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Abstract Background A surgical resection is currently the preferred treatment for esophageal cancer if the tumor is considered to be resectable without evidence of distant metastases (cT1-3 N0-1 M0). A high percentage of irradical resections is reported in studies using neoadjuvant chemotherapy followed by surgery versus surgery alone and in trials in which patients are treated with surgery alone. Improvement of locoregional control by using neoadjuvant chemoradiotherapy might therefore improve the prognosis in these patients. We previously reported that after neoadjuvant chemoradiotherapy with weekly administrations of Carboplatin and Paclitaxel combined with concurrent radiotherapy nearly always a complete R0-resection could be performed. The concept that this neoadjuvant chemoradiotherapy regimen improves overall survival has, however, to be proven in a randomized phase III trial. Methods/design The CROSS trial is a multicenter, randomized phase III, clinical trial. The study compares neoadjuvant chemoradiotherapy followed by surgery with surgery alone in patients with potentially curable esophageal cancer, with inclusion of 175 patients per arm. The objectives of the CROSS trial are to compare median survival rates and quality of life (before, during and after treatment), pathological responses, progression free survival, the number of R0 resections, treatment toxicity and costs between patients treated with neoadjuvant chemoradiotherapy followed by surgery with surgery alone for surgically resectable esophageal adenocarcinoma or squamous cell carcinoma. Over a 5 week period concurrent chemoradiotherapy will be applied on an outpatient basis. Paclitaxel (50 mg/m2) and Carboplatin (Area-Under-Curve = 2) are administered by i.v. infusion on days 1, 8, 15, 22, and 29. External beam radiation with a total dose of 41.4 Gy is given in 23 fractions of 1.8 Gy, 5 fractions a week. After completion of the protocol, patients will be followed up every 3 months for the first year, every 6 months for the second year, and then at the end of each year until 5 years after treatment. Quality of life questionnaires will be filled out during the first year of follow-up. Discussion This study will contribute to the evidence on any benefits of neoadjuvant treatment in esophageal cancer patients using a promising chemoradiotherapy regimen. Trial registration ISRCTN80832026

Purpose. Fatigue is a chronic problem in liver transplant recipients and may influence daily functioning and health-related quality of life (HRQoL). This study aimed to evaluate the effects of a fatigue-reducing physical rehabilitation programme on daily functioning, participation, HRQoL, anxiety and depression among liver transplant recipients. Method. Eighteen fatigued liver transplant recipients (mean age 51 years, 10 men/8 women) participated in a 12-week rehabilitation programme, which included supervised exercise training and daily physical activity counselling. We assessed pre- and post-programme health-related daily functioning, participation, HRQoL, anxiety and depression using questionnaires. Results. After the programme, patients showed improvements in daily functioning (23.6%, p = 0.007), the participation domain 'autonomy outdoors' (34.1%, p = 0.001), and the HRQoL domains 'physical functioning' (11.5%, p = 0.007) and 'vitality' (21.5%, p = 0.022). Anxiety and depression were unchanged post-programme. Conclusions. Rehabilitation using supervised exercise training and daily physical activity counselling can positively influence daily functioning, participation and HRQoL among fatigued liver transplant recipients. [ABSTRACT FROM AUTHOR]

Purpose: Preoperative chemoradiotherapy according to the chemoradiotherapy for esophageal cancer followed by surgery study (CROSS) has become a standard of care for patients with locally advanced resectable esophageal or junctional cancer. We aimed to assess long-term outcome of this regimen., Methods: From 2004 through 2008, we randomly assigned 366 patients to either five weekly cycles of carboplatin and paclitaxel with concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery, or surgery alone. Follow-up data were collected through 2018. Cox regression analyses were performed to compare overall survival, cause-specific survival, and risks of locoregional and distant relapse. The effect of neoadjuvant chemoradiotherapy beyond 5 years of follow-up was tested with time-dependent Cox regression and landmark analyses., Results: The median follow-up was 147 months (interquartile range, 134-157). Patients receiving neoadjuvant chemoradiotherapy had better overall survival (hazard ratio [HR], 0.70; 95% CI, 0.55 to 0.89). The effect of neoadjuvant chemoradiotherapy on overall survival was not time-dependent ( P value for interaction, P = .73), and landmark analyses suggested a stable effect on overall survival up to 10 years of follow-up. The absolute 10-year overall survival benefit was 13% (38% v 25%). Neoadjuvant chemoradiotherapy reduced risk of death from esophageal cancer (HR, 0.60; 95% CI, 0.46 to 0.80). Death from other causes was similar between study arms (HR, 1.17; 95% CI, 0.68 to 1.99). Although a clear effect on isolated locoregional (HR, 0.40; 95% CI, 0.21 to 0.72) and synchronous locoregional plus distant relapse (HR, 0.43; 95% CI, 0.26 to 0.72) persisted, isolated distant relapse was comparable (HR, 0.76; 95% CI, 0.52 to 1.13)., Conclusion: The overall survival benefit of patients with locally advanced resectable esophageal or junctional cancer who receive preoperative chemoradiotherapy according to CROSS persists for at least 10 years., Competing Interests: Mark I. Van Berge HenegouwenConsulting or Advisory Role: Medtronic, Johnson & Johnson, Mylan, Alesi SurgicalResearch Funding: Olympus, StrykerTravel, Accommodations, Expenses: Johnson & Johnson Hanneke W. M. Van LaarhovenConsulting or Advisory Role: Lilly/ImClone, Nordic Group, Bristol Myers Squibb, ServierResearch Funding: Bristol Myers Squibb, Bayer Schering Pharma, Celgene, Janssen-Cilag, Lilly, Nordic Group, Philips Healthcare, Roche, Merck Sharp & Dohme, Servier, Merck KGaATravel, Accommodations, Expenses: AstraZeneca Grard A. P. NieuwenhuijzenHonoraria: Medtronic, LillyConsulting or Advisory Role: MedtronicResearch Funding: Medtronic Geke A. P. HospersConsulting or Advisory Role: Roche, MSD, Amgen, Bristol Myers Squibb, NovartisResearch Funding: Bristol Myers Squibb, Seerave Foundation Cornelis J. A. PuntConsulting or Advisory Role: Nordic Bioscience Henk M. W. VerheulConsulting or Advisory Role: Glycostem Ewout W. SteyerbergPatents, Royalties, Other Intellectual Property: Royalties from Springer for a book “Clinical Prediction Models”No other potential conflicts of interest were reported.

Objective: The aim was to compare leak rate between hand-sewn end-to-end anastomosis (ETE) and semi-mechanical anastomosis (SMA) after esophagectomy with gastric tube reconstruction., Background Data: The optimal surgical technique for creation of an anastomosis in the neck after esophagectomy is unclear., Methods: Patients with esophageal cancer undergoing esophagectomy with gastric tube reconstruction and cervical anastomosis were eligible for participation after written informed consent. Patients were randomized in 1:1 ratio. Primary endpoint was anastomotic leak rate defined as external drainage of saliva from the site of the anastomosis or intra-thoracic manifestation of leak. Secondary endpoints included anastomotic stricture rate at one year follow up, number of endoscopic dilatations, dysphagia-score, hospital stay, morbidity, and mortality. Patients were blinded for intervention., Results: Between August 2011 and July 2014, 174 patients with esophageal cancer underwent esophagectomy. Ninety-three patients were randomized to ETE (n = 44) or SMA (n = 49). Anastomotic leak occurred in 9 of 44 patients (20%) in the ETE group and 12 of 49 patients (24%) in the SMA group (absolute difference 4%, 95% CI -13% to +21%; p = .804). There was no significant difference in dysphagia at 1 year postoperatively (ETE 25% vs. SMA 20%; p = .628), in stricture rate (ETE 25% vs. 19% in SMA, p = .46), nor in median hospital stay (17 days in the ETE group, 13 days in the SMA group), morbidity (82% vs. 73%, p = .460) or mortality (0% vs. 4%, p = .175) between the groups., (© 2020 The Authors. Journal of Surgical Oncology Published by Wiley Periodicals LLC.)

Purpose To compare pre-agreed health-related quality of life (HRQOL) domains in patients with esophageal or junctional cancer who received neoadjuvant chemoradiotherapy (nCRT) followed by surgery or surgery alone. Secondary aims were to examine the effect of nCRT on HRQOL before surgery and the effect of surgery on HRQOL. Patients and Methods Patients were randomly assigned to nCRT (carboplatin plus paclitaxel with concurrent 41.4-Gy radiotherapy) followed by surgery or surgery alone. HRQOL was measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and -Oesophageal Cancer Module (QLQ-OES24) questionnaires pretreatment and at 3, 6, 9, and 12 months postoperatively. The nCRT group also received preoperative questionnaires. Physical functioning (PF; QLQ-C30) and eating problems (EA; QLQ-OES24) were chosen as predefined primary end points. Predefined secondary end points were global QOL (GQOL; QLQ-C30), fatigue (FA; QLQ-C30), and emotional problems (EM; QLQ-OES24). Results A total of 363 patients were analyzed. No statistically significant differences in postoperative HRQOL were found between treatment groups. In the nCRT group, PF, EA, GQOL, FA, and EM scores deteriorated 1 week after nCRT (Cohen's d: -0.93, P < .001; 0.47, P < .001; -0.84, P < .001; 1.45, P < .001; and 0.32, P = .001, respectively). In both treatment groups, all end points declined 3 months postoperatively compared with baseline (Cohen's d: -1.00, 0.33, -0.47, -0.34, and 0.33, respectively; all P < .001), followed by a continuous gradual improvement. EA, GQOL, and EM were restored to baseline levels during follow-up, whereas PF and FA remained impaired 1 year postoperatively (Cohen's d: 0.52 and -0.53, respectively; both P < .001). Conclusion Although HRQOL declined during nCRT, no effect of nCRT was apparent on postoperative HRQOL compared with surgery alone. In addition to the improvement in survival, these findings support the view that nCRT according to the Chemoradiotherapy for Esophageal Cancer Followed by Surgery Study-regimen can be regarded as a standard of care.

Background: Intratumor heterogeneity has been demonstrated in several cancer types, following a model of branched evolution. It is unknown to which extent intratumor heterogeneity is applicable to esophageal adenocarcinoma. Therefore the aim of this study was to characterise intratumor heterogeneity in esophageal adenocarcinoma., Methods: Multiregional targeted sequencing of four commonly altered genes was performed on 19 tumor regions collected from five esophageal adenocarcinomas. Alterations were classified as homogeneous or heterogeneous based on mutational and loss of heterozygosity analysis., Results: Identical TP53 mutations and homogeneously loss of heterozygosity of the TP53 locus were identified in all separated tumor regions in each of five adenocarcinomas, and in the corresponding Barrett's esophagus and tumor positive lymph node of one primary tumor. Loss of heterozygosity of the P16 locus was homogeneous among all tumor regions in four adenocarcinomas, and an identical pattern of loss of heterozygosity was present in the Barrett's esophagus. Loss of heterozygosity of the SMAD4 and APC loci was observed in a heterogeneous pattern., Conclusions: Known driver alterations, such as TP53 and P16 are homogeneously present within each adenocarcinoma, and therefore occur early during carcinogenesis and subsequently clonally expand throughout the entire tumor. However, loss of heterozygosity of the SMAD4 and APC loci shows a heterogeneous pattern, indicating intratumor heterogeneity of esophageal adenocarcinoma.

Background: Anastomotic leakage is a severe complication after esophagectomy. The objective was to investigate the diagnostic and predictive value of routine contrast swallow study and endoscopy for the detection of anastomotic dehiscence in patients after esophagectomy., Methods: All patients who underwent contrast swallow and/or endoscopy within 7 days after oesophagectomy for cancer between January 2005 and December 2009 were selected from an institutional database., Results: Some 173 patients underwent endoscopy, and 184 patients underwent a contrast swallow study. The sensitivity of endoscopy for anastomotic leakage requiring intervention is 56 %, specificity 41 %, positive predictive value (PPV) 8 %, and negative predictive value (NPV) 95 %. The sensitivity of contrast swallow study for detecting leakage requiring intervention in patients without signs of leakage was 20 %, specificity 20 %, PPV 3 %, and NPV 97 %., Conclusions: In patients without clinical suspicion of leakage, there is no benefit to perform routine examinations.

Background & Aims: Extracellular microRNAs (miRNAs) in serum and bile are currently under intense investigation for biomarker purposes in liver disease. However, the directions and pathways by which miRNAs are released from hepatic cells remains largely unknown. Here, we investigated the release of hepatocyte and cholangiocyte-derived miRNAs (HDmiRs and CDmiRs) into blood and bile during various (patho)physiological hepatic conditions., Methods: MiRNA release was analysed using longitudinally collected tissue and paired bile and serum samples (n = 124) that were obtained from liver transplant recipients during follow-up., Results: Cell-type specificity of HDmiRs and CDmiRs was confirmed in liver and common bile duct biopsies (P < 0.001). Analysis of paired bile and serum samples showed up to 20-times higher miRNA-levels in bile compared to serum (P < 0.0001). Fractionation of bile showed the majority of miRNAs being present in the unpelletable supernatant, where protein conjunctions protect miRNAs against degradation (P < 0.0001). During episodes of liver injury and histologically proven rejection in liver transplant recipients, relative HDmiR-levels in bile decreased while its levels in serum increased (P ≤ 0.015). Simultaneously, relative CDmiR-levels in bile significantly increased, while their levels in serum decreased. Related to liver excretory function, a strong positive correlation was observed between HDmiR-122 levels and bilirubin excretion into bile (R = 0.694, P < 0.0001), whereas CDmiRs showed an inverse correlation (P < 0.05)., Conclusion: During impaired excretory function and injury, the liver shows polarized release of extracellular HDmiRs and CDmiRs. This sheds new light on the biology of hepatic miRNA release which is relevant for the interpretation of hepatic miRNAs as biomarkers., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Chronic hepatitis C virus (HCV) infection compromises long-term outcomes of liver transplantation. Although glucocorticosteroid-based immunosuppression is commonly used, discussion is ongoing on the effect of prednisolone (Pred) on HCV recurrence and response to antiviral therapy post transplantation. Recently, new drugs (direct-acting antivirals) have been approved for the treatment of HCV, however, it remains unknown whether their antiviral activity is affected by Pred. The aim of this study was to investigate the effects of Pred on the antiviral activity of asunaprevir (Asu), daclatasvir (Dac), ribavirin (RBV), and interferon-alpha (IFN-α), and on plasmacytoid dendritic cells (PDCs), the main IFN-α-producing immune cells., Methods: The effects of Pred and antiviral compounds were tested in both a subgenomic and infectious HCV replication model. Furthermore, effects were tested on human PDCs stimulated with a Toll-like receptor-7 ligand., Result: Pred did not directly affect HCV replication and did not inhibit the antiviral action of Asu, Dac, RBV, or IFN-α. Stimulated PDCs potently suppressed HCV replication. This suppression was reversed by treating PDCs with Pred. Pred significantly decreased IFN-α production by PDCs without affecting cell viability. When Asu and Dac were combined with PDCs, a significant cooperative antiviral effect was observed., Conclusion: This study shows that Pred acts on the antiviral function of PDCs. Pred does not affect the antiviral action of Asu, Dac, RBV, or IFN-α. This implies that there is no contraindication to combine antiviral therapies with Pred in the post-transplantation management of HCV recurrence., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Initial results of the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) comparing neoadjuvant chemoradiotherapy plus surgery versus surgery alone in patients with squamous cell carcinoma and adenocarcinoma of the oesophagus or oesophagogastric junction showed a significant increase in 5-year overall survival in favour of the neoadjuvant chemoradiotherapy plus surgery group after a median of 45 months' follow-up. In this Article, we report the long-term results after a minimum follow-up of 5 years., Methods: Patients with clinically resectable, locally advanced cancer of the oesophagus or oesophagogastric junction (clinical stage T1N1M0 or T2-3N0-1M0, according to the TNM cancer staging system, sixth edition) were randomly assigned in a 1:1 ratio with permuted blocks of four or six to receive either weekly administration of five cycles of neoadjuvant chemoradiotherapy (intravenous carboplatin [AUC 2 mg/mL per min] and intravenous paclitaxel [50 mg/m(2) of body-surface area] for 23 days) with concurrent radiotherapy (41·4 Gy, given in 23 fractions of 1·8 Gy on 5 days per week) followed by surgery, or surgery alone. The primary endpoint was overall survival, analysed by intention-to-treat. No adverse event data were collected beyond those noted in the initial report of the trial. This trial is registered with the Netherlands Trial Register, number NTR487, and has been completed., Findings: Between March 30, 2004, and Dec 2, 2008, 368 patients from eight participating centres (five academic centres and three large non-academic teaching hospitals) in the Netherlands were enrolled into this study and randomly assigned to the two treatment groups: 180 to surgery plus neoadjuvant chemoradiotherapy and 188 to surgery alone. Two patients in the neoadjuvant chemoradiotherapy group withdrew consent, so a total of 366 patients were analysed (178 in the neoadjuvant chemoradiotherapy plus surgery group and 188 in the surgery alone group). Of 171 patients who received any neoadjuvant chemoradiotherapy in this group, 162 (95%) were able to complete the entire neoadjuvant chemoradiotherapy regimen. After a median follow-up for surviving patients of 84·1 months (range 61·1-116·8, IQR 70·7-96·6), median overall survival was 48·6 months (95% CI 32·1-65·1) in the neoadjuvant chemoradiotherapy plus surgery group and 24·0 months (14·2-33·7) in the surgery alone group (HR 0·68 [95% CI 0·53-0·88]; log-rank p=0·003). Median overall survival for patients with squamous cell carcinomas was 81·6 months (95% CI 47·2-116·0) in the neoadjuvant chemoradiotherapy plus surgery group and 21·1 months (15·4-26·7) in the surgery alone group (HR 0·48 [95% CI 0·28-0·83]; log-rank p=0·008); for patients with adenocarcinomas, it was 43·2 months (24·9-61·4) in the neoadjuvant chemoradiotherapy plus surgery group and 27·1 months (13·0-41·2) in the surgery alone group (HR 0·73 [95% CI 0·55-0·98]; log-rank p=0·038)., Interpretation: Long-term follow-up confirms the overall survival benefits for neoadjuvant chemoradiotherapy when added to surgery in patients with resectable oesophageal or oesophagogastric junctional cancer. This improvement is clinically relevant for both squamous cell carcinoma and adenocarcinoma subtypes. Therefore, neoadjuvant chemoradiotherapy according to the CROSS trial followed by surgical resection should be regarded as a standard of care for patients with resectable locally advanced oesophageal or oesophagogastric junctional cancer., Funding: Dutch Cancer Foundation (KWF Kankerbestrijding)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

After organ transplantation, recipient T cells contribute to graft rejection. Mesenchymal stromal cells from the bone marrow (BM-MSCs) are known to suppress allogeneic T-cell responses, suggesting a possible clinical application of MSCs in organ transplantation. Human liver grafts harbor resident populations of MSCs (L-MSCs). We aimed to determine the immunosuppressive effects of these graft-derived MSCs on allogeneic T-cell responses and to compare these with the effects of BM-MSCs. BM-MSCs were harvested from aspirates and L-MSCs from liver graft perfusates. We cultured them for 21 days and compared their suppressive effects with the effects of BM-MSCs on allogeneic T-cell responses. Proliferation, cytotoxic degranulation, and interferon-gamma production of alloreactive T cells were more potently suppressed by L-MSCs than BM-MSCs. Suppression was mediated by both cell-cell contact and secreted factors. In addition, L-MSCs showed ex vivo a higher expression of PD-L1 than BM-MSCs, which was associated with inhibition of T-cell proliferation and cytotoxic degranulation in vitro. Blocking PD-L1 partly abrogated the inhibition of cytotoxic degranulation by L-MSCs. In addition, blocking indoleamine 2,3-dioxygenase partly abrogated the inhibitive effects of L-MSCs, but not BM-MSCs, on T-cell proliferation. In conclusion, liver graft-derived MSC suppression of allogeneic T-cell responses is stronger than BM-MSCs, which may be related to in situ priming and mobilization from the graft. These graft-derived MSCs may therefore be relevant in transplantation by promoting allohyporesponsiveness.

Objective: Recently, single nucleotide polymorphisms (SNPs) associated with esophageal adenocarcinoma (EAC) and Barrett's esophagus (BE) were identified; rs10419226 (CRTC1), rs11789015 (BARX1), rs2687201 (FOXP1), rs2178146 (FOXF1), rs3111601 (FOXF1), and rs9936833 (FOXF1). These findings indicate that genetic susceptibility could play a role in the initiation of EAC in BE patients. The aim of this study was to validate the association between these previously identified SNPs and the risk of EAC in an independent and large case-control study., Design: Six SNPs found to be associated with EAC and BE were genotyped by a multiplex SNaPshot analysis in 1071 EAC patients diagnosed and treated in the Netherlands. Allele frequencies were compared to a control group derived from the Rotterdam Study, a population-based prospective cohort study (n = 6206). Logistic regression analysis and meta-analysis were performed to calculate odds ratios (OR)., Results: Rs10419226 (CRTC1) showed a significantly increased EAC risk for the minor allele (OR = 1.17, P = 0.001), and rs11789015 (BARX1) showed a significantly decreased risk for the minor allele (OR = 0.85, P = 0.004) in the logistic regression analysis. The meta-analysis of the original GWAS and the current study revealed an improved level of significance for rs10419226 (CRTC1) (OR = 1.18, P = 6.66 × 10(-10)) and rs11789015 (BARX1) (OR = 0.83, P = 1.13 × 10(-8))., Conclusions: This independent and large Dutch case-control study confirms the association of rs10419226 (CRTC1) and rs11789015 (BARX1) with the risk of EAC. These findings suggest a contribution of the patient genetic make-up to the development of EAC and might contribute to gain more insight in the etiology of this cancer.

Epidemiological studies indicate that vitamin D exerts a protective effect on the development of various solid cancers. However, concerns have been raised regarding the potential deleterious role of high vitamin D levels in the development of esophageal adenocarcinoma (EAC). This study investigated genetic variation in the vitamin D receptor (VDR) in relation to its expression and risk of Barrett esophagus (BE) and EAC. VDR gene regulation was investigated by immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR) and gel shift assays. Fifteen haplotype tagging single-nucleotide polymorphisms (SNPs) of the VDR gene were analyzed in 858 patients with reflux esophagitis (RE), BE or EAC and 202 healthy controls. VDR mRNA expression was higher in BE compared with squamous epithelium. VDR protein was located in the nucleus in BE. An rs1989969T/rs2238135G haplotype was identified in the 5' regulatory region of the VDR gene. It was associated with an approximately two-fold reduced risk of RE, BE and EAC. Analysis of a replication cohort was done for BE that confirmed this. The rs1989969T allele causes a GATA-1 transcription factor binding site to appear. The signaling of GATA-1, which is regarded as a negative transcriptional regulator, could explain the findings for rs1989969. The rs2238135G allele was associated with a significantly reduced VDR expression in BE; for the rs1989969T allele, a trend in reduced VDR expression was observed. We identified a VDR haplotype associated with reduced esophageal VDR expression and a reduced incidence of RE, BE and EAC. This VDR haplotype could be useful in identifying individuals who benefit most from vitamin D chemoprevention.

Background: Patients with locoregionally advanced oesophageal tumours or disputable distant metastases are referred for induction chemotherapy with the aim to downstage the tumour before an oesophagectomy is considered., Study Design: Patients who underwent induction chemotherapy between January 2005 and December 2012 were identified from an institutional database. Treatment plan was discussed in the multidisciplinary team. Response to chemotherapy was assessed by CT. Survival was calculated using the Kaplan Meier method. Uni- and multivariable analyses were performed to identify prognostic factors for survival., Results: In total 124 patients received induction chemotherapy mainly for locoregionally advanced disease (n = 80). Surgery was withheld in 35 patients because of progressive disease (n = 16) and persistent unresectability (n = 19). The median overall survival of this group was 13 months (IQR: 8-19). The remaining 89 patients underwent surgery of which 13 still had unresectable tumour or distant metastases. Of the 76 patients that underwent an oesophagectomy, 50 patients had tumour free resection margins (66%) with an estimated 5-year survival of 37%. A positive resection margin (HR 4.148, 95% CI 2.298-7.488, p < 0.0001) was associated with a worse survival in univariable analysis, but only pathological lymph node status with increasing hazard ratio's (6.283-10.283, p = 0.001) remained significant after multivariable analysis., Conclusion: Induction chemotherapy downstages the tumour and facilitates a radical oesophagectomy in patients with advanced oesophageal cancer. Pathological lymph node status is an independent prognostic factor for overall survival., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Human esophageal adenocarcinoma (EAC) cell lines have made a substantial contribution to elucidating mechanisms of carcinogenesis and drug discovery. Model research on EAC relies almost entirely on a relatively small set of established tumor cell lines because appropriate animal models are lacking. Nowadays, more than 20% of all fundamental translational research studies regarding EAC are partially or entirely based on these cell lines. The ready availability of these cell lines to investigators worldwide have resulted in more than 250 publications, including many examples of important biomedical discoveries. The high genomic similarities (but certainly not completely identical) between the EAC cell lines and their original tumors provide rational for their use. Recently, in a collaborative effort all available EAC cell lines have been verified resulting in the establishment of a reliable panel of 10 EAC cell lines. It could be expected that the value of these cell lines increases as unlimited source of tumor material because new biomedical techniques require more tumor cells and the supply of viable tumor cells is diminishing because of neoadjuvant chemo(radio)therapy of patients with EAC. Here, we review the history of the EAC cell lines and their utility in translational research and biomedical discovery., (© 2013 Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.)

Objectives: We aimed to examine the association between total number of resected nodes and survival in patients after esophagectomy with and without nCRT., Background: Most studies concerning the potentially positive effect of extended lymphadenectomy on survival have been performed in patients who underwent surgery alone. As nCRT is known to frequently "sterilize" regional nodes, it is unclear whether extended lymphadenectomy after nCRT is still useful., Methods: Patients from the randomized CROSS-trial who completed the entire protocol (ie, surgery alone or chemoradiotherapy + surgery) were included. With Cox regression models, we compared the impact of number of resected nodes as well as resected positive nodes on survival in both groups., Results: One hundred sixty-one patients underwent surgery alone, and 159 patients received multimodality treatment. The median (interquartile range) number of resected nodes was 18 (12-27) and 14 (9-21), with 2 (1-6) and 0 (0-1) resected positive nodes, respectively. Persistent lymph node positivity after nCRT had a greater negative prognostic impact on survival as compared with lymph node positivity after surgery alone. The total number of resected nodes was significantly associated with survival for patients in the surgery-alone arm (hazard ratio per 10 additionally resected nodes, 0.76; P=0.007), but not in the multimodality arm (hazard ratio 1.00; P=0.98)., Conclusions: The number of resected nodes had a prognostic impact on survival in patients after surgery alone, but its therapeutic value is still controversial. After nCRT, the number of resected nodes was not associated with survival. These data question the indication for maximization of lymphadenectomy after nCRT.

The aim of this cross-sectional study was to analyze the incidence of incisional hernia after liver transplantation (LT), to determine potential risk factors for their development, and to assess their impact on health-related quality of life (HRQoL). Patients who underwent LT through a J-shaped incision with a minimum follow-up of three months were included. Follow-up was conducted at the outpatient clinic. Short Form 36 (SF-36) and body image questionnaire (BIQ) were used for the assessment of HRQoL. A total of 140 patients was evaluated. The mean follow-up period was 33 (SD 20) months. Sixty patients (43%) were diagnosed with an incisional hernia. Multivariate analysis revealed surgical site infection (OR 5.27, p = 0.001), advanced age (OR 1.05, p = 0.003), and prolonged ICU stay (OR 1.54, p = 0.022) to be independent risk factors for development of incisional hernia after LT. Patients with an incisional hernia experienced significantly diminished HRQoL with respect to physical, social, and mental aspects. In conclusion, patients who undergo LT exhibit a high incidence of incisional hernia, which has a considerable impact on HRQoL. Development of incisional hernia was shown to be related to surgical site infection, advanced age, and prolonged ICU stay., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: It is hypothesized that increasing physical fitness and daily physical activity can lead to a reduction in fatigue. However, standard medical care following liver transplantation seldom includes rehabilitation that focuses on physical fitness and physical activity., Objective: The aim of this study was to explore whether a rehabilitation program can reduce fatigue in recipients of liver transplants. Furthermore, effects on physical fitness, physical activity, and cardiovascular risk were studied, and adherence, satisfaction, and adverse events were assessed., Design: This was an uncontrolled intervention study., Setting: The study took place in an outpatient rehabilitation clinic., Patients: Eighteen recipients of a liver transplant who were fatigued participated in a 12-week rehabilitation program including physical exercise training and counseling on physical activity. The primary outcome measure was fatigue. Other outcome measures were: aerobic capacity, muscle strength, body fat, daily physical activity, lipid profile, and glycemic control. All measurements were performed before and after the rehabilitation program. Adherence, satisfaction, and adverse events were registered., Results: After the program, participants were significantly less fatigued, and the percentage of individuals with severe fatigue was 22% to 53% lower than before the program. In addition, aerobic capacity and knee flexion strength were significantly higher, and body fat was significantly lower after the program. Participants were able to perform physical exercise at the target training intensity, no adverse events were registered, and attendance (93%) and mean patient satisfaction (8.5 out of 10, range=7-10) were high., Limitations: No control group was used in the study., Conclusions: A rehabilitation program consisting of exercise training and physical activity counseling is well tolerated and seems promising in reducing fatigue and improving fitness among recipients of liver transplants., (© 2014 American Physical Therapy Association.)

Background: Esophageal cancer is increasingly recognized in younger patients. We compared clinicopathological characteristics, treatment, and survival of patients aged ≤50 years with patients aged >50 years diagnosed with esophageal cancer in the Netherlands., Methods: From the nationwide Netherlands Cancer Registry we identified all patients diagnosed with esophageal cancer between January 2000 and January 2011. Proportions were compared using the χ(2) test for categorical variables. Overall and relative survival was calculated., Results: Eleven percent of the patients (n = 1,466) were aged ≤50 years and adenocarcinoma was the most common tumor type (73.6%). Grade of tumor differentiation was comparable between both age groups (P = 0.460) as well as T-stage (P = 0.058). Younger patients presented more often with positive lymph nodes (70.1% vs. 66.4%, P = 0.010) and distant metastasis (50.5% vs. 44.7%, P < 0.001) but had surgery more often as compared to older patients: 40.6% versus 37.9%, P = 0.047. There was no significant difference in the 5-year relative survival between both age groups: 18.1% versus 17.2%, P > 0.05. A subgroup analysis among patients diagnosed with adenocarcinoma revealed similar results., Conclusions: Young patients with esophageal cancer present with more advanced disease stage and received more often treatment. However, they show comparable relative survival rates with their older counterparts., (© 2013 Wiley Periodicals, Inc.)

Human mesenchymal stem/stromal cells (MSCs) have been explored in a number of clinical trials as a possible method of treating various diseases. However, the effect of long-term cell expansion in vitro on physiological function and genetic stability is still poorly understood. In this study, MSC cultures derived from bone marrow and liver were evaluated for the presence of aberrant cells following long-term expansion. In 46 independent cultures, four batches of transformed MSCs (TMCs) were found, which were all beyond the culture period of five weeks. These aberrant cells were first identified based on the appearance of abnormal cytology and the acquirement of growth advantage. Despite common MSC markers being diminished or absent, TMCs remain highly susceptible to lysis by allogenic natural killer (NK) cells. When transplanted into immunodeficient mice, TMCs formed sarcoma-like tumors, whereas parental MSCs did not form tumors in mice. Using a combination of high-resolution genome-wide DNA array and short-tandem repeat profiling, we confirmed the origin of TMCs and excluded the possibility of human cell line contamination. Additional genomic duplication and deletions were observed in TMCs, which may be associated with the transformation event. Using gene and microRNA expression arrays, a number of genes were identified that were differentially expressed between TMCs and their normal parental counterparts, which may potentially serve as biomarkers to screen cultures for evidence of early transformation events. In conclusion, the spontaneous transformation of MSCs resulting in tumorigenesis is rare and occurs after relatively long-term (beyond five weeks) culture. However, as an added safety measure, cultures of MSCs can potentially be screened based on a novel gene expression signature.

Background: The location of positive lymph nodes has been abandoned in the seventh classification of the TNM staging system for esophageal adenocarcinoma. The present study evaluates whether distribution of involved nodes relative to the diaphragm in addition to TNM 7 further refines prediction., Methods: Pathology reports of patients who underwent esophagectomy between 2000 and 2008 for adenocarcinoma of the esophagus were reviewed and staging was performed according to the seventh UICC-AJCC staging system. In addition, lymph node involvement of nodal stations above and below the diaphragm was investigated by endoscopic ultrasonography (EUS) in a separate cohort of patients who were scheduled for esophagectomy between 2008 and 2009 at two institutions. Survival was calculated by the Kaplan-Meier method, and multivariate analysis was performed with a Cox regression model., Results: Some 327 patients who had undergone esophagectomy for cancer were included. Multivariate analysis revealed that patients with from three to six involved lymph nodes in the resection specimen on both sides of the diaphragm had a twofold higher chance of dying compared to patients with the same number of involved lymph nodes on one side of the diaphragm. EUS assessment of lymph node metastases relative to the diaphragm in 102 patients showed that nodal involvement on both sides of the diaphragm was associated with worse survival than when nodes on one side or no nodes are involved [HR (95 % CI) 2.38 (1.15-4.90)]., Conclusions: A combined staging system that incorporates distribution of lymph nodes relative to the diaphragm refines prognostication after esophagectomy as assessed in the resected specimen and pretreatment as assessed by EUS. This improved staging has the potential to have a great impact on clinical decision making as to whether to embark upon potentially curative or palliative treatments.

Objective: Preoperative weight loss might increase the risk of postoperative morbidity and mortality after esophagectomy for cancer. We hypothesized that patients with esophageal cancer with >10% weight loss during the 3 months before their diagnosis would be at an increased risk of postoperative complications, have a longer length of stay, and have worse overall survival., Methods: In the present hospital-based cohort study, all patients who had undergone surgery for esophageal cancer in 1990 to 2010 at the Erasmus University Medical Center Rotterdam were included. Weight loss was defined as "no, or limited" (≤10%) or "severe" (>10%). Logistic regression analysis was used to estimate the relative risk of complications, expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Hazard ratios were calculated to assess the length of hospital stay and survival. The risk estimates were adjusted for potential confounding factors., Results: Of 922 included patients, 155 (17%) had experienced severe weight loss. These patients had no increased risk of early surgical, early nonsurgical, or late surgical complications (OR, 0.83 and 95% CI, 0.54-1.24; OR, 0.90 and 95% CI, 0.63-1.30; OR, 1.14 and 95% CI, 0.79-1.66, respectively) and had no increased length of stay (hazard ratio, 1.09; 95% CI, 0.89-1.35). Preoperative weight loss was followed by increased 5-year mortality (hazard ratio, 1.34; 95% CI, 1.02-1.74)., Conclusions: A >10% preoperative weight loss was followed by decreased 5-year survival after esophageal cancer surgery but no increased risk of postoperative complications., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background & Aims: Ischemic-type biliary lesions (ITBL) are the second most common cause of graft loss after liver transplantation. Though the exact pathophysiology of ITBL is unknown, bile duct injury during graft preservation is considered to be a major cause. Here we investigated whether the release of cholangiocyte-derived microRNAs (CDmiRs) during graft preservation is predictive of the development of ITBL after liver transplantation., Methods: Graft preservation solutions (perfusates) and paired liver biopsies collected at the end of cold ischemia were analysed by RT-qPCR for CDmiR-30e, CDmiR-222, and CDmiR-296 and hepatocyte-derived miRNAs (HDmiRs) HDmiR-122 and HDmiR-148a. MicroRNAs in perfusates were evaluated on their stability by incubation and fractionation experiments. MicroRNA profiles in perfusates from grafts that developed ITBL (n=20) and grafts without biliary strictures (n=37) were compared., Results: MicroRNAs in perfusates were proven to be stable and protected against degradation by interacting proteins. Ratios between HDmiRs/CDmiRs were significantly higher in perfusates obtained from grafts that developed ITBL (p<0.01) and were identified as an independent risk factor by multivariate analysis (p<0.01, HR: 6.89). The discriminative power of HDmiRs/CDmiRs in perfusates was validated by analysis of separate brain death- (DBD) and cardiac death donors (DBD; p ≤ 0.016) and was superior to expression in liver biopsies (C=0.77 in perfusates vs. C<0.50 in biopsies)., Conclusions: This study demonstrates that differential release of CDmiRs during graft preservation is predictive of the development of ITBL after liver transplantation. This provides new evidence for the link between graft-related bile duct injury and the risk for later development of ITBL., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Ischemic-type biliary lesions (ITBLs) are a major cause of morbidity after liver transplantation (LT). Their assumed underlying pathophysiological mechanism is ischemia/reperfusion injury of the biliary tree, in which the portal circulation has been proposed recently to have a role. The aim of this study was to investigate whether early histological changes, particularly in the portal vein, predispose patients to ITBLs. A case-control study of 22 LT recipients was performed through a retrospective assessment of more than 30 histological parameters in 44 intraoperative liver biopsy samples taken after cold ischemia (time 0) and portal reperfusion (time 1). Eleven grafts developed ITBLs requiring retransplantation (the ITBL group), and 11 matched controls had normally functioning grafts 11 years after LT on average (the non-ITBL group). Additionally, 11 liver biopsy samples from hemihepatectomies performed for metastases of colorectal cancer (CRC) were assessed similarly. Analyses showed no significant histological differences at time 0 between the ITBL and non-ITBL groups. However, the time 1 biopsy samples from the ITBL group showed smaller portal vein branches (PVBs) significantly more often than the samples from the non-ITBL group, which also showed persisting paraportal collateral vessels. Larger PVBs and paraportal collateral vessels were also found in the CRC group. A morphometric analysis confirmed these findings and showed that PVB measurements were significantly lower for the ITBL group at time 1 versus the ITBL group at time 0 and the non-ITBL and CRC groups (they were largest in the CRC group). Thus, the PVB dimensions decreased in the ITBL group in comparison with the time 0 biopsy samples, and they were significantly smaller at time 1 in comparison with the dimensions for the non-ITBL and CRC groups. In conclusion, a smaller PVB lumen size in postreperfusion biopsy samples from liver grafts, suggesting a relatively decreased portal blood flow, is associated with a higher incidence of ITBLs. These findings support recent clinical studies suggesting a possible pathophysiological role of portal blood flow in the oxygenation of the biliary tree after LT., (Copyright © 2013 American Association for the Study of Liver Diseases.)

Aim: To investigate the effects of mammalian target of rapamycin (mTOR) inhibition on liver regeneration and autophagy in a surgical resection model., Methods: C57BL/6 mice were subjected to a 70% partial hepatectomy (PH) and treated intraperitoneally every 24 h with a combination of the mTOR inhibitor rapamycin (2.5 mg/kg per day) and the steroid dexamethasone (2.0 mg/kg per day) in phosphate buffered saline (PBS) or with PBS alone as vehicle control. In the immunosuppressant group, part of the group was treated subcutaneously 4 h prior to and 24 h after PH with a combination of human recombinant interleukin 6 (IL-6; 500 μg/kg per day) and hepatocyte growth factor (HGF; 100 μg/kg per day) in PBS. Animals were sacrificed 2, 3 or 5 d after PH and liver tissue and blood were collected for further analysis. Immunohistochemical staining for 5-Bromo-2'-deoxyuridine (BrdU) was used to quantify hepatocyte proliferation. Western blotting was used to detect hepatic microtubule-associated protein 1 light chain 3 (LC3)-II protein expression as a marker for autophagy. Hepatic gene expression levels of proliferation-, inflammation- and angiogenesis-related genes were examined by real-time reverse transcription-polymerase chain reaction and serum bilirubin and transaminase levels were analyzed at the clinical chemical core facility of the Erasmus MC-University Medical Center., Results: mTOR inhibition significantly suppressed regeneration, shown by decreased hepatocyte proliferation (2% vs 12% BrdU positive hepatocyte nuclei at day 2, P < 0.01; 0.8% vs 1.4% at day 5, P = 0.02) and liver weight reconstitution (63% vs 76% of initial total liver weight at day 3, P = 0.04), and furthermore increased serum transaminase levels (aspartate aminotransferase 641 U/L vs 185 U/L at day 2, P = 0.02). Expression of the autophagy marker LC3-II, which was reduced during normal liver regeneration, increased after mTOR inhibition (46% increase at day 2, P = 0.04). Hepatic gene expression showed an increased inflammation-related response [tumor necrosis factor (TNF)-α 3.2-fold upregulation at day 2, P = 0.03; IL-1Ra 6.0-fold upregulation at day 2 and 42.3-fold upregulation at day 5, P < 0.01] and a reduced expression of cell cycle progression and angiogenesis-related factors (HGF 40% reduction at day 2; vascular endothelial growth factor receptor 2 50% reduction at days 2 and 5; angiopoietin 1 60% reduction at day 2, all P ≤ 0.01). Treatment with the regeneration stimulating cytokine IL-6 and growth factor HGF could overcome the inhibitory effect on liver weight (75% of initial total liver weight at day 3, P = 0.02 vs immunosuppression alone and P = 0.90 vs controls) and partially reversed gene expression changes caused by rapamycin (TNF-α and IL-1Ra levels at day 2 were restored to control levels). However, no significant changes in hepatocyte proliferation, serum injury markers or autophagy were found., Conclusion: mTOR inhibition severely impairs liver regeneration and increases autophagy after PH. These effects are partly reversed by stimulation of the IL-6 and HGF pathways.

Recent evidence indicates there is a role for small membrane vesicles, including exosomes, as vehicles for intercellular communication. Exosomes secreted by most cell types can mediate transfer of proteins, mRNAs, and microRNAs, but their role in the transmission of infectious agents is less established. Recent studies have shown that hepatocyte-derived exosomes containing hepatitis C virus (HCV) RNA can activate innate immune cells, but the role of exosomes in the transmission of HCV between hepatocytes remains unknown. In this study, we investigated whether exosomes transfer HCV in the presence of neutralizing antibodies. Purified exosomes isolated from HCV-infected human hepatoma Huh7.5.1 cells were shown to contain full-length viral RNA, viral protein, and particles, as determined by RT-PCR, mass spectrometry, and transmission electron microscopy. Exosomes from HCV-infected cells were capable of transmitting infection to naive human hepatoma Huh7.5.1 cells and establishing a productive infection. Even with subgenomic replicons, lacking structural viral proteins, exosome-mediated transmission of HCV RNA was observed. Treatment with patient-derived IgGs showed a variable degree of neutralization of exosome-mediated infection compared with free virus. In conclusion, this study showed that hepatic exosomes can transmit productive HCV infection in vitro and are partially resistant to antibody neutralization. This discovery sheds light on neutralizing antibodies resistant to HCV transmission by exosomes as a potential immune evasion mechanism.

Purpose: Patients with liver cirrhosis scheduled for liver transplantation often present with a concurrent umbilical hernia. Optimal management of these patients is not clear. The objective of this study was to compare the outcomes of patients who underwent umbilical hernia correction during liver transplantation through a separate infra-umbilical incision with those who underwent correction through the same incision used to perform the liver transplantation., Methods: In the period between 1990 and 2011, all 27 patients with umbilical hernia and liver cirrhosis who underwent hernia correction during liver transplantation were identified in our hospital database. In 17 cases, umbilical hernia repair was performed through a separate infra-umbilical incision (separate incision group) and 10 were corrected from within the abdominal cavity without a separate incision (same incision group). Six patients died during follow-up; no deaths were attributable to intraoperative umbilical hernia repair. All 21 patients who were alive visited the outpatient clinic to detect recurrent umbilical hernia., Results: One recurrent umbilical hernia was diagnosed in the separate incision group (6 %) and four (40 %) in the same incision group (p = 0.047). Two patients in the same incision group required repair of the recurrent umbilical hernia; one of whom underwent emergency surgery for bowel incarceration. The one recurrent hernia in the separate incision group was corrected electively., Conclusion: In the event of liver transplantation, umbilical hernia repair through a separate infra-umbilical incision is preferred over correction through the same incision used to perform the transplantation.