Needs, preferences, and patient participation for a randomized controlled trial on postneoadjuvant complete tumor response: A qualitative study of patients with esophageal cancer.

PURPOSE: For patients with clinical complete response of non-metastatic esophageal cancer (EC) after neoadjuvant chemoradiotherapy (nCRT) or neoadjuvant chemotherapy (nCT), the two treatment options obligate postneoadjuvant surgery as the current standard treatment (surgery on principle) versus active surveillance with surgery as needed only in recurring loco-regional tumor as a possible future alternative or standard exist. Since these treatments are presumably equivalent in terms of overall survival, patient-centered information can encourage the discussion with the treating physician and can make it easier for patients to make trade-offs between the advantages and disadvantages of the treatment alternatives in a highly distressed situation. METHODS: A qualitative prospective cross-sectional study was conducted to create patient-centered information material that is based on patients' preferences, needs, and concerns regarding the two treatment options, and to investigate the potential participation in a consecutive randomized controlled trial (RCT). Therefore, EC patients (N = 11) were asked about their attitudes. RESULTS: Concerns about the surgery and possible postoperative impairments in quality of life were identified as most mentioned negative aspects of surgery on principle, and recurrence and progression fear and the concern that surgery cannot be avoided anyways as most named negative aspects of surgery as needed. In regard to the participation in an RCT, making a contribution to science and the hope that the novel therapy would be superior to the established one were relevant arguments to participate. On the other hand, the lack of a proactive selection of treatment was named an important barrier to participation in an RCT. CONCLUSION: The importance of adapting medical conversations to the patients' lack of expertise and their exceptional cognitive and emotional situation is stressed. Results of this study can be used to improve patient-centered information and the recruitment of patients in RCTs in cancer.

[Technique of Colon Interposition for Oesophageal Replacement for Oesophageal Cancer]. / Technik der Koloninterposition zum Ösophagusersatz beim Ösophaguskarzinom.

Nowadays, it is only relatively rare and in selected situations that colonic interposition is chosen rather than the stomach as a reconstructive organ for replacing the oesophagus. The colon is a reliable organ for tubular replacement of the oesophagus when the stomach is not available for reconstruction. Colon interposition is a complex and complicated operation. It requires a specific indication and thorough preoperative preparation. From a technical point of view, colon interposition places high demands on the selection and surgical dissection of the vascular supply to the reconstructed organ. The reconstruction route and elevation of the interposition graft to the proximal oesophagus and the need to create 3 or 4 gastrointestinal anastomoses also place significantly higher demands than reconstruction using a gastric tube. Overall, despite the significant surgery-related morbidity, good functional results and a good quality of life can usually be achieved. The surgical technique applied in our own practice is described in detail. An overview from literature on the results of colonic interposition is given, particularly with regard to surgical complications and quality of life after colon interposition.

[Technique of Colon Interposition for Oesophageal Replacement for Oesophageal Cancer]. / Technik der Koloninterposition zum Ösophagusersatz beim Ösophaguskarzinom.

Nowadays, it is only relatively rare and in selected situations that colonic interposition is chosen rather than the stomach as a reconstructive organ for replacing the oesophagus. The colon is a reliable organ for tubular replacement of the oesophagus when the stomach is not available for reconstruction. Colon interposition is a complex and complicated operation. It requires a specific indication and thorough preoperative preparation. From a technical point of view, colon interposition places high demands on the selection and surgical dissection of the vascular supply to the reconstructed organ. The reconstruction route and elevation of the interposition graft to the proximal oesophagus and the need to create 3 or 4 gastrointestinal anastomoses also place significantly higher demands than reconstruction using a gastric tube. Overall, despite the significant surgery-related morbidity, good functional results and a good quality of life can usually be achieved. The surgical technique applied in our own practice is described in detail. An overview from literature on the results of colonic interposition is given, particularly with regard to surgical complications and quality of life after colon interposition.

Oncological recurrence following pathological complete response after neoadjuvant treatment in patients with esophageal cancer - a retrospective cohort study.

BACKGROUND: To evaluate recurrence in patients with post-neoadjuvant pathological complete response (pCR) and in patients with complete response of primary tumor but persisting lymphatic spread of disease (non-pCR, ypT0ypN +) of esophageal cancer. METHODS: Seventy-five patients (63 pCR, 12 non-pCR) were analyzed retrospectively. Pattern and incidence of local and distant recurrence as well as the impact on overall (OS) and disease-free survival (DFS) were evaluated. The efficacy of neoadjuvant chemotherapy according to FLOT protocol was compared to neoadjuvant chemoradiation according to CROSS protocol. RESULTS: In the pCR group, isolated local recurrence was diagnosed in 3%, while no isolated local recurrence was observed in the non-pCR group due to the high incidence of distant recurrence. Distant recurrence was most common in both cohorts (isolated distant recurrence: pCR group 10% to non-pCR group 55%; simultaneous distant and local recurrence: pCR group 3% to non-pCR group 18%). Median time to distant recurrence was 5.5 months, and median time to local recurrence was 8.0 months. Cumulative incidence of distant recurrence (with and without simultaneous local recurrence) was 16% (± 6%) in pCR patients and 79% (± 13%) in non-pCR patients (hazard ratio (HR) 0.123) estimated by Kaplan-Meier method. OS (HR 0.231) and DFS (HR 0.226) were significantly improved in patients with pCR compared to patients with non-pCR. Advantages for FLOT protocol compared to CROSS protocol, especially with regard to distant control of disease (HR 0.278), were observed (OS (HR 0.361), DFS (HR 0.226)). CONCLUSION: Distant recurrence is the predominant site of treatment failure in patients with pCR and non-pCR grade 1a regression, whereby recurrence rates are much higher in patients with non-pCR.

Pathological complete response in multimodal treatment of esophageal cancer: a retrospective cohort study.

To evaluate pathological complete response (pCR, ypT0ypN0) after neoadjuvant treatment compared with non-complete response (non-CR) in patients with esophageal cancer (EC), and 393 patients were retrospectively analyzed. Survival probability was analyzed in patients with: (i) pCR vs non-CR; (ii) complete response of the primary tumor but persisting lymphatic metastases (non-CR-T0N+) and (iii) pCR and tumor-free lymphnodes exhibiting signs of postneoadjuvant regression vs. no signs of regression. (i) Median overall survival (mOS) was favorable in patients with pCR (pCR: mOS not reached vs. non-CR: 41 months, P < 0.001). Multivariate analysis revealed that grade of regression was not an independent predictor for prolonged survival. Instead, the achieved postneoadjuvant TNM-stage (T-stage: Hazard ratio [HR] ypT3-T4 vs. ypT0-T2: 1.837; N-stage: HR ypN1-N3 vs. ypN0: 2.046; Postneoadjuvant M-stage: HR ypM1 vs. ycM0: 2.709), the residual tumor (R)-classification (HR R1 vs. R0: 4.195) and the histologic subtype of EC (HR ESCC vs. EAC: 1.688) were prognostic factors. Patients with non-CR-T0N+ have a devastating prognosis, similar to those with local non-CR and lymphatic metastases (non-CR-T + N+) (non-CR-T0N+: 22.0 months, non-CR-T + N-: mOS not reached, non-CR-T + N+: 23.0 months; P-values: non-CR-T0N+ vs. non-CR-T + N-: 0.016; non-CR-T0N+ vs. non-CR-T + N+: 0.956; non-CR-T + N- vs. non-CR-T + N+: <0.001). Regressive changes in lymphnodes after neoadjuvant treatment did not influence survival-probability in patients with pCR (mOS not reached in each group; EAC-patients: P = 0.0919; ESCC-patients: P = 0.828). Particularly, the achieved postneoadjuvant ypTNM-stage influences the survival probability of patients with EC. Patients with non-CR-T0N+ have a dismal prognosis, and only true pathological complete response with ypT0ypN0 offers superior survival probabilities.

[Robot-assisted Total Gastrectomy with D2 Lymphadenectomy and Intracorporal Reconstruction]. / Robotisch assistierte totale Gastrektomie mit D2-Lymphadenektomie und intrakorporaler Rekonstruktion.

Robot-assisted total gastrectomy for gastric cancer is a demanding operation that is increasingly being performed, not only in Asia but also in specialised centres in Europe. The minimally invasive resection - and above all the lymphadenectomy and the minimally invasive intracorporal reconstruction by oesophagojejunostomy - are technically demanding surgical steps. These techniques are performed internationally in different variations, but have not yet been well standardised. In the video presented, we show the DaVinci Xi-assisted minimally invasive technique of total gastrectomy with D2 lymphadenectomy and intracorporal reconstruction using side-to-side oesophagojejunostomy with linear stapling.

Perioperative FLOT chemotherapy plus surgery for oligometastatic esophagogastric adenocarcinoma: surgical outcome and overall survival.

BACKGROUND: Guidelines do not recommend surgery for patients with oligometastatic disease from esophagogastric adenocarcinoma (EGAC), although some studies suggest a more favorable survival. We analyzed the outcome of oligometastatic EGAC receiving FLOT chemotherapy followed by surgery. METHODS: The data of patients with either pre-therapeutic, post-neoadjuvant or intraoperative clinical diagnosis of oligometastatic EGAC were extracted from a prospective database of the 2009-2018 treatment period. 48 consecutive patients were identified with oligometastatic disease, who underwent perioperative chemotherapy plus surgery. We retrospectively analyzed surgical outcome and overall survival. RESULTS: The overall 5-year survival was 18%. 12 patients (25%) with pre-therapeutic oligometastatic EGAC, who had no histologic vital tumor evidence of metastases after surgery had a survival rate of 48% compared to an 11% 5-year survival rate of 36 patients (75%), who had histologic vital tumor metastatic evidence after FLOT chemotherapy and surgical resection (p = 0.012). The survival rates after R0, R1 and R2 (non-resected metastases) resection were 21% (n = 33), 0% (n = 4) and 17% (n = 11), respectively (p = 0.273). CONCLUSION: Oligometastatic EGAC is associated with poor overall survival even after complete resection of all tumor manifestations. The subgroup of patients with a complete histologic response of metastatic lesions to neoadjuvant FLOT shows 5-year survival rates similar to non-metastatic EGAC. Trial registration Not applicable.

Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma.

Despite recent advances in therapy, liver metastasis from melanoma is still associated with poor prognosis. Although targeting the mTOR signaling pathway exerts potent anti-tumor activity, little is known about specific mTORC2 inhibition regarding liver metastasis. Using the novel mTORC2 specific inhibitor JR-AB2-011, we show significantly reduced migration and invasion capacity by impaired activation of MMP2 in melanoma cells. In addition, blockade of mTORC2 induces cell death by non-apoptotic pathways and reduces tumor cell proliferation rate dose-dependently. Furthermore, a significant reduction of liver metastasis was detected in a syngeneic murine metastasis model upon therapy with JR-AB2-011 as determined by in vivo imaging and necropsy. Hence, our study for the first time highlights the impact of the pharmacological blockade of mTORC2 as a potent novel anti-cancer approach for liver metastasis from melanoma.

The effect of pasireotide on intestinal anastomotic healing with and without whole-body irradiation in a rat model.

OBJECTIVE: To examine pasireotide's effect on intestinal anastomotic healing under physiological conditions and following preoperative whole-body irradiation. MATERIAL AND METHODS: Forty-five male Wistar rats received an ileoileal end-to-end anastomosis. Group 1 (Co, n = 9) served as control. Group 2 (SOM, n = 10) received pasireotide (60 mg/kg) 6 days preoperatively. Group 3 (R-Co, n = 13) was subjected to 8 Gy whole-body irradiation 4 days preoperatively. Finally, group 4 (R-SOM, n = 13) received pasireotide 6 days preoperatively and whole-body irradiation 4 days preoperatively. On postoperative day 4, anastomotic bursting pressure, histology, IGF-1 staining, and collagen density were examined. RESULTS: Mortality was higher in irradiated animals (30.8% vs. 5.3%, p = 0.021), and anastomotic bursting pressure was significantly lower (median, R-Co = 83 mmHg; R-SOM = 101 mmHg; Co = 149.5 mmHg; SOM = 169 mmHg). Inflammation measured by leukocyte infiltration following irradiation was reduced (p = 0.023), and less collagen was observed, though this was not statistically significant. Bursting pressure did not significantly differ between Co and SOM and between R-Co and R-SOM animals respectively. Semi-quantitative scoring of IGF-1, fibroblast bridging, or collagen density did not reveal significant differences among the groups. CONCLUSION: Whole-body irradiation decreases the quality of intestinal anastomotic wound healing and increases mortality. Pasireotide does not significantly lessen this detrimental effect.

Epidural analgesia and avoidance of blood transfusion are associated with reduced mortality in patients with postoperative pulmonary complications following thoracotomic esophagectomy: a retrospective cohort study of 335 patients.

BACKGROUND: Postoperative pulmonary complications (PPCs) represent the most frequent complications after esophagectomy. The aim of this study was to identify modifiable risk factors for PPCs and 90-days mortality related to PPCs after esophagectomy in esophageal cancer patients. METHODS: This is a single center retrospective cohort study of 335 patients suffering from esophageal cancer who underwent esophagectomy between 1996 and 2014 at a university hospital center. Statistical processing was conducted using univariate and multivariate stepwise logistic regression analysis of patient-specific and procedural risk factors for PPCs and mortality. RESULTS: The incidence of PPCs was 52% (175/335) and the 90-days mortality rate of patients with PPCs was 8% (26/335) in this study cohort. The univariate and multivariate analysis revealed the following independent risk factors for PPCs and its associated mortality. ASA score ≥ 3 was the only independent patient-specific risk factor for the incidence of PPCs and 90-days mortality of patients with an odds ratio for PPCs being 1.7 (1.1-2.6 95% CI) and an odds ratio of 2.6 (1.1-6.2 95% CI) for 90-days mortality. The multivariate approach depicted two independent procedural risk factors including transfusion of packed red blood cells (PRBCs) odds ratio of 1.9 (1.2-3 95% CI) for PPCs and an odds ratio of 5.0 (2.0-12.6 95% CI) for 90-days mortality; absence of thoracic epidural anesthesia (TEA) revealed the highest odds ratio 2.0 (1.01-3.8 95% CI) for PPCs and an odds ratio of 3.9 (1.6-9.7 95% CI) for 90-days mortality. CONCLUSION: In esophageal cancer patients undergoing esophagectomy via thoracotomy, epidural analgesia and the avoidance of intraoperative blood transfusion are significantly associated with a reduced 90-days mortality related to PPCs.

[Prevention and Surgical Therapy of Chylothorax]. / Prävention und operative Therapie des Chylothorax.

BACKGROUND: Chylothorax is a rare complication after thoracic trauma or surgery, especially oesophagectomy, which, if left untreated, can be potentially life-threatening. METHODS: This article provides an overview of the existing literature on the prevention and surgical therapy of chylothorax. RESULTS: The risk of chyle leakage after oesophagectomy increases with the difficulty of mediastinal dissection and is reported to be around 3% for oesophagectomy. With this risk, there is the possibility of a prophylactic intraoperative ligature of the thoracic duct, either as a selective or mass ligation. Meta-analyses confirm the effectiveness of this measure, with a reduction in the risk to less than 1%. In the case of postoperative chylothorax, a conservative therapeutic trial may be undertaken with drainage of up to 1000 ml per day for up to one week. If there is any indication of persistent leakage, rapid surgical reintervention appears appropriate. This can be either transthoracic or transhiatal as a selective or mass ligation and has a probability of success of over 90%. CONCLUSION: The prophylactic primary or therapeutic secondary ligature of the thoracic duct is an effective surgical preventive measure and therapy of postoperative chyle leakage.

Form follows function: Morphological and immunohistological insights into epithelial-mesenchymal transition characteristics of tumor buds.

In cancer biology, the architectural concept "form follows function" is reflected by cell morphology, migration, and epithelial-mesenchymal transition protein pattern. In vivo, features of epithelial-mesenchymal transition have been associated with tumor budding, which correlates significantly with patient outcome. Hereby, the majority of tumor buds are not truly detached but still connected to a major tumor mass. For detailed insights into the different tumor bud types and the process of tumor budding, we quantified tumor cells according to histomorphological and immunohistological epithelial-mesenchymal transition characteristics. Three-dimensional reconstruction from adenocarcinomas (pancreatic, colorectal, lung, and ductal breast cancers) was performed as published. Tumor cell morphology and epithelial-mesenchymal transition characteristics (represented by zinc finger E-box-binding homeobox 1 and E-Cadherin) were analyzed qualitatively and quantitatively in a three-dimensional context. Tumor buds were classified into main tumor mass, connected tumor bud, and isolated tumor bud. Cell morphology and epithelial-mesenchymal transition marker expression were assessed for each tumor cell. Epithelial-mesenchymal transition characteristics between isolated tumor bud and connected tumor bud demonstrated no significant differences or trends. Tumor cell count correlated significantly with epithelial-mesenchymal transition and histomorphological characteristics. Regression curve analysis revealed initially a loss of membranous E-Cadherin, followed by expression of cytoplasmic E-Cadherin and subsequent expression of nuclear zinc finger E-box-binding homeobox 1. Morphologic changes followed later in this sequence. Our data demonstrate that connected and isolated tumor buds are equal concerning immunohistochemical epithelial-mesenchymal transition characteristics and histomorphology. Our data also give an insight in the process of tumor budding. While there is a notion that the epithelial-mesenchymal transition zinc finger E-box-binding homeobox 1-E-Cadherin cascade is initiated by zinc finger E-box-binding homeobox 1, our results are contrary and outline other possible pathways influencing the regulation of E-Cadherin.

Internet-based perioperative exercise program in patients with Barrett's carcinoma scheduled for esophagectomy [iPEP - study] a prospective randomized-controlled trial.

BACKGROUND: Patients undergoing surgery for esophageal cancer have a high risk for postoperative deterioration of lung function and pulmonary complications. This is partly due to one-lung ventilation during thoracotomy. This often accounts for prolonged stay on intensive care units, delayed postoperative reconvalescence and reduced quality of life. Socioeconomic disadvantages can result from these problems. Physical preconditioning has become a crucial leverage to optimize fitness and lung function in patients scheduled for esophagectomy, in particular during the time period of neoadjuvant therapy. METHODS/STUDY DESIGN: We designed a prospective multicenter randomized-controlled trial. The objective is to evaluate the impact of an internet-based exercise program on postoperative respiratory parameters and pneumonia rates in patients with Barrett's carcinoma scheduled for esophagectomy. Patients are randomly assigned to either execute internet-based perioperative exercise program (iPEP), including daily endurance, resistance and ventilation training or treatment as usual (TAU). During neoadjuvant therapy and recovery, patients in the intervention group receive an individually designed intensive exercise program based on functional measurements at baseline. Personal feedback of the supervisor with customized training programs is provided in weekly intervals. DISCUSSION: This study will evaluate if an intensive individually adapted training program via online supervision during neoadjuvant therapy will improve cardiorespiratory fitness and reduce pulmonary complications following esophagectomy for Barrett's cancer. TRIAL REGISTRATION: NCT02478996 , registered 26 May 2015.

Hybrid minimally invasive esophagectomy vs. open esophagectomy: a matched case analysis in 120 patients.

PURPOSE: In esophageal surgery, total minimally invasive techniques compete with hybrid and robot-assisted procedures. The benefit of the individual techniques for the patient remains vague. At our institution, the hybrid minimally invasive laparoscopic-thoracotomic esophagectomy (HMIE) has been routinely applied since 2013. We conducted this retrospective study to analyze the perioperative outcome. METHODS: Since 2013, 60 patients were operated in HMIE technique for esophageal cancer. Each of these patients was paired according to the criteria of gender, BMI, age, tumor histology, pulmonary preexisting conditions, and a history of smoking with a patient treated by open esophagectomy (OE). Perioperative parameters were extracted from our prospectively maintained database and compared among the groups. RESULTS: The HMIE and OE groups were homogeneous in terms of patient- and tumor-related data. There was no difference in lymph nodes harvested (22 vs. 20, p = 0.459) and R0-resection rate (95 vs. 93%, p = 0.500). The operation time for the HMIE was significantly shorter (329 vs. 407 min, p < 0.001). There was no difference between the groups with respect to surgical complications (37 vs. 37%, p = 0.575), but the patients undergoing hybrid technique showed more delayed gastric emptying (23 vs. 10%, p = 0.042). Pulmonary morbidity was significantly reduced after HMIE (20 vs. 42%, p = 0.009). This affected both the occurrence of pneumonia and pleural effusions. The difference in the overall complication rate was not significant (50 vs. 60%, p = 0.179), but life-threatening complications (Clavien/Dindo 4/5) were less frequent (2 vs. 12%, p = 0.031). Overall, there was significantly less need for transfusion after HMIE (18 vs. 50%, p < 0.001), and hospital (and IMC) stay was significantly shorter (14 (6) vs. 18 (7) days, p = 0.002 (0.003)). The multivariate analysis confirms the surgical procedure as an independent risk factor for the development of pulmonary complications (OR 3.2, p = 0.011). Furthermore, preexisting pulmonary conditions were identified as a risk factor (OR 3.6, p = 0.006). CONCLUSION: Our retrospective analysis shows that reduction of postoperative pulmonary morbidity, perioperative blood loss, and shortening of hospital stay can be achieved by HMIE. The procedure is safe, and the rate of surgical complications and oncological radicality is comparable to the conventional procedure.

Management and outcome of esophageal stenting for spontaneous esophageal perforations.

Treatment of spontaneous esophageal perforation (SEP) consists of different conservative, surgical and endoscopic treatment modalities. In this study, we evaluated the clinical efficacy and the outcome of covered self-expanding stent (CSES) treatment of SEP. All patients with SEP treated by CSES at our institution between 2005 and 2014 were included in this prospective single-center study. The data were collected from a prospective database based on clinical, endoscopic and operative reports. Follow-up data were procured by contacting the patients or their family doctors. The patient data were analyzed concerning course of treatment, leakage sealing rate, complications, and mortality. Patients with iatrogenic or malignant perforations were excluded. In total, 16 patients underwent endoscopic CSES placement for SEP between 2005 and 2014. Sealing of the leakage was immediately successful in 50% (8 patients). A second stent was placed in 5 patients, but did not achieve sealing of the perforation in any case, requiring a switch in treatment to a surgical procedure (n=4) or drainage of the persisting leakage (n=4). In-hospital mortality was 13%. Only delayed treatment was identified as a risk factor for inferior outcome. Patients with successful CSES treatment had a shorter ICU- and hospital stay and had a reduced risk of developing esophageal stenosis (RR: 0.4) or persisting dysphagia despite treatment (RR: 0.33). Endoscopic treatment of SEP is beneficial to the patient if immediately successful, but in our experience, failure rates are higher than described in the literature. Secondary placement of CSES was not successful when initial stent treatment failed, while both surgical intervention and drainage of the perforation showed good results in sealing the leakage.

Postoperative fluid overload is a risk factor for adverse surgical outcome in patients undergoing esophagectomy for esophageal cancer: a retrospective study in 335 patients.

BACKGROUND: Restrictive intraoperative fluid management is increasingly recommended for patients undergoing esophagectomy. Controversy still exists about the impact of postoperative fluid management on perioperative outcome. METHODS: We retrospectively examined 335 patients who had undergone esophagectomy for esophageal cancer at the University Hospital Freiburg between 1996 and 2014 to investigate the relation between intra- and postoperative fluid management and postoperative morbidity after esophagectomy. RESULTS: Perioperative morbidity was 75%, the in-hospital mortality 8%. A fluid balance above average on the operation day was strongly associated with a higher rate of postoperative mortality (21% vs 3%, p < 0.001) and morbidity (83% vs 66%, p = 0.001). Univariate analysis for risk factors for adverse surgical outcome (Clavien ≥ III) identified ASA-score (p = 0.002), smoking (p = 0.036), reconstruction by colonic interposition (p = 0.036), cervical anastomosis (p = 0.017), blood transfusion (p = 0.038) and total fluid balance on the operation day and on POD 4 (p = 0.001) as risk factors. Multivariate analysis confirmed only ASA-score (p = 0.001) and total fluid balance (p = 0.001) as independent predictors of adverse surgical outcome. CONCLUSION: Intra- and postoperative fluid overload is strongly associated with increased postoperative morbidity. Our results suggest restrictive intra- and especially postoperative fluid management to optimize the outcome after esophagectomy.

Response of esophageal cancer cells to epigenetic inhibitors is mediated via altered thioredoxin activity.

We previously showed that histone deacetylase inhibitor (HDACi) and 5-azacytidine (AZA) treatment selectively induced cell death of esophageal cancer cells. The mechanisms of cancer selectivity, however, remained unclear. Here we examined whether the cancer selectivity of HDACi/AZA treatment is mediated by the thioredoxin (Trx) system and reactive oxygen species (ROS) in esophageal cancer cells. For this, we first analyzed human tissue specimens of 37 esophageal cancer patients by immunohistochemistry for Trx, Trx-interacting protein (TXNIP) and Trx reductase (TXNRD). This revealed a loss or at least reduction of nuclear Trx in esophageal cancer cells, compared with normal epithelial cells (P<0.001). Although no differences were observed for TXNIP, TXNRD was more frequently expressed in cancer cells (P<0.001). In the two main histotypes of esophageal squamous cell carcinomas (ESCCs, n=19) and esophageal adenomcarcinomas (EAC, n=16), similar Trx, TXNIP and TXNRD expression patterns were observed. Also in vitro, nuclear Trx was only detectable in non-neoplastic Het-1A cells, but not in OE21/ESCC or OE33/EAC cell lines. Moreover, the two cancer cell lines showed an increased Trx activity, being significant for OE21 (P=0.0237). After treatment with HDACi and/or AZA, ROS were exclusively increased in both cancer cell lines (P=0.048-0.017), with parallel decrease of Trx activity. This was variably accompanied by increased TXNIP levels upon AZA, MS-275 or MS-275/AZA treatment for 6 or 24 h in OE21, but not in Het-1A or OE33 cells. In summary, this study evaluated Trx and its associated proteins TXNIP and TXNRD for the first time in esophageal cancers. The analyses revealed an altered subcellular localization of Trx and strong upregulation of TXNRD in esophageal cancer cells. Moreover, HDACi and AZA disrupted Trx function and induced accumulation of ROS with subsequent apoptosis in esophageal cancer cells exclusively. Trx function is hence an important cellular mediator conferring non-neoplastic cell resistance for HDACi and/or AZA.

KRAS mutations in pancreatic circulating tumor cells: a pilot study.

Pancreatic ductal adenocarcinoma (PDAC) is most often diagnosed in a metastatic stage. Circulating tumor cells (CTC) in the blood are hypothesized as the means of systemic dissemination. We aimed to isolate and characterize CTC to evaluate their significance as prognostic markers in PDAC. Blood obtained from healthy donors and patients with PDAC before therapy was filtered with ScreenCell® filtration devices for size-based CTC isolation. Captured cells were analyzed by immunofluorescence for an epithelial to mesenchymal transition (EMT) marker (zinc finger E-box binding homebox 1 (ZEB1)) and an epithelial antigen (cytokeratin (CK)). Molecular analysis of parallel specimens evaluated the KRAS mutation status of the CTC. The survival of each patient after study was recorded. As demonstrated by either cytology or finding of a KRAS mutation, CTC were detected in 18 of 21 patients (86 %) with proven PDAC: 8 out of 10 patients (80 %) with early stage (UICC IIA/IIB) and 10 out of 11 (91 %) with late stage (UICC III/IV) disease. CTC were not found in any of the 10 control patients (p < 0.001). The presence of CTC did not adversely affect median survival: 16 months in CTC-positive (n = 18) vs. 10 months in CTC-negative (n = 3) patients. Neither ZEB1 nor cytological characteristics correlated with overall survival, although ZEB1 was found almost exclusively in CTC of patients with established metastases. Patients with a CTC KRAS mutation (CTC-KRAS (mut)) had a substantially better survival, 19.4 vs. 7.4 months than patients with wild type KRAS (p = 0.015). With ScreenCell filtration, CTC are commonly found in PDAC (86 %). Molecular and genetic characterization, including mutations such as KRAS, may prove useful for prognosis.

ESOPEC: prospective randomized controlled multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (NCT02509286).

BACKGROUND: Recent randomized controlled trials comparing neoadjuvant chemoradiation plus surgery or perioperative chemotherapy plus surgery with surgery alone showed significant survival benefits for combined modality treatment of patients with localized esophageal adenocarcinoma. However, head-to-head comparisons of neoadjuvant chemoradiation and perioperative chemotherapy applying contemporary treatment protocols are lacking. The present trial was initiated to obtain valid information whether neoadjuvant chemoradiation or perioperative chemotherapy yields better survival in the treatment of localized esophageal adenocarcinoma. METHODS/DESIGN: The ESOPEC trial is an investigator-initiated multicenter prospective randomized controlled two-arm trial, comparing the efficacy of neoadjuvant chemoradiation (CROSS protocol: 41.4Gy plus carboplatin/paclitaxel) followed by surgery versus perioperative chemotherapy and surgery (FLOT protocol: 5-FU/leucovorin/oxaliplatin/docetaxel) for the curative treatment of localized esophageal adenocarcinoma. Patients with cT1cN + cM0 and cT2-4acNxcM0 esophageal and junctional adenocarcinoma are eligible. The trial aims to include 438 participants who are centrally randomized to one of the two treatment groups in a 1:1 ratio stratified by N-stage and study site. The primary endpoint of the trial is overall survival assessed with a minimum follow-up of 36 months. Secondary objectives are progression-free survival, recurrence-free survival, site of failure, postoperative morbidity and mortality, duration of hospitalization as well as quality of life. DISCUSSION: The ESOPEC trial compares perioperative chemotherapy according to the FLOT protocol to neoadjuvant chemoradiation according to the CROSS protocol in multimodal treatment of non-metastasized recectable adenocarcinoma of the esophagus and the gastroesophageal junction. The goal of the trial is identify the superior protocol with regard to patient survival, treatment morbidity and quality of life. TRIAL REGISTRATION: NCT02509286 (July 22, 2015).