Premature mortality for patients after completely resected early adenocarcinoma of the esophagus or stomach.

OBJECTIVE: To establish the life expectancy burden of esophago-gastric cancer by analyzing years of life lost (YLL) for a Western patient population after treatment of early esophageal (EAC) or early gastric (GAC) adenocarcinoma. BACKGROUND: For patients with early EAC or GAC, the short-term prognosis after surgical resection is very good. Little data is available regarding long-term prognosis when compared to the general population. METHODS: Two hundred and fourteen patients with pT1 EAC (n = 112) or GAC (n = 102) were included in the study. Patients with EAC underwent transthoracic en-bloc esophagectomy; those with GAC had total or subtotal gastrectomy with D2-lymphadenectomy. Surviving patients had a median follow-up of approximately 14 years. YLL was calculated using average life expectancy data from Germany. RESULTS: Patients with EAC were younger (median age 61 years) than those with GAC (66 years) (p = 0.031). The male:female ratio was 10:1 for EAC and 3:2 for GAC (p < 0.001). Multivariate survival analysis showed the age of the patients ≥60 years and the existence of lymph node metastasis was associated with poor prognosis. The median YLL for all patients who died over follow-up was 8.0 years. For patients under 60 years, it was approximately 20 years, and for older patients, approximately 5 years (p < 0.001) without difference in tumor stage between these age cohorts. YLL did not differ for GAC vs. EAC. CONCLUSION: After surgical resection, the prognostic burden as measured by YLL is relevant for all patients with early esophageal and gastric adenocarcinomas and especially for younger patients. Reasons for YLL need further studies.

Surgical approach to advanced Siewert II cancer: beyond the borders? The West Side.

The surgical approach to Siewert type II cancer should be individualized as there is no "one size fits all" option. Criteria for individualization are epidemiological, functional, oncologic and surgical items. However, our preferred procedure for advanced adenocarcinoma of the esophagogastric junction type II is esophagectomy, if this or transhiatal extended gastrectomy are both possible with R0 resection. Esophagectomy has the advantages of a longer esophageal safety margin, complete mediastinal lymphadenectomy, easier anastomosis, routine minimal invasive gastrolysis with abdominal lymphadenectomy and preservation of a gastric reservoir.

Does VO2peak Provide a Prognostic Value in Esophagectomy and Gastrectomy for Post-operative Outcomes?

BACKGROUND/AIM: Esophagectomy and gastrectomy are procedures with considerable physical burden and intense post-operative care of which the patient's physical condition seems to be a relevant predictor. The gold standard of the cardiorespiratory fitness is the peak oxygen consumption (VO2peak). This pilot study examined the prognostic value of VO2peak on post-surgery outcomes in esophageal and gastric cancer patients. PATIENTS AND METHODS: In this prospective cross-sectional study, patients scheduled for esophagectomy or gastrectomy were examined 24 h before the surgery regarding their VO2peak. The post-operative complications according to Clavien-Dindo grade IIIb/IV/V, Intensive-Care-Unit days, and overall hospital stay were documented following surgery. In a subset, body weight changes from surgery until hospital discharge and first aftercare visit were recorded. RESULTS: The functional capacity was significantly reduced in 34/35 of the included patients compared to matched norm-values (p<0.01). The only significant correlation was found between VO2peak values and body weight change from surgery to the first aftercare visit. A subgroup comparison of patients with a VO2peak <17 ml/min/kg and ≥17 ml/min/kg suggested small, non-significant differences in post-surgery outcomes and significant differences in the body weight change from surgery to hospital discharge, favoring the higher-VO2peak subgroup. CONCLUSION: The impaired functional capacity following esophagectomy or gastrectomy may strengthen the rational for exercise programs during neoadjuvant and pre-surgery phases. The prognostic value of VO2peak on post-operative outcomes remains uncertain due to noticeable descriptive differences, but no significant correlations, potentially limited by the smallsized population. Nonetheless, a correlation between VO2peak and body weight change post-surgery was observed and indicates a potential prognostic value of VO2peak.

Neoadjuvant chemoradiation changes podoplanin expression in esophageal cancer patients.

BACKGROUND: Locally advanced adenocarcinoma of the esophagus (EAC) and squamous cell carcinoma (ESCC) result in a worse prognosis. Neoadjuvant treatment improves survival, however, only for responders. The transmembrane glycoprotein podoplanin is overexpressed in squamous cell carcinomas, miRNA-363 is associated to its regulation in head and neck cancer. AIM: To predict therapy response and prognosis markers, and targets for novel therapies would individualize treatments leading to more favourable outcomes. METHODS: Expression of podoplanin protein has been visualized by immunohistochemistry in surgical specimens of 195 esophageal cancer patients who underwent transthoracic esophagectomy: 90 ESCC and 105 EAC with clinical T2-3, Nx, M0. One hundred and six patients received neoadjuvant chemoradiation. RNA was extracted from paraffin-embedded tissue, and miRNA-363 quantified by real-time TaqMan-real-time-PCR. D2-40 mab staining of > 5% was scored as high podoplanin expression (HPE). We related podoplanin and miRNA-363 expression to histopathologic response after neoadjuvant treatment and clinicopathological characteristics, such as histological tumor type, survival rate or clinical tumor category. RESULTS: We confirmed expression of membrane-bound podoplanin in 90 ESCC patients. 26% showed HPE of > 5%. In addition, absence in EAC patients (only 2% with HPE) was shown. Lower podoplanin expression has been detected in resection-specimen of 58 ESCC patients after neoadjuvant (RTx/CTx) treatment, only 11% with HPE, compared to 50% HPE of 32 non-pretreated primary surgery patients, P = 0.0001. This difference of podoplanin expression was confirmed comparing pre-treatment biopsies with matching post-treatment surgical specimens, P < 0.001. Podoplanin has been identified as a prognostic marker in 32 patients that underwent primary surgery without neoadjuvant treatment. Low (0-5%) podoplanin expression was associated with better prognosis compared to patients with HPE, P = 0.013. Podoplanin expression has been associated with post-transcriptional regulation by miRNA-363. At a cut-off value of miR-363 < 7, lower miR-363 expression correlated with HPE in surgical tissue specimens of primary surgery patients, P = 0.013. Therefore, ESCC patients with miRNA-363 expression < 7 had a worse prognosis than patients expressing miRNA-363 ≥ 7, P = 0.049. CONCLUSION: Analysis of the molecular process that leads to decrease in podoplanin expression during neoadjuvant treatment and its regulation may provide novel markers and targets to improve targeted therapy of ESCC.

Different response rates to chemotherapy between Japanese and German esophageal squamous cell carcinoma: patients may be influenced by ERCC1 or ABCB1.

Aim: To find out differences in biomarkers between Japanese and German patients responsible for response after neoadjuvant radio/chemotherapy and survival for esophageal squamous cell carcinoma. Materials & methods: A total of 60 patients from Japan and 127 patients from Germany with esophageal squamous cell carcinoma were analyzed according to three SNPs by real-time PCR. Results: The distribution of the genotypes of ERCC1 rs16115 and ABCB1 C3435T rs1045642 was significantly different between both patients' groups. Japanese patients had significantly less good response to 5-fluorouracil/cisplatin chemotherapy. The influence of the three SNPs on response varied between patients from Japan and Germany. Conclusion: Different expressions of ERCC1 and ABCB1 SNPs of Japanese patients compared with the German patients partially explain the different response.

Propensity score-matched comparison between open and minimal invasive hybrid esophagectomy for esophageal adenocarcinoma.

BACKGROUND: This study compared the outcome between patients who had an open and those who had a hybrid esophagectomy for T1 or T3 esophageal adenocarcinoma (eAC). No clear data are available concerning this question based on T-category. METHODS: Two groups of patients with esophagectomy and high intrathoracic esophagogastrostomy for eAC were analyzed: hybrid (laparoscopy + right thoracotomy) (n = 835) and open (laparotomy + right thoracotomy) (n = 188). Outcome criteria were 30- and 90-day mortality, R0-resection rate (R0), number of resected lymph nodes (rLNs), and 5-year survival rate (5y-SR). For each type of surgery, three patient groups were analyzed: pT1-carcinoma (group-1), cT3Nx and neoadjuvant chemoradiation (group-2), and pT3N0-3 without neoadjuvant therapy (group-3). The comparison was based on a propensity score matching in relation of 1:2 for open versus hybrid. RESULTS: In group-1 (38 open vs 76 hybrid) R0-resection (100%), 30-day mortality (0%), 90-day mortality (2.6% vs 0%), and rLNs (median 29.5 vs 28.5) were not significantly different. The pN0-rate was 76% in the open and 92% in the hybrid group (p = 0.036). Accordingly, the 5y-SR was 69% and 87% (p = 0.016), but the prognosis of the subgroups pT1pN0 or pT1pN+ was not significantly different between open or hybrid. In group-2 (68 open vs 135 hybrid) R0-resection (97%), 30-day (0% vs 0.7%) and 90-day (4%) mortality, rLNs (28.5 vs 26), and 5y-SR (36% vs 41%) were not significantly different. In group-3 (37 open vs 75 hybrid) R0, postoperative mortality, rLNs, and 5y-SR were not significantly different. CONCLUSION: In a propensity score-matched comparison of patients with an open or hybrid esophagectomy for esophageal adenocarcinoma the quality of oncologic resection, postoperative mortality and prognosis are not different.

External Validation of Pretreatment Pathological Tumor Extent in Patients with Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal Cancer.

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.

Upregulation of miR-17-92 cluster is associated with progression and lymph node metastasis in oesophageal adenocarcinoma.

The occurrence of lymph node metastasis (LNM) and depth of tumour infiltration are significant prognostic factors in oesophageal adenocarcinoma (OAC), however no reliable prognostic biomarkers have been established so far. Aim of this study was to characterize microRNAs (miRs) of OAC patients, who primarily underwent oesophagectomy, in order to identify specific alterations during tumour progression and LNM. MicroRNA array-based quantification analysis of 754 miRs, including tumour specimens of 12 patients with pT2 OAC from three different centres (detection group), was performed. We identified miR-17, miR-19a/b, miR-20a, and miR-106a, showing the best predictive power for LNM. These miRs were validated by quantitative real time-PCR (qRT-PCR) in 43 patients with different tumour stages (pT1: n = 21; pT2: n = 12 and pT3: n = 10) (training group) (p < 0.05), demonstrating that increasing levels of identified miRs were associated with advanced depth of tumour infiltration. These findings were verified in another independent group of 46 pT2 OAC patients (validation group). Quantitative RT-PCR analysis of the miR-panel confirmed these results except for miR-19a (p < 0.05 each). Logistic regression analysis identified miR-17 and miR-20a (p = 0.025 and p = 0.022, respectively) to be independent variables for prediction of LNM. The mathematical prediction model was used in the validation group, and the estimated prognosis was compared to the actual postsurgical follow-up. This comprehensive data demonstrated the importance of miR-17-92 cluster and miR-106a for progression as well as LNM in OAC indicating that those might be feasible prognostic biomarkers.

Neoadjuvant chemoradiation for patients with advanced oesophageal cancer - which response grading system best impacts prognostic discrimination?

AIMS: Neoadjuvant chemoradiation reduces tumour volume and improves the R0 resection rate, followed by extended survival for patients with advanced oesophageal cancer. The degree of tumour regression has high prognostic relevance. To date, there is still no generally accepted tumour regression grading system. The aim of this study was to compare the prognostic discrimination power of different histological regression grading systems: (i) the fibrosis/tumour ratio within the primary tumour (Mandard classification), (ii) the percentage of residual vital tumour cells (VTC) compared to the original primary tumour (Cologne Regression) and (iii) the ypT category, in patients with cT3 carcinoma of the oesophagus after neoadjuvant chemoradiation. METHODS AND RESULTS: This study included 216 patients with oesophageal cancer clinically staged as cT3NxM0 and treated from 2009 to 2012 with standardised chemoradiation followed by oesophagectomy [median age 62 years, 176 (81%) male and 138 (64%) adenocarcinoma patients]. The subgroup frequencies of the three classification systems were ypT category: ypT0 = 18%, ypT1 = 14%, ypT2 = 23%, ypT3 = 44%, ypT4 = 1%; Mandard classification: TRG1 = 18%, TRG2 = 26%, TRG3 = 24%, TRG4 = 30%, TRG5 = 2%; and Cologne Regression Scale: no tumour = 18%, 1-10% VTC = 27%, 10-50% VTC = 26% and >50% VTC = 29%. The Mandard and Cologne Regression classifications showed better prognostic differentiation for the subgroups than the ypT category. The four-tiered Cologne Regression system had a good prognostic relevance. Comparing results of the re-evaluated Cologne Regression classification with the classification by routine pathological report showed very good inter-rater agreement, with kappa value 0.891. CONCLUSION: Compared to the original primary tumour, the tumour regression grading system using the percentage of residual vital tumour has prognostic relevance.

Somatic alterations in circulating cell-free DNA of oesophageal carcinoma patients during primary staging are indicative for post-surgical tumour recurrence.

Oesophageal cancer (OC) has high mortality. This study aims at determining the feasibility of liquid biopsies for genomic profiling in early stage OC, comparing two different technologies for mutational analysis in circulating cell -free DNA (ccfDNA) and evaluating the clinical impact of these somatic alterations during primary staging. In 25 patients with locally advanced OC, endoscopic tumour biopsies and simultaneous blood samples were taken during primary staging. Genomic DNA from biopsies and ccfDNA were analysed for mutations using a 12 gene panel next-generation sequencing (NGS) assay as well as digital droplet PCR (ddPCR). Genetic data was correlated with patients' outcome. In 21 of the tested biopsies (84%) at least one somatic mutation was detected by NGS. Mutations detected by NGS were detectable by ddPCR with similar allele frequencies. In three out of the 21 patients with proven mutations, the same mutations were also detectable in ccfDNA using NGS (14%). In contrast, ddPCR detected mutations in ccfDNA of five additional patients (8/21, 38%). Post-surgical outcome analysis was performed for those patients who had received complete tumour resection (n = 16). Five of them suffered from an early relapse within the first year after surgery, including four with detectable somatic mutations in ccfDNA during primary staging. Taken together, we showed a higher sensitivity for ddPCR compared to NGS in detecting mutated ccfDNA in OC. Detection of somatically altered ccfDNA during primary staging seems to be indicative for post-surgical tumour recurrence.

Cancer of the gastroesophageal junction: a diagnosis, classification, and management review.

Management of gastroesophageal junction (GEJ) adenocarcinoma is a controversial topic. The rising incidence of this cancer requires a clear consensus to ensure proper management. Application of oncological principles for tumors of the esophagus or stomach is not possible because of comparative differences in the biology of GEJ adenocarcinoma, leading to different therapeutic options. Staging work-up with endoscopy, endosonography, and PET is essential to inform the choice of neoadjuvant treatment and surgical approach to GEJ adenocarcinoma. Surgery remains the only curative treatment and should be undertaken in specialized centers.

Upregulation of insulin-like growth factor II mRNA-binding protein 3 (IMP3) has negative prognostic impact on early invasive (pT1) adenocarcinoma of the esophagus.

PURPOSE: Therapeutic decisions in esophageal adenocarcinomas (EAC) restricted to mucosa (pT1a) or submucosa (pT1b) depend mainly on classic histomorphology-based criteria like tumor grading or lymphovascular invasion with limited success. There is a strong need for reliable pre-therapeutical biomarker-based evaluation also applicable on endoscopically obtained biopsies. METHODS: Patients who underwent esophagectomy due to EAC in a high volume center between 1999 and 2016 were included. Tissue microarrays (TMA) were retrospectively established from the formalin-fixed and paraffin-embedded material of the resected specimens and immunohistochemically stained using a monoclonal primary antibody specific for IMP3. IMP3 staining intensity was scored manually according to a 3-tier-scoring system (negative, weak and strong). RESULTS: 371 EACs were interpretable for analysis. 109 patients (29%) had early invasive (pT1a/pT1b) and 262 patients (71%) locally advanced EAC (> pT2). 259 EACs (70%) revealed positive immunostaining for IMP3 including 167 strongly and 92 weakly positive. Early EAC had significantly lower IMP3 expression compared to advanced tumor stages (p < 0.0001). IMP3 positive pT1 EAC revealed higher levels of lymph node metastases (LNM) (p = 0.0001) and pT1b tumors showed higher rates of IMP3 positivity compared to pT1a (p = 0.007). Subdividing the submucosa in thirds, there was a significant trend for higher IMP3 expression with deeper tumor infiltration from pT1a to pT1b (sm3) (p = 0.0001). There was an association between IMP3 expression and shortened survival in pT1 EAC (p = 0.038). CONCLUSIONS: IMP3 expression correlates with depth of tumor infiltration, rate of LNM and is associated with worse outcome. Thus, IMP3 might be useful for therapeutic decisions in early-invasive EAC.

Total minimally invasive esophagectomy for esophageal adenocarcinoma reduces postoperative pain and pneumonia compared to hybrid esophagectomy.

BACKGROUND: The impact of total minimally invasive esophagectomy (MIE) on early postoperative outcome and patient's survival is a matter of recent discussion. METHODS: We performed a 1:2 propensity score-matched comparison of 20 patients who underwent 3D-MIE and high intrathoracic esophagogastrostomy with 40 patients who underwent hybrid esophagectomy (HYBRID) with laparoscopic gastric mobilization and open transthoracic esophagectomy and the same anastomosis for esophageal adenocarcinoma in 2014 and 2015. Matching criteria were tumor localization, age, gender, and neoadjuvant treatment. RESULTS: Both groups did not differ regarding overall postoperative complications (MIE 55% vs. HYBRID 50%, p = 0.715) and anastomotic leakage (MIE 15% vs. HYBRID 5%, p = 0.186). A significant difference was seen regarding the rate of postoperative pneumonia (MIE 5% vs. HYBRID 27.5%; p = 0.040) and the postoperative ICU stay (MIE median 1 day vs. HYBRID median 2 days, p < 0.001). The R0-resection rate was 100% in both groups and median number of dissected lymph nodes was 32 for MIE and 35 for HYBRID (p = 0.236). Significant differences between both groups were noticed for postoperative number of patients with use of opiate demand medication and numeric rating scale for pain (NRSP maximum pain, median) both in favor of the MIE group (MIE 25%, NRSP 2 vs. HYBRID 60%, NRSP 4; p = 0.011, p < 0.001). Overall 2-year survival rate was 85% in both groups. CONCLUSION: Total minimally invasive esophagectomy is superior to hybrid esophagectomy in regard of postoperative pain and rate of pneumonia. No differences exist for postoperative surgical complications or short-term prognosis.

Prognosis of patients with superficial T1 esophageal cancer who underwent endoscopic resection before esophagectomy-A propensity score-matched comparison.

BACKGROUND: The aim of this retrospective study was to compare the prognosis of patients with esophageal cancer after non-curative endoscopic resection (ER) followed by esophagectomy (ER + S) with that of patients after primary surgery (PS). METHODS: Between 2000 and 2015, 287 patients had esophagectomy for T1 esophageal cancer. 81 of these patients underwent at least one ER in curative intention before surgery (7 squamous cell carcinomas, 74 adenocarcinomas). Indications for esophagectomy were R1-resection, submucosal infiltration, multifocality, long-segment Barrett esophagus, recurrence, postinterventional stenosis or a combination of these factors. Using propensity-score matching with gender, age, year of diagnosis, tumor localization, mucosal/submucosal infiltration and histology, the clinicopathologic and survival data of these patients were compared to those of 81 patients after PS (median follow-up: 5.5 years). RESULTS: There were no significant differences between both groups concerning number of resected lymph nodes and percentage of nodal metastasis (9.3% total). 9% of esophagectomy specimens after ER showed pT2/pT3-tumors. The 5-year survival rate was 86% in the PS and 85% in the ER + S group (p = 0.498). The disease-free survival was 85% in patients with ER + S and 98% in PS (p < 0.005). The recurrence rate after esophagectomy was higher after ER + S compared to PS (p = 0.015). More than 3 months time delay between ER and surgery was associated with reduced survival, but only within the first postinterventional year. CONCLUSIONS: As the disease-free survival was inferior in the ER + S compared to the PS group the indication for ER, especially repeated ERs, should be restricted to cases with high expectation of success.

Impact of Extracapsular Lymph Node Involvement After Neoadjuvant Chemoradiation Therapy Followed by Surgery in Carcinoma of the Esophagus: A Multicenter Study.

OBJECTIVES: The current study aims to examine the impact of extracapsular lymph node involvement (EC-LNI) on survival for both esophageal adenocarcinoma (AC) and squamous cell carcinoma (SCC) treated with neoadjuvant chemoradiation therapy (nCRT) followed by surgery. BACKGROUND: Studies have demonstrated the negative prognostic value of EC-LNI in primary surgery, but its impact after nCRT remains unclear. METHODS: From the databases of 6 European high-volume centers 1505 patients with R0 resections were withheld. Oncologic variables, including ypT, ypN, number of positive lymph nodes, and lymph node capsular status: EC-LNI and intracapsular lymph node involvement (IC-LNI), were examined. Statistical analysis was performed by Cox proportional hazards modeling. RESULTS: In SCC 182 patients (31.6%) had positive lymph nodes, of whom 60 (33.0%) showed EC-LNI. In AC 391 patients (42.1%) had positive lymph nodes, of whom 147 (37.6%) showed EC-LNI. Overall 5-year survival (O5YS) in SCC was 42.0%. Presence of EC-LNI meant a significantly worse O5YS than IC-LNI or pN0 (10.6%, 39.5%, and 47.4%, respectively; P < 0.05). O5YS in AC was 41.2%. No significant difference was observed between EC-LNI and IC-LNI (P = 0.322). In the multivariate analysis, among the examined possible prognosticators, presence of EC-LNI showed the highest hazard ratio (2.29, confidence interval: 1.52-3.47) as an independent prognosticator for overall survival in SCC, but it was not in AC. CONCLUSIONS: Based on this international multicenter study, the presence of EC-LNI after nCRT is at least as important as N-stage for survival and EC-LNI is the strongest prognosticator for overall survival in SCC but not in AC.

Somatic BRCA1-associated protein 1 (BAP1) loss is an early and rare event in esophageal adenocarcinoma.

Esophageal cancer is the eighth most common malignant tumor worldwide, and the number of incidences of esophageal adenocarcinoma is increasing in the Western world. Despite improvements in perioperative treatment, the overall survival rate of patients with esophageal adenocarcinoma remains poor. Breast cancer type 1 susceptibility protein (BRCA1)-associated protein (BAP1) is located on chromosome 3p21, and it is an enzyme with ubiquitin carboxyl hydrolase activity that regulates cell growth. It interacts with BRCA1, and the nuclear localization of BAP1 is required for its tumor suppressor function. BAP1 is frequently mutated in uveal melanomas, malignant mesothelioma and several carcinomas, including a subtype of renal cell carcinoma, intrahepatic cholangiocarcinoma and squamous cell carcinoma of the esophagus. Furthermore, several germline-associated mutations of tumors have been described (BAP1 hereditary cancer syndrome). However, the importance and frequency of BAP1 alterations in adenocarcinoma of the esophagus remain to be elucidated. In the present study, tissue microarrays of 332 resected adenocarcinomas (including a few cases of concomitant Barrett dysplasia) of the esophagus were constructed. The tumor tissue was analyzed using immunohistochemistry to investigate the levels of BAP1 expression. Fibroblasts or inflammatory cells served as an internal positive control. Three adenocarcinomas revealed nuclear loss of BAP1 (0.9%). One case with concomitant Barrett dysplasia also exhibited a loss of BAP1. Of the resected adenocarcinomas, 329 of them exhibited an intact and uniform strong nuclear staining pattern. To the best of our knowledge, this is the first description of BAP1 deficiency in adenocarcinomas of the esophagus. Furthermore, it has been demonstrated that BAP1 loss is possibly an early event in esophageal adenocarcinoma. These results warrant further functional and clinical evaluation.

Current and future treatment options for esophageal cancer in the elderly.

INTRODUCTION: Esophageal cancer is the eighth most common cancer globally and has the sixth worst prognosis because of its aggressiveness and poor survival. Data regarding cancer treatment in older patients is limited because the elderly have been under-represented in clinical trials. Therefore, we reviewed the existing literature regarding treatment results for elderly patients (70+ years). Areas covered: We used pubmed to analyze the actual literature according to elderly esophageal cancer patients with subheading of incidence, esophagectomy, chemoradiation or chemotherapy. The main points of interest were treatment options for patients with Barrett's esophagus or early carcinoma, advanced tumor stages, and inoperable cancer. Expert opinion: The incidence of esophageal cancer has been increasing over the past thirty years, with a rapid increase of esophageal adenocarcinoma in Western industrialized nations. Patients aged over 60 years have been particularly affected. In this review, we have shown that elderly patients with esophageal cancer have various alternatives for adequate treatment. Clinical evaluation of comorbidity is necessary to make treatment decisions. Therapeutic options for early carcinomas are endoscopic or surgical resection. For elderly patients with advanced carcinomas, preoperative chemoradiation or chemotherapy should be discussed.

High protein and mRNA expression levels of TUBB3 (class III ß-tubulin) are associated with aggressive tumor features in esophageal adenocarcinomas.

BACKGROUND: Esophageal adenocarcinomas show an increasing incidence in the Western world and their overall survival remains low. Microtubules are multifunctional cytoskeletal proteins involved in crucial cellular roles, including maintenance of cell shape, intracellular transport, meiosis, and mitosis. Microtubulus-TUBB3 was found overexpressed in several carcinomas suggesting a significant role in cancer development. High levels of TUBB3 expression were also described to be associated with poor clinical outcome in various cancers. It was shown that overexpression of TUBB3 could be related to reduced efficiency of taxane-based targeting anticancer drugs in several cancer types. RESULTS: There is a statistically significant association between high TUBB3 protein and TUBB3 mRNA expression and shortened survival (p<0,0001). Prognostic impact of TUBB3 expression is seen in patients with and without multimodal treatment. Multivariate analysis revealed a strong TUBB3 expression to be an independent prognosis factor. Validation of protein expression by mRNA in situ hybridization underlines the credibility of the immunohistochemical results. DISCUSSION: Our study emphasized the significant importance of TUBB3 in esophageal adenocarcinoma. TUBB3 serves as an independent prognostic marker and may be a valuable biomarker for routine application in esophageal adenocarcinoma especially to address the need for adjuvant treatment in individuals following neoadjuvant therapy and surgery. Future prospective studies are needed which include the results of TUBB3 in preoperative biopsy material to proof the prognostic impact of TUBB3. MATERIALS AND METHODS: 280 esophageal adenocarcinomas that underwent primary surgical resection or resection after neoadjuvant therapy were analyzed by mRNA-in-situ-hybridization (RNAscope®) and by immunohistochemistry (TUBB3 rabbit monoclonal antibody; Epitomics).