OS and predictors of poor OS were analyzed.ResultsThe median OS of the 142 ED-SCLC patients was 9.3 months and the median age was 68 years. In total, 129 (90.8%) patients had a history of smoking, and 60 (42.3%) had COPD. Thirty-five (24.6%) patients were assigned to the DLco < 60% group. Multivariate analysis revealed that DLco < 60% (odds ratio [OR], 1.609; 95% confidence interval [CI], 1.062–2.437; P = 0.025), number of metastases (OR, 1.488; 95% CI, 1.262–1.756; P < 0.001), and < 4 cycles of first-line chemotherapy (OR, 3.793; 95% CI, 2.530–5.686; P < 0.001) were associated with poor OS. Forty (28.2%) patients received < 4 cycles of first-line chemotherapy; the most common reason for this was death (n = 22, 55%) from grade 4 febrile neutropenia (n = 15), infection (n = 5), or massive hemoptysis (n = 2). The DLco < 60% group had a shorter median OS than the DLco ≥ 60% group (10.6 ± 0.8 vs. 4.9 ± 0.9 months, P = 0.003).ConclusionsIn this study, approximately one quarter of the ED-SCLC patients had DLco < 60%. Low DLco (but not forced expiratory volume in 1 s or forced vital capacity), a large number of metastases, and < 4 cycles of first-line chemotherapy were independent risk factors for poor survival outcomes in patients with ED-SCLC.