Prognostic significance of the endoscopic ultrasound defined lymph node metastasis count in esophageal cancer

The key prognostic factor which predicts outcome after esophagectomy for cancer is the number of malignant lymph node metastases, but data regarding the accuracy of endoscopic ultrasound (EUS) in determining and predicting the metastatic lymph node count preoperatively are limited. The aim of this study was to assess the prognostic significance of EUS defined lymph node metastasis count (eLNMC) in patients diagnosed with esophageal cancer. Two hundred and sixty‐seven consecutive patients (median age 63 years, 187 months) underwent specialist EUS followed by stage directed multidisciplinary treatment (183 esophagectomy [64 neoadjuvant chemotherapy, 19 neoadjuvant chemoradiotherapy], 79 definitive chemoradiotherapy, and 5 palliative therapy). The eLNMC was subdivided into four groups (0, 1, 2 to 4, >4) and the primary measure of outcome was survival. Survival was related to EUS tumor (T) stage (P < 0.0001), EUS node (N) stage (P < 0.0001), EUS tumor length (p < 0.0001), and eLNMC (P < 0.0001). Multivariable analysis revealed EUS tumor length (hazard ratio [HR] 1.071, 95% CI 1.008–1.138, P= 0.027) and eLNMC (HR 1.302, 95% CI 1.133–1.496, P= 0.0001) to be significantly and independently associated with survival. Median and 2‐year survival for patients with 0, 1, 2–4, and >4 lymph node metastases were: 44 months and 71%, 36 months and 59%, 24 months and 50%, and 17 months and 32%, respectively. The total number of EUS defined lymph node metastases was an important and significant prognostic indicator.     

Original article: Upregulation of caspase‐3 expression in esophageal cancer correlates with favorable prognosis: an immunohistochemical study from a high incidence area in northern China

Caspase‐3 plays an important role as the key effector during apoptosis, but there are very few studies of caspase‐3 in esophageal squamous cell carcinoma (ESCC). The purpose of this study was to investigate the expression and prognostic significance of caspase‐3 in ESCC from Linzhou City, a high incidence area in northern China. All 64 patients underwent esophagectomy for ESCC between January 2002 and December were enrolled in this study. Caspase‐3 expression was assessed by immunohistochemistry (IHC) in primary ESCC and paired normal esophageal epithelium. The positive rate of caspase‐3 expression was higher in ESCC than in normal esophageal epithelium (79.7% vs. 50.0%, Chi‐square = 12.372, P= 0.001). Caspase‐3 expression was correlated with tumor cell differentiation (Phi = 0.717, P < 0.001), tumor infiltration depth (Phi =?0.334, P= 0.008), and pathologic TNM (pTNM) staging (rs =?0.268, P= 0.032). Patients in caspase‐3 positive group had a significantly better 5‐year overall survival than those in the negative group (77.4% vs. 35.9%, χ²= 7.344, P= 0.007). Our results showed that caspase‐3 expression was upregulated in ESCC compared with normal esophageal epithelium in population of Chinese high incidence area, and patients with caspase‐3 positive expression had better prognosis. Therefore, caspase‐3 immunostaining could be a simple and useful tool for predicting survival in ESCC patients.     

Prognostic impact of eosinophils in peripheral blood and tumor site in patients with esophageal squamous cell carcinoma treated with concurrent chemoradiotherapy

To date, no effective biological markers have been identified for predicting the prognosis of esophageal cancer patients. Recent studies have shown that eosinophils are independent prognostic factors in some cancers. This study aimed to identify the prognostic impact of eosinophils in esophageal squamous cell carcinoma patients treated with concurrent chemoradiotherapy (CCRT).This study enrolled 136 patients who received CCRT for locally advanced unresectable esophageal squamous cell carcinoma (ESCC). We evaluated the survival time and clinical pathological characteristics of eosinophils. The Kaplan–Meier method was used to estimate survival data. The log-rank test was used for univariate analysis and the Cox proportional hazards regression model was used to conduct a multivariate analysis.Kaplan–Meier analysis revealed that high eosinophil infiltration correlated with better overall survival (OS) (P = .008) and better progression-free survival (PFS) (P = .015). The increase in absolute eosinophil count after CCRT also enhanced OS (P = .005) and PFS (P = .007). The PFS and OS in patients with high blood eosinophil count before CCRT (>2%) was better than those with low blood eosinophil count(<2%) (P = .006 and P = .001, respectively). Additionally, the multivariate analysis revealed that disease stage and high eosinophil infiltration, increased peripheral blood absolute eosinophil count after CCRT, and high peripheral blood eosinophil count before CCRT were independent prognostic indicators.High eosinophil count of tumor site, increased peripheral blood absolute eosinophil count after CCRT, and high peripheral blood eosinophil count before CCRT are favorable prognostic factors for patients with ESCC treated with CCRT.     

The expression of CXCR4 and its relationship with matrix metalloproteinase‐9/vascular endothelial growth factor in esophageal squamous cell cancer

Esophageal cancer (EC) is a highly aggressive neoplasm with poor prognosis. The main reason for this disappointing outcome is the strong behavior of esophageal cancer cell's invasion and metastasis. CXC chemokine receptor 4 (CXCR4) was found to be expressed in many tumors and significantly correlated with invasion, angiogenesis, metastasis, and prognosis. In the present study, we investigated the expressions of CXCR4, matrix metalloproteinase‐9 (MMP‐9), and vascular endothelial growth factor (VEGF) in esophageal squamous cell cancer (ESCC) and analyzed the relationship among the three proteins. Sections of paraffin‐embedded tissues were obtained from 127 patients with ESCC undergoing esophagectomy at Zhongshan Hospital, Fudan University in 2005. The CXCR4, MMP‐9, and VEGF expressions in EC tissues were evaluated according to the immunohistochemical staining area and intensity. The correlations between patients' prognosis and covariates were analyzed by Kaplan–Meier method (univariate analysis) and Cox regression (multivariate analysis). The overall expression rate of CXCR4, MMP‐9, and VEGF was 88.2%, 93.7%, and 79.5%, respectively. CXCR4 expression was significantly associated with tumor grade, tumor size, tumor depth, regional lymph node metastasis, and tumor, node, metastasis (TNM) stage (P < 0.05). MMP‐9 expression was significantly associated with age and tumor grade (P < 0.05). VEGF expression was significantly associated with tumor grade, tumor depth, and TNM stage (P < 0.05). CXCR4 expression was positively correlated with MMP‐9 expression (P < 0.01, r= 0.365) and VEGF expression (P < 0.01, r= 0.380). However, there was no significant correlation between MMP‐9 and VEGF expression (P > 0.05). In univariate analysis, CXCR4 expression, tumor size, tumor depth, lymph node metastasis, and TNM stage were correlated with patients' prognosis (P < 0.05); in multivariate analysis, tumor size and lymph node metastasis were the independent factors of poor prognosis. CXCR4 was highly expressed in ESCC and correlated with MMP‐9, VEGF, clinicopathological features and prognosis. We speculated CXCR4 play an important role during the progression of this disease and there might be some regulatory mechanism existing between CXCR4 and MMP‐9/VEGF in ESCC.     

Comparison of the prognostic value of the 6th and 7th editions of the Union for International Cancer Control TNM staging system in patients with lower esophageal cancer undergoing neoadjuvant chemotherapy followed by surgery

Carcinoma of the esophagus is classified according to the Union for International Cancer Control (UICC) TNM staging system. The 7th edition of the UICC TNM staging system was published in 2009. This is the first study to compare the prognostic value of the TNM 6th and 7th editions in patients with esophageal carcinoma treated with chemotherapy followed by surgery. Two hundred forty‐three patients with esophageal carcinoma were retrospectively selected from two referral centers. All patients received chemotherapy before surgery. Histopathologic data from the resection specimens were retrieved and restaged according to the TNM 7th edition. Disease‐specific survival curves were plotted for depth of tumor invasion (ypT), lymph node status (ypN), and ypTNM stage and then compared. Median follow‐up after surgery was 2.5 years (range 0.2–9 years). Survival analysis using the log‐rank method revealed that there was a significant difference in survival between ypT4 disease and ypT3 disease (P= 0.003), but no difference between ypT0, ypT1, ypT2, and ypT3 categories irrespective of TNM edition used. Survival probability was significantly different between ypN0 and ypN1 (P= 0.001 for TNM 6th and 7th edition), as well as ypN2 and ypN3 (TNM 7th edition, P= 0.004), but not between ypN1 and ypN2 (TNM 7th edition, P= 0.89). Neither the TNM 6th nor 7th edition T staging provides accurate survival probability stratification. However, the advantage of the 7th edition is the introduction of a third tier in survival stratification for patients with nodal involvement.     

Common single nucleotide polymorphism of hypoxia‐inducible factor‐1α and its impact on the clinicopathological features of esophageal squamous cell carcinoma

OBJECTIVE: Angiogenesis is one of the most important molecular events in solid tumor development and growth, in which hypoxia‐inducible factor (HIF)‐1α is a key regulator and plays an important role. Studies have shown that a single nucleotide polymorphism (C1772T) in the HIF‐1α gene exerts a large effect on the phenotype of human head and neck squamous cell carcinoma and renal cell carcinoma. But the impact of the C1772T polymorphism on the clinicopathological features of human esophageal squamous cell carcinoma (ESCC) remains unknown, and thus it is the main focus of our study. METHODS: The C1772T genotype of 95 ESCC patients and 104 healthy controls were studied by using the polymerase chain reaction and restriction fragment length polymorphism. Mutations were confirmed by direct DNA sequencing. The impact of C1772T on tumor size, invasive depth, lymph node metastasis, distant metastasis, histological grade and TNM stage was also studied. RESULTS: The genotype frequency observed in the patients and controls was 11.58% versus 10.58%, respectively, for genotype C/T (P > 0.05). Genotype T/T was not found in our study. Larger tumors and a higher rate of lymph node metastasis was found for the C/T group. CONCLUSIONS: Although there is no significant difference of genotype distribution between ESCC patients and healthy controls, genotype C/T is associated with larger tumor and higher rate of lymph node metastasis.     

Clinical effect of E‐series of prostaglandin receptor 2 and epidermal growth factor receptor signal pathways in the development of esophageal squamous cell carcinoma

Signal pathways mediated by epidermal growth factor receptor (EGFR) and E‐series of prostaglandin receptors (EPs) are closely correlated to the pathogenesis of tumor. This experiment was designed to investigate the expression and clinical significance of EP2 and EGFR in esophageal squamous cell carcinoma (ESCC). Tissue samples were collected reterospectively from 87 patients with ESCC (first diagnosed). The patients were followed up for 5 years after radical surgery. The expression of EP‐2 and EGFR were examined by tissue chip technology and immunohistochemistry methods. Clinicopathological and prognostic impact were evaluated. Overexpression of EGFR and EP‐2 was more observed in ESCC than the control group (58.6% vs. 13.9%; 52.9% vs. 4.88%, P < 0.001, respectively); which correlated with tumor infiltration depth, lymph node metastasis, and tumor‐lymph node‐metastasis staging. Both the EP‐2 and EGFR overexpression were detected in 39 specimens and exhibited the positive correlation (P < 0.001, r = 0.404). Overexpression of EP2 and EGFR exhibited significant correlation with worse 5‐year overall survival than those with negative result (17.6% vs. 27.8%, P = 0.011; 10.9% vs. 34.1%, P < 0.001, respectively). Cox proportional hazard model showed that the T‐staging, lymph node metastasis, and EGFR overexpression were the independent risk factors of the prognosis. The present study exhibited that the overexpression of EP2 and EGFR in ESCC tissues might play an important role in carcinogenesis and the progression of ESCC.     

Association between the thoroughness of the histopathological examination and survival in patients with esophageal squamous cell carcinoma who achieve pathological complete response after chemoradiotherapy

The College of American Pathologists guidelines recommend examining at least four representative tumor blocks for determining pathological T stage in patients with primarily resected esophageal cancer. Whether the same pathological requirements are adequate in patients undergoing esophagectomy following neoadjuvant chemoradiotherapy (nCRT) remains unclear. We hypothesized that current examination protocols may underestimate the presence of microscopical residual disease after nCRT, potentially leading to under‐staging. We retrospectively reviewed the records of patients with esophageal squamous cancer (ESCC) who were diagnosed as having pathological complete response (pCR) following nCRT. The thoroughness of the pathological examination in pCR patients was examined using (i) the number of blocks examined in suspicious tumor area (≤4 vs. >4), and (ii) the block quotient (calculated as the pretreatment tumor length divided by the number of blocks examined in suspicious tumor area). A total of 91 patients were enrolled. The mean number of blocks used to confirm pCR was 4.8 (range: 2–14). The 5‐year overall survival (OS) and disease‐free survival (DFS) in the entire cohort were 55% and 65%, respectively. Multivariate analyses identified the block quotient as the only independent predictor of OS and DFS. Receiver operating characteristic curve analysis indicated an optimal cutoff value of 1.4 for the block quotient. Among the patients who achieved pCR, the 5‐year DFS differed significantly between subjects with a low (≤1.4) or high (>1.4) block quotient (76% vs. 47%, respectively, P = 0.03). The block quotient (calculated by the pretreatment tumor length divided by the number of blocks) – which reflects the meticulousness of the histopathological examination for confirming pCR – is associated with survival in ESCC patients.     

Factors associated with the efficacy of miniprobe endoscopic ultrasonography after conventional endoscopy for the prediction of invasion depth of early gastric cancer

Background: This study aimed to compare the accuracy of conventional endoscopy (CE) and endoscopic ultrasonography (EUS) to predict tumor invasion depth and to determine factors associated with higher accuracy of additional miniprobe EUS after CE.

Methods: Between May 2009 and February 2015, 273 lesions in 266 patients were subjected to miniprobe EUS after CE and curative treatment for well-to-moderately differentiated early gastric cancer (EGC). We reviewed preoperative CE and EUS findings and compared them to the pathologic findings.

Results: The accuracy of CE and EUS to estimate the invasion depth of EGCs was 78.8% (215/273) and 83.9% (229/273) (p?=?.124), respectively. Using multivariate analysis, irregular depressed surface (odds ratio [OR] 8.11; 95% confidence interval [CI]: 2.79–23.53), fold change (OR 7.22; 95% CI: 2.33–22.38), size >2?cm (OR 2.72; 95% CI: 1.15–6.42) and ulcer scar (OR 2.64; 95% CI: 1.07–6.49) were associated with the higher accuracy of EUS than that of CE.

Conclusions: Routine assessment using miniprobe EUS did not increase the accuracy of predicting invasion depth, compared to CE. However, EUS could be helpful in the treatment decision-making process for EGCs with lesions having irregular surfaces, fold change, size >2?cm, or ulcer scar.     

Concordance of studies for nodal staging is prognostic for worse survival in esophageal cancer

Pretreatment clinical staging in esophageal cancer influences prognosis and treatment strategy. Current staging strategies utilize multiple imaging modalities, and often the results are contradictory. No studies have examined the implications of concordance of computed tomography (CT), positron emission tomography (PET), and endoscopic ultrasound (EUS) when used for the evaluation of nodal disease. The objective of this study was to determine if concordance of CT, PET, or EUS for nodal disease predicts worse overall survival. We reviewed 615 esophageal cancer patients with pretreatment CT, PET, and EUS that underwent esophagectomy for survival outcomes based on concordance of studies for nodal disease. Concordant N+ is defined as two or three studies positive for nodal disease; non‐concordant N+ is defined as only one positive study. Node‐positive disease by any study predicted shorter survival than node‐negative disease (42% vs. 73% 5‐year survival; P < 0.001). Additionally, non‐concordant N+ patients had shorter survival than N? patients (52% vs. 73% 5‐year survival; P < 0.001). Concordant N+ patients had shorter survival than non‐concordant N+ patients (38‐ vs. 61‐month median survival; P = 0.017). There were no statistically significant differences in survival based on specific combinations of studies. When PET was disregarded, patients with both CT+ and EUS+ had shorter survival than patients with either CT+ or EUS+ (39‐ vs. 58‐month median survival; P = 0.029). Pretreatment CT, PET, or EUS concordance for node‐positive disease predicts shorter overall survival in patients that undergo esophagectomy for esophageal cancer. Predicting survival in esophageal cancer should consider the synergistic capabilities of CT, PET, and EUS in evaluating nodal status.     

Prognostic and clinical impact of sarcopenia in esophageal squamous cell carcinoma

Recently, depletion of skeletal muscle mass (sarcopenia) has been linked to poor prognosis in several types of cancers, but has not been investigated in esophageal squamous cell carcinoma (ESCC). This retrospective study investigates the relationship between sarcopenia and clinical outcome in ESCC patients treated by surgical resection or definitive chemoradiation therapy (dCRT). The study was retrospectively conducted in a single academic hospital in Kumamoto, Japan, and involved 325 ESCC patients (256 surgical cases and 69 dCRT cases) treated between April 2005 and April 2011. Skeletal muscle mass was quantified by radiologic measures using standard computed tomography scans. The skeletal muscle tissue in the 325 ESCC patients was distributed as follows: mean: 47.10; median: 46.88; standard deviation (SD): 7.39; range: 31.48–71.11; interquartile range, 46.29–47.90. Skeletal muscle tissue was greater in male patients than in female patients (P < 0.0001), but was independent of other clinical and tumor features. Sarcopenia was not significantly associated with overall survival (log rank P = 0.54). Lymph node involvement significantly altered the relationship between sarcopenia and survival rate (P for interaction = 0.026). Sarcopenia significantly reduced the overall survival of patients without lymph node involvement (log rank P = 0.035), but was uncorrelated with overall survival in patients with lymph involvement (log rank, P = 0.31). The anastomosis leakage rate was significantly higher in the sarcopenia group than in the non‐sarcopenia group (P = 0.032), but other surgical complications did not significantly differ between the two groups. Sarcopenia in ESCC patients without lymph node involvement is associated with poor prognosis, indicating sarcopenia as a potential biomarker for identifying patients likely to experience an inferior outcome. Moreover, sarcopenia was associated with anastomosis leakage but no other short‐term surgical outcome.     

Comparison of salvage chemoradiation versus salvage surgery for recurrent esophageal squamous cell carcinoma after definitive radiochemotherapy or radiotherapy alone

A consensus treatment strategy for esophageal squamous cell carcinoma (ESCC) patients who recur after definitive radiochemotherapy/radiotherapy has not been established. This study compared the outcomes in ESCC patients who underwent salvage surgery, salvage chemoradiation (CRT) or best supportive care (BSC) for local recurrence. Ninety‐five patients with clinical stage I to III ESCC who had completely responded to the initial definitive radiochemotherapy or radiotherapy alone and developed local recurrence were enrolled in this study. Fifty‐one of them received salvage esophagectomy, and R0 resection was performed in 41 patients, 36 underwent salvage CRT, and the remaining eight patients received BSC only. The 5‐year overall survival was 4.6% for the 87 patients receiving salvage surgery or CRT, while all patients in the BSC group died within 12.0 months, the difference was statistically significant (P = 0.018). The 1‐, 3‐, 5‐year survival rates in the salvage surgery and salvage CRT groups were 45.1%, 20.0%, 6.9% and 51.7%, 12.2%, 3.1%, respectively, there was no difference of overall survival between the two groups (P = 0.697). Patients also presented with lymph node relapse had inferior survival compared to those with isolated local tumor recurrence after salvage therapy. In the salvage surgery group, infections occurred in eight patients, and three developed anastomotic leakage. In the salvage CRT group, grade 2–4 esophagitis and radiation pneumonitis was observed in 19 and 3 patients, respectively. Seven patients (19.4%) developed esophagotracheal fistula or esophageal perforation. This study of salvage CRT versus salvage surgery for recurrent ESCC after definitive radiochemotherapy or radiotherapy alone did not demonstrate a statistically significant survival difference, but the frequency of complications including esophagotracheal fistula and esophageal perforation following salvage CRT was high.     

Prognostic relevance and therapeutic implications of centromere protein F expression in patients with esophageal squamous cell carcinoma

Centromere protein F (CENP‐F), a cell cycle‐regulated centromere protein, has been shown to affect numerous tumorigenic processes. This study aimed to clarify the prognostic significance of CENP‐F expression in patients with esophageal squamous cell carcinoma (ESCC). The levels of CENP‐F messenger RNA and protein were higher in ESCC cell lines than in the normal tissues. An immunohistochemical analysis of paired tissue specimens showed that the CENP‐F expression was higher in tumorous tissues than in the adjacent non‐tumorous tissues (P < 0.001). Moreover, there was a significant correlation between CENP‐F expression and gender (P = 0.012), clinical stage (P = 0.039), and T classification (P = 0.026). Patients with higher CENP‐F expression had shorter overall survival than those with lower CENP‐F expression (P = 0.009). Multivariate Cox analysis indicated that CENP‐F expression is an independent prognostic factor for overall survival (hazard ratio = 0.582, 95% confidence interval = 0.397–0.804, P = 0.041). Importantly, it was found that zoledronic acid (ZOL) could significantly enhance the chemotherapeutic sensitivity of ESCC cell lines with high CENP‐F expression to cisplatin, although ZOL alone only exhibited a minor inhibitory effect to ESCC cells. In summary, these findings demonstrate that CENP‐F may serve as a valuable molecular marker for predicting the prognosis of ESCC patients. In addition, the data indicate a potential benefit of combining ZOL with cisplatin in ESCC, suggesting that CENP‐F expression may have therapeutic implications.     

Clinicopathological significance of cyclooxygenase‐2 and cell cycle‐regulatory proteins expression in patients with esophageal squamous cell carcinoma

The aim of this study was to examine the expression of the molecular markers cyclooxygenase‐2 (COX‐2), Ki‐67, cyclin A, and p27 in patients with esophageal squamous cell carcinoma (ESCC), to ascertain the relationship of these makers with the clinicopathological significance of the patients, and to assess the additional prognostic value of the expression profile of these proteins for ESCC patients. The expression levels of COX‐2, Ki‐67, cyclin A, and p27 proteins of a series of primarily resected ESCC samples were determined by immunohistochemistry method. Clinicopathological and molecular factors affecting survival were analyzed by multivariate analysis. A total of 78 specimens were included in this study. Expression of COX‐2 was observed in 43 (55.1%) cases, and high levels of expression of Ki‐67, p27, and cyclin A were observed in 57 (73.0%), 33 (42.3%), 43 (55.1%) cases, respectively. The results of univariate survival analysis indicated that more advanced tumor stage, lymph node involvement, systemic dissemination, the levels of expression of COX‐2, Ki‐67, cyclin A, and p27 were associated with survival (all P‐value < 0.05). Multifactorial survival analysis revealed that only lymph node involvement, over‐expression of cyclin A, and low p27 expression were associated with the survival of the patients (hazard ratios = 2.83, 4.7, 2.9, respectively; P= 0.025, 0.042, 0.005, respectively). Among the molecular markers assessed, the expression of cell proliferation markers cyclin A and p27 are independent prognostic factors in patients with ESCC, whereas neither COX‐2 nor Ki‐67 is of independent prognostic value.     

Impact of body mass index on postoperative complications and long‐term survival in patients with esophageal squamous cell cancer

Undernutrition and cachexia have been suggested to be risk factors for postoperative complications and survival in cancer patients. The aim of this study was to investigate whether body mass index (BMI) is related to the short‐term and long‐term outcomes in patients who undergo an esophagectomy for the resection of esophageal squamous cell cancer (ESCC). Three hundred forty patients who underwent an esophagectomy for the resection of ESCC between 2003 and 2008 were retrospectively reviewed. The patients were divided into two groups: an L‐BMI group characterized by a BMI < 18.5 kg/m² and an N‐BMI group characterized by a BMI ≥ 18.5 kg/m². Clinical and pathological outcome were compared between groups. The study included 40 patients in the L‐BMI group and 300 patients in the N‐BMI group. A clinicopathological assessment showed that nodal involvement was seen more frequently in the L‐BMI group (P = 0.016). Pulmonary complications seemed to occur more frequently in the L‐BMI group (P = 0.006). The 5‐year overall survival rate was higher in the N‐BMI group (63.6%) than in the L‐BMI group (32.3%) (P < 0.001). The 5‐year disease‐free survival rate was also higher in the N‐BMI group (58.0%) than in the L‐BMI group (33.6%) (P = 0.001). In multivariate analysis, the BMI (hazard ratio, 2.154; 95% CI, 1.349–3.440, P = 0.001) was found to be an independent prognostic factor for overall survival. Our data suggested that a lower BMI not only increased pulmonary complications but also impaired overall and disease‐free survival after an esophagectomy for the resection of ESCC.     

Comparative study between endoscopic ultrasonography and positron emission tomography‐computed tomography in staging patients with esophageal squamous cell carcinoma

Treatment strategy of esophageal cancer mainly depends on accurate staging. At present, no single ideal staging modality is superior to another in preoperative tumor‐node‐metastasis (TNM) staging of patients with esophageal cancer. We aimed to investigate the efficacy of endoscopic ultrasonography (EUS) and positron emission tomography‐computed tomography (PET‐CT) for staging of esophageal cancer. We retrospectively studied 118 consecutive patients with esophageal squamous cell carcinoma who underwent esophagectomy with or without neoadjuvant chemoradiotherapy (CRT) over a near 3‐year period between January 2005 and November 2008 at a tertiary hospital in Taiwan. Patients were separated into two groups: without neoadjuvant CRT (group 1, n= 28) and with CRT (group 2, n= 90). Medical records of demographic data and reports of EUS and PET‐CT of patients before surgery were reviewed. A database of clinical staging by EUS and PET‐CT was compared with one of pathological staging. The accuracies of T staging by EUS in groups 1 and 2 were 85.2% and 34.9%. The accuracies of N staging by EUS in groups 1 and 2 were 55.6% and 39.8%. The accuracies of T and N staging by means of PET‐CT scan were 100% and 54.5% in group 1, and were 69.4% and 86.1% in group 2, respectively. In group 2, 38 of 90 patients (42.2%) achieved pathologic complete remission. Among them, two of 34 (5.9%) and 12 of 17 (70.6%) patients were identified as tumor‐free by post‐CRT EUS and PET‐CT, respectively. EUS is useful for initial staging of esophageal cancer. PET‐CT is a more reliable modality for monitoring treatment response and restaging. Furthermore, the accuracy of PET‐CT with regard to N staging is higher in patients who have undergone CRT than those who have not.     

Three‐dimensional telomere architecture of esophageal squamous cell carcinoma: comparison of tumor and normal epithelial cells

Telomeres are repetitive nucleotide sequences (TTAGGG)n located at the ends of chromosomes that function to preserve chromosomal integrity and prevent terminal end‐to‐end fusions. Telomere loss or dysfunction results in breakage–bridge–fusion cycles, aneuploidy, gene amplification and chromosomal rearrangements, which can lead to genomic instability and promote carcinogenesis. Evaluating the hypothesis that changes in telomeres contribute to the development of esophageal squamous cell carcinoma (ESCC) and to determine whether there are differences between young and old patients, we compared the three‐dimensional (3D) nuclear telomere architecture in ESCC tumor cells with that of normal epithelial cells obtained from the same patient. Patients were equally divided by age into two groups, one comprising those less than 45 years of age and the other consisting of those over 80 years of age. Tumor and normal epithelial cells located at least 10 cm from the border of the tumor were biopsied in ESCC patients. Hematoxylin and eosin staining was performed for each sample to confirm and identify the cancer and normal epithelial cells. This study was based on quantitative 3D fluorescence in situ hybridization (Q‐FISH), 3D imaging and 3D analysis of paraffin‐embedded slides. The 3D telomere architecture data were computer analyzed using 100 nuclei per slide. The following were the main parameters compared: the number of signals (number of telomeres), signal intensity (telomere length), number of telomere aggregates, and nuclear volume. Tumor and normal epithelial samples from 16 patients were compared. The normal epithelial cells had more telomere signals and higher intensities than the tumor cells, with P‐values of P < 0.0001 and P = 0.0078, respectively. There were no statistically significant differences in the numbers of telomere aggregates or the nuclear volumes between the tumor and normal epithelial cells. Secondary analyses examined the effects of age on 3D telomere architecture and found no statistically significant differences in any parameter tested between the young and old patients in either the tumor or epithelial cells. The 3D nuclear telomeric signature was able to detect differences in telomere architecture between the ESCC and normal epithelial tissues. However, there were no differences observed between the young and old patients.     

Early on-treatment predictions of clinical outcomes using alpha-fetoprotein and des-gamma-carboxy prothrombin responses in patients with advanced hepatocellular carcinoma

Background and Aim: The clinical utility of alpha‐fetoprotein (AFP) and des‐γ‐carboxy prothrombin (DCP) as a predictor of treatment outcome in patients with advanced hepatocellular carcinoma (HCC) receiving hepatic artery infusional chemotherapy (HAIC) or concurrent chemoradiation therapy (CCRT) has been poorly defined. Methods: Between January 2003 and December 2007, we enrolled 127 treatment‐naïve patients who received HAIC (n = 60) or CCRT (n = 67) as an initial treatment modality. An AFP or DCP response was defined as a reduction of more than 20% from the baseline level. Results: AFP responders showed significantly better overall survival (OS) than non‐responders among patients with HAIC (median 17.3 vs 6.4 months, P < 0.001) and with CCRT (median 17.6 vs 8.7 months, P = 0.014). DCP responders in the CCRT group also showed significantly better progression‐free survival (PFS) than non‐responders (median 9.2 vs 3.1 months, P < 0.001). Multivariate Cox regression analyses showed that AFP response was independently predictive of OS in both groups (P = 0.009 in HAIC and P = 0.008 in CCRT) whereas DCP only predicted PFS in patients with CCRT (P = 0.015). Conclusions: Early on‐treatment AFP response was predictive of OS in treatment‐naïve patients with advanced HCC receiving HAIC and CCRT as an initial treatment modality. Furthermore, DCP response was useful for predicting PFS in patients with CCRT.     

Expression and prognostic relevance of p21WAF1 in stage III esophageal squamous cell carcinoma

The prognostic effect of p21^WAF1 expression on esophageal squamous cell carcinoma patients is controversial. Further clarifying the effect of this protein is beneficial for optimizing the patient outcomes. In the current study, we investigated the expression of p21^WAF1 protein in 189 specimens of stage III ESCC by immunohistochemistry. As shown by the Kaplan–Meier curve, the overall survival rate of the positive‐expression group was significantly higher than that of the negative‐expression group (P < 0.05). No significant correlation was observed between p21^WAF1 expression and clinicopathological parameters in terms of gender, age, tumor location, tumor grade, pathological stage, and number of regional lymph node metastases (P > 0.05). We concluded that p21^WAF1 played an intricate role in the tumorigenesis and development of ESCC. p21^WAF1 could serve as a positive prognostic predictor for stage III ESCC patients.