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1.  mTOR signaling in liver regeneration: Rapamycin combined with growth factor treatment 
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.
doi:10.5500/wjt.v3.i3.36
PMCID: PMC3832859  PMID: 24255881
Hepatocyte proliferation; Autophagy; Microtubule-associated protein 1 light chain 3; Partial hepatectomy; Rapamycin
2.  Comparison of the 6th and 7th Editions of the UICC-AJCC TNM Classification for Esophageal Cancer 
Annals of Surgical Oncology  2012;19(7):2142-2148.
Background
The new 7th edition of the Union for International Cancer Control–American Joint Committee on Cancer (UICC-AJCC) tumor, node, metastasis (TNM) staging system is the ratification of data-driven recommendations from the Worldwide Esophageal Cancer Collaboration database. Generalizability remains questionable for single institutions. The present study serves as a validation of the 7th edition of the TNM system in a prospective cohort of patients with predominantly adenocarcinomas from a single institution.
Methods
Included were patients who underwent transhiatal esophagectomy with curative intent between 1991 and 2008 for invasive carcinoma of the esophagus or gastroesophageal junction. Excluded were patients who had received neoadjuvant chemo(radio)therapy, patients after a noncurative resection and patients who died in the hospital. Tumors were staged according to both the 6th and the 7th editions of the UICC-AJCC staging systems. Survival was calculated by the Kaplan–Meier method, and multivariate analysis was performed with a Cox regression model. The likelihood ratio chi-square test related to the Cox regression model and the Akaike information criterion were used for measuring goodness of fit.
Results
A study population of 358 patients was identified. All patients underwent transhiatal esophagectomy for adenocarcinoma. Overall 5-year survival rate was 38%. Univariate analysis revealed that pT stage, pN stage, and pM stage significantly predicted overall survival. Prediction was best for the 7th edition, stratifying for all substages.
Conclusions
The application of the 7th UICC-AJCC staging system results in a better prognostic stratification of overall survival compared to the 6th edition. The fact that the 7th edition performs better predominantly in patients with adenocarcinomas who underwent a transhiatal surgical approach, in addition to findings from earlier research in other cohorts, supports its generalizability for different esophageal cancer practices.
doi:10.1245/s10434-012-2218-5
PMCID: PMC3381120  PMID: 22395974
3.  Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: Long-term results of a randomized controlled trial 
BMC Cancer  2011;11:181.
Background
This is a randomized, controlled trial of preoperative chemotherapy in patients undergoing surgery for oesophageal squamous cell carcinoma (OSCC). Patients were allocated to chemotherapy, consisting of 2-4 cycles of cisplatin and etoposide, followed by surgery (CS group) or surgery alone (S group). Initial results reported only in abstract form in 1997, demonstrated an advantage for overall survival in the CS group. The results of this trial have been updated and discussed in the timeframe in which this study was performed.
Methods
This trial recruited 169 patients with OSCC, 85 patients assigned to preoperative chemotherapy and 84 patients underwent immediate surgery. The primary study endpoint was overall survival (OS), secondary endpoints were disease free survival (DFS) and pattern of failure. Survival has been determined from Kaplan-Meier curves and treatment comparisons made with the log-rank test.
Results
There were 148 deaths, 71 in the CS and 77 in the S group. Median OS time was 16 months in the CS group compared with 12 months in the S group; 2-year survival rates were 42% and 30%; and 5-year survival rates were 26% and 17%, respectively. Intention to treat analysis showed a significant overall survival benefit for patients in the CS group (P = 0.03, by the log-rank test; hazard ratio [HR] 0.71; 95%CI 0.51-0.98). DFS (from landmark time of 6 months after date of randomisation) was also better in the CS-group than in the S group (P = 0.02, by the log-rank test; HR 0.72; 95%CI 0.52-1.0). No difference in failure pattern was observed between both treatment arms.
Conclusions
Preoperative chemotherapy with a combination of etoposide and cisplatin significantly improved overall survival in patients with OSCC.
doi:10.1186/1471-2407-11-181
PMCID: PMC3123658  PMID: 21595951
4.  Verification and Unmasking of Widely Used Human Esophageal Adenocarcinoma Cell Lines 
For decades, hundreds of different human tumor type–specific cell lines have been used in experimental cancer research as models for their respective tumors. The veracity of experimental results for a specific tumor type relies on the correct derivation of the cell line. In a worldwide effort, we verified the authenticity of all available esophageal adenocarcinoma (EAC) cell lines. We proved that the frequently used cell lines SEG-1 and BIC-1 and the SK-GT-5 cell line are in fact cell lines from other tumor types. Experimental results based on these contaminated cell lines have led to ongoing clinical trials recruiting EAC patients, to more than 100 scientific publications, and to at least three National Institutes of Health cancer research grants and 11 US patents, which emphasizes the importance of our findings. Widespread use of contaminated cell lines threatens the development of treatment strategies for EAC.
doi:10.1093/jnci/djp499
PMCID: PMC2902814  PMID: 20075370
5.  Functional Polymorphisms Associated with Disease-Free Survival in Resected Carcinoma of the Esophagus 
Purpose
The aim of this study was to determine whether clinical outcome after surgical resection of esophageal adenocarcinoma (EAC) or esophageal squamous cell carcinoma (ESCC) could be predicted by functional polymorphisms in different proto-oncogenes and tumor suppressor genes.
Experimental Design
Six single nucleotide polymorphisms (SNPs) in the AURKA (rs2273535), ERBB2 (rs1136201), MDM2 (rs2279744), CDH1 (rs5030625), CDKN2A (rs11515), and TP73 (rs2273953) genes were genotyped in a consecutive cohort of 346 esophageal cancer patients, who had underwent surgical resection with curative intent. Associations with disease-free survival (DFS) were analyzed with Kaplan–Meier curves and Cox regression, adjusting for potential confounders.
Results
Univariate analysis showed no significant associations between the tested polymorphisms and DFS in patients with EAC or ESCC. However, in a multivariate analysis, patients with EAC carrying the heterozygous MDM2 (rs2279744) T/G genotype had significantly improved DFS compared with patients carrying the wild-type genotype (adjusted hazard ratio (AHR), 0.63; 95% confidence interval (CI) [0.45–0.88]). Patients with EAC harboring the homozygous CDH1 (rs5030625) GA/GA genotype had a significantly reduced survival as compared with patients carrying the wild-type genotype AHR 4.0, 95% CI [1.4–11].
Conclusions
In a large cohort of esophageal cancer patients, the MDM2 T/G and CDH1 GA/GA genotype confer risk of death in patients with EAC. These data suggest that inter-individual differences in germ-line DNA have an impact on DFS in patients with EAC.
doi:10.1007/s11605-010-1358-9
PMCID: PMC3023032  PMID: 20922573
Esophagus; Adenocarcinoma; Squamous cell carcinoma; Polymorphism; SNP
6.  Early and long-term morbidity after total laryngopharyngectomy 
To determine the early and long-term morbidity of patients treated with a total laryngopharyngectomy and reconstruction using a jejunum interposition or gastric pull-up procedure. It is a retrospective study; and it is conducted in tertiairy referral center. Sixty-three patients were included in whom 70 reconstructions were performed (51 jejunum interpositions and 19 gastric pull-up procedures) between 1990 and 2007. The studied parameters were success rate of the reconstruction, early and long-term complication rate, and functional outcome including quality of life. Subjective quality of life analysis was determined by two questionnaires: the EORTC Quality of Life Questionnaire (QLQ)-C30 Dutch version 3.0, and the EORTC-Head and Neck (H & N 35). The success rates were 84 and 74%, respectively. The procedures were associated with a high complication rate (63% after jejunum interposition and 89% after gastric pull-up), and a lengthy rehabilitation. Surviving patients were found to have a good long-term quality of life. Complete oral intake was achieved in 97%, and speech rehabilitation in 95%. These procedures are associated with significant morbidity, high complication rates, lengthy rehabilitation, but a good long-term quality of life.
doi:10.1007/s00405-010-1244-9
PMCID: PMC2908431  PMID: 20372916
Jejunum interposition; Gastric pull-up; Laryngopharyngectomy; Functional results; Reconstruction
7.  Delay in Diagnostic Workup and Treatment of Esophageal Cancer 
Introduction
Esophageal cancer should preferably be detected and treated at an early stage, but this may be prohibited by late onset of symptoms and delays in referral, diagnostic workup, and treatment. The aim of this study was to investigate the impact of these delays on outcome in patients with esophageal cancer.
Methods
For 491 patients undergoing esophagectomy for cancer between 1991 and 2007, patients’ short- and long-term outcome were analyzed according to different time intervals between onset of symptoms, diagnosis, and surgical treatment.
Results
Length of prehospital delay (from onset of symptoms until endoscopic diagnosis) did not affect patient’s short- or long-term outcome. A shorter hospital delay between establishing the diagnosis of esophageal cancer on endoscopy and surgery was associated with lower overall morbidity and in-hospital mortality. Patients of ASA classes I and II experienced a shorter hospital delay than patients of ASA classes III and IV. Length of hospital delay between endoscopic diagnosis and surgery did not affect pathological tumor–node–metastasis stage or R0-resection rate. Longer hospital delay did not result in worse survival: Overall survival after esophagectomy for cancer was not significantly different between patients with hospital delay <5, 5–8, or >8 weeks (24.7%, 21.7%, and 32.3%, respectively; p = 0.12).
Conclusion
A longer hospital delay (between endoscopic diagnosis and surgery) resulted in worse patient’s short-term outcome (higher overall morbidity and mortality rates) but not in a worse long-term outcome (overall survival). This may be explained by a more time-consuming diagnostic workup in patients with a poorer physical status and not by tumor progression.
doi:10.1007/s11605-009-1109-y
PMCID: PMC2820689  PMID: 20012379
Esophageal cancer; Diagnostic workup; Delay; Waiting list; Survival
8.  Preoperative and Early Postoperative Quality of Life Predict Survival in Potentially Curable Patients with Esophageal Cancer 
Annals of Surgical Oncology  2009;17(1):23-30.
Background
In patients with esophageal cancer, evidence for prognostic significance of preoperative quality of life (QoL) is limited, while the prognostic significance of postoperative QoL has not been investigated at all.
Aim
To determine whether preoperative and postoperative QoL measurements can predict survival independently from clinical and pathological factors, in patients with potentially curable esophageal adenocarcinoma.
Methods
A randomized controlled trial was performed from 1994 to 2000 in two academic medical centres, comparing transthoracic and transhiatal esophagectomy. QoL questionnaires were sent before and 3 months after surgery (Medical Outcome Study Short Form-20 and Rotterdam Symptom Checklist). Uni- and multivariate Cox regression analyses were used to examine firstly the prognostic value of preoperative QoL and several clinical factors, and secondly of postoperative QoL, several clinical factors, and pathological staging.
Results
Out of 220 randomized patients, 199 participated in the QoL-study. In the multivariate preoperative model physical symptom scale (p = 0.021), tumor length (p = 0.034), and endosonographic T-stage (p = 0.003) were predictive for overall survival. In the postoperative multivariate analysis, social functioning (p = 0.035), pain (p = 0.026), and activity level (p = 0.037) predicted survival, besides pathological T-stage (p < 0.001) and N-stage (p < 0.001).
Conclusion
In the present paper the first large consecutive series of potentially curable esophageal cancer patients is presented in whom prospectively collected QoL data before and after potentially curative surgical resection were used to predict survival. Both preoperative (physical symptoms) and postoperative (social functioning, pain, and activity level) QoL subscales are independent predictors of survival in potentially curable patients with esophageal adenocarcinoma.
doi:10.1245/s10434-009-0731-y
PMCID: PMC2805800  PMID: 19830496
9.  Neoadjuvant Chemoradiotherapy for Esophageal Cancer: A Review of Meta-Analyses 
World Journal of Surgery  2009;33(12):2606-2614.
Background
Most randomized controlled trials (RCTs) that have compared neoadjuvant chemoradiation followed by surgery with surgery alone for locally advanced esophageal cancer have shown no difference in survival between the two treatments. Meta-analyses on neoadjuvant chemoradiation in esophageal cancer, however, are discordant.
Methods
For the present study, published meta-analyses on neoadjuvant chemoradiation for esophageal cancer were identified from the PubMed database and critically appraised in order to make a judgment on the applicability of neoadjuvant chemoradiation in clinical practice and decision making.
Results
Two of the six meta-analyses examined did not show a significant survival benefit in patients with resectable esophageal cancer. Differences in the studies included and statistical methods applied might account for this. Moreover, there was heterogeneity between the RCTs included in the meta-analyses with regard to the patients included, tumor histology, and radiotherapy and chemotherapy regimes. Also, surgical technique was not uniform. No data on individual patients were available for most meta-analyses. The RCTs included in the meta-analyses were of inadequate sample size. All were started in the nineties, and hence methods for diagnosis, staging, treatment delivery, and outcome measurement reflect clinical practice during that decade.
Conclusions
The current data on neoadjuvant chemoradiation for esophageal cancer strongly indicate the need for designing future high-quality trials that will contribute to a better understanding of the role of neoadjuvant treatment for resectable cancer of the esophagus and help to identify patient subgroups that would benefit most.
doi:10.1007/s00268-009-0223-z
PMCID: PMC2840665  PMID: 19760309
10.  Combined antiviral activity of interferon-α and RNA interference directed against hepatitis C without affecting vector delivery and gene silencing 
The current standard interferon-alpha (IFN-α)-based therapy for chronic hepatitis C virus (HCV) infection is only effective in approximately half of the patients, prompting the need for alternative treatments. RNA interference (RNAi) represents novel approach to combat HCV by sequence-specific targeting of viral or host factors involved in infection. Monotherapy of RNAi, however, may lead to therapeutic resistance by mutational escape of the virus. Here, we proposed that combining lentiviral vector-mediated RNAi and IFN-α could be more effective and avoid therapeutic resistance. In this study, we found that IFN-α treatment did not interfere with RNAi-mediated gene silencing. RNAi and IFN-α act independently on HCV replication showing combined antiviral activity when used simultaneously or sequentially. Transduction of mouse hepatocytes in vivo and in vitro was not effected by IFN-α treatment. In conclusion, RNAi and IFN-α can be effectively combined without cross-interference and may represent a promising combinational strategy for the treatment of hepatitis C.
doi:10.1007/s00109-009-0470-3
PMCID: PMC2700866  PMID: 19404587
RNAi; IFN-α; Gene therapy; Lentiviral vector; HCV
11.  NEOadjuvant therapy monitoring with PET and CT in Esophageal Cancer (NEOPEC-trial) 
Background
Surgical resection is the preferred treatment of potentially curable esophageal cancer. To improve long term patient outcome, many institutes apply neoadjuvant chemoradiotherapy. In a large proportion of patients no response to chemoradiotherapy is achieved. These patients suffer from toxic and ineffective neoadjuvant treatment, while appropriate surgical therapy is delayed. For this reason a diagnostic test that allows for accurate prediction of tumor response early during chemoradiotherapy is of crucial importance. CT-scan and endoscopic ultrasound have limited accuracy in predicting histopathologic tumor response. Data suggest that metabolic changes in tumor tissue as measured by FDG-PET predict response better. This study aims to compare FDG-PET and CT-scan for the early prediction of non-response to preoperative chemoradiotherapy in patients with potentially curable esophageal cancer.
Methods/design
Prognostic accuracy study, embedded in a randomized multicenter Dutch trial comparing neoadjuvant chemoradiotherapy for 5 weeks followed by surgery versus surgery alone for esophageal cancer. This prognostic accuracy study is performed only in the neoadjuvant arm of the randomized trial. In 6 centers, 150 consecutive patients will be included over a 3 year period. FDG-PET and CT-scan will be performed before and 2 weeks after the start of the chemoradiotherapy. All patients complete the 5 weeks regimen of neoadjuvant chemoradiotherapy, regardless the test results. Pathological examination of the surgical resection specimen will be used as reference standard. Responders are defined as patients with < 10% viable residual tumor cells (Mandard-score).
Difference in accuracy (area under ROC curve) and negative predictive value between FDG-PET and CT-scan are primary endpoints. Furthermore, an economic evaluation will be performed, comparing survival and costs associated with the use of FDG-PET (or CT-scan) to predict tumor response with survival and costs of neoadjuvant chemoradiotherapy without prediction of response (reference strategy).
Discussion
The NEOPEC-trial could be the first sufficiently powered study that helps justify implementation of FDG-PET for response-monitoring in patients with esophageal cancer in clinical practice.
Trial registration
ISRCTN45750457
doi:10.1186/1756-6649-8-3
PMCID: PMC3301128  PMID: 18671847
12.  Physical fitness, fatigue, and quality of life after liver transplantation 
Fatigue is often experienced after liver transplantation. The aims of this cross-sectional study were to assess physical fitness (cardiorespiratory fitness, neuromuscular fitness, body composition) in liver transplant recipients and to explore whether physical fitness is related to severity of fatigue. In addition, we explored the relationship between physical fitness and health-related quality of life. Included were 18 patients 1–5 years after transplantation (aged 48.0 ± 11.8 years) with varying severity of fatigue. Peak oxygen uptake during cycle ergometry, 6-min walk distance, isokinetic muscle strength of the knee extensors, body mass index, waist circumference, skinfold thickness, severity of fatigue, and health-related quality of life were measured. Cardiorespiratory fitness in the liver transplant recipients was on average 16–34% lower than normative values (P ≤ 0.05). Furthermore, the prevalence of obesity seemed to be higher than in the general population (17 vs. 10%). We found no deficit in neuromuscular fitness. Cardiorespiratory fitness was the only fitness component that was related with severity of fatigue (rs = −0.61 to rs = -0.50, P ≤ 0.05). Particularly cardiorespiratory fitness was related with several aspects of health-related quality of life (rs = 0.48 to rs = 0.70, P ≤ 0.05). Results of our study imply that cardiorespiratory fitness and body composition are impaired in liver transplant recipients and that fitness is related with severity of fatigue (only cardiorespiratory fitness) and quality of life (particularly cardiorespiratory fitness) in this group. These findings have implications for the development of rehabilitation programs for liver transplant recipients.
doi:10.1007/s00421-007-0435-6
PMCID: PMC1914221  PMID: 17364193
Liver transplantation; Fatigue; Peak oxygen uptake; Isokinetic muscle strength; Body composition
13.  Optimizing intensive care capacity using individual length-of-stay prediction models 
Critical Care  2007;11(2):R42.
Introduction
Effective planning of elective surgical procedures requiring postoperative intensive care is important in preventing cancellations and empty intensive care unit (ICU) beds. To improve planning, we constructed, validated and tested three models designed to predict length of stay (LOS) in the ICU in individual patients.
Methods
Retrospective data were collected from 518 consecutive patients who underwent oesophagectomy with reconstruction for carcinoma between January 1997 and April 2005. Three multivariable linear regression models for LOS, namely preoperative, postoperative and intra-ICU, were constructed using these data. Internal validation was assessed using bootstrap sampling in order to obtain validated estimates of the explained variance (r2). To determine the potential gain of the best performing model in day-to-day clinical practice, prospective data from a second cohort of 65 consecutive patients undergoing oesophagectomy between May 2005 and April 2006 were used in the model, and the predictive performance of the model was compared with prediction based on mean LOS.
Results
The intra-ICU model had an r2 of 45% after internal validation. Important prognostic variables for LOS included greater patient age, comorbidity, type of surgical approach, intraoperative respiratory minute volume and complications occurring within 72 hours in the ICU. The potential gain of the best model in day-to-day clinical practice was determined relative to mean LOS. Use of the model reduced the deficit number (underestimation) of ICU days by 65 and increased the excess number (overestimation) of ICU days by 23 for the cohort of 65 patients. A conservative analysis conducted in the second, prospective cohort of patients revealed that 7% more oesophagectomies could have been accommodated, and 15% of cancelled procedures could have been prevented.
Conclusion
Patient characteristics can be used to create models that will help in predicting LOS in the ICU. This will result in more efficient use of ICU beds and fewer cancellations.
doi:10.1186/cc5730
PMCID: PMC2206463  PMID: 17389032

Results 1-13 (13)