Wen-Yu Chuang

High expression of phosphorylated 4E-binding protein 1 is an adverse prognostic factor in esophageal squamous cell carcinoma

Cell signaling pathways play important roles in oncogenesis. Among a large number of signaling regulators in different pathways, 4E-binding protein 1 (4E-BP1) was found to be a key factor, which converges several oncogenic signals, phosphorylates the molecules, and drives the downstream proliferative signals. Recent studies showed that high expression of phosphorylated 4E-BP-1 (p-4E-BP1) is associated with poor prognosis, tumor progression, or nodal metastasis in different human cancers, but its prognostic significance in esophageal cancer remains undefined. In this study, we investigated the expression levels of p-4E-BP1 with two different phosphorylation sites Thr37/46 and Thr70 by immunohistochemistry and their prognostic significance in 78 cases of surgically resected esophageal squamous cell carcinoma (SCC) for the first time. We found no correlation of p-4E-BP1 expression with age, gender, preoperative concurrent chemoradiotherapy, tumor grade, pT classification, pN, pM, or pStage. Multivariate Cox regression analysis showed that high expression of p-4E-BP-1 Thr37/46 was an independent adverse prognostic factor, with a hazard ratio of 1.73 (95% confidence interval = 1.03–2.90) and a p value of 0.038. Stratifying the patients with other prognostic factors, we found that the effect of p-4E-BP1 Thr37/46 on survival was significant only in patients with relatively early stage disease (pT1/pT2, pN0, or pStage I/II; p = 0.0047, 0.012, and 0.011, respectively). Our data suggest that assessment of p-4E-BP1 expression could identify a subpopulation of earlier stage esophageal SCC patients with poor prognosis. These patients could be possible candidates for future studies on more aggressive treatment or target therapy.

Prognostic significance of high podoplanin expression after chemoradiotherapy in esophageal squamous cell carcinoma patients.

The correlation between high tumor podoplanin (PP) immunoreactivity and poor outcome in patients with non‐chemoradiotherapy(CRT) pretreated upper aerodigestive tract squamous cell carcinoma (SCC) has been reported recently. Little is known about the implication of PP expression after CRT. Therefore, we conducted this study.

High phosphorylated 4E-binding protein 1 expression after chemoradiotherapy is a predictor for locoregional recurrence and worse survival in esophageal squamous cell carcinoma patients.

As a well‐known pivotal factor of 4E‐binding protein 1 (4E‐BP1) in controlling cancer proliferation, high expression of its phosphorylated form (p‐4E‐BP1) has been reported to be associated with poor outcome in various human cancers without pretreated with chemoradiotherapy (CRT). However, no data is available regarding the implication of p‐4E‐BP1 expression after CRT. Therefore, we conducted this study.

Correlation Between Tumor Regression Grade and Clinicopathological Parameters in Patients With Squamous Cell Carcinoma of the Esophagus Who Received Neoadjuvant Chemoradiotherapy.

AbstractThe aim of this study was 2-fold: first, to assess the prognostic significance on overall survival (OS) of the 3-point tumor regression grade (TRG) in patients with esophageal squamous cell carcinoma (ESCC) who received neoadjuvant chemoradiotherapy (nCRT); second, to investigate the associations of TRG with the clinicopathological characteristics of the study patients.A total of 357 ESCC patients were retrospectively enrolled. The 3-point TRG was determined by assessing the percentage of viable residual tumor cells (VRTC) in the resected specimens as follows: TRG 1, 0% VRTC; TRG 2, 1% to 50% VRTC; and TRG 3, >50% VRTC.A TRG of 1, 2, and 3 was found in 32.2%, 38.9%, and 28.9% of the specimens, respectively. High TRG values were significantly associated with advanced pretreatment clinical stage, longer tumor length, and higher posttreatment tumor depth of invasion (yT), the presence of lymph node metastases (LNM), and lymphovascular invasion. We observed a stepwise decrease in 5-year OS rates with increasing TRG, as follows: 51% for patients with a TRG of 1, 28% for patients with a TRG of 2, and 22% for patients with a TRG of 3 (P < 0.001). TRG and LNM were independent predictors of OS in multivariate analysis. Notably, the prognostic impact of TRG on OS was greater in patients without LNM (P < 0.001) and ypT3 disease (P = 0.021).TRG is independently associated with OS in ESCC patients treated with nCRT. The interrelationships between TRG, LNM, and depth of tumor invasion may improve the prognostic stratification in esophageal cancer.

Prognostic Significance of Immunohistochemically Detected Lymph Node Micrometastases in pT0N0 Esophageal Squamous Cell Carcinoma

Pathological complete response (pCR) after chemoradiotherapy (CRT) is the best predictor of survival in patients with squamous cell carcinoma (SCC) of the esophagus. Although no adjuvant treatment is recommended for individuals who achieve pCR, approximately 30% of these patients develop a recurrence. We applied an immunohistochemistry (IHC) stain on resected lymph nodes to evaluate the incidence of lymph node micrometastases (LNMs) and its prognostic significance.

Role of podoplanin expression in squamous cell carcinoma of upper aerodigestive tract.

Podoplanin, a type-1 transmembrane glycoprotein, was originally named due to its expression in renal podocytes of rats. It was subsequently detected in a variety of normal human tissues, including lymphatic endothelium. Although podoplanin has been identified as the endogenous ligand of C-type lectin-like receptor 2 (CLEC-2) on platelets, its physiological functions and pathways remain largely unknown. A role in lymphangiogenesis has been suggested, since podoplanin-deficient mice were found to die at birth with a phenotype of dilated, malfunctioning lymphatic vessels and lymphedema. Podoplanin is invariably expressed in some tumors, such as lymphangioma, seminoma and follicular dendritic cell tumor, but tumor cell expression of podoplanin is highly variable in squamous cell carcinoma (SCC). It has been found that high podoplanin expression is associated with lymph node metastasis and poor prognosis in SCC of the upper aerodigestive tract. Now there is growing evidence that podoplanin is also involved in carcinogenesis, cell motility, tumor invasiveness, platelet aggregation and hematogenous metastasis. Additionally, animal studies confirmed some in vivo effects of podoplanin-overexpressing tumors, including formation of more tumor lymphatic vessels, larger lymph node metastases, more platelet aggregation, and more pulmonary metastases. Several recently developed anti-podoplanin antibodies, such as NZ-1, P2-0 and hP2-0, have been shown to attenuate podoplanin-induced platelet aggregation and prevent experimental hematogenous metastasis in nude mice. These antibodies may be applied in preclinical and clinical studies to evaluate the possibility of podoplanin-targeted therapy.

Transketolase Serves a Poor Prognosticator in Esophageal Cancer by Promoting Cell Invasion via Epithelial-Mesenchymal Transition

Background: To characterize the potential function and clinical significance of Transketolase (TKT) in esophageal cancer. Methods: High invasive esophageal squamous cell carcinoma (ESCC) cell line CE48T/VGH was used. Cellular functions in response to TKT modulation were examined, including cell growth, migration and invasion. The underlying molecules involved in the TKT regulatory mechanism were determined by western blot and confocal microscopic analysis. Clinically, TKT expressions in 76 ESCC patients were assessed by immunohistochemical (IHC) method, and the association with treatment outcome was determined. Results: TKT silencing inhibited cell migration and invasion but had a minimal effect on cell growth. This TKT silencing also induced the reversion of epithelial-mesenchymal transition (EMT), as evidenced by the spindle to cuboidal morphological change, increased the expression of epithelial markers (γ-catenin), and decreased the levels of mesenchymal markers (fibronectin and N-cadherin). Mechanically, TKT was shown to modulate the EMT through the pERK-Slug/Snail-associated signaling pathway. Clinically, a high level of TKT in the cancer tissues of patients with esophageal squamous cell carcinoma was associated with poor survival (P = 0.042). In the multivariate analysis, a high TKT level was also shown to be an independent unfavorable prognostic factor (Odds ratio: 1.827, 95% confidence interval: 1.045-3.196, P = 0.035). Conclusions: TKT contributes to esophageal cancer by promoting cell invasion via meditating EMT process. Clinically, the over-expression of TKT in ESCC patients predicts poorer survival. TKT inhibition may be a useful strategy to intervene in cancer cell invasion and metastasis, which may lead to better prognosis for ESCC patients.

Pleomorphic mantle cell lymphoma morphologically mimicking diffuse large B-cell lymphoma: common cyclin D1 negativity and a simple immunohistochemical algorithm to avoid the diagnostic pitfall

To characterize the clinicopathological and genetic features of pleomorphic mantle cell lymphoma (PMCL), which morphologically mimics diffuse large B cell lymphoma (DLBCL).

Characterization of residual tumours at the primary site in patients with a near pathological complete response after neoadjuvant chemoradiotherapy for oesophageal cancer.

A ‘surgery as needed’ strategy has been proposed for patients with oesophageal cancer who truly achieve a pathological complete response (pCR) following neoadjuvant chemoradiotherapy (nCRT). However, the ability to detect residual disease remains problematic. This study investigated the anatomical locations and pathological characteristics of residual cancer in patients with oesophageal squamous cell carcinoma (SCC) who achieved a near pCR following nCRT.

Low PD-L1 Expression Strongly Correlates with Local Recurrence in Epstein-Barr Virus-Positive Nasopharyngeal Carcinoma after Radiation-Based Therapy

The prognostic value of programmed death-ligand 1 (PD-L1) expression in nasopharyngeal carcinoma (NPC) is controversial, with previous studies showing conflicting results. Most NPCs in endemic areas are Epstein-Barr virus (EBV)-positive. Our aim was to evaluate the clinical significance of PD-L1 expression in EBV-positive NPC. We retrospectively analyzed PD-L1 expression on tumor cells (TCs) and immune cells (ICs) by immunohistochemistry in 208 EBV-positive NPC patients who underwent radiotherapy (203 with concurrent chemotherapy). The percentages of TCs and ICs expressing PD-L1 were evaluated respectively. There was a strong correlation between local recurrence and low PD-L1 expression on ICs (p = 0.0012), TCs (p = 0.013) or both (p = 0.000044), whereas all clinical parameters had no influence on local recurrence. Using multivariate analysis, low PD-L1 expression on ICs was an independent adverse prognostic factor (p = 0.0080; HR = 1.88; 95% CI = 1.18–3.00) for disease-free survival. High PD-L1 expression on both ICs and TCs was an independent favorable prognostic factor (p = 0.022; HR = 0.46; 95% CI = 0.24–0.89) for overall survival. We show for the first time that low PD-L1 expression on ICs and TCs strongly correlates with local recurrence in EBV-positive NPC patients after radiation-based therapy. A simple immunohistochemical study for PD-L1 can identify patients prone to local recurrence, and such patients might benefit from more aggressive treatment in future clinical trials.