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Background This study was conducted to validate a pretreatment (i.e. prior to neoadjuvant chemoradiotherapy) pathological staging system in the resection specimen after neoadjuvant chemoradiotherapy for esophageal cancer. The study investigated the prognostic value of pretreatment pathological T and N categories (prepT and prepN categories) in both an independent and a combined patient cohort. Methods Patients with esophageal cancer treated with neoadjuvant chemotherapy and esophagectomy between 2012 and 2015 were included. PrepT and prepN categories were estimated based on the extent of tumor regression and regressional changes of lymph nodes in the resection specimen. The difference in Akaike’s information criterion (ΔAIC) was used to assess prognostic performance. PrepN and ypN categories were combined to determine the effect of nodal sterilization on prognosis. A multivariable Cox regression model was used to identify combined prepN and ypN categories as independent prognostic factors. Results The prognostic strength of the prepT category was better than the cT and ypT categories (ΔAIC 7.7 vs. 3.0 and 2.9, respectively), and the prognostic strength of the prepN category was better than the cN category and similar to the ypN category (ΔAIC 29.2 vs. − 1.0 and 27.9, respectively). PrepN + patients who became ypN0 had significantly worse survival than prepN0 patients (2-year overall survival 69% vs. 86% in 137 patients; p = 0.044). Similar results were found in a combined cohort of 317 patients (2-year overall survival 62% vs. 85%; p = 0.002). Combined prepN/ypN stage was independently associated with overall survival. Conclusions These results independently confirm the prognostic value of prepTNM staging. PrepTNM staging is of additional prognostic value to cTNM and ypTNM. PrepN0/ypN0 patients have a better survival than prepN +/ypN0 patients.

The role of glucose transporter 14 (GLUT-14/SLC2A14) in tumor biology is entirely unknown, and the significance of hypoxia inducible factor 1-alpha (HIF1-α) for gastric adenocarcinoma is controversial. The impact of GLUT-1/SLC2A1 has never been confirmed in a Caucasian cohort. Between 1996 and 2007, 124 patients underwent gastrectomy for gastric adenocarcinoma. Tumor sections were incubated with GLUT-1, GLUT-14, and HIF1-α antibodies. Expression was analyzed for correlations with histopathology, marker coexpression, and patient survival by uni- and multivariate analyses. Expressions of GLUT-1, GLUT-14, and HIF1-α were detectable in 50, 77.4, and 27.1 %, respectively. Expression of GLUT-1 was associated with pT-category (p = 0.019), pN-category (p = 0.019), tubular (WHO, p = 0.008), and intestinal (Lauren classification; p = 0.002) histologic subtypes. Expression of GLUT-14 was correlated with pT category (p = 0.043), whereas HIF1-α did not show any correlation with histopathology or survival. The median survival period was 14 months (95 % confidence interval [CI] 9.2–18.8 months) for GLUT-1-positive patients and 55 months (95 % CI 25.8–84.2; p = 0.01) for GLUT-1-negative patients. An inferior prognosis also was seen for GLUT-14-positive cases compared with GLUT-14-negative cases (p = 0.004). Thus, worst survival was seen with both GLUT-1- and GLUT-14-positive expression followed by single-positive and then double-negative cases (p = 0.004). In multivariate analysis including International Union Against Cancer (UICC) stages, R category, Lauren classification, surgery alone versus neoadjuvant/perioperative chemotherapy, and marker expression as covariates, GLUT-1 (p = 0.011) and GLUT-14 (p = 0.025) kept their prognostic independence. The study findings suggest that detection of GLUT-1 and GLUT-14 is of high prognostic value. It gives additional information to UICC stages and identifies patients with inferior prognosis. If confirmed in prospective studies, these markers need to be considered for future classification systems.

Multiple studies have shown that promoter methylation of tumor suppressor genes underlies esophageal carcinogenesis. Hypothetically, methylation resulting in tumor suppressor gene inactivation might result in tumors that are unresponsive to chemotherapy and radiation. Accordingly, our aim was to investigate if aberrant methylation of the apoptosis-related gene Death-Associated Protein Kinase (DAPK) could be used as a predictor of response to neoadjuvant therapy in locally advanced cancer of the esophagus.Tumor and normal esophageal tissues were obtained from 50 patients with locally advanced cancer of the esophagus prior to neoadjuvant radiochemotherapy. DAPK methylation analysis was performed on all samples by methylation-specific real-time polymerase chain reaction (PCR).Seventeen (34%) patients showed a major and 33 (66%) a minor histomorphological response to neoadjuvant therapy. DAPK methylation was detectable in normal esophageal tissues with a frequency of 10% and in tumor tissue with a frequency of 78%. The median methylation level for DAPK was 2.7 x 10(-3) in tumor compared with 0.1 x 10(-3) in normal tissues (p0.001). DAPK methylation was not associated with response to neoadjuvant therapy or prognosis after esophagectomy.Aberrant DAPK methylation in tumor tissues is significantly higher compared with matching normal esophageal tissues, suggesting a fundamental role of this epigenetic alteration in the pathogenesis of this disease. The level of DAPK methylation in pretreatment biopsies of patients with locally advanced cancer of the esophagus is no marker for the prediction of histomorphological regression or prognosis following neoadjuvant chemoradiation in this disease.

There is increasing evidence regarding extracapsular lymph node involvement (LNI) as a prognostic factor for recurrence and poor prognosis in gastrointestinal malignancies. The aim of this study was to assess the prevalence and prognostic impact of LNI in patients with resected esophageal cancer, comparing adenocarcinoma (AC) and squamous cell carcinoma (SCC). Between 1997 and 2006, 243 consecutive patients with resected esophageal cancer without neoadjuvant therapy (103 SCC, 140 AC) were studied. A total of 738 lymph node metastases were reexamined. Survival was analyzed according to intra- and extracapsular LNI. Median survival in patients with extracapsular LNI was 13 months [range 11–14 months, 95% confidence interval (CI)] compared with 28 months (21–34 months, 95% CI) for those with intracapsular LNI alone (p = 0.017). Node-positive patients with AC showed a prevalence of 66% extracapsular LNI compared with 35% in patients with SCC (p < 0.001). The number of resected lymph nodes and the frequency of pN1 cases were comparable between AC and SCC. However the number of infiltrated LN was significantly (p = 0.005) higher in patients with pN1 AC (median = 5) compared with pN1 SCC (median = 3). We conclude that extracapsular LNI is an independent negative prognostic factor which occurs more frequently in esophageal AC than SCC.

Neoadjuvant treatment modalities for esophageal cancer were developed to improve local tumor control as well as to reduce lymph node metastases and distant metastases in patients with locally advanced esophageal cancer. The influence on nodal micrometastasis has not yet been evaluated.This study includes 52 patients with localized (cT2-4, Nx, M0) esophageal cancers (21 adenocarcinomas, 31 squamous cell cancers) who received neoadjuvant chemoradiation (36Gy, 5-FU, cisplatin) followed by transthoracic en bloc esophagectomy with two field lymphadenectomy. The extent of histomorphologic regression was categorized into major (10%) and minor response (10% vital residual tumor cells) as recently reported. A total of 1186 lymph nodes were diagnosed as negative for metastases by routine histopathological analysis and were further examined for the presence of isolated tumor cells with the monoclonal anti-epithelial antibody AE1/AE3.Twenty-two tumors (42.3%) showed a major histopathologic response whereas in 30 tumors (57.7%) only a minor response was present. Of 32 patients with a pN0 category, major response was present in 19 (59.4%) tumors, whereas 13 (40.6%) tumors showed minor response. Nine (69%) out of 13 patients with minor response had AE1/AE3-positive cells in their lymph nodes, whereas only four (21%) out of 19 pN0-patients with major response showed nodal micrometastasis (P = 0.013, chi(2)-test).If tumors show a major histomorphologic response following neoadjuvant chemoradiation, the presence of nodal micrometastasis is significantly reduced compared to those with minor response.

Extension of lymphadenectomy in gastric cancer is controversial, and preoperative diagnosis of lymph node metastases (LNM) is difficult. Therefore, knowledge-based systems such as the Maruyama computer program (MCP) are being developed. MCP shows good prognostic value for the compartments; however, for different lymph node groups (LNG) there are a large number of false positives. The aim of this study was to evaluate artificial neural networks (ANN) for predicting LNM in patients with gastric cancer and to compare the predictive power with that of MCP. A total of 135 consecutive patients who underwent D2 gastrectomy were included. We applied a single-layer perceptron to the data of 4302 patients from the National Cancer Center, Tokyo, and compared the results with those from the MCP. Prediction of N+ or N0 with ANN-1 (Borrmann classification, T category, and tumor size and location) had an accuracy of 79%. The predictive value for LNM in each of the LNG varied: ANN-1, 64% to 86%; MCP, 42% to 70%. We constructed another ANN by using the additional parameter of metastases in LNG 3 as an example of sentinel node. The accuracy of this ANN was 93%. Using an ANN, LNM in each LNG can be accurately predicted. Additional knowledge about one lymph node improves the results.

Currently, patients with locally advanced esophageal cancer receive neoadjuvant chemoradiotherapy but only about half of these patients benefit from this treatment. GNAS T393C has been shown to predict the postoperative course in solid tumors and may therefore be useful for treatment stratification. The aim of the present study was to determine if the single-nucleotide polymorphism GNAS T393C can be used for treatment stratification in esophageal cancer patients. A total of 596 patients underwent surgical resection for esophageal carcinoma from 1996 to 2008; 279 patients received chemoradiotherapy prior to surgery (RTX-SURG group). All patients and a reference group of 820 healthy White individuals were genotyped for GNAS T393C. The 5-year-survival rate for the 317 patients who underwent esophagectomy as initial treatment (SURG group) was 57 % for homozygous C-allele carriers (n = 99) and 43 % for T-allele carriers (n = 218; log- rank test p = 0.025). Multivariate analysis revealed the GNAS T393C genotype (p = 0.034), pT (p

Studies have shown that along with primary tumor response, lymph node status after RTx/CTx is one of the most important prognostic factors for advanced esophageal carcinoma. The goal of our study was to investigate the influence of neoadjuvant radiochemotherapy (RTx/CTx) on lymph nodes (LN). From 1997 until 2006, 297 patients underwent surgery for advanced esophageal carcinoma. Of these, 192 received preoperative chemoradiation (5-FU, cisplatin, 36 Gy). The following matched subgroups were chosen: Group I, 20 with surgery alone: 10 adenocarcinoma (AC), 10 squamous cell carcinoma (SCC); Group II, 20 with minor response (10 AC, 10 SCC); Group III, 20 with major response (10 AC, 10 SCC). Tumor response was graded as “minor” or “major” according to the Cologne Regression Scale, the LN size determined by the largest measured diameter. A total of 1967 LNs from 60 patients were examined. Of these, 161 LNs showed metastasis. The median number of LNs examined per patient was not significantly higher in group I compared with the group with pretreatment (32 vs 31). Group I and group II showed LN metastasis (LNM) in 65% of cases, and group III in only 20% (p = 0.011). LNMs after pretreatment had significantly smaller median diameters (5.0 mm) than those without (7.0 mm) (p

The prognostic importance of various clinical variables (age, sex, association with myasthenia gravis), staging according to Masaoka, histologic type according to the Marino/Kirchner/Müller-Hermelink (MKM-H) classification, and residual tumor category (R category) was evaluated in a retrospective analysis.Eighty-two patients with epithelial thymic tumors (ETTs) treated in the period 1969-1993 were evaluated, and archived specimens were histologically reclassified according to the classification of MKM-H.Age, sex, and association with myasthenia gravis were of no prognostic importance. The R category is of significant prognostic importance, with 5- and 10-year survival rates of 93.6% and 87.3%, respectively, for R0 resections compared with 0% at 5 years for R1 and R2 resections (p0.001). Staging (Masaoka) proved to be a prognostic factor (5-/10-year survival: stage I, 100%/90.9%; II, 95%/88.2%; III, 55.9%/46.6%; and IV, 10.8%/ 10.8%; p0.001). Histologic typing according to MKM-H is also of significant prognostic importance (5/10 year survival: thymomas: medullary, 100%/100%; mixed, 100%/100%, predominantly cortical, 68.6%/68.6%; cortical, 65.8%/65.8%; thymic carcinomas: well-differentiated type, 62.3%/44.5%; thymic carcinomas other than well-differentiated type, 33.6%/26.9%; p0.001). Multivariate analysis demonstrated that staging (p0.001), R category (p0.026), and MKM-H classification (p0.028) have an independent impact on survival.Staging (Masaoka), R category, and histologic classification (MKM-H) are important independent prognostic factors for patients with epithelial thymic tumors. Complete (R0) surgical resections should be the ultimate goal in the clinical management of patients with epithelial thymic tumors.