Mesothelin expression in esophageal adenocarcinoma and squamous cell carcinoma and its possible impact on future treatment strategies.
- 作者列表："Moentenich V","Comut E","Gebauer F","Tuchscherer A","Bruns C","Schroeder W","Buettner R","Alakus H","Loeser H","Zander T","Quaas A
Background:Mesothelin is expressed at very low levels by normal mesothelial cells but is overexpressed in several human cancers. This makes mesothelin a promising target for immunotherapy. Limited data exist about mesothelin expression in esophageal carcinoma. In a current clinical trial, the highly potent anti-mesothelin antibody anetumab ravtansine is used in patients with mesothelin-positive tumors. Response rates are correlated with mesothelin expression (using the Ventana antibody) in tumor cells. No data are available on expression levels using the Ventana antibody. Most data have been generated using the Novocastra antibody. As patients are selected for clinical trials based on antibody staining of tumor samples, a comparison of these two available antibodies is crucial. Methods:We analyzed 481 esophageal carcinomas [373 esophageal adenocarcinomas (EACs), 108 esophageal squamous cell carcinomas (ESCCs)] using two different monoclonal antibodies (Novocastra and Ventana) for mesothelin expression (low-mid and high-level expression, as used in one clinical trial). We also checked for the correlation of these results with clinical and molecular data. Results:We revealed different staining results for both antibodies in EACs: Ventana: 53.6% (low expression: 25.3%; high expression: 28.3%) and Novocastra: 35.7% (low expression: 21.2%; high expression 14.5%). In ESCC we found comparable staining results: Ventana: 13.3% (low expression: 9.5%; high expression: 3.8%) and Novocastra: 13% (low expression: 11.1%; high expression: 1.9%). ARID1a-deficient EAC patients demonstrated significantly higher rates of mesothelin-positive tumors than ARID1a intact EAC patients. No correlations were found with other molecular alterations (TP53 mutation, ERBB2 amplification) or survival rates. Conclusion:To the best of our knowledge, this is the largest study analyzing the importance of mesothelin expression in esophageal carcinoma. This study revealed a significant number of mesothelin-positive esophageal carcinomas, especially adenocarcinomas. New therapeutic targets are urgently required to improve the outcome of patients with locally advanced or metastasized esophageal carcinoma. The inhibition of mesothelin can be a new attractive target.
背景: 间皮素在正常间皮细胞中以非常低的水平表达，但在几种人类癌症中过表达。这使得间皮素成为免疫治疗的一个有希望的靶点。关于间皮素在食管癌中表达的数据有限。在目前的临床试验中，高效抗间皮素抗体 anetumab ravtansine 用于间皮素阳性肿瘤患者。反应率与肿瘤细胞中的间皮素表达 (使用 Ventana 抗体) 相关。没有关于使用 Ventana 抗体的表达水平的数据。大多数数据都是使用 Novocastra 抗体生成的。由于根据肿瘤样本的抗体染色选择患者进行临床试验，这两种可用抗体的比较至关重要。 方法: 我们使用两种不同的单克隆抗体 (Novocastra 和 Ventana) 分析了 481 例食管癌 [373 例食管腺癌 (EACs)，108 例食管鳞状细胞癌 (ESCCs)] 用于间皮素表达 (中低和高水平表达，如在一项临床试验中使用)。我们还检查了这些结果与临床和分子数据的相关性。 结果: 我们发现 EACs 中两种抗体的染色结果不同: Ventana: 53.6% (低表达: 25.3%; 高表达: 28.3%) 和 Novocastra: 35.7% (低表达: 21.2%; 高表达 14.5%)。在 ESCC 中，我们发现具有可比性的染色结果: Ventana: 13.3% (低表达: 9.5%; 高表达: 3.8%) 和 Novocastra: 13% (低表达: 11.1%; 高表达: 1.9%)。ARID1a-deficient EAC 患者间皮素阳性肿瘤发生率显著高于 ARID1a 完整 EAC 患者。未发现与其他分子改变 (TP53 突变、 ERBB2 扩增) 或生存率相关。 结论: 据我们所知，这是分析间皮素在食管癌中表达重要性的最大研究。本研究发现了大量间皮素阳性食管癌，尤其是腺癌。迫切需要新的治疗靶点来改善局部晚期或转移性食管癌患者的预后。间皮素的抑制可以成为一个新的有吸引力的目标。
METHODS:PURPOSE:The purpose of this study was to compare the survival and toxicities in cervical esophageal squamous cell carcinoma (CESCC) treated by concurrent chemoradiothrapy with either three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) techniques. Materials and Methods:A total of 112 consecutive CESCC patients were retrospectively reviewed. 3D-CRT and IMRT groups had been analyzed by propensity score matching method, with sex, age, Karnofsky performance status, induction chemotherapy, and tumor stage well matched. The Kaplan-Meier method and Cox proportional hazards model were used for overall survival (OS) and progression-free survival (PFS). Toxicities were compared between two groups by Fisher exact test. RESULTS:With a median follow-up time of 34.9 months, the 3-year OS (p=0.927) and PFS (p=0.859) rate was 49.6% and 45.8% in 3D-CRT group, compared with 54.4% and 42.8% in IMRT group. The rates of grade ≥ 3 esophagitis, grade ≥ 2 pneumonitis, esophageal stricture, and hemorrhage were comparable between two groups, while the rate of tracheostomy dependence was much higher in IMRT group than 3D-CRT group (14.3% vs.1.8%, p=0.032). Radiotherapy technique (hazard ratio [HR], 0.09; 95% confidence interval [CI], 0.01 to 0.79) and pretreatment hoarseness (HR, 0.12; 95% CI 0.02 to 0.70) were independently prognostic of tracheostomy dependence. CONCLUSION:No survival benefits had been observed while comparing IMRT versus 3D-CRT in CESCC patients. IMRT with fraction dose escalation and pretreatment hoarseness were considered to be associated with a higher risk for tracheostomy dependence. Radiation dose escalation beyond 60 Gy should be taken into account carefully when using IMRT with hypofractionated regimen.
METHODS::The radial force of esophageal stents may not completely change during extraction and therefore, the procedure of stent removal may cause tissue damage. The present study reports the manufacture of 2 novel detachable stents, which were designed to reduce tissue damage through their capacity to be taken or fall apart prior to removal and evaluated the supporting properties of these stents and the extent of local mucosal injury during their removal. The stents were manufactured by braiding, heat-setting, coating and connecting. The properties of the stents were evaluated by determining the following parameters: Expansion point, softening point, stent flexibility, radial compression ratio and radial force. A total of 18 rabbits with induced esophageal stricture were randomly assigned to 3 groups as follows: Detachable stent (DS) group, biodegradable stent (BS) group and control group. The stricture rate, complications, survival, degradation and stent removal were observed over 8 weeks. The stents of the DS and BS groups provided a similar supporting effect. The stricture rate, incidence of complications and survival were also similar between the 2 groups, while significant differences were noted between the DS and control groups and between the BS and control groups. In the BS group, the stents were degraded and moved to the stomach within 7 weeks (2 in 6 weeks and 3 in 7 weeks). The debris was extracted using biopsy forceps. In the DS group, all stents were easy to remove and 2 cases exhibited minor hemorrhage. In conclusion, the 2 types of novel detachable stent provided an equally efficient supporting effect in vitro and in vivo and may reduce the incidence of secondary injury during stent removal.
METHODS:BACKGROUND:Immune imbalance and inflammation have been suggested as key factors of Barrett's esophagus (BE) pathway towards adenocarcinoma. The neutrophil-lymphocyte ratio (NLR) indirectly reflects the relation between innate and adaptive immune systems and has been studied in premalignant conditions as a biomarker for cancer diagnosis. Our aim was to investigate if increasing values of NLR correlated with advancing stages of BE progression to dysplasia and neoplasia. METHODS:We retrospectively analyzed data of patients with biopsies reporting BE between 2013 and 2017 and with a complete blood count within 6 months from the endoscopy, as well as patients with esophageal adenocarcinoma (EAC). NLR was calculated as neutrophil count/lymphocyte count. Cases (n = 113) were classified as non-dysplastic BE (NDBE, n = 72), dysplastic BE (DBE, n = 11) and EAC (n = 30). RESULTS:NLR progressively increased across groups (NDBE, 1.92 ± 0.7; DBE, 2.92 ± 1.1; EAC 4.54 ± 2.9), with a significant correlation between its increasing value and the presence of dysplasia or neoplasia (r = 0.53, p 2.27 was able to diagnose EAC with 80% sensitivity and 71% specificity (area under the curve = 0.8). CONCLUSION:NLR correlates with advancing stages of BE progression, a finding that reinforces the role of immune imbalance in EAC carcinogenesis and suggests a possible use of this marker for risk stratification on surveillance strategies.