Esophageal Squamous Carcinoma Research Articles

Epigenetic silencing schlafen-11 sensitizes esophageal cancer to ATM inhibitor

BACKGROUND Targeting DNA damage response (DDR) pathway is a cutting-edge strategy. It has been reported that Schlafen-11 (SLFN11) contributes to increase chemosensitivity by participating in DDR. However, the detailed mechanism is unclear. AIM To investigate the role of SLFN11 in DDR and the application of synthetic lethal in esophageal cancer with SLFN11 defects. METHODS To reach the purpose, eight esophageal squamous carcinoma cell lines, 142 esophageal dysplasia (ED) and 1007 primary esophageal squamous cell carcinoma (ESCC) samples and various techniques were utilized, including methylation-specific polymerase chain reaction, CRISPR/Cas9 technique, Western blot, colony formation assay, and xenograft mouse model. RESULTS Methylation of SLFN11 was exhibited in 9.15% of (13/142) ED and 25.62% of primary (258/1007) ESCC cases, and its expression was regulated by promoter region methylation. SLFN11 methylation was significantly associated with tumor differentiation and tumor size (both P < 0.05). However, no significant associations were observed between promoter region methylation and age, gender, smoking, alcohol consumption, TNM stage, or lymph node metastasis. Utilizing DNA damaged model induced by low dose cisplatin, SLFN11 was found to activate non-homologous end-joining and ATR/CHK1 signaling pathways, while inhibiting the ATM/CHK2 signaling pathway. Epigenetic silencing of SLFN11 was found to sensitize the ESCC cells to ATM inhibitor (AZD0156), both in vitro and in vivo . CONCLUSION SLFN11 is frequently methylated in human ESCC. Methylation of SLFN11 is sensitive marker of ATM inhibitor in ESCC.

Clinico-pathological study of esophageal mucoepidermoid carcinoma: a 10-year survival from a single center

BackgroundMucoepidermoid Carcinoma of the Esophagus (MECE) is a relatively rare tumor type, with most of the current data derived from case reports or small sample studies. This retrospective study reports on the 10-year survival data and detailed clinicopathological characteristics of 48 patients with esophageal MEC.MethodsData were collected from 48 patients who underwent curative surgery for esophageal MEC at the Fourth Hospital of Hebei Medical University between January 1, 2004, and December 31, 2020. These were compared with contemporaneous cases of Esophageal Squamous Cell Carcinoma (ESCC) and Esophageal Adenocarcinoma (EAC). Using the Kaplan-Meier method and multivariate Cox regression analysis, we investigated the clinicopathological factors affecting the survival of patients with MEC.ResultsThe incidence of MECE was predominantly higher in males, with a male-to-female ratio of approximately 7:1. The mid-thoracic segment emerged as the most common site of occurrence. A mere 6.3% of cases were correctly diagnosed preoperatively. The lymph node metastasis rate stood at 35.4%. The overall 1-year, 3-year, 5-year, and 10-year survival rates for all patients were 85.4%, 52.1%, 37.0%, and 31.0%, respectively. Post 1:1 propensity score matching, no significant statistical difference was observed in the Overall Survival (OS) between MEC patients and those with Esophageal Squamous Cell Carcinoma (ESCC) and Esophageal Adenocarcinoma (EAC) (P = 0.119, P = 0.669). Univariate analysis indicated that T staging and N staging were the primary factors influencing the prognosis of esophageal MEC.ConclusionsMECE occurs more frequently in males than females, with the mid-thoracic segment being the most common site of occurrence. The rate of accurate preoperative endoscopic diagnosis is low. The characteristic of having a short lesion length yet exhibiting significant extramural invasion may be a crucial clinicopathological feature of MECE. The OS of patients with MEC does not appear to significantly differ from those with esophageal squamous carcinoma and adenocarcinoma.

Regulation of TMEM100 expression by epigenetic modification, effects on proliferation and invasion of esophageal squamous carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy with a high morbidity and mortality rate. TMEM100 has been shown to be suppressor gene in a variety of tumors, but there are no reports on the role of TMEM100 in esophageal cancer (EC). To investigate epigenetic regulation of TMEM100 expression in ESCC and the effect of TMEM100 on ESCC proliferation and invasion. Firstly, we found the expression of TMEM100 in EC through The Cancer Genome Atlas database. The correlation between TMEM100 gene expression and the survival of patients with EC was further confirmed through Kaplan-Meier analysis. We then added the demethylating agent 5-AZA to ESCC cell lines to explore the regulation of TMEM100 expression by epigenetic modification. To observe the effect of TMEM100 expression on tumor proliferation and invasion by overexpressing TMEM100. Finally, we performed gene set enrichment analysis using the Kyoto Encyclopaedia of Genes and Genomes Orthology-Based Annotation System database to look for pathways that might be affected by TMEM100 and verified the effect of TMEM100 expression on the mitogen-activated protein kinases (MAPK) pathway. In the present study, by bioinformatic analysis we found that TMEM100 was lowly expressed in EC patients compared to normal subjects. Kaplan-meier survival analysis showed that low expression of TMEM100 was associated with poor prognosis in patients with EC. Then, we found that the demethylating agent 5-AZA resulted in increased expression of TMEM100 in ESCC cells [quantitative real-time PCR (qRT-PCR) and western blotting]. Subsequently, we confirmed that overexpression of TMEM100 leads to its increased expression in ESCC cells (qRT-PCR and western blotting). Overexpression of TMEM100 also inhibited proliferation, invasion and migration of ESCC cells (cell counting kit-8 and clone formation assays). Next, by enrichment analysis, we found that the gene set was significantly enriched in the MAPK signaling pathway. The involvement of TMEM100 in the regulation of MAPK signaling pathway in ESCC cell was subsequently verified by western blotting. TMEM100 is a suppressor gene in ESCC, and its low expression may lead to aberrant activation of the MAPK pathway. Promoter methylation may play a key role in regulating TMEM100 expression.

HRU-Net: A high-resolution convolutional neural network for esophageal cancer radiotherapy target segmentation

Background and objectiveThe effective segmentation of esophageal squamous carcinoma lesions in CT scans is significant for auxiliary diagnosis and treatment. However, accurate lesion segmentation is still a challenging task due to the irregular form of the esophagus and small size, the inconsistency of spatio-temporal structure, and low contrast of esophagus and its peripheral tissues in medical images. The objective of this study is to improve the segmentation effect of esophageal squamous cell carcinoma lesions. MethodsIt is critical for a segmentation network to effectively extract 3D discriminative features to distinguish esophageal cancers from some visually closed adjacent esophageal tissues and organs. In this work, an efficient HRU-Net architecture (High-Resolution U-Net) was exploited for esophageal cancer and esophageal carcinoma segmentation in CT slices. Based on the idea of localization first and segmentation later, the HRU-Net locates the esophageal region before segmentation. In addition, an Resolution Fusion Module (RFM) was designed to integrate the information of adjacent resolution feature maps to obtain strong semantic information, as well as preserve the high-resolution features. ResultsCompared with the other five typical methods, the devised HRU-Net is capable of generating superior segmentation results. ConclusionsOur proposed HRU-NET improves the accuracy of segmentation for squamous esophageal cancer. Compared to other models, our model performs the best. The designed method may improve the efficiency of clinical diagnosis of esophageal squamous cell carcinoma lesions.

Characteristics of the oral and gastric microbiome in patients with early-stage intramucosal esophageal squamous cell carcinoma

BackgroundOral microbiome dysbacteriosis has been reported to be associated with the pathogenesis of advanced esophageal cancer. However, few studies investigated the potential role of oral and gastric microbiota in early-stage intramucosal esophageal squamous carcinoma (EIESC).MethodA total of 104 samples were collected from 31 patients with EIESC and 21 healthy controls. The compositions of oral and gastric microbiota were analyzed using 16 S rRNA V3-V4 amplicon sequencing. Linear discriminant analysis effect size (LEfSe) analysis was performed to assess taxonomic differences between groups. The correlation between oral microbiota and clinicopathological factors was evaluated using Spearman correlation analysis. Additionally, co-occurrence networks were established and random forest models were utilized to identify significant microbial biomarkers for distinguishing between the EIESC and control groups.ResultsA total of 292 oral genera and 223 species were identified in both EIESC and healthy controls. Six oral genera were remarkably enriched in EIESC groups, including the genera Porphyromonas, Shigella, Subdoligranulum, Leptotrichia, Paludibacter, and Odoribacter. LEfSe analysis identified genera Porphyromonas and Leptotrichia with LDA scores > 3. In the random forest model, Porphyromonas endodontalis ranked the top microbial biomarker to differentiate EIESC from controls. The elimination rate of Porphyromonas endodontalis from the oral cavity to the stomach was also dramatically decreased in the EIESC group than controls. In the microbial co-occurrence network, Porphyromonas endodontalis was positively correlated with Prevotella tannerae and Prevotella intermedia and was negatively correlated with Veillonella dispar.ConclusionOur study potentially indicates that the dysbacteriosis of both the oral and gastric microbiome was associated with EIESC. Larger scale studies and experimental animal models are urgently needed to confirm the possible role of microbial dysbacteriosis in the pathogenesis of EIESC. (Chinese Clinical Trial Registry Center, ChiCTR2200063464, Registered 07 September 2022, https://www.chictr.org.cn/showproj.html?proj=178563)

Identification and validation of prognostic and immunotherapeutic responses in esophageal squamous carcinoma based on hypoxia phenotype-related genes.

The study aimed to investigate the clinical significance of the interaction between hypoxia and the immune system in esophageal squamous cell carcinoma (ESCC) microenvironment. A comprehensive evaluation of 13 hypoxia phenotype-related genes (HPRs) was conducted using data from TCGA-ESCC and two GEO cohorts. Three distinct HPRclusters were identified, and the HPRscore was established as an independent prognostic factor (p = 0.001), with higher scores indicating poorer prognosis. The HPRscore was validated in various immunotherapy cohorts, demonstrating its efficacy in evaluating immunotherapy and chemotherapy outcomes. Additionally, phenome-wide association study (PheWAS) analysis showed that PKP1 had no significant correlation with other traits at the gene level. PKP1 was identified as a potential prognostic marker for ESCC, with upregulated expression observed in ESCC patients. In vitro experiments showed that the knockdown of PKP1 inhibited ESCC cell proliferation and migration. These findings suggest that the novel HPRscore and PKP1 may serve as prognostic tools and therapeutic targets for ESCC patients.

COL8A1 Regulates Esophageal Squamous Carcinoma Proliferation and Invasion Through PI3K/AKT Pathway.

Esophageal squamous carcinoma (ESCC) is a gastrointestinal malignancy with a high mortality, but the tumorigenesis is still unclear, restricting the target therapy development of ESCC. We explored the role of COL8A1 in ESCC development. Tissue microarrays were used to investigate the expression level of COL8A1 in ESCC tissues. The association between COL8A1 and the overall survival of ESCC patients was assessed. The effect of differential COL8A1 expression on tumor growth was investigated by the xenograft model. The regulation of COL8A1 on tumor growth, migration, and invasion was studied by using ESCC cell lines. The signal transduction pathways involved in COL8A1 were bioinformatically profiled and validated. The COL8A1 was significantly expressed in cancerous tissues and was associated with poor prognosis in patients with ESCC. In vivo, the tumor growth obviously declined after inhibition of the COL8A1 expression. The abilities of cell proliferation and invasion were both decreased when the expression of COL8A1 was knockdown in ESCC cell line. Furthermore, we found the inactivation of the PI3K/AKT pathway that was mediated by knockdown of COL8A1 in ESCC cells, which was reversed with COL8A1 overexpression, whereas the cell proliferation and invasion ability were restored. This is the first report that COL8A1 promote ESCC progression, which hopefully will provide a theoretical basis for clinical targeting of ESCC.

Prognostic Risk Models Using Epithelial Cells Identify β-Sitosterol as a Potential Therapeutic Target Against Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is an aggressive and fatal malignancy that leads to epithelial cancer. The association between epithelial cell heterogeneity, prognosis, and immune response in this cancer remains uncertain. This study aimed to investigate epithelial cell heterogeneity in ESCC and develop a predictive risk model using the identified cell types. Single-cell RNA sequencing (scRNA-seq) and differential ESCC gene data were accessed from the Gene Expression Omnibus. Functional enrichment analysis, inferCNV, cell development trajectories, and intercellular communication were analyzed following epithelial cell characterization. Differentially expressed ESCC (n = 773) and epithelial cell marker genes (n = 3407) were intersected to obtain core genes, and epithelial cell-related prognostic genes were identified. LASSO regression analysis was used to construct a prognostic model. The external dataset GSE53624 was used to further validate the stability of the model. Drug sensitivity predictions, and immune cell infiltration were analyzed. Molecular docking clarified the possible therapeutic role of β-sitosterol in ESCC. Finally, wound healing assay, cell colony, and transwell assay were constructed to detect the effects of the core gene PDLIM2 on ESCC cell proliferation, invasion, and migration. Eight cell clusters were identified, and epithelial cells were categorized into tumor and paratumor groups. The tumor group possessed more chromosomal variants than the paratumor group. Epithelial cells were associated with multiple cell types and significantly correlated with the Wnt, transforming growth factor, and epidermal growth factor signaling pathways. From 231 intersected genes, five core genes were screened for use in the risk model: CTSL, LAPTM4B, MYO10, NCF2, and PDLIM2. These genes may contribute to the cancerous transformation of normal esophageal epithelial cells and thereby act as biomarkers and potential therapeutic targets in patients with ESCC. β-Sitosterol furthermore displayed excellent docking potential with these genes. Meanwhile, further experiments demonstrated that the gene PDLIM2 plays a major role in the progression of oesophageal squamous carcinoma. We successfully developed a risk model for the prognosis of ESCC based on epithelial cells that addresses the response of ESCC to immunotherapy and offers novel cancer treatment options.

Biofunctional study on chemoresistance in esophageal squamous carcinoma cells induced by missense mutation of NOTCH1 p.E450K.

Neoadjuvant chemotherapy (nCT) combined with surgery is one of the main strategies for the treatment of resectable locally advanced esophageal squamous cell carcinoma (ESCC). However, nearly 40% of patients did not benefit from nCT, and the detection rate of NOTCH1 missense mutation was significantly increased in patients who did not respond to chemotherapy, suggesting that the missense mutation may be related to tumor chemoresistance. We aim to explore the effect of a NOTCH1 missense mutation on cell phenotype, to interpret the biofunctional changes in cell lines with a NOTCH1 missense mutation and to analyze the effect of a NOTCH1 missense mutation on drug resistance in ESCC cell lines. Sanger sequencing was used to evaluate the exon mutations in the NOTCH1 ligand binding region of candidate ESCC cell lines. After screening, KYSE450 and KYSE140 cells were selected as the research objects, and point mutation cell lines [KYSE140-mutant-type (MT) and KYSE450-MT] were constructed by CRISPR/Cas9 technology. Then, functional experiments were performed with the four cell lines [KYSE450-MT/wild-type (WT) and KYSE140-MT/WT]. The drug resistance of ESCC cell lines was assessed with a drug sensitivity test, and the proliferation, invasion and migration of ESCC lines were evaluated by proliferation test, scratch test and Transwell test. The cell cycle status of ESCC cells was assessed using flow cytometry. Drug sensitivity tests showed that the NOTCH1 p.E450K point mutation caused chemotherapy resistance in KYSE140 and KYSE450 ESCC cell lines. Cell proliferation, Wound scratch and Transwell assays showed that the NOTCH1 p.E450K point mutation enhanced the proliferation, invasion and migration abilities of KYSE140 and KYSE450 cells. Flow cytometry analysis showed that the NOTCH1 p.E450K point mutation caused an increase in KYSE140 and KYSE450 cells in S phase. The NOTCH1 p.E450K point mutation causes chemotherapy resistance in KYSE140 and KYSE450 ESCC cells. Cell functional experiments showed that the NOTCH1 p.E450K point mutation enhanced the proliferation, migration and invasion abilities of KYSE140 and KYSE450 cells and increased the number of cells in S phase.

Diagnostic Accuracy of JES Classification for Prediction of Invasion Depth in Superficial Esophageal Squamous Carcinoma: Meta-Analysis.

Prediction of the depth of invasion in superficial oesophageal squamous carcinoma (SESC) is an important factor for choosing the treatment. Recently, the Japan Esophageal Society (JES) designed a magnifying endoscopy classification based on the Inoue and Arima classifications. The aim of this study was to conduct a meta-analysis of the published literature on JES classification. Meta-Disc version 1.4, Review Manager 5.4 as well as stata 14.0 were used. The analysis combined sensitivity and specificity with the respective 95% CI, to draw a summary receiver operating characteristic curve (SROC), and estimated the area under curve (AUC) for overdiagnosis and underdiagnosis for each type B. Eight studies were included in the meta-analysis comprising 1279 patients. Type B1 has high sensitivity (0.86, 95%CI: 0.83-0.88) and specificity (0.84, 95%CI: 0.81-0.88) for the prediction of EP/LPM classifications. The AUC was calculated to be 0.92 with a high proportion of underdiagnosis (17%). The sensitivity and specificity of type B2 were 0.66 (95% CI, 0.6-0.72) and 0.84 (95% CI, 0.82-0.86) respectively. The overdiagnosis and underdiagnosis of type B2 were 14% and 39%. Type B3, sensitivity was low (0.49, 95% CI: 0.41-0.56), with high specificity and AUC (specificity: 0.99; AUC: 0.95). JES classification is a useful and reliable modality for predicting the depth of invasion of SESC, but other modalities should be considered for additional assessment when type B2 is detected. Key Words: JES classification, Superficial oesophageal squamous carcinoma, Depth of invasion, Magnifying endoscopy, Meta-analysis.

Cysteine protease inhibitor 1 promotes metastasis by mediating an oxidative phosphorylation/MEK/ERK axis in esophageal squamous carcinoma cancer

Cysteine protease inhibitor 1 (CST1) is a cystatin superfamily protein that inhibits cysteine protease activity and is reported to be involved in the development of many malignancies. Mitochondrial oxidative phosphorylation (OXPHOS) also plays an important role in cancer cell growth regulation. However, the relationship and roles of CST1 and OXPHOS in esophageal squamous cell carcinoma (ESCC) remains unclear. In our pilot study, CST1 was shown the potential of promoting ESCC migration and invasion by the activation of MEK/ERK pathway. Transcriptome sequencing analysis revealed that CST1 is closely associated with OXPHOS. Based on a real-time ATP rate assay, mitochondrial complex I enzyme activity assay, immunofluorescence, co-immunoprecipitation, and addition of the OXPHOS inhibitor Rotenone and MEK/ERK inhibitor PD98059, we determined that CST1 affects mitochondrial complex I enzyme activity by interacting with the GRIM19 protein to elevate OXPHOS levels, and a reciprocal regulatory relationship exists between OXPHOS and the MEK/ERK pathway in ESCC cells. Finally, an in vivo study demonstrated the potential of CST1 in ESCC metastasis through regulation of the OXPHOS and MEK/ERK pathways. This study is the first to reveal the oncogenic role of CST1 in ESCC development by enhancing mitochondrial respiratory chain complex I activity to activate the OXPHOS/MEK/ERK axis, and then promote ESCC metastasis, suggesting that CST1/OXPHOS is a promising target for ESCC treatment.

ASO Author Reflections: COL8A1 Regulates Esophageal Squamous Carcinoma.

ASO Author Reflections: COL8A1 Regulates Esophageal Squamous Carcinoma.

A pathway-based computational framework for identification of a new modal of multi-omics biomarkers and its application in esophageal cancer

BackgroundThe pathway-based strategy has been recently proposed for identifying biomarkers with the advantages of higher biological interpretability and cross-data robustness than the conventional gene-based strategy. However, its utility in clinical applications has been limited due to the high computational complexity and ill-defined performance. ObjectiveThe current study presents a machine learning-based computational framework using multi-omics data for identifying a new modal of biomarkers, called pathway-derived core biomarkers, which have the advantages of both gene-based and pathway-based biomarkers. MethodsMachine-learning methods and gene-pathway network were integrated to select the pathway-derived core biomarkers. Multiple machine-learning algorithms were used to construct and validate the diagnostic models of the biomarkers based on more than 1400 multi-omics clinical samples of esophageal squamous cell carcinoma (ESCC). ResultsThe results showed that the classifier models based on the new modal biomarkers achieved superior performance in the training datasets with an average AUC/accuracy of 0.98/0.95 and 0.89/0.81 for mRNAs and miRNA, respectively, higher than the currently known classifier models based on the conventional gene-based strategy and pathway-based strategy. In the testing cohorts, the AUC/accuracy increased by 6.1 %/7.3 % than the models based on the native gene-based biomarkers. The improved performance was further confirmed in independent validation cohorts. Specifically, the sensitivity/specificity increased by ∼3 % and the variance significantly decreased by ∼69 % compared with that of the native gene-based biomarkers. Importantly, the pathway-derived core biomarkers also recovered 45 % more previously reported biomarkers than the gene-based biomarkers and are more functionally relevant to the ESCC etiology (involved in 14 versus 7 pathways related with ESCC or other cancer), highlighting the cross-data robustness of this new modal of biomarkers via enhanced functional relevance. ConclusionsThe results demonstrated that the new modal of biomarkers not only have improved predicting performance and robustness, but also exhibit higher functional interpretability thus leading to the potential application in cancer diagnosis.

Chylopericardium following esophagectomy: a case report and systematic review

BackgroundChylopericardium is a rare condition characterized by the accumulation of chyle in the pericardial space. It is most commonly caused by thoracic duct injury. Chylopericardium following esophagectomy is extremely rare but can cause life-threatening complications. This report presents a case of chylopericardium post-esophagectomy, resulting in cardiac tamponade and cardiac arrest. A systematic literature review was also conducted to facilitate the understanding of this rare condition.Case presentationA 41-year-old male was admitted to our hospital with intermediate to highly differentiated squamous cell carcinoma of the mid-thoracic esophagus (clinical T4NxM0). He underwent thoracoscopic-laparoscopic esophagectomy with cervical anastomosis. On postoperative day 1, patient had a cardiac arrest secondary to cardiac tamponade, requiring emergency ultrasound-guided drainage. The drained fluid was initially serous but became chylous after the administration of enteral nutritional emulsion. As a result of significant daily pericardial drainage, patient subsequently underwent thoracic duct ligation. The amount of drainage was substantially reduced post-thoracic duct ligation. Over a period of 2 years and 7 months, patient recovered well and tolerated full oral diet. A comprehensive literature review was conducted and 4 reported cases were identified. Among these cases, three patients developed pericardial tamponade secondary to chylopericardium post-esophagectomy.ConclusionChylopericardium is a rare but serious complication post-esophagectomy. Prompt echocardiography and thorough pericardial fluid analysis are crucial for diagnosis. Thoracic duct ligation has been shown to be an effective management approach for this condition.

Bioinformatics Analysis and Verification of Metabolic Abnormalities in Esophageal Squamous Carcinoma.

Although esophageal carcinoma (EC) is one of the most common cancers in the world, details of its pathogenesis remain unclear. Metabolic reprogramming is a main feature of EC. Mitochondrial dysfunction, especially the decrease in mitochondrial complex I (MTCI), plays an important role in the occurrence and development of EC. The objective of the study was to analyze and validate the metabolic abnormalities and the role of MTCI in esophageal squamous cell carcinoma. In this work, we collected transcriptomic data from 160 esophageal squamous carcinoma samples and 11 normal tissue samples from The Cancer Genome Atlas (TCGA). The OmicsBean and GEPIA2 were used to conduct an analysis of differential gene expression and survival in clinical samples. Rotenone was used to inhibit the MTCI activity. Subsequently, we detected lactate production, glucose uptake, and ATP production. A total of 1710 genes were identified as being significantly differentially expressed. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis suggested that these differentially expressed genes (DEGs) were significantly enriched in various pathways related to carcinoma tumorigenesis and progression. Moreover, we further identified abnormalities in metabolic pathways, in particular, the significantly low expression of multiple subunits of MTCI genes (ND1, ND2, ND3, ND4, ND4L, ND5, and ND6). Rotenone was used to inhibit the MTCI activity of EC109 cells, and it was found that the decrease in MTCI activity promoted HIF1A expression, glucose consumption, lactate production, ATP production, and cell migration. Our results indicated the occurrence of abnormal metabolism involving decreased mitochondrial complex I activity and increased glycolysis in esophageal squamous cell carcinoma (ESCC), which might be related to its development and degree of malignancy.

Camrelizumab in combination with chemotherapy versus concurrent chemoradiotherapy for the conversion of locally advanced unresectable oesophageal squamous carcinoma: protocol for a two-arm, open-label phase II trial

IntroductionOesophageal cancer (OC) has higher morbidity and mortality rate than most other malignancies. The standard treatment for unresectable locally advanced oesophageal squamous cell carcinoma (OSCC) is concurrent chemoradiotherapy, with tumour...

Study on the effect of different durations of decalcification and depigmentation on programmed death ligand 1 immunohistochemical staining.

Programmed death ligand 1 (PD-L1) score is an important companion diagnosis to predict the response to immunotherapy. Immunohistochemistry can accurately assess the expression of PD-L1 in routine paraffin-embedded tissue. However, whether decalcified or depigmented tissue is still accurate and can be used as a companion diagnosis is controversial. This study attempts to resolve this controversy by analyzing the effects of decalcification and depigmentation at different times on PD-L1 expression. Placental tissues were selected for tissue microarray, decalcification was performed according to time gradients of 6, 12, 24, 36, and 48 h, and depigmentation was performed according to time gradients of 1, 5, 15, 30, and 60 min. The intensity of PD-L1 expression at different time points was observed and quantified. Ten PD-L1-positive esophageal squamous carcinoma samples were selected for decalcification treatment, and the PD-L1. Combined Positive Score (CPS), Tumor Proportion Score (TPS) and Immunocyte Proportion Score (IPS) and the positivity rates were compared before and after decalcification. After the placenta was decalcified, the intensity of PD-L1 positivity diminished, and the average optical density (AOD) value decreased with the prolongation of decalcification time and decreased significantly (P<0.05) at 24 h compared with the control group, and significantly (P<0.01) at 36 and 48 h compared with the control group. The intensity of PD-L1 positivity was weakened considerably after the treatment with potassium permanganate depigmentation. In addition, the AOD value decreased significantly (P<0.01) after the depigmentation time reached 5 min compared with the control group. Ten cases of PD-L1 positive esophageal squamous carcinoma were treated with 24 h decalcification, although the PD-L1 score decreased to a certain degree (P>0.05), and the positivity rate could reach 90%. After 36 h treatment, PD-L1 scores decreased, the CPS and IPS scores decreased significantly (P<0.05), and the positive rate was only 50%. Potassium permanganate depigmentation significantly reduces PD-L1 expression, even for a shorter time, affecting the accuracy of the results. The accuracy of PD-L1 remained high within 24 h decalcification. The above results have certain reference value for clinical selection of immunotherapy.

A phase 2 study of fruquintinib in combination with S-1 for second-line treatment of esophageal squamous cell carcinoma after first-line immunotherapy failure.

323 Background: Patients with advanced esophageal squamous carcinoma (ESCC) who experience progression after first-line immunotherapy face a challenging treatment landscape. The potential of anti-vascular therapy combined with chemotherapy in the treatment of esophageal cancer is well-established. Mechanistically, anti-angiogenic agents can promote the normalization of tumor vasculature and facilitate the access of chemotherapeutic agents to tumor targets. Considering the compromised physical condition of advanced ESCC patients, there is a preference for more convenient oral medications. Therefore, we conducted this phase II study to assess the clinical efficacy and safety of combining fruquintinib with S-1 in treating advanced ESCC patients following first-line immunotherapy failure. Methods: This open-label, single-arm, phase II study consists of dose-finding and dose-expansion phases, enrolling advanced or metastatic ESCC patients after first-line immunotherapy failure. The dose-finding phase followed a 3+3 design. Patients received fruquintinib (3mg, 4mg, 5mg, d1-d14, q3w, respectively), in combination with S-1 (40mg, 50mg, 60mg, bid, d1-d14, q3w, based on body surface area (BSA)), until unacceptable toxicities, progressive disease, or death. The initial fruquintinib dose was 4 mg d1-d14, q3w, in combination with an appropriate S-1 dose. Additional patients were enrolled in the dose-expansion phase and received the maximum tolerated dose determined in the dose-finding phase. Results: As of August 1, 2023, seven patients were enrolled in the dose-finding phase. One patient withdrew consent during the DLT assessment period. Among the patients administered a 4mg dose of fruquintinib, one out of three achieved a confirmed partial response (PR) after 7 cycles of treatment. Additionally, two out of three patients at the 5mg dose level achieved PR after 2 cycles of treatment, resulting in an overall response rate (ORR) of 50% (3/6). The disease control rate (DCR) was 100% (6/6). The median progression-free survival (PFS) was observed to be 4.93 months (95% CI: 1.93 – 10.73), with overall survival (OS) at 10.73 months (95% CI: 2.1 – 10.73). In terms of safety, no dose-limiting toxicities (DLTs) were reported at 4mg dose level. While DLTs were observed in two out of the three patients at the 5mg dose level. The most common treatment-related adverse events (TRAE) across all grades were fatigue (5/7) and extremity pain (4/7). Grade 3 TRAE were identified in 5 patients, with hypertension (2/7), mucositis (2/7), and fatigue (2/7) being reported. No grade 4 or higher TRAEs were observed. Conclusions: Potential benefits were demonstrated when using fruquintinib in combination with S-1 for the treatment of ESCC patients after immunotherapy failure. The efficacy and safety of fruquintinib and S-1 will be further investigated in this trial later. Clinical trial information: NCT05636150 .

An observational study on treatment patterns and outcomes among patients with metastatic or recurrent esophageal cancer: Real-world data and empirical analyses in Japan (POME).

289 Background: There has been little information on treatment patterns and factors affecting outcomes of metastatic or recurrent esophageal cancer (EC) in clinical practice before the marketing of immune checkpoint inhibitors. This study aimed to investigate the treatment patterns and outcomes among patients (pts) with EC treated with systemic chemotherapy (CTx). Methods: This was a retrospective chart review study and included pts with histologically diagnosed esophageal squamous or adenosquamous carcinoma who started systemic CTx for metastatic or recurrent disease between January 1, 2013 and December 31, 2018 at 16 institutions in Japan. With a cutoff date of December 31, 2020, the treatment patterns and outcomes, including response rate (RR), progression-free survival (PFS), and overall survival (OS) for first through third CTx, were analyzed. Results: A total of 891 pts were included in this analysis. The median age (range) was 67 (23-90) years, 84.9% of pts were male, histological types were squamous cell carcinoma in 99.0% and adenosquamous carcinoma in 1.0%, and disease status was metastatic in 35.8% of pts. Most common first-, second-, and third-line regimens were fluoropyrimidine-based (72.4%), taxane-based (64.6%), and taxane-based (48.2%), respectively. Of the pts who received the first-line CTx, the second- and third-line CTx were administered in 51.2% and 21.4% of pts, respectively. The RR from first- to third-line CTx was 24.2%, 6.5%, and 2.2%, and mPFS was 4.1 months (mo) (95% CI 3.7-4.5), 3.1 mo (95% CI 2.8-3.6), and 3.0 mo (95% CI 2.5-4.2), respectively. The mOS from the first-, second-, and third-line CTx were 12.6 mo (95%CI 11.4-13.6), 8.3 mo (95% CI 7.7-9.6), and 8.0 mo (95% CI 7.1-9.5), respectively. As for OS from first-line CTx, a trend of improvement was shown before (median 11.9 mo, 95% CI 10.6-13.3) or after (median 13.2 mo, 95% CI 11.3-14.5) the median time of treatment initiation (March 2016). Pts with recurrent disease (mOS 26.6 mo, 95% CI 24.7-28.6) had a better prognosis than those with stage 4 disease at initial diagnosis (mOS 14.9 mo, 95% CI 13.2-16.3). Of the 293 pts who relapsed after esophagectomy with perioperative CTx or radical chemoradiotherapy, the time from the last day of CTx administration to relapse was less than 6 mo (early recurrence) in 123 (42.0%) pts and more than 6 mo (late recurrence) in 170 (58.0%) pts. The prognosis for pts with early recurrence (mOS 16.3 mo, 95% CI 13.7-20.2) was worse than for pts with late recurrence (mOS 32.9 mo, 95% CI 28.9-35.5). Conclusions: The results of this study revealed the actual treatment and prognosis of metastatic or recurrent EC in clinical practice. This real-world data might identify unmet needs and provide important information for the development of treatments in future.

Applying Untargeted Lipidomics to Evaluate the Efficacy of Combined Neoadjuvant Chemotherapy and Immunotherapy for Esophageal Squamous Carcinoma Treatment.

Esophageal squamous cell carcinoma (ESCC) is an aggressive malignant tumor with a poor prognosis due to insidious symptoms that make early diagnosis difficult. Despite the combination of multiple treatment modalities, the recurrence and mortality rates of ESCC remain high. Neoadjuvant chemotherapy combined with immunotherapy is an emerging treatment modality that improves the prognosis of patients with ESCC. However, owing to the presence of hyperprogression and pseudoprogression, the currently used methods cannot accurately evaluate the efficacy of this therapy in patients, thus creating an evaluation bias and depriving these patients of the opportunity to benefit. We used untargeted lipidomics to identify the differences in lipid composition between cancer specimens and normal tissue specimens in the neoadjuvant chemotherapy combined with the immunotherapy group and the surgery-alone group of esophageal cancer patients and constructed a prediction model based on sphingomyelin 12:1;2O/30:0 and triglyceride (TG) 60:3 | TG 18:0_24:1_18 using a machine learning approach, which helps to better evaluate the neoadjuvant efficacy of combination therapy and better guide the treatment of ESCC.