Expression and correlation of PD-L1 and HER2 in oesophageal squamous cell carcinoma.

AIMS: In recent years, patients with programmed cell death-Ligand 1 (PD-L1)-positive oesophageal squamous cell carcinoma (OSCC) have been able to benefit from immunotherapy. However, method for improving the treatment efficacy of PD-L1-positive patients is a problem that needs further consideration. Studies on the relationship between human epidermal growth factor receptor 2 (HER2) and PD-L1 expression have recently been reported in certain cancers, but the relationship between PD-L1 and HER2 expression in OSCC is still unclear. METHODS: A total of 263 patients with OSCC were included in the study. PD-L1 protein expression and HER2 protein expression were analysed by immunohistochemistry (IHC), and fluorescence in situ hybridisation (FISH) was performed to assess HER2 gene amplification. The significance of differences between HER2 status, PD-L1 status and clinicopathological parameters was assessed. The relationship between PD-L1 status and HER2 status was examined. RESULTS: Of the 263 OSCC cases, the PD-L1-positive expression rates were 39.2% and 77.2% in OSCC for Tumour Proportion Score (TPS) and Combined Positive Score (CPS), respectively, and PD-L1 expression was associated with the degree of tumour differentiation. The HER2 expression was positive in 24% (63/263) of cases based on IHC and FISH. HER2 expression was not significantly associated with clinicopathological characteristics. PD-L1 TPS expression and CPS expression were significantly positively correlated with HER2 expression in OSCC. CONCLUSIONS: PD-L1 expression was significantly positively correlated with HER2 expression in OSCC. The results provide valuable insight for the future application of HER2-targeted therapy combined with immunotherapy in OSCC.

The prognostic significance of the circumferential resection margin in esophageal squamous cell carcinoma patients without neoadjuvant treatment.

BACKGROUND: Circumferential resection margin (CRM) is very important in esophageal cancer, but its diagnostic criteria has not been unified. The College of American Pathologists (CAP) and the Royal College of Pathologists (RCP) provide two different criteria. The aim of this study is to evaluate the long-term prognostic significance of CRM status with different CRM criteria in esophageal squamous cell carcinoma (ESCC). METHODS: Influence of CRM status according to the CAP and RCP criteria on long-term survival of 838 patients with resected pT3 tumors and without neoadjuvant therapy was analyzed. Patients stratified into three groups on the basis of tumor distance from the CRM (CRM > 1 mm, 0-1 mm, and 0 mm) were also analysed. RESULTS: Positive CRM was found in 59 (7%) patients according to the CAP criteria and 317 (37.8%) patients according to the RCP criteria. Univariate and multivariate survival analysis showed that CRM status, according to three different criteria, was independent prognostic factor. However, subgroup analysis showed that the prognostic value of CRM status was limited to certain metastatic lymph node load. In pN0 subgroup, patients with CRM > 1 mm had better prognosis than patients with CRM 0-1 mm. Patients with CRM 0 mm had worse outcome than patients with CRM > 0 mm in pN1-2 subgroup. But CRM status had no prognosis value in pN3 subgroup. CONCLUSIONS: The CRM status is an important prognostic factor in ESCC patients, but this effect was limited to patients without or with less lymph node metastasis (pN0-2). In clinical practice, we recommend the 1 mm-three-tier criteria as it provides more prognostic value than the traditional two-tier criteria.

Esophageal squamous cell carcinoma or high-grade dysplasia overlying leiomyoma, rare but not to be neglected.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) and leiomyoma are common tumors. The coexistence of these two tumors can be classified into two types: the overlying type and the separate type. The overlying type is rare. METHODS: We report 12 cases of the overlying type treated by endoscopic submucosal dissection (ESD). They underwent pre-ESD endoscopic examination with white-light imaging, iodine staining, narrow-band imaging, endoscopic ultrasound, and biopsy. The clinical, endoscopic and pathologic characteristics were reviewed. RESULTS: Among the 12 patients, 3 were female and 9 were male. The age range was 49-76 years. They accounted for 4.0% of 300 cases of esophageal leiomyoma and 1.3% of 955 cases of superficial ESCC or high-grade dysplasia treated by endoscopic resection. After endoscopic examination and biopsy, ESCC or high-grade dysplasia, combined with leiomyoma was considered in four cases; leiomyoma was considered but without the squamous lesion (underdiagnosis) in another case; and leiomyoma was mistaken for submucosal ESCC (overdiagnosis) in the other seven cases. ESD specimens showed that nine cases were intramucosal or submucosal ESCC, and three cases were high-grade dysplasia, overlying leiomyoma originating from the muscularis mucosae or muscularis propria. The 12 cases were successfully treated by ESD, with no recurrence during follow-up. CONCLUSIONS: We must keep in mind that ESCC or high-grade dysplasia can occur overlying leiomyoma. These cases are rare but should not be neglected, especially in high-risk areas for ESCC. These patients can receive appropriate treatment if overdiagnosis or underdiagnosis can be avoided.

HER2 expression and relevant clinicopathological features in esophageal squamous cell carcinoma in a Chinese population.

BACKGROUND: Despite great progress in surgery and other treatments, the prognosis of patients with esophageal squamous cell carcinoma (ESCC) is still very poor. HER2 has strong therapeutic implications in certain cancers, such as breast cancer and gastric cancer. However, literature on the frequency of HER2 expression in ESCC is scarce. In the present study, HER2 protein expression, HER2 gene amplification and the relationship between HER2 status and clinicopathological characteristics were evaluated in a large cohort of Chinese ESCC patients. METHODS: A total of 857 consecutive ESCC patients who received radical esophagectomy without neoadjuvant therapy between January 2014 and October 2015 were included in this retrospective study. HER2 protein expression was analyzed by immunohistochemistry (IHC), and its correlation with clinicopathological parameters was assessed. In addition, 65 cases, including 13 HER2 overexpression (3+) cases and 52 HER2 equivocal (2+) cases from the 857-case cohort, and another 104 ESCC cases, including 1 HER2 overexpression (3+) case, 3 HER2 equivocal (2+) cases and 100 HER2 negative (1+/0) cases, were selected to construct tissue microarrays (TMAs). Dual-color in situ hybridization (DISH) was performed on the TMAs to assess HER2 gene amplification and the relationship with clinicopathological parameters. RESULTS: We found HER2 overexpression (3+) status in 1.5% (13/857) of cases and HER2 equivocal (2+) status in 6.1% (52/857) of cases. HER2 IHC expression was significantly associated with gender (P = 0.028). However, there were no significant correlations between HER2 IHC expression and age, tumor differentiation, pT stage, pN stage, pM stage and pTNM stage (P > 0.05). Regarding the 169 cases analyzed by DISH, 14 (of 14, 100%) HER2 overexpression (3+) cases, 10 (of 55, 18.2%) HER2 equivocal (2+) cases, and 0 (of 100, 0%) HER2 negative (1+/0) cases showed HER2 gene amplification. HER2 gene amplification was not significantly associated with clinicopathological characteristics such as age, gender, tumor differentiation, pT stage, pN stage, pM stage and pTNM stage (P > 0.05). CONCLUSIONS: Approximately 1.5% of the Chinese ESCC patients had HER2 overexpression based on IHC. IHC and DISH had a high concordance rate. These results provide valuable insight for the future treatment of ESCC.

RASSF6-TRIM16 axis promotes cell proliferation, migration and invasion in esophageal squamous cell carcinoma.

Ras-association (RA) domain family number 6 (RASSF6) is a member of the Ras-association domain protein family. It is epigenetically inactive and negatively regulates the malignant progression of some tumors. However, its precise role in esophageal squamous cell carcinoma (ESCC) has not been reported. In this study, we performed immunohistochemistry (IHC) assay. The results show that RASSF6 is upregulated in ESCC and that the elevated expression level of RASSF6 is associated with lymph node metastasis and poor survival of ESCC patients. Consistent with the clinical observations, the upregulation of RASSF6 greatly promotes ESCC cell proliferation, migration and invasion as well as the cell cycle transition to G1/S phase in vitro. According to models in vivo, the downregulation of RASSF6 considerably inhibits ESCC tumor growth and lung metastasis. Mechanistically, RASSF6 negatively regulates the tumor suppressor tripartite-motif-containing protein 16 (TRIM16) by promoting its ubiquitination-dependent degradation and eventually activates pathways associated with the cell cycle and epithelial-mesenchymal transition (EMT). Together, these results indicate that the RASSF6-TRIM16 axis is a key effector in ESCC progression and that RASSF6 serves as a potential target for the treatment of ESCC.

PD-L1 expression and its clinicopathological correlation in advanced esophageal squamous cell carcinoma in a Chinese population.

BACKGROUND: Programmed death ligand 1 (PD-L1) is a ligand for the inhibitory programmed cell death protein 1 (PD-1), which are targeted by several anti-PD-1 and PD-L1 drugs for a variety of human cancers. However, only a few studies have evaluated PD-L1 expression in esophageal squamous cell carcinoma (ESCC) with a large Chinese cohort. Our present study is to evaluate the association of PD-L1 expression with clinicopathological features on ESCC. METHODS: Using tissue microarray and immunohistochemistry, PD-L1 expression on tumor cells and tumor-infiltrating immune cells was studied in 378 advanced ESCC patients without neoadjuvant chemoradiotherapy. Its correlation with clinicopathological parameters was analyzed. RESULTS: PD-L1 was expressed on 29.9% (113/378) ESCC tumor cells and 40.2% (152/378) tumor-infiltrating immune cells. PD-L1 expression in tumor cells was significantly correlated with age, degree of differentiation, T stage, N stage and metachronous hematogenous metastasis, and PD-L1 expression in tumor-infiltrating immune cells was significantly associated with N stage (P < 0.05). Patients with PD-L1 expression in tumor cells had poor disease-free survival (Hazard ratio [HR] = 1.436, P = 0.009). There was a positive association between tumor cells and tumor-infiltrating immune cells for PD-L1 expression (r = 0.16, P = 0.002). However, PD-L1 expression in tumor-infiltrating immune cells was not significantly correlated with disease-free survival and overall survival. CONCLUSIONS: PD-L1 expression in tumor cells and tumor infiltrating immune cells is not only an indicator for immunotherapy, but also significantly related with age, differentiation, stage, metastasis and disease free survival.

Six Zn(II) and Cd(II) coordination polymers assembled from a similar binuclear building unit: tunable structures and luminescence properties.

Six Zn(ii) and Cd(ii) coordination polymers were constructed by treating a 2-substituted 8-hydroxyquinolinate ligand containing a pyridyl group with zinc or cadmium salts, and characterized by a variety of techniques. Interestingly, based on a similar binuclear Zn(ii) or Cd(ii) building unit, the supramolecular structures of the six coordination polymers () exhibit an unprecedented structural diversification due to the different choices of metal salts. and represent a novel 2D framework containing 1D infinite right- and left-handed helical chains. and are 2D coordination frameworks based on binuclear Cd(ii) building units. For and , the L ligands can bridge binuclear building units forming a 1D infinite chain. Interestingly, the adjacent Cd2O2 planes of the 1D chain in are in parallel with each other, while the dihedral angle between the two Zn2O2 planes in is 83.43°. Photoluminescence properties revealed that the six coordination polymers exhibit redshifted emission maximum compared with the free ligand HL, which can be ascribed to an increased conformational rigidity and the fabrication of coplanar binuclear building units M2L2 in . Coordination polymers also display distinct fluorescence lifetimes and quantum yields because of their different metal centers and supramolecular structures.

Three Mn(II) coordination polymers with a bispyridyl-based quinolinate ligand: the anion-controlled tunable structural and magnetic properties.

Three new Mn(ii) coordination polymers, namely [Mn3L6·2H2O] (), [MnL2] (), and [MnL2·2H2O] (), were prepared by solvothermal reactions of Mn(ii) salts with a bispyridyl-based quinolinate ligand. All complexes were characterized by elemental analysis, IR spectra, powder and single-crystal X-ray crystallography. Single crystal X-ray studies show that these coordination polymers exhibit a structural diversification due to the different counteranions (OAc(-), Cl(-), and NO3(-)). Complex has a 2D supramolecular structure with a cyclic tetramer Mn3L6 secondary building unit. Complex possesses a rhombohedral grid network containing a type of meso-helical chain (P + M) constructed via the metal-ligand coordination interaction. Complex features a 3D non-porous structure based on the arrangement of 2D grids. Magnetic susceptibility measurements indicate that the three Mn(ii) polymers show disparate magnetic properties due to their different supramolecular structures.