Treatment Of Esophageal Carcinoma Research Articles

Dihydroartemisinin suppresses the tumorigenesis of esophageal carcinoma by elevating DAB2IP expression in a NFIC-dependent manner.

Dihydroartemisinin (DHA) has been identified to have the anticancer and anti-inflammatory activities. Disabled homolog 2 interacting protein (DAB2IP) is a well-recognized tumor suppressor. Both DHA and DAB2IP were proven to have suppressing effects on esophageal carcinoma (ESCA) tumorigenesis. However, whether DHA regulated ESCA cells via DAB2IP and its mechanism are still vague. Functional analyses were conducted using MTT, tube formation, sphere formation, and transwell assays in vitro as well as Tumor formation experiments in mice. Levels of genes and proteins were assayed by qRT-PCR and western blotting analyses. The interaction between DAB2IP and Nuclear Factor I C (NFIC) was confirmed using bioinformatics analysis and dual-luciferase reporter assay.DHA treatment suppressed ESCA cell angiogenesis, stemmess, migration, and invasion. DAB2IP level was decreased in ESCA tissues and cells, and DHA elevated DAB2IP expression in ESCA cells. Functionally, DAB2IP overexpression impaired ESCA cell angiogenesis, stemmess, migration and invasion. Mechanistically, NFIC had binding sites on the promoter region and directly targeted DAB2IP. DHA could up-regulate DAB2IP expression via NFIC. Moreover, NFIC was also decreased in ESCA tissues and cells, and its overexpression had anticancer activity in ESCA cells. In addition, DAB2IP knockdown reversed the anticancer effects of NFIC or DHA on ESCA cells. In further in vivo analysis, DHA also suppressed ESCA growth by regulating DAB2IP expression.DHA suppressed the tumorigenesis of ESCA by elevating DAB2IP expression in an NFIC-dependent manner, suggesting the potential clinical application of DHA in ESCA treatment.

Identification and Characterization of PrognosticMacrophage Subpopulations for HumanEsophagealCarcinoma.

The aim of the present study was to investigate the relationship between the cellular ecosystem and the progression of esophageal carcinoma (ESCA) based on the evolution of macrophages and to analyze the potential of using macrophages as a new therapeutic approach in ESCA treatment. Macrophage-based immunotherapy could be used for treating ESCA patients, but its clinical application is limited by the intra-tumor heterogeneity of macrophages. The objective of this study was to analyze the diversity, differentiation trajectory, and intercellular communication of macrophages in ESCA and its prognostic significance. Single-cell RNA sequencing (scRNA-seq) data in the GSE154763 dataset were downloaded from Gene Expression Omnibus (GEO) to identify cell clusters and annotate cell types using the Seurat R package. The scRNA-seq profiles of macrophages were extracted, and cluster analysis was performed to identify macrophage subsets. The differentiation trajectories of macrophage subgroups were visualized employing Monocle2. Finally, ligand-receptor pairs and communication intensity among the classified subgroups were analyzed using CellChat. A total of 8 cell types were identified between ESCA tissues and paracancer tissues. The most abundant macrophages in ESCA tissues were further divided into 5 cell clusters. Compared with the normal tissues, the proportion of HSPA6+ macrophages in ESCA tissues increased the most, and the number of ligand-receptor pairs that mediated the communication of HSPA6+ macrophages with mast cells and monocytes also increased significantly. More importantly, a high proportion of HSPA6+ macrophages was inversely correlated with the survival outcomes for ESCA patients. This study analyzed the diversity, distribution and differentiation trajectory of macrophages in ESCA tissues at single-cell level and classified a prognostic macrophage subtype (HSPA6+ macrophages) of ESCA, providing a theoretical basis for macrophage-targeted therapy in ESCA.

The Association of Change in Weight During Radiotherapy Treatment With Clinical Outcomes in Patients With Stage I–III Esophageal Cancer

Esophageal carcinoma (EC) and nutritional status are strongly linked due to swallowing disruptions and treatment-related toxicities. Therefore, malnutrition and weight loss (WL) occur in 85% and 79% of EC patients, respectively. WL is frequently associated with worse EC patient outcomes, however, WL during radiation therapy (RT) and EC patient outcomes have not been well established. The purpose of this study is to retrospectively review the association of WL during RT treatment of EC with clinical outcomes. Non-metastatic EC patients from our institution treated between 2010 and 2018, receiving total prescribed dose >40 Gy and aged >18 years, were included. Patients were analyzed by WL during RT, with categories of ≥5% vs. <5% and ≥10% vs. <10%. Patient characteristics and treatment regimens were similar across all WL groups. In univariate analysis, ≥5% and ≥10% WL were significantly associated with both worse overall survival (OS) and progression-free survival (PFS), and ≥10% WL was significantly associated with increased local recurrence. In multivariate analysis, ≥5% WL was significantly associated with OS and PFS. With both ≥5% and ≥10% WL throughout the radiation treatment being detrimental to OS and PFS. The importance of nutritional support in EC patients receiving radiotherapy is further validated.

Dosimetric rationale and preliminary experience in proton plus carbon-ion radiotherapy for esophageal carcinoma: a retrospective analysis

BackgroundConcurrent chemoradiotherapy has been standard of care for unresectable esophageal carcinoma. There were no reports on proton radiotherapy (PRT) plus carbon-ion radiotherapy (CIRT) with pencil beam scanning (PBS) for esophageal carcinoma. This study evaluated the tolerability and efficiency of proton and sequential carbon-ion boost radiotherapy for esophageal carcinoma.MethodsFrom April 2017 to July 2020, 20 patients with primary esophageal carcinoma at stages II–IV were treated with PRT plus sequential CIRT with PBS. A median relative biological effectiveness-weighted PRT dose of 50 Gy in 25 fractions, and a sequential CIRT dose of 21 Gy in 7 fractions were delivered. Respiratory motion management was used if the tumor moved > 5 mm during the breathing cycle. A dosimetric comparison of photon intensity-modulated radiotherapy (IMRT), PRT, and CIRT was performed. The median times and rates of survivals were estimated using the Kaplan–Meier method. Comparison of the dose-volume parameters of the organs at risk employed the Wilcoxon matched-pairs test.ResultsTwenty patients (15 men and 5 women, median age 70 years) were included in the analysis. With a median follow-up period of 25.0 months, the 2-year overall survival and progression-free survival rates were 69.2% and 57.4%, respectively. The patients tolerated radiotherapy and chemotherapy well. Grades 1, 2, 3, and 4 acute hematological toxicities were detected in 25%, 30%, 10%, and 30% of patients, respectively. Grades 3–5 acute non-hematological toxicities were not observed. Late toxicity events included grades 1, 2, and 3 in 50%, 20%, and 10% (pulmonary and esophageal toxicity in each) of patients. Grades 4–5 late toxicities were not noted. PRT or CIRT produced lower doses to organs at risk than did photon IMRT, especially the maximum dose delivered to the spinal cord and the mean doses delivered to the lungs and heart.ConclusionsPRT plus CIRT with PBS appears to be a safe and effective treatment for esophageal carcinoma. PRT and CIRT delivered lower doses to organs at risk than did photon IMRT. Further investigation is warranted.

CACA guidelines for holistic integrative management of esophageal carcinoma

Esophageal carcinoma (EC) is a common malignant tumor of the upper digestive tract worldwide. An analysis of the latest data from cancer centers in China showed that the incidence of EC and the number of deaths due to EC in China in 2015 were 266,000 and 188,000, respectively, ranking sixth (6.3%) and fourth (8.0%) among all malignant tumors. The early diagnosis and treatment of EC and standardized diagnosis and treatment are important tasks for EC healthcare professionals in various centers across the country. At present, the 8th edition of the EC staging system jointly released by Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) is the most recent, authoritative and widely used EC staging standard. The EC professional committee of the Chinese Anti-Cancer Association also organizes the "EC Standardization Campaign in China" every year to promote the development of EC diagnostic and treatment norms throughout the country. Since 2011, the EC Committee of the Chinese Anti-Cancer Association has published the Guidelines for Standardized Diagnosis and Treatment of EC. Considering the increasing number of EC clinical studies and the continuous progress in diagnostic and treatment technologies in recent years, the updated Guidelines will include the latest progress in the diagnosis and treatment of EC, with a goal of promoting the forward development of EC diagnosis and treatment in clinical practice.

E2F1 Reduces Sorafenib's Sensitivity of Esophageal Carcinoma Cells via Modulating the miR-29c-3p/COL11A1 Signaling Axis.

Esophageal carcinoma (ESCA) is a common malignancy characterized by high morbidity and mortality. Our work managed to dissect the modulatory mechanism of E2F1/miR-29c-3p/COL11A1 in the malignant progression and sensitivity of ESCA cells to sorafenib. Via bioinformatics approaches, we identified the target miRNA. Subsequently, CCK-8, cell cycle analysis, and flow cytometry were used to check the biological influences of miR-29c-3p on ESCA cells. TransmiR, mirDIP, miRPathDB, and miRDB databases were used as tools for the prediction of upstream transcription factors and downstream genes of miR-29c-3p. The targeting relationship of genes was detected via RNA immunoprecipitation and chromatin immunoprecipitation, which was further validated by dual-luciferase assay. Finally, in vitro experiments revealed the way E2F1/miR-29c-3p/COL11A1 affected sorafenib's sensitivity, and in vivo experiments were used to verify the way E2F1 and sorafenib impacted ESCA tumor growth. miR-29c-3p, downregulated in ESCA, could suppress ESCA cell viability, arrest the cell cycle in the G0/G1 phase, and impel apoptosis. E2F1 was found to be upregulated in ESCA and it could abate the transcriptional activity of miR-29c-3p. COL11A1 was found to be a downstream target of miR-29c-3p to enhance cell viability, induce cell cycle arrest in S phase, and constrain apoptosis. Cellular and animal experiments together demonstrated that E2F1 abated the sorafenib's sensitivity of ESCA cells via miR-29c-3p/COL11A1. E2F1 affected the viability, cell cycle, and apoptosis of ESCA cells by modulating miR-29c-3p/COL11A1, and it attenuated the sensitivity of ESCA cells to sorafenib, shedding new light on the treatment of ESCA.

Chemoradiotherapy Combined with Brachytherapy for the Definitive Treatment of Esophageal Carcinoma.

This study aims to investigate the effect of dose escalation with brachytherapy (BT) as an addition to definitive chemoradiotherapy (CRT) on local control and survival in esophageal cancer. From 2001 to 2020, 183 patients with locally limited or locally advanced esophageal cancer received definitive CRT with or without brachytherapy in a two-center study. External-beam radiotherapy was delivered at 50.4 Gy in 1.8 Gy daily fractions, followed by a sequential boost to the primary tumor of 9 Gy in 1.8 Gy daily fractions if indicated. Intraluminal high dose rate (HDR) Ir-192 brachytherapy was performed on 71 patients at 10 Gy in two fractions, with one fraction per week. The combined systemic therapy schedules used included 5-fluorouracil/cisplatin or 5-fluorouracil alone. Cisplatin was not administered in patients receiving brachytherapy. The median local progression-free survival was significantly extended in the BT group (18.7 vs. 6.0 months; p < 0.0001), and the median local control was also significantly prolonged (30.5 vs. 11.3 months, p = 0.008). Overall survival (OS) significantly increased in the BT group (median OS 22.7 vs. 9.1 months, p < 0.0001). No significant difference in the overall rate of acute toxicities was observed; however, the rate of acute esophagitis was significantly higher in the BT group (94.4% vs. 81.2%). Likewise, the overall rate of late toxicities (43.7% vs. 18.8%) was significantly higher in the BT group, including the rate of esophageal stenosis (22.5% vs. 9.8%). There was no difference in the occurrence of life-threatening or lethal late toxicities (grades 4 and 5). Brachytherapy, after chemoradiation with single-agent 5-FU, represents a safe and effective alternative for dose escalation in the definitive treatment of esophageal cancer.

Targeting epigenetic deregulations for the management of esophageal carcinoma: recent advances and emerging approaches.

Ranking from seventh in incidence to sixth in mortality, esophageal carcinoma is considered a severe malignancy of food pipe. Later-stage diagnosis, drug resistance, and a high mortality rate contribute to its lethality. Esophageal squamous cell carcinoma and esophageal adenocarcinoma are the two main histological subtypes of esophageal carcinoma, with squamous cell carcinoma alone accounting for more than eighty percent of its cases. While genetic anomalies are well known in esophageal cancer, accountability of epigenetic deregulations is also being explored for the recent two decades. DNA methylation, histone modifications, and functional non-coding RNAs are the crucial epigenetic players involved in the modulation of different malignancies, including esophageal carcinoma. Targeting these epigenetic aberrations will provide new insights into the development of biomarker tools for risk stratification, early diagnosis, and effective therapeutic intervention. This review discusses different epigenetic alterations, emphasizing the most significant developments in esophageal cancer epigenetics and their potential implication for the detection, prognosis, and treatment of esophageal carcinoma. Further, the preclinical and clinical status of various epigenetic drugs has also been reviewed.

Pattern of relapse following three-field lymphadenectomy of esophageal carcinoma and related factors predictive of recurrence

PurposeFor treatment of esophageal carcinoma, the optimal postoperative radiotherapy target volume after three-field lymph node dissection (3-FLD) had not been determined. We analyzed local recurrence pattern of thoracic esophageal carcinoma and risk factors of lymph node recurrence after 3-FLD without prophylactic radiotherapy. Material and methodsWe reviewed 1282 patients with thoracic esophageal squamous cell carcinoma (ESCC) who were treated with 3-FLD without radiotherapy from 2010 to 2018 and analysed local recurrence patterns and risk factors of lymph node recurrence, in order to provide a reference for determination of the radiotherapy target volume for thoracic ESCC. ResultsThe lymph node recurrence accounted for 91.0% of treatment failures. The mediastinal, cervical and abdominal lymph node recurrence accounted for 84.92%, 36.07% and 22.30%, respectively (χ2=264.776, P=0.000). The superior, middle and inferior mediastinal lymph node recurrence rates were 67.54%, 27.87% and 0.98%, respectively (χ2=313.600, P=0.000). Cervical metastases were significantly associated with N stage and Preoperative cervical lymph node status. Abdominal metastases were significantly associated with the number of preoperative abdominal lymph node metastases (LNM), tumor location and N stage. ConclusionsThe main pattern of local-regional recurrence might be lymph node metastasis after radical 3-FLD without radiotherapy in esophageal carcinoma. The dangerous lymph node recurrence regions included neck, superior and middle mediastinum. The abdominal areas might be irradiated for lower TEC patients with preoperative abdominal LNM.

MiR-129-2-3p Inhibits Esophageal Carcinoma Cell Proliferation, Migration, and Invasion via Targeting DNMT3B.

The study aims to explore the regulatory mechanism of miR-129-2-3p underlying esophageal carcinoma (EC) cell progression and generate new ideas for targeted treatment of EC. Mature miRNA expression data and total RNA sequencing data of EC in the TCGAESCA dataset were utilized to explore differentially expressed miRNAs (DEmiRNAs). StarBase database was then utilized to predict targets of miRNA. MiR-129-2-3p and DNMT3B expression in EC cell lines was assayed through qRT-PCR and Western blot. CCK-8, scratch healing, and transwell assays were conducted to assess the impact of miR-129-2-3p on EC cell phenotypes. In addition, a dual-luciferase assay was completed to identify the binding relationship between DNMT3B and miR-129-2-3p. MiR-129-2-3p was noticeably less expressed in EC cell lines, while DNMT3B was highly expressed. MiR-129-2-3p could bind to DNMT3B. Furthermore, in vitro functional experiments uncovered that overexpressed miR-129-2-3p repressed EC cell progression while further overexpressing DNMT3B would restore the above inhibitory effect. MiR-129-2-3p is a cancer repressor in EC cells, and it could target DNMT3B, thus hampering the progression of EC cells.

Significance Of Dietary Factors In Occurrence, Prevention And Treatment Of Esophageal Carcinoma

Significance Of Dietary Factors In Occurrence, Prevention And Treatment Of Esophageal Carcinoma

Chloroquine Sensitizes Esophageal Carcinoma EC109 Cells to Paclitaxel by Inhibiting Autophagy.

As an autophagy inhibitor, chloroquine (CQ) showed anti-tumor effect on several types of cancer and paclitaxel (PTX) is widely used in the treatment of esophageal carcinoma patients, but chemoresistance remains a major hurdle for PTX application due to the cytoprotective autophagy. Therefore, the aim of this study was to investigate whether CQ could elevate the anti-tumor effect of PTX on esophageal carcinoma cell line EC109 and explore the potential molecular mechanisms. We confirmed the suppressive effect of PTX on EC109 by MTT, scratch test, transwell and soft agar assay. And, we detected the key proteins in Akt/mTOR pathway, as well as the autophagy marker LC3 and p62 through Western Blot. In addition, GFP-LC3 plasmid was transfected into EC109 cells to monitor the autophagosome after CQ and PTX treatment. Ultimately, we observed the alterations in the proliferation and colony formation abilities of EC109 after knocking down mTOR by shRNA. We confirmed PTX could suppress the proliferation, migration and colony formation (all P < 0.05) abilities of EC109, and CQ could sensitize the inhibition effect of PTX by inhibiting autophagy through Akt/mTOR pathway. Furthermore, inhibiting Akt/mTOR pathway initiated autophagy and enhanced the sensitivity of EC109 to CQ and PTX. In summary, we suggest CQ could be used as a potential chemosensitizer for PTX in esophageal carcinoma treatment.

Cost-effectiveness analysis of pembrolizumab vs. chemotherapy as second-line treatment for advanced esophageal carcinoma in the United States.

The national Comprehensive Cancer Network has suggested pembrolizumab as a second-line therapy for esophageal squamous cell carcinoma (ESCC) patients with a programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 10. However, despite the increased survival rate associated with pembrolizumab in these patient population, the high cost of pembrolizumab may influence its antitumor effect. This study aimed to evaluate the cost-effectiveness of pembrolizumab compared to chemotherapy as second-line treatments for esophageal carcinoma (EC) based on KEYNOTE-181 trial. A Markov model was constructed using TreeAge 2021 based on three different groups: all intent-to-treat patients (ITT population), patients with ESCC (ESCC population), and patients with a PD-L1 CPS ≥10 (CPS ≥10 population). Incremental cost, Incremental effect, Life-years, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER) were calculated. Analyses were conducted on the setting of a willingness-to-pay threshold of $150,000 from the US perspective. The ICERs for pembrolizumab were $157,589.545 per QALY, $60,238.823 per QALY, and $100,114.929 per QALY compared with chemotherapy in the ITT, ESCC, and CPS≥10 populations, respectively. The ICER of the ITT population was higher than $150,000, suggesting that pembrolizumab was not a cost-effective treatment scheme in patients with a PD-L1 CPS ≤ 10 or esophageal adenocarcinoma. The ICER was < $150,000 in the ESCC and CPS≥10 populations, indicating that pembrolizumab was cost-effective in these two subgroups. The determining of pembrolizumab as a cost-effective second-line therapy for EC in the United States depends on the histologic type and PD-L1 expression.

Impact of fiducial markers placement on the delineation of target volumes in radiation therapy for oesophageal cancer: FIDUCOR study.

This prospective monocentric phase II study (FIDUCOR-study, NCT02526134) aimed to assess the impact of fiducial markers (FMs) implantation on conformal chemo-radiation therapy (CRT) planning in oesophageal carcinoma (EC) patients. Fifteen EC patients were enrolled in the study. Each patient underwent two simulation CT-scans before (CT1) and after (CT2) FMs implantation, in the same position. FMs (3 mm length gold markers, preloaded in a 22G needle) were implanted after sedation, under endoscopic ultrasound (EUS) and X-Ray guidance, and were placed at the tumor's extremities, and in the visible lymph nodes. Target delineation and treatment plan were both performed first on CT1 with the assistance of diagnosis CT, gastroscopy and EUS details, and second on CT2 using FMs and CT-data. The value of FMs implantation was assessed by the difference of growth-tumor-volume (GTV) and clinical-target-volume (CTV) between CT1-based and CT2-based delineation. A significant difference was defined as a ≥5 mm-difference on axial(x) or coronal(y) slices, a ≥10mm-difference on sagittal slices, or a ≥20%-difference in GTV. The impact on dose distribution in organs at risk (OAR) (lung, heart, liver) was also studied. Between 09/2014 and 12/2015, 15 patients could achieve fiducial procedures, without any complication. One FM migration occurred. We observed a significant modification of the GTV-dimension in 100% of the cases (15/15, 95%CI: [78.2;100.0]), mainly due to a difference in sagittal dimension with a mean variation of 11.2 mm and a difference&gt; 10 mm for 8/15 patients (53.3%). One patient had a significant isocenter displacement as high as 20 mm. The oesophagus tumor was not seen on the CT-scan in one patient due to its small size. One patient had a distant lymph node metastasis not visible on CT-scan. We observed no significant impact on OAR distribution. In our study, FMs-implantation under EUS had a positive impact on accurate volume definition in EC-patients (modification of GTV in 15/15 patients). Close cooperation between gastroenterologist and radiation oncologist has the potential to improve local treatment of oesophagealcarcinoma.

601. SINGLE-PORT VATS ESOPHAGECTOMY. SAFE AND FEASIBLE TECHNIQUE

Abstract Minimally invasive esophagectomy represents the gold standard for the treatment of esophageal carcinoma. The improvement of surgical techniques and the development of the single port vats for the thoracic time represent a safe and efficacy option. We show some technical aspects showing the feasibility of this approach and the potential troubles to face up. We show a single port vats esophagectomy combined with full laparoscopy in a patient with esophageal adenocarcinoma and esophageal stent. Patient discharged in 7post operative day. Course was uneventful. The minimally invasive approach represents the gold standard for the treatment of esophageal carcinoma. Single port vats may be a feasible and safe option.

350. SALVAGE RADIATION THERAPY FOR OLIGO-RECURRENCES AFTER RADICAL TREATMENT OF ESOPHAGEAL CANCER

Abstract Loco-regional recurrences following surgery or radical radiation therapy for esophageal cancers represent a significant clinical problem. We performed a retrospective study to assess the safety and efficacy of salvage radiation for oligo-recurrence after primary curative therapy for esophageal cancer. Esophageal cancer patients treated with salvage radiotherapy between January 2011 and March 2020 at our institution were screened. Patients were included if they had undergone prior treatment for esophageal carcinoma with curative intent using either surgery or radiotherapy and had developed local/locoregional/isolated distant recurrences. Recurrences were diagnosed based on CT scan or/and FDG PET-CT scan. Treatment plan was discussed in a multi-disciplinary tumour board and patients were followed up as per institution policy. Survival rates were estimated using the Kaplan–Meier method and data was analyzed using IBM SPSS Statistics for Windows (Version 26.0. Armonk, NY: IBM Corp.) Oligo-recurrence was diagnosed in 33 patients; thirty patients had loco-regional-recurrence (LRR), 3 had distant metastasis); 28 patients underwent surgery as initial treatment; 5 received definitive RT. Recurrence was detected at a median of 21 months. Of the 30 patients with LRR, 25 patients received chemo-radiation and 5 received RT alone. At a median follow-up of 18 months, 20 patients were alive and 61% had controlled disease. Overall survival at 1- &amp; 2- year were 83% and 65% respectively. Concurrent chemotherapy administration and RT dose of &amp;gt;56Gy were independent predictors for OS. No grade 3/4 acute or chronic toxicity were observed. Salvage RT with or without concomitant chemotherapy for loco-regional recurrences after surgery for esophageal cancer is safe and effective. Advanced, modern RT techniques may reduce treatment related morbidity and improve outcomes.

Immunohistochemical analyses of paraffin-embedded sections after primary surgery or trimodality treatment in esophageal carcinoma

BackgroundThe microscopic tumor extension before, during or after radiochemotherapy (RCHT) and its correlation with the tumor microenvironment (TME) are presently unknown. This information is, however, crucial in the era of image-guided, adaptive high-precision photon or particle therapy. Materials and methodsIn this pilot study, we analyzed formalin-fixed paraffin-embedded (FFPE) tumor resection specimen from patients with histologically confirmed squamous cell carcinoma (SCC; n = 10) or adenocarcinoma (A; n = 10) of the esophagus, having undergone neoadjuvant radiochemotherapy followed by resection (NRCHT + R) or resection (R)]. FFPE tissue sections were analyzed by immunohistochemistry regarding tumor hypoxia (HIF-1α), proliferation (Ki67), immune status (PD1), cancer cell stemness (CXCR4), and p53 mutation status. Marker expression in HIF-1α subvolumes was part of a sub-analysis. Statistical analyses were performed using one-sided Mann-Whitney tests and Bland-Altman analysis. ResultsIn both SCC and AC patients, the overall percentages of positive tumor cells among the five TME markers, namely HIF-1α, Ki67, p53, CXCR4 and PD1 after NRCHT were lower than in the R cohort. However, only PD1 in SCC and Ki67 in AC showed significant association (Ki67: p = 0.03, PD1: p = 0.02). In the sub-analysis of hypoxic subvolumes among the AC patients, the percentage of positive tumor cells within hypoxic regions were statistically significantly lower in the NRCHT than in the R cohort across all the markers except for PD1. ConclusionIn this pilot study, we showed changes in the TME induced by NRCHT in both SCC and AC. These findings will be correlated with microscopic tumor extension measurements in a subsequent cohort of patients.

MiR-145-3p Hampers the Malignant Progression of Esophageal Carcinoma via CXCL5 Downregulation.

Esophageal carcinoma (EC) is the most prevalent malignant tumor that occurs frequently worldwide. The early diagnostic biomarkers are crucial for EC treatment. miRNA can regulate EC progression, with diagnostic and prognostic value. Herein, differentially expressed miRNAs and mRNAs (DEmRNAs) in EC were predicted based on TCGA database. The target mRNAs of miRNA were predicted through databases, which were then intersected with DEmRNAs. Next, the correlation between miRNA and candidate mRNAs was analyzed. qRT-PCR was introduced to analyze expression of miR-145-3p and CXCL5 mRNA in EC cell lines, and western blot was performed to assess protein expression of CXCL5. Cell proliferation, migration, invasion, and apoptosis in EC were examined through CCK-8, wound healing, Transwell invasion, and flow cytometry assays. Moreover, targeting relationship between miR-145-3p and CXCL5 was verified through luciferase reporter gene analysis. The experimental results revealed a decreased miR-145-3p expression and an increased CXCL5 expression in EC. Enforced expression of miR-145-3p hindered proliferation, migration, invasion, and stimulated apoptosis of EC cells by repressing CXCL5. This study manifested that miR-145-3p may be a tumor suppressor in EC, and miR-145-3p/CXCL5 axis restrained the malignant progression of EC. These results supply an underlying target for prognosis and treatment of EC patients.

A microarray expression profile and bioinformatic analysis of circular RNA in human esophageal carcinoma

Recent studies indicate that non-coding circular RNAs (circRNAs) are involved in the development of esophageal carcinoma (EC). This study aimed to identify differential expression of circRNAs in EC, which can provide potential biomarkers and therapeutic targets for EC treatment and improve the understanding of tumorigenesis mechanism. First, samples (n=5) of EC tissues and adjacent normal tissue were sent for circRNA microarray detection, Second, further bioinformatic analysis was performed, including circRNA-microRNA (miRNA), co-expression network analysis, Spearman correlation test, and cancer-related circRNA-miRNA axis analysis. Finally, the expression of circRNA that our analysis predicted to be hub genes was verified in samples (n=15) of EC tissues and adjacent normal tissue by real-time polymerase chain reaction (RT-PCR). Microarray identified 102 upregulated and 67 significantly downregulated circRNAs were in EC patients' tumors relative to adjacent normal tissue. One upregulated circRNA (hsa_circRNA_401955) showed the most connection with MREs, therefore was regarded as the hub gene by the Spearman correlation test. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that four primary pathways (mRNA surveillance, cytoskeleton actin regulation, spliceosome, and the NOD-like receptor signaling pathway) were predicted in the hub circRNA's five connected miRNA response elements (MREs). Furthermore, cancer-related circRNA-miRNA axis analyses showed that hsa_circRNA_100375 and its four connected MREs participated in the cancer-related pathway. RT-PCR showed that hsa_circRNA_100375 and hsa_circRNA_401955 were significantly increased in the tumor tissues of EC patients. Abnormal expression of circRNAs was involved in the tumorigenesis of EC. Key circRNAs, namely hsa_circRNA_401955 and hsa_circRNA_100375, may be as potential biomarkers and therapeutic targets for the treatment of EC.

Immunotherapy in Squamous Cell Cancer of the Esophagus

Treatment of esophageal carcinoma has changed dramatically following several landmark trials, which have proven the benefit of immunotherapy. The selective PD-1 (programmed cell death ligand-1)-inhibitor nivolumab has been shown to improve DFS in the adjuvant therapy setting (CheckMate-577). In the first-line treatment, PD-L1 positive (CPS ≥ 10) squamous cell carcinoma patients (pts) have been shown to have an increased OS following treatment with the PD-1-inhibitor pembrolizumab in combination with chemotherapy (KEYNOTE-590). Nivolumab also improved overall survival in the first line setting either combined with ipilimumab or with chemotherapy (CheckMate 648) compared to chemotherapy alone. In Asian first-line patients, phase III trials investigating camrelizumab (ESCORT 1), toripalimab (JUPITER 06), or sintilimab (ORIENT 15) in addition to chemotherapy also showed significant survival benefits. In the second-line setting, monotherapy with nivolumab (ATTRACTION-03), pembrolizumab (KEYNOTE-181), camrelizumab (ESCORT), and tislelizumab (RATIONALE 302) demonstrated a benefit in OS in comparison to chemotherapy. Here we will review these trials and integrate them into the current treatment algorithm.