The activation of asparagine synthetase by the transcription factor FOXM1 plays a pivotal role in the initiation and progression of ESCC.

This study explores the role of the transcription factor FOXM1 in the initiation and progression of oesophageal squamous cell carcinoma (ESCC). Our findings reveal that FOXM1 is highly expressed in ESCC and correlates with the prognosis of the disease. The relationship between FOXM1 and asparagine synthetase (ASNS) is investigated, and the study demonstrates that FOXM1 activates ASNS, impacting the tumour stemness of ESCC. In this study, we reveal the association between FOXM1 and ESCC development, as well as FOXM1's promotion of migration and proliferation in ESCC cells. The study also highlights FOXM1's regulation of ASNS transcription and the functional role of ASNS in ESCC metastasis and growth. Furthermore, the study explores the impact of FOXM1 and ASNS on ESCC stemness and their potential implications for chemotherapy resistance.

Overexpression of serum HMGB1 and IDO in esophageal squamous cell carcinoma patients: potential clinical auxiliary diagnostic markers and immunotherapeutic targets.

Background: High mobility group box 1 (HMGB1) and indoleamino-2, 3-dioxygenase (IDO) participate in the occurrence and development of esophageal squamous cell carcinoma (ESCC), regulate the tumor immune microenvironment, and are closely related to tumor growth and metastasis. However, the regulatory mechanism of serum HMGB1 and IDO has not been clarified and needs further exploration. Methods: Blood samples of 55 ESCC patients initially hospitalized in the Fourth Hospital of Hebei Medical University from August 2021 to January 2022 were selected as the ESCC group, and relevant clinical data were collected, and blood samples from 40 healthy people during the same period were selected as the control group. Serum HMGB1 and IDO levels were determined by ELISA, and lymphocyte subsets in peripheral blood of all subjects were detected by flow cytometry. The correlation between the expression levels of HMGB1 and IDO in ESCC cells was detected by Western blot. Results: Serum HMGB1 and IDO levels were significantly increased in ESCC patients, and with the progression of ESCC patients, serum HMGB1 and IDO levels were also gradually increased; serum HMGB1 was significantly correlated with IDO; serum HMGB1 and IDO combined with CEA and SCC-Ag were of high value in predicting the clinical progression of ESCC patients; the absolute counts of CD4+CD28+T cells and CD8+CD28+T cells in high HMGB1 group were significantly lower than those in low HMGB1 group, while the percentage of CD4+PD-1+T cells was significantly higher than that in low HMGB1 group; the percentage and absolute counts of CD4+CD28+T cells and the absolute counts of CD8+CD28+T cells in high IDO group were significantly lower than those in the low IDO group, while the percentage of CD8+PD-1+T cells was significantly higher than that in the low IDO group; increased serum HMGB1 and IDO expression levels were closely related to poor prognosis in ESCC patients; and HMGB1 may promote IDO expression by activating NF-κB signaling pathway. Conclusion: Serum HMGB1 and IDO have a synergistic effect, they inhibit immune function and promote tumor progression in ESCC patients, and also lead to poor prognosis.

ADAR promotes USP38 auto-deubiquitylation and stabilization in an RNA editing-independent manner in Esophageal Squamous Cell Carcinoma.

Esophageal cancer is mainly divided into esophageal adenocarcinoma (EADC) and esophageal squamous cell carcinoma (ESCC). China is one of the high-incidence areas of esophageal cancer, of which about 90% are ESCC. The deubiquitinase USP38 has been reported to play significant roles in several biological processes, including inflammatory responses, antiviral infection, cell proliferation, migration, invasion, DNA damage repair, and chemotherapy resistance. However, the role and mechanisms of USP38 in ESCC development remain still unclear. Furthermore, although many substrates of USP38 have been identified, few upstream regulatory factors of USP38 have been identified. In this study, we found that USP38 was significantly upregulated in esophageal cancer tissues. Knockdown of USP38 inhibited ESCC growth. USP38 stabilized itself through auto-deubiquitylation. In addition, we demonstrate that ADAR could enhance the stability of USP38 protein and facilitate USP38 auto-deubiquitylation by interacting with USP38 in an RNA editing-independent manner. ADAR inhibition of ESCC cell proliferation depended on USP38. In summary, these results highlight that the potential of targeting the ADAR-USP38 axis for ESCC treatment.

Clinical features and risk of multiple primary malignancies after endoscopic treatment in patients with early esophageal squamous cell carcinoma: a retrospective cohort study.

Background: The incidence of multiple primary malignancies (MPMs) after early esophageal cancer is increasing. This study aimed to explore the clinical features of patients with MPMs and identify independent risk factors for the development of MPMs after endoscopic treatment in early esophageal squamous cell carcinoma (ESCC) patients. Methods: Patients diagnosed as early ESCC at Beijing Friendship Hospital were retrospectively analyzed. Independent factors affecting MPMs were selected by univariate and multivariate Cox regression analyses. Results: Among 299 patients with early ESCC, the mean age was 64.22 years; 219 were male (73.24%). Of these, 32 patients (10.70%) developed MPMs during a follow-up period of 120 months; 10 were metachronous and 22 synchronous. Multivariate Cox analysis showed that alcohol drinking ≥5 standard drinks/day [hazard ratio (HR) =4.21, 95% confidence interval (CI): 1.79-9.90, P<0.001], lower location (HR =2.49, 95% CI: 1.18-5.22, P=0.02), submucosal infiltration depth (HR =3.38, 95% CI: 1.31-8.69, P=0.01), and multiple lesions (HR =2.41, 95% CI: 1.15-5.04, P=0.02) were independent risk factors for developing MPMs in patients with early esophageal cancer. Conclusions: Early ESCC is associated with a high risk of developing MPMs. Monitoring the development of MPMs in patients with early ESCC based on identified risk factors is of great importance.

Construction and analysis of protein-protein interaction network for esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a prevalent malignant tumor of the digestive tract. Clinical findings reveal that the five-year survival rate for mid-to late-stage ESCC patients is merely around 20 %, whereas those diagnosed at an early stage can achieve up to a 95 % survival rate. Consequently, early detection is paramount to improving ESCC patient survival. Protein markers are essential for diagnosing diseases, and the identification of new candidate proteins associated with ESCC through the protein-protein interaction (PPI) network is aimed for in this paper. The PPI network related to ESCC was constructed using protein data, comprising 2094 nodes and 19,660 edges. To assess the nodes' importance in the network, three metrics-degree centrality, betweenness centrality, and closeness centrality-were employed, leading to the identification of 81 key proteins. Subsequently, the biological significance of these proteins in the network was explored, combining biomedical knowledge from three perspectives: network, node, and cluster. The results demonstrated that 52 out of 81 key proteins were confirmed to be linked to ESCC. Among the remaining 29 unreported proteins, 18 displayed significant biological significance, indicating their potential as protein markers related to ESCC.

miR-30c-5p inhibits esophageal squamous cell carcinoma progression by repressing the PI3K/AKT signaling pathway.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors, with high incidence and poor prognosis. Revealing mechanisms of ESCC progression and developing new therapeutic targets remains crucial. The aim of this study was to elucidate the molecular mechanism of miR-30c-5p in regulating the malignant progression of ESCC. METHODS: TCGA, GEO, and other datasets were used to analyze the differential expression of miR-30c-5p in ESCC and adjacent tissues, and its impact on prognosis. Then the effects of miR-30c-5p on the proliferation, migration, and invasion of TE-1 and Eca9706 cells were investigated through proliferation experiments, transwell and wounding healing assays. The regulatory mechanism of miR-30c-5p on the PI3K/AKT signaling pathway and its interaction in cancer progression were investigated through Western blots, dual-luciferase reporter assay, and rescue experiments. RESULTS: miR-30c-5p was significantly downregulated in ESCC tissue and represented a poor prognosis. miR-30c-5p mimic significantly inhibited the proliferation, migration, and invasion ability of ESCC, while miR-30c-5p inhibitor significantly promoted tumor cell progression. Through bioinformatic analysis and experimental results, miR-30c-5p interacted directly with PIK3CA mRNA and inhibited subsequent signaling pathway activation. PIK3CA activator could eliminate the inhibitory effects of miR-30c-5p mimic on the progression of ESCC, while PIK3CA inhibitors could rescue the promoting effect of miR-30c-5p inhibitor group cells. CONCLUSIONS: In summary, we found that miR-30c-5p inhibited the proliferation, invasion and migration of ESCC by inhibiting PI3K/AKT signaling pathway for the first time, and this study is expected to provide a novel insight and potential therapeutic target for managing ESCC.

Pterostilbene suppresses the growth of esophageal squamous cell carcinoma by inhibiting glycolysis and PKM2/STAT3/c-MYC signaling pathway.

Pterostilbene (PTS) is a dietary phytochemical that has shown antitumor activity in many types of cancer, but the molecular mechanism remains unclear. It has also not been adequately studied on PTS against esophageal squamous cell carcinoma (ESCC). Thus, this study investigated the effect of PTS on ESCC in vitro and in vivo and explored the underlying molecular mechanism. We found that PTS can inhibit the proliferation, colony formation, and migration of ESCC cells. According to the bioinformatics analysis of proteomics, PTS had a great influence on the metabolic process of ESCC cells. KEGG analysis showed that PTS down-regulated the pyruvate metabolism pathway. Moreover, PTS can inhibit the PK activity, glucose consumption, and lactate production in ESCC cells. By administration of PTS into xenograft mice, experiment results demonstrated that PTS can suppress tumor progress and the PKM2/STAT3/c-MYC signaling pathway. We found that PTS inhibited the PKM2/STAT3/c-MYC signaling pathway by targeting PKM2 in ESCC cells. Collectively, this study revealed that PTS inhibited ESCC growth by suppressing PKM2 mediated aerobic glycolysis and PKM2/STAT3/c-MYC signaling pathway, which enriching the anti-tumor molecular mechanism of PTS and providing a theoretical basis for its clinical application.

SORBS2-Mediated inhibition of malignant behaviors in esophageal squamous cell carcinoma through TIMP3.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is characterized by high invasiveness and poor prognosis. The role of Sorbin and SH3 domain-containing protein 2 (SORBS2) in ESCC remains largely unexplored. METHODS: The expression levels of SORBS2 in ESCC were detected using RNA-seq and proteomics data. The biological functions of SORBS2 in ESCC were investigated through in vivo and in vitro experiments. The mechanism of SORBS2 was explored using RIP-seq technology, which identified the key downstream molecule metalloproteinase-3 (TIMP3). The interaction between SORBS2 and TIMP3, including specific binding sites, was validated through RIP-qPCR and RNA pull-down assays. The impact of altered SORBS2 expression in ESCC on HUVECs was assessed using endothelial tube formation assays. RESULTS: SORBS2 expression was significantly downregulated in ESCC tissues, and its decreased expression was associated with poor prognosis. Overexpression of SORBS2 in ESCC cell lines inhibited cell proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, SORBS2 bound to the 3' UTR of TIMP3 mRNA, enhancing its stability and thereby regulating TIMP3 expression. Rescue experiments demonstrated that increased TIMP3 expression could reverse the promotive effects of SORBS2 knockdown on ESCC, confirming TIMP3 as a critical downstream molecule of SORBS2. Furthermore, downregulation of SORBS2 in ESCC cells was associated with activation of HUVEC functions, whereas upregulation of TIMP3 could reverse this effect. The SORBS2/TIMP3 axis may exert tumor suppressive effects by influencing extracellular matrix degradation. CONCLUSION: This study confirms that SORBS2 inhibits ESCC tumor progression by regulating extracellular matrix degradation through TIMP3, providing a potential therapeutic target for future treatment interventions.

Patterns of regional lymph node metastasis predict postoperative overall survival and disease-free survival in locally advanced esophageal squamous cell carcinoma.

Background: Lymph nodal characteristics are highly significant in predicting the survival of patients with esophageal squamous cell carcinoma (ESCC). However, there is currently a scarcity of studies examining their role in locally advanced ESCC. In the present study, we attempted to depict the patterns of regional lymph node metastasis and investigate their predictive potential in locally advanced ESCC. Methods: Patients with locally advanced ESCC underwent esophagectomy at the Department of Thoracic Surgery, The First Affiliated Hospital of Shantou University Medical College were included. Kaplan-Meier curve was used to compare the survival differences between groups. Cox regression was constructed to screen the independent risk factors. Results: A total of 439 patients were included. We identified 10% as the optimal cutoff value for positive lymph node ratio (PLNR) with X-tile software. Statistically significant differences were found in both overall survival (OS, P<0.001) and disease-free survival (DFS, P<0.001) among different PLNR groups. PLNR [hazard ratio (HR): 1.85, P<0.001] and metastatic lymph nodes along the left gastric artery (HR: 1.63, P=0.02) were the independent prognostic factors for OS. While PLNR (HR: 1.77, P<0.001) and metastatic total main bronchus lymph nodes (HR: 2.78, P=0.047) were the independent prognostic factors for DFS. Conclusions: We discovered that higher PLNR is associated with poorer OS and DFS of locally advanced ESCC. The lymph nodes along the left gastric artery and the total main bronchus lymph nodes were independent prognosticators for OS and DFS, respectively.

Neoadjuvant camrelizumab followed by concurrent camrelizumab plus chemotherapy for locally advanced esophageal squamous cell carcinoma: a single-arm, phase II study.

Background: Neoadjuvant therapy combining camrelizumab with chemotherapy has emerged as a promising approach for treating locally advanced esophageal squamous cell carcinoma (ESCC). However, the optimal strategy for integrating immunotherapy with chemotherapy remains to be fully defined. This single-arm phase II study aimed to evaluate the efficacy and safety of neoadjuvant therapy with camrelizumab induction followed by camrelizumab plus chemotherapy in locally advanced ESCC. Methods: Patients with clinical stage cT2-4N0M0 or cTxN1-3M0 ESCC were enrolled in the study. Patients received one dose of camrelizumab (200 mg) followed by docetaxel (75 mg/m2) and nedaplatin (75 mg/m2) plus camrelizumab (200 mg) every 3 weeks for two cycles, and then underwent surgery within 3-4 weeks. The primary endpoint was the major pathological response (MPR) rate. The secondary endpoints included the pathological complete response (pCR) rate, R0 resection rate, downstaging rate, disease-free survival (DFS), overall survival (OS), and safety. Results: In total, 55 patients were enrolled in the study between 16 April 2020 and 30 October 2021. Of these 55 patients, 53 (96.4%) completed neoadjuvant therapy, and 48 (87.3%) underwent surgery. The MPR rate was 77.1% [37/48, 95% confidence interval (CI): 62.7-88.0%]. The pCR (ypT0N0) rate was 39.6% (19/48, 95% CI: 25.8-54.7%). All the patients had R0 resections. Primary tumor downstaging occurred in 44 (91.7%) patients, and nodal downstaging occurred in 19 (39.6%) patients. The 2-year DFS rate was 68.9% (95% CI: 53.0-80.4%), and the 2-year OS rate was 74.7% (95% CI: 60.2-84.6%). Grade ≥3 treatment-related adverse events (TRAEs) were observed in 7 (12.7%) patients. Conclusions: In conclusion, neoadjuvant camrelizumab followed by camrelizumab plus chemotherapy showed promising efficacy in treating locally advanced ESCC and had a manageable safety profile.

Prognostic prediction model for patients with pathological T1N0 stage esophageal squamous cell carcinoma undergone esophagectomy.

Background: There is a shortage of reliable predictive models to provide valuable prognostic information for early esophageal squamous cell carcinoma (ESCC) without lymph node metastasis (LNM). We aimed to develop and validate a nomogram using the prognostic factors in T1N0 ESCC patients. Methods: Patients with pathological T1N0 ESCC who underwent esophagectomy between 2014 and 2021 at three institutes were reviewed. The prognostic factors were evaluated by Cox proportional hazards model and a nomogram was developed. Patients were divided into high- and low-risk groups based on cut-off value of total points in the nomogram. Overall survival (OS) was estimated by the Kaplan-Meier method and compared using the log-rank test. Results: A total of 275 patients were included and split into training (n=180) and external validation (n=95) cohorts. In the training cohort, multivariable analysis showed that the surgical approach, T1 substage, and carcinoembryonic antigen (CEA) level were independent prognostic factors. The developed nomogram had relatively high performance, with the area under the receiver operating characteristic (ROC) curve (AUC) of 0.783, 0.711 and 0.612 for 1-, 3-, and 5-year OS, respectively. The calibration curves showed that the predicted probability was in good agreement with the actual probability. Forty-seven was determined as cut-off value of total points. High-risk group (n=148) showed a significant poor OS than low-risk group (n=127) (P<0.001). Conclusions: Left surgical approach, stage T1b, and higher CEA were associated with poorer prognosis in T1N0 ESCC patients. The nomogram demonstrated a good performance to predict the individual survival.

CircJPH1 regulates the NF-κB/HERC5 axis to promote the malignant progression of esophageal squamous cell carcinoma through binding to XRCC6.

Esophageal squamous cell carcinoma (ESCC) is a prevalent and malignant cancer with an unknown pathogenesis and a poor prognosis; therefore, the identification of effective biomarkers and targets is crucial for its diagnosis and treatment. Circular (circ)RNAs are prominent functional biomarkers and therapeutic targets in various diseases, particularly cancer, due to their widespread expression and regulatory mechanisms. Our study aimed to investigate the therapeutic potential of circRNA for ESCC. We identified Hsa_circ_0137111 for the first time as one of the most significantly up-regulated genes in ESCC sequencing and named it circJPH1. The results of the present study demonstrated an enhanced expression of circJPH1 in ESCC tissues. Moreover, circJPH1-knockdown could significantly inhibit the proliferation, migration, and invasion of ESCC cells, while its overexpression promoted these characteristics. In addition, circJPH1 promoted ESCC cell tumor growth in vivo. For the first time, mass spectrometry and RNA pull-down analysis revealed the interaction of X-ray repair cross-complementary 6 (XRCC6) protein with circJPH1, thereby promoting its nuclear translocation. Consequently, the nuclear factor kappa-B (NF-κB) signaling pathway was activated, leading to an up-regulation of HECT and RLD domain containing E3 ubiquitin protein ligase 5 (HERC5), thereby promoting ESCC progression. In summary, the present study elucidated the regulatory impact of circJPH1 on ESCC progression in vitro and in vivo, thereby indicating its potential role in ESCC treatment.

Identification and Validation of MYADM as a Novel Prognostic Marker Related to EMT in ESCC.

Background: Esophageal squamous cell carcinoma (ESCC), one of the most aggressive gastrointestinal malignancies, remains an enormous challenge in terms of medical treatment and prognostic improvement. Based on the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases in R language, the myeloid-associated differentiation marker (MYADM) was confirmed using bioinformatics analysis and experimental verification. MYADM is upregulated in multiple cancer types; however, the oncogenic mechanism by which MYADM promotes ESCC remains largely unknown. Methods: In the present study, we used weighted gene coexpression network analysis to filter four hub genes (AKAP12, ITGA1, JAM2, and MYADM) in GSE45670 and GSE23400 that are related to the malignant progression of ESCC. Transcription factors and target miRNAs of the hub genes were predicted using the TarBase and JASPRAR databases, respectively, and a regulatory network was established. MYADM was selected based on the analysis of expression differences and prognostic value in ESCC. Next, we confirmed the level of MYADM in ESCC samples using immunohistochemistry of the tissue microarray. The molecular mechanisms of MYADM were further elucidated by experimental analyses, including Transwell assays, wound healing assays, and CCK8. Results: The correlation between MYADM levels and the clinical data of patients with ESCC was confirmed, including tumor differentiation, the node and metastasis stage, T stage, lymphatic metastasis, and postoperative distant metastasis. MYADM was significantly upregulated in ESCC and positively correlated with overall survival. MYADM induced cell proliferation, migration, invasion, and wound healing via the epithelial to mesenchymal transition (EMT) pathway in multiple experiments. Moreover, our results supported the hypothesis that MYADM promotes EMT during paclitaxel resistance. Conclusion: MYADM is closely correlated with ESCC progression, metastasis, and paclitaxel resistance and could be regarded as a novel biomarker and therapeutic target for ESCC patients.

CAFs-derived Exosomal miR-889-3p Might Repress M1 Macrophage Polarization to Boost ESCC Development by Regulating STAT1.

Cancer-associated fibroblasts (CAFs) represent one of the major components of the tumor stroma, which might create an immunosuppressive tumor microenvironment by inducing and functionally polarizing protumoral macrophages. Previous studies indicated that exosomes derived from CAFs might transmit regulating signals and boost esophageal squamous cell carcinoma (ESCC) development. This study is designed to explore the role and mechanism of CAFs-derived exosomal microRNA-889-3p (miR-889-3p) in ESCC progression. Macrophage polarization was detected using flow cytometry. miR-889-3p, Tumor necrosis factor alpha (TNF-α), and inducible nitric oxide synthase (iNOS) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferation, cycle progression, migration, and invasion were assessed using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), scratch assay, and Transwell assays. α-SMA, FAP, CD63, CD81, and signal transducer and activator of transcription 1 (STAT1) protein levels were detected using western blot. Exosomes were characterized using an electron microscope and nanoparticle tracking analysis (NTA). Binding between miR-889-3p and STAT1 was predicted by Starbase, and verified by a dual-luciferase reporter and RNA pull-down. The effect of CAFs-derived exosomal miR-889-3p on ESCC tumor growth in vivo was detected using mice xenograft assay. miR-889-3p level was decreased in LPS-induced M0 macrophages. CAF-derived exosomal miR-889-3p knockdown suppressed ESCC proliferation, migration, and invasion. CAFs might transfer miR-889-3p to M0 macrophages via exosomes. STAT1 was a target of miR-889-3p. Besides, in vivo studies confirmed that CAFs-derived exosomal miR-889-3p can accelerate ESCC tumor growth by regulating STAT1. CAFs-derived exosomal miR-889-3p facilitates esophageal squamous cell carcinoma cell proliferation, migration, and invasion by inhibiting M1 macrophage polarization through down-regulation of STAT1, providing a promising therapeutic target for ESCC.

Tetraspanins in digestive­system cancers: Expression, function and therapeutic potential (Review).

The tetraspanin family of membrane proteins is essential for controlling different biological processes such as cell migration, penetration, adhesion, growth, apoptosis, angiogenesis and metastasis. The present review summarized the current knowledge regarding the expression and roles of tetraspanins in different types of cancer of the digestive system, including gastric, liver, colorectal, pancreatic, esophageal and oral cancer. Depending on the type and context of cancer, tetraspanins can act as either tumor promoters or suppressors. In the present review, the importance of tetraspanins in serving as biomarkers and targets for different types of digestive system­related cancer was emphasized. Additionally, the molecular mechanisms underlying the involvement of tetraspanins in cancer progression and metastasis were explored. Furthermore, the current challenges are addressed and future research directions for advancing investigations related to tetraspanins in the context of digestive system malignancies are proposed.

Impact of Mitophagy-Related Genes on the Diagnosis and Development of Esophageal Squamous Cell Carcinoma via Single-Cell RNA-seq Analysis and Machine Learning Algorithms.

As a treatment for esophageal squamous cell carcinoma (ESCC), which is common and fatal, mitophagy is a conserved cellular mechanism that selectively removes damaged mitochondria and is crucial for cellular homeostasis. While tumor development and resistance to anticancer therapies are related to ESCC, their role in ESCC remains unclear. Here, we investigated the relationship between mitophagy-related genes (MRGs) and ESCC to provide novel insights into the role of mitophagy in ESCC prognosis and diagnosis prediction. First, we identified MRGs from the GeneCards database and examined them at both the single-cell and transcriptome levels. Key genes were selected and a prognostic model was constructed using least absolute shrinkage and selection operator analysis. External validation was performed using the GSE53624 dataset and Kaplan-Meier survival analysis was performed to identify PYCARD as a gene significantly associated with survival in ESCC. We then examined the effect of PYCARD on ESCC cell proliferation and migration and identified 169 MRGs at the single-cell and transcriptome levels, as well as the high-risk groups associated with cancer-related pathways. Thirteen key genes were selected for model construction via multiple machine learning algorithms. PYCARD, which is upregulated in patients with ESCC, was negatively correlated with prognosis and its knockdown inhibited ESCC cell proliferation and migration. Our ESCC prediction model based on mitophagy-related genes demonstrated promising results and provides more options for the management and clinical treatment of ESCC patients. Moreover, targeting or regulating PYCARD levels might offer new therapeutic strategies for ESCC patients in clinical settings.

The Spinal Instability Neoplastic Score correlates with epidural spinal cord compression -a retrospective cohort of 256 surgically treated patients with spinal metastases.

BACKGROUND: Bone metastases can compromise the integrity of the spinal canal and cause epidural spinal cord compression (ESCC). The Spinal Instability Neoplastic Score (SINS) was developed in order to evaluate spinal instability due to a neoplastic process. The SINS has reached wide acceptance among clinicans but its prognostic value is still controversial. The aim was to investigate the correlation between the SINS and ESCC and the association between SINS and ambulation before and survival after surgery. METHODS: Correlations were assessed between SINS and grades of ESCC in patients who underwent spine surgery for spinal metastases. CT and MRI were used to calculate SINS and the grades of ESCC respectively. Correlations were analyzed with the Spearman's correlation test. Postoperative survival was estimated with Kaplan-Meier analysis and survival curves were compared with the log-rank test. The Cox proportional hazard model was used to assess the effect of prognostic variables including age, ambulation before surgery, SINS, and the Karnofsky Performance Status (KPS) as covariates. RESULTS: The study included 256 patients (196 men and 60 women) with a median age of 70 (24-88) years. The mean SINS was 10. One hundred fifty-two patients (59%) had lost ambulation before surgery. One hundred and one patients had grades 0-2 and 155 patients had grade 3 according to the ESCC-scale. SINS correlated with the grades of ESCC (p = 0.001). The SINS score was not associated with ambulation before surgery (p = 0.63). The median postoperative survival was 10 months, and there was no difference in postoperative survival between the SINS categories (p = 0.25). The ability to walk before surgery and a high KPS were associated with longer postoperative survival. CONCLUSION: SINS correlated with grades of ESCC, which implies that higher SINS may be considered as an indicator of risk for developing ESCC. The SINS was not associated with ambulation before or survival after surgery.

The SRC family kinase inhibitor NXP900 demonstrates potent antitumor activity in squamous cell carcinomas.

NXP900 is a selective and potent SRC family kinase (SFK) inhibitor, currently being dosed in a phase 1 clinical trial, that locks SRC in the "closed" conformation, thereby inhibiting both kinase-dependent catalytic activity and kinase-independent functions. In contrast, several multi-targeted kinase inhibitors that inhibit SRC, including dasatinib and bosutinib, bind their target in the active "open" conformation, allowing SRC and other SFKs to act as a scaffold to promote tumorigenesis through non-catalytic functions. NXP900 exhibits a unique target selectivity profile with sub-nanomolar activity against SFK members over other kinases. This results in highly potent and specific SFK pathway inhibition. Here, we demonstrate that esophageal squamous cell carcinomas and head and neck squamous cell carcinomas are exquisitely sensitive to NXP900 treatment in cell culture and in vivo, and we identify a patient population that could benefit from treatment with NXP900.

The identification of heterogeneous reactive oxygen subtypes in esophageal squamous cell carcinoma to aid patient prognosis and immunotherapy.

Introduction: Esophageal cancer is increasingly recognized as a significant global malignancy. The main pathological subtype of this cancer is esophageal squamous cell carcinoma (ESCC), which displays a higher degree of malignancy and a poorer prognosis. Reactive oxygen species (ROS) play a critical role in modulating the immune response to tumors, and understanding the regulation of ROS in ESCC could lead to novel and improved therapeutic strategies for ESCC patients. Methods: A consensus matrix derived from genes involved in the ROS pathway revealed two subtypes of ROS. These subtypes were categorized as ROS-active or ROS-suppressive based on their level of ROS activity. The heterogeneity among the different ROS subtypes was then explored from various perspectives, including gene function, immune response, genomic stability, and immunotherapy. In order to assess the prognosis and the potential benefits of immunotherapy, a ROS activity score (RAS) was developed using the identified ROS subtypes. In vitro experiments were performed to confirm the impact of core RAS genes on the proliferative activity of esophageal cancer cell lines. Results: Two distinctive subtypes of ROS were identified. The first subtype, referred to as ROS-active, exhibited elevated ROS activity, enhanced involvement in cancer-associated immune pathways, and increased infiltration of effector immune cells. The second subtype, named ROS-suppressive, demonstrated weaker ROS activity but displayed more pronounced dysregulation in the cell cycle and a denser extracellular matrix, indicating malignant characteristics. Genomic stability, particularly in terms of copy number variation (CNV) events, differed between the two ROS subtypes. By developing a RAS model, reliable risk assessment for overall survival (OS) in patients with ESCC was achieved, and the model demonstrated strong predictive capabilities in real-world immunotherapy cohorts. Moreover, the core gene LDLRAD1 within the RAS model was found to enhance proliferative activity in esophageal cancer cell lines. Conclusion: Based on the ROS pathway, we successfully identified two distinct subtypes in ESCC: the ROS-active subtype and the ROS-suppressive subtype. These subtypes were utilized to evaluate prognosis and the sensitivity to immunotherapy.

Reduction in chemotherapy relative dose intensity decreases overall survival of neoadjuvant chemoradiotherapy in patients with locally advanced esophageal carcinoma.

BACKGROUND: Many patients undergo dose reduction or early termination of chemotherapy to reduce chemoradiotherapy-related toxicity, which may increase their risk of survival. However, this strategy may result in underdosing patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC). This study aimed to analyze the relationship between the relative dose intensity (RDI) and survival outcomes in patients with LA-ESCC. METHODS: This retrospective study assessed patients with LA-ESCC (cT2N + M0, cT3-4NanyM0) receiving neoadjuvant chemoradiotherapy (NCRT) with curative-intent esophagectomy. The patients received 2 courses of paclitaxel plus carboplatin (TC) combination radiotherapy prior to undergoing surgery. During NCRT, RDI was computed, defined as the received dose as a percentage of the standard dose, and the incidence of dose delays was estimated (≥ 7 days in any course cycle). The best RDI cutoff value (0.7) was obtained using ROC curve. The Kaplan-Meier survival curves were compared using the log-rank test, the treatment effect was measured using hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: We included 132 patients in this study, divided into RDI < 0.7 and RDI ≥ 0.7 groups using cut-off value of 0.7. RDI grade was an independent prognostic factor for OS. Baseline demographic and clinical characteristics were well balanced between the groups. There was no evidence that patients with RDI < 0.7 experienced less toxicity or those with RDI ≥ 0.7 resulted in more toxicity. However, patients with RDI < 0.7 who were given reduced doses had a worse overall survival [HR 0.49, 95% CI 0.27-0.88, P = 0.015]. The risk of a lower RDI increased with a longer dose delay time (P < 0.001). CONCLUSION: The RDI below 0.7 for avoiding chemoradiotherapy toxicity administration led to a reduction in the dose intensity of treatment and decreased overall survival.