CD147 expression lacks prognostic relevance in esophageal cancer

Introduction The role of CD147 as an important indicator of tumor prognosis remains controversially discussed in literature. We focused on the prognostic significance of CD147 expression in esophageal cancer patients. While some studies report that CD147 is an unfavorable prognostic factor in esophageal squamous cell carcinoma, others showed no significant correlation. However, only one study draws attention to the significance of CD147 in esophageal adenocarcinoma, which is one of the most rapidly increasing neoplasms in the western world. Methods To finally clarify the impact of CD147 as a prognostic factor, especially for esophageal adenocarcinomas, we analyzed CD147 expression in a tissue microarray of 359 esophageal adenocarcinomas and 254 esophageal squamous cell cancer specimens. For the immuno-histochemical analysis, we used a primary antibody specific for CD147. Staining intensity and proportion of positive tumor cells were scored (negative, weak, moderate, strong staining). These findings were compared to normal esophageal tissue and correlated to the histopathological tumor phenotype and survival data. Results CD147 expression was detectable in weak intensities in benign esophageal tissue (85.78%) and expressed in predominately moderate to strong intensities in esophageal cancer (88.34%). Strong CD147 immunostaining was linked to increased infiltration depth (p = 0.015) and differentiation (p = 0.016) in esophageal squamous cell cancer but revealed no significant correlation with histopathology of adenocarcinoma. Moreover, CD147 intensity was unrelated to overall survival in this collective for both subtypes of esophageal cancer. Conclusion Thus, our data show that CD147 has no prognostic value, neither in esophageal adenocarcinoma nor squamous cell carcinoma.

Tissue Type Differences in ABCB1 Expression and Paclitaxel Tissue Pharmacokinetics in Patients With Esophageal Cancer

Background: Data from previous work suggests that there is no correlation between systemic (plasma) paclitaxel exposure and efficacy in patients treated for esophageal cancer. In this trial, we investigated ATP-binding cassette efflux transporter expression and intratumoral pharmacokinetics of paclitaxel to identify changes which could be a first sign of chemoresistance.Methods: Patients with esophageal cancer treated with paclitaxel and carboplatin (± concomitant radiotherapy) were included. During the first and last cycle of weekly paclitaxel, blood samples and biopsies of esophageal mucosa and tumor tissue were taken. Changes in paclitaxel exposure and expression of ABCB1 (P-glycoprotein) over time were studied in both tumor tissue and normal appearing esophageal mucosa.Results: ABCB1 was significantly higher expressed in tumor tissue compared to esophageal tissue, during both the first and last cycle of paclitaxel (cycle 1: p < 0.01; cycle 5/6: p = 0.01). Interestingly, ABCB1 expression was significantly higher in adenocarcinoma than in squamous cell carcinoma (p < 0.01). During the first cycle, a trend towards a higher intratumoral paclitaxel concentration was observed compared to the esophageal mucosa concentration (RD:43%; 95%CI: −3% to 111% p = 0.07). Intratumoral and plasma paclitaxel concentrations were significantly correlated during the first cycle (AUC0–48 h: r = 0.72; p < 0.01).Conclusion: Higher ABCB1 expression in tumor tissue, and differences between histological tumor types might partly explain why tumors respond differently to systemic treatment. Resistance by altered intratumoral paclitaxel concentrations could not be demonstrated because the majority of the biopsies taken at the last cycle of paclitaxel did contain a low amount of tumor cells or no tumor.

Nonthermal Irreversible Electroporation to the Esophagus: Evaluation of Acute and Long‐Term Pathological Effects in a Rabbit Model

Background Esophageal ulceration and fistula are severe complications of pulmonary vein isolation using thermal ablation. Nonthermal irreversible electroporation (NTIRE) is a promising new technology for pulmonary vein isolation in patients with atrial fibrillation. NTIRE ablation technology has been used to treat atrial fibrillation; however, the effects of NTIRE on esophageal tissue have not been clearly described. Methods and Results A typical NTIRE electrical protocol was directly applied to esophagi in 84 New Zealand rabbits. Finite element modeling and histological analysis with 120 slices were used to analyze electric field intensity distribution and subsequent tissue changes. A parameter combination of 2000 V/cm multiplied by 90 pulses output is determined to be an effective ablation parameters combination. Within 16 weeks after ablation, no obvious lumen stenosis, epithelial erythema, erosion, ulcer, or fistula was observed in the esophageal tissue. NTIRE effectively results in esophageal cell ablation to death, and subsequently, signs of recovery gradually appear: creeping replacement and regeneration of epithelial basal cells, repair and regeneration of muscle cells, structural remodeling of the muscle layer, and finally the restoration of clear anatomical structures in all layers. Conclusions Monophasic, bipolar NTIRE delivered using plate electrodes in a novel esophageal injury model demonstrates no histopathologic changes to the esophagus at 16 weeks. Data of this study suggest that electroporation ablation is a safe modality for pulsed electroporation ablation near the esophagus.

BRCA1/Trp53 heterozygosity and replication stress drive esophageal cancer development in a mouse model

BRCA1 germline mutations are associated with an increased risk of breast and ovarian cancer. Recent findings of others suggest that BRCA1 mutation carriers also bear an increased risk of esophageal and gastric cancer. Here, we employ a Brca1/Trp53 mouse model to show that unresolved replication stress (RS) in BRCA1 heterozygous cells drives esophageal tumorigenesis in a model of the human equivalent. This model employs 4-nitroquinoline-1-oxide (4NQO) as an RS-inducing agent. Upon drinking 4NQO-containing water, Brca1 heterozygous mice formed squamous cell carcinomas of the distal esophagus and forestomach at a much higher frequency and speed (∼90 to 120 d) than did wild-type (WT) mice, which remained largely tumor free. Their esophageal tissue, but not that of WT control mice, revealed evidence of overt RS as reflected by intracellular CHK1 phosphorylation and 53BP1 staining. These Brca1 mutant tumors also revealed higher genome mutation rates than those of control animals; the mutational signature SBS4, which is associated with tobacco-induced tumorigenesis; and a loss of Brca1 heterozygosity (LOH). This uniquely accelerated Brca1 tumor model is also relevant to human esophageal squamous cell carcinoma, an often lethal tumor.

Clonally expanded, GPR15-expressing pathogenic effector TH2 cells are associated with eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is an allergic disorder characterized by the recruitment of eosinophils to the esophagus, resulting in chronic inflammation. We sought to understand the cellular populations present in tissue biopsies of patients with EoE and to determine how these populations are altered between active disease and remission. To this end, we analyzed cells obtained from esophageal biopsies, duodenal biopsies, and peripheral blood of patients with EoE diagnosed with active disease or remission with single-cell RNA and T cell receptor (TCR) sequencing. Pathogenic effector TH2 (peTH2) cells present in the esophageal biopsies of patients with active disease expressed distinct gene signatures associated with the synthesis of eicosanoids. The esophageal tissue–resident peTH2 population also exhibited clonal expansion, suggesting antigen-specific activation. Peripheral CRTH2+CD161− and CRTH2+CD161+ memory CD4+ T cells were enriched for either a conventional TH2 phenotype or a peTH2 phenotype, respectively. These cells also exhibited substantial clonal expansion and convergence of TCR sequences, suggesting that they are expanded in response to a defined set of antigens. The esophagus-homing receptor GPR15 was up-regulated by peripheral peTH2 clonotypes that were also detected in the esophagus. Finally, GPR15+ peTH2 cells were enriched among milk-reactive CD4+ T cells in patients with milk-triggered disease, suggesting that these cells are an expanded, food antigen–specific population with enhanced esophagus homing potential.

Increased lysophosphatidylcholine acyltransferase 1 expression is unrelated to prognosis of esophageal cancer patients

Introduction Lysophosphatidylcholine acyltransferase 1 (LPCAT1) has repeatedly been suggested to be associated with tumorigenesis. To evaluate the role of LPCAT1 in esophageal cancer, LPCAT1 immunostaining was analyzed on a tissue microarray containing samples from esophageal cancer patients. Results In benign esophageal tissue, LPCAT1 staining was detectable in low intensities. LPCAT1 staining was increased in malignant as compared to benign esophageal tissue and was found in high intensity in 26.4% of 288 interpretable esophageal adenocarcinomas (EACs) and in 23.2% of 211 squamous cell carcinomas (ESCCs). Increased LPCAT1 staining was linked to undifferentiated tumor grading in both subtypes of EACs and ESCCs (p = 0.0273 and p = 0.0085). Conclusion However, LPCAT1 was not associated with prognosis of EAC and ESCC patients (p = 0.6838 and p = 0.4695) and thus cannot be considered a prognostic biomarker in esophageal cancers.

DEEP LEARNING TISSUE ANALYSIS DIAGNOSES AND PREDICTS TREATMENT RESPONSE IN EOSINOPHILIC ESOPHAGITIS

Background: Eoinophilic Esophagitis (EoE) is a chronic inflammatory condition diagnosed by >=15 eosinophils (Eos) per high-power field (HPF). There is no gold standard for clinical remission and Eo-associated metrics are poorly correlated with symptoms. Deep learning can be used to explore the relationships of tissue features with clinical response. Objectives: To determine if deep learning can elucidate tissue patterns in EoE that predict treatments or symptoms at remission. Methods: We created two deep learning models using esophageal biopsies from histologically normal and EoE patients: one to identify Eos in esophageal biopsies and a second to broadly classify esophageal tissue as EoE vs. normal. We used these models to analyze biopsies at diagnosis and first remission timepoint, as defined by <15 Eos/HPF, in a subset of 19 treatment-naive patients. Differences in deep learning metrics between patient groups were assessed using Wilcoxon Rank-Sum tests. Results: All initial patients were symptomatic at diagnosis and a majority were still suffering from dysphagia at remission. The Eo identification model had a low mean (SD) error of -0.3 (11.5) Eos/HPF. Higher peak and average Eo counts at diagnosis were associated with higher likelihood of being on a food-elimination diet at remission than steroids or proton-pump inhibitor (p<0.05). The EoE classification model had an F1-score of 0.97 for distinguishing normal tissue from EoE. There was a significant decrease from diagnosis in the percentage of EoE-classified tissue among asymptomatic remission patients (p<0.05). Conclusions: Deep learning may have utility in diagnosing EoE and predicting future treatment response at diagnosis and resolution of symptoms at follow-up.

Experimental and Numerical Investigation of Heat Transfer Through Porcine Heart and Esophageal Tissue

Atrial fibrillation is a heart condition commonly treated by cardiac ablation procedures. Since the esophagus is positioned in close proximity to the heart, esophageal thermal damage can occur during ablation. In this study, we investigate the temperature rise on the inner esophagus surface using a 2D temperature sensor array. An experimental study was performed to measure temperature by the sensor array placed on inner porcine esophagus tissue as a constant temperature heat source is applied to the inner porcine atrial tissue. A numerical model was developed to complement the experimental study.