Tilanus, H.W.

Overestimation of hematopoietic stem cell frequencies in human liver grafts (Article)

2013-04-10T00:00:00Z

Genetic polymorphisms in innate immunity receptors do not predict the risk of bacterial and fungal infections and acute rejection after liver transplantation (Article)

2013-04-01T00:00:00Z

Introduction: We studied the influence of a broad range of genetic variants in recipient and donor innate immunity receptors on bacterial and fungal infections and acute rejection after liver transplantation (LT). Methods: Seventy-six polymorphisms in TLR 1-10, NOD2, LBP, CD14, MD2, SIGIRR, Ficolins 1, -2, and -3, MASP 1, -2, and -3, and the complement receptor C1qR1 were determined in 188 LT recipients and 135 of their donors. Associations with clinically significant infections and acute rejection were analyzed for 50 polymorphisms. Significant associations were validated in an independent cohort of 181 recipients and 167 donors. Results: Three recipient polymorphisms and 3 donor polymorphisms were associated with infections in the identification cohort, but none of these associations were confirmed in the validation cohort. Three donor polymorphisms were associated with acute rejection in the identification cohort, but not in the validation cohort. Conclusion: In contrast to their effect in the general population, 50 common genetic variations in innate immunity receptors do not influence susceptibility to bacterial/fungal infections after LT. In addition, no reproducible associations with acute rejection after LT were observed. Likely, transplant-related factors play a superior role as risk factors for bacterial/fungal infections and acute rejection after LT.

Hepatic cell-to-cell transmission of small silencing RNA can extend the therapeutic reach of RNA interference (RNAi) (Article)

2011-12-23T00:00:00Z

Background/aims: RNA interference (RNAi), a sequence-specific gene silencing technology triggered by small interfering RNA (siRNA), represents promising new avenues for treatment of various liver diseases including hepatitis C virus (HCV) infection. In plants and invertebrates, RNAi provides an important mechanism of cellular defence against viral pathogens and is dependent on the spread of siRNA to neighbouring cells. A study was undertaken to investigate whether vector-delivered RNAi can transfer between hepatic cells in vitro and in mice, and whether this exchange could extend the therapeutic effect of RNAi against HCV infection. Methods: Transmission of RNAi was investigated in culture by assessing silencing of HCV replication and expression of viral entry receptor CD81 using a human hepatic cell line and primary B lymphocytes transduced with siRNA-expressing vectors. In vivo transmission between hepatic cells was investigated in NOD/SCID mice. Involvement of exosomes was demonstrated by purification, uptake and mass spectrometric analysis. Results: Human and mouse liver cells, as well as primary human B cells, were found to have the ability to exchange small RNAs, including cellular endogenous microRNA and delivered siRNA targeting HCV or CD81. The transmission of RNAi was largely independent of cell contact and partially mediated by exosomes. Evidence of RNAi transmission in vivo was observed in NOD/SCID mice engrafted with human hepatoma cells producing CD81 siRNA, causing suppression of CD81 expression in mouse hepatocytes. Conclusion: Both human and mouse hepatic cells exchange small silencing RNAs, partially mediated by shuttling of exosomes. Transmission of siRNA potentially extends the therapeutic reach of RNAi-based therapies against HCV as well as other liver diseases. Copyright Article author (or their employer) 2011.

Impact of a multidisciplinary tumour board meeting for upper-GI malignancies on clinical decision making: a prospective cohort study (Article)

2011-12-22T00:00:00Z

Background/aims: The Dutch guidelines for diagnosis and treatment of upper-GI malignancies recommend review of patients by a multidisciplinary tumour board (MDT). The purpose of this study was to determine the effect on clinical decision making of an MDT for patients with upper-GI malignancies. Methods: All physicians participating in the MDT completed an electronic standardised case form to delineate their proposed treatment plan for the patients they presented, including the intent of treatment and the modality of treatment. This therapeutic or diagnostic proposal was then compared with the plan on which consensus was reached by the MDT. Results: A total of 252/280 (90.0%) forms were completed and suitable for analysis. In 87/252 (34.5%) of the case presentations, the MDT altered the proposed plan of management. In 29/87 (33.3%) cases, a more extensive diagnostic work-up was decided upon. In 8/87 (9.2%) cases the curative intent of the proposed treatment was altered to palliation only. In 2/75 (2.7%) cases, however, it was decided that a patient could be treated with curative intent instead of the proposed palliative intent. Conclusion: In over 1/3 of cases, the diagnostic work-up or treatment plan is altered after evaluation by a multidisciplinary tumour board. This study supports Dutch guidelines recommending discussion of patients with upper-GI malignancies by a multidisciplinary tumour board.

Donor and recipient HLA/KIR genotypes do not predict liver transplantation outcome (Article)

2011-09-01T00:00:00Z

Whether or not Natural Killer (NK) cells affect the immune response to solid organ allografts is still controversial. Main determinants of NK-cell activation are specific HLA/killer-cell immunoglobulin-like receptors (KIR) interactions that, in transplantation, may induce NK-cell alloreactivity. So far, in liver transplantation (LTX) donor-versus-recipient alloreactivity has not been investigated; in addition, studies of predicted recipient-versus-donor NK-cell alloreactivity have led to contradicting results. We typed a cohort of LTX donors and recipients for HLA-C/Bw4 and KIRs. We estimated the effect of NK-cell alloreactivity, as predicted by classically used models, in the donor-versus-recipient direction. The results indicate that HLA/KIR mismatches in the donor-versus-recipient direction do not predict graft rejection nor graft or patient survival, suggesting that donor-derived NK cells do not play a major role in LTX outcome. In addition, when considering predicted NK-cell alloreactivity in the reverse direction (recipient-versus-donor), we first confirmed that donor HLA-C genotype was not associated with acute rejection, graft or patient survival and secondly we found that none of the models describing NK-cell alloreactivity could predict LTX outcome. Overall our observations suggest that, in contrast to what is shown in haematopoietic stem cell transplantation, donor-derived NK cells may not contribute in preventing liver graft rejection, and that recipient-versus-donor NK-cell alloreactivity does not predict LTX outcome.

End-to-end versus end-to-side esophagogastrostomy after esophageal cancer resection: A prospective randomized study (Article)

2011-08-01T00:00:00Z

Objective: To compare single-layered hand-sewn cervical end-to-side (ETS) anastomosis with end-to-end (ETE) anastomosis in a prospective randomized fashion. Background: The preferred organ used for reconstruction after esophagectomy for cancer is the stomach. Previous studies attempted to define the optimal site of anastomosis and anastomotic techniques. However, anastomotic stricture formation and leakage still remain an important clinical problem. Methods: From May 2005 to September 2007, 128 patients (64 in each group) were randomized between ETE and ETS anastomosis after esophagectomy for cancer with gastric tube reconstruction. Routine contrast swallow studies and endoscopy were performed. Anastomotic stricture within 1 year, requiring dilatation, was the primary endpoint. Secondary endpoints were anastomotic leak rate and mortality. Results: Ninety-nine men and 29 women underwent esophagectomy and gastric tube reconstruction. Benign stenosis of the anastomosis, for which dilatation was required, occurred more often in the ETE group (40% vs. ETS 18%, P < 0.01) after 1 year of follow-up. The overall (clinical and radiological) anastomotic leak rate was lower in the ETE group (22% vs. ETS 41%, P = 0.04). Patients with an ETE anastomosis suffered less often from pneumonia; 17% versus ETS 44%, P = 0.002 and had subsequently significantly shorter in-hospital stay (15 days vs. 22 days, P = 0.02). In-hospital mortality did not differ between both groups. Conclusion: ETS anastomosis is associated with a lower anastomotic stricture rate, compared to ETE anastomosis. However, prevention of stricture formation was at high costs with increased anastomotic leakage and longer in-hospital stay. This study is registered with the Dutch Trial Registry and carries the ID number OND1317772. Copyright

A prospective study on elective umbilical hernia repair in patients with liver cirrhosis and ascites (Article)

2011-06-01T00:00:00Z

Background: Patients with both cirrhosis and ascites have a 20% risk of developing umbilical hernia. A retrospective study from our center comparing conservative management of umbilical hernia with elective repair in these patients showed a significant risk of mortality as a result of hernia incarceration in conservatively treated patients. The goal of this study was to assess the safety and efficacy of elective umbilical hernia repair in these patients prospectively. Methods: Patients with liver cirrhosis and ascites presenting with an umbilical hernia were included in this study. For all patients, the expected time to liver transplantation was more than 3 months, and they did not have a patent umbilical vein in the hernia sac. The following data were collected prospectively for all patients: Child-Pugh-Turcotte (CPT) classification, model for end-stage liver disease (MELD) score, kidney failure, cardiovascular comorbidity, operation-related complications, and duration of hospital stay. Mortality rates were registered in hospital records and verified in government records during follow-up. Mortality rates were registered in hospital records and verified in government records during follow-up. On completion of the study, a retrospective survey was performed to search for any patients who met the study inclusion criteria but were left out of the study cohort. Results: In total, 30 patients (25 males) underwent operation at a mean age of 58 years (standard deviation [SD] ± 9 years). Of these 30 patients, 6 were classified as CPT grade A (20%), 19 (63%) as grade B, and 5 (17%) as grade C. The patients' median MELD score was 12 (interquartile range [IQR], 8-16). In 10 (33%) of the 30 patients hernia repair was performed with mesh. The median duration of hospital stay was 3 days (IQR, 2-4). None of the patients were admitted to the intensive care unit. Postoperative complications included pneumonia and decompensation of cirrhosis (1 case each,) resulting in prolonged hospital stay for those 2 patients. After a median follow-up period of 25 months (IQR, 14-34), 2 (7%) of the 30 patients died; neither of the deaths were attributable to the umbilical hernia repair. A total of 2 patients suffered recurrence. Conclusion: Elective umbilical hernia repair is safe and the preferred approach in cirrhotic patients with ascites.

Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: Long-term results of a randomized controlled trial (Article)

2011-05-19T00:00:00Z

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.

Mobilization of hepatic mesenchymal stem cells from human liver grafts (Article)

2011-05-01T00:00:00Z

Extensive studies have demonstrated the potential applications of bone marrow-derived mesenchymal stem cells (BM-MSCs) as regenerative or immunosuppressive treatments in the setting of organ transplantation. The aims of the present study were to explore the presence and mobilization of mesenchymal stem cells (MSCs) in adult human liver grafts and to compare their functional capacities to those of BM-MSCs. The culturing of liver graft preservation fluids (perfusates) or end-stage liver disease tissues resulted in the expansion of MSCs. Liver-derived mesenchymal stem cells (L-MSCs) were equivalent to BM-MSCs in adipogenic and osteogenic differentiation and in wingless-type-stimulated proliferative responses. Moreover, the genome-wide gene expression was very similar, with a 2-fold or greater difference found in only 82 of the 32,321 genes (0.25%). L-MSC differentiation into a hepatocyte lineage was demonstrated in immunodeficient mice and in vitro by the ability to support a hepatitis C virus infection. Furthermore, a subset of engrafted MSCs survived over the long term in vivo and maintained stem cell characteristics. Like BM-MSCs, L-MSCs were found to be immunosuppressive; this was shown by significant inhibition of T cell proliferation. In conclusion, the adult human liver contains an MSC population with a regenerative and immunoregulatory capacity that can potentially contribute to tissue repair and immunomodulation after liver transplantation.

Disturbance of the microRNA pathway by commonly used lentiviral shRNA libraries limits the application for screening host factors involved in hepatitis C virus infection (Article)

2011-04-06T00:00:00Z

RNA interference (RNAi) is widely used as a screening tool for the identification of host genes involved in viral infection. Due to the limitation of raw small interfering RNA (siRNA), we tested two commonly used short hairpin RNA (shRNA) lentiviral libraries to identify host factors involved in hepatitis C virus (HCV) infection. It was found that these shRNA library vectors caused non-specific disturbance of HCV replication that was not due to toxicity or interferon response, but related to the high shRNA levels disturbing the endogenous microRNA biogenesis. The high shRNA levels achieved with these vectors reduced the levels of mature microRNAs, including miR-122 known to promote HCV replication. Our findings extend the caution of potential off-target effects of lentiviral shRNA libraries which appear unsuitable to screen microRNA regulated phenotypes, such as HCV replication.

Ribavirin enhances interferon-stimulated gene transcription by activation of the interferon-stimulated response element (Article)

2011-04-01T00:00:00Z

AAV-mediated gene therapy for liver diseases: The prime candidate for clinical application? (Article)

2011-03-01T00:00:00Z

Introduction: Diseases of the liver represent a major health problem. Often treatments are ineffective, prompting the need for new therapeutic strategies. From extensive preclinical studies, gene therapy in particular mediated by adeno-associated virus (AAV)-derived vectors, has now emerged as the prime candidate for clinical application. AAV-mediated gene therapy for inherited liver diseases has now become a clinical reality, in particular for the treatment of hemophilia B. Areas covered: This review provides a summary of current literature on AAV-mediated gene therapies for both inherited and acquired liver diseases and outlines different strategies to overcome current clinical limitations. The unique properties of AAV over other viral vectors are highlighted as well as the current challenges which are faced for wide-ranging clinical application. Expert opinion: Despite the extensive positive results from animal models, successful application in clinical settings is hampered by immunological barriers. However, immune suppression and other strategies can be employed to overcome these limitations. Given some of their unique advantages, AAV vectors are currently the most obvious candidate for hepatic gene therapy applications, however, serotype-related issues of immune reactivity still represent a formidable barrier for clinical success.

Fluorodeoxyglucose positron emission tomography for evaluating early response during neoadjuvant chemoradiotherapy in patients with potentially curable esophageal cancer (Article)

2011-01-01T00:00:00Z

Background: Neoadjuvant chemoradiotherapy before surgery can improve survival in patients with potentially curable esophageal cancer, but not all patients respond. Fluorodeoxyglucose positron emission tomography (FDG-PET) has been proposed to identify nonresponders early during neoadjuvant chemoradiotherapy. The aim of the present study was to determine whether FDG-PET could differentiate between responding and nonresponding esophageal tumors early in the course of neoadjuvant chemoradiotherapy. Methods: This clinical trial comprised serial FDG-PET before and 14 days after start of chemoradiotherapy in patients with potentially curable esophageal carcinoma. Histopathologic responders were defined as patients with no or less than 10% viable tumor cells (Mandard score on resection specimen). PET response was measured using the standardized uptake value (SUV). Receiver operating characteristic analysis was used to evaluate the ability of SUV in distinguishing between histopathologic responders and nonresponders. Results: In 100 included patients, 64 were histopathologic responders. The median SUV decrease 14 days after the start of therapy was 30.9% for histopathologic responders and 1.7% for nonresponders (P = 0.001). In receiver operating characteristic analysis, the area under the curve was 0.71 (95% CI = 0.60-0.82). Using a 0% SUV decrease cutoff value, PET correctly identified 58 of 64 responders (sensitivity 91%) and 18 of 36 nonresponders (specificity 50%). The corresponding positive and negative predictive values were 76% and 75%, respectively. Background: SUV decrease 14 days after the start of chemoradiotherapy was significantly associated with histopathologic tumor response, but its accuracy in detecting nonresponders was too low to justify the clinical use of FDG-PET for early discontinuation of neoadjuvant chemoradiotherapy in patients with potentially curable esophageal cancer.

Functional Polymorphisms Associated with Disease-Free Survival in Resected Carcinoma of the Esophagus (Article)

2011-01-01T00:00:00Z

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 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.

Results of a two-center study comparing hepatic fibrosis progression in HCV-positive liver transplant patients receiving cyclosporine or tacrolimus (Article)

2010-12-01T00:00:00Z

A 2-center retrospective analysis was performed in 60 patients undergoing liver transplantation for hepatitis C virus (HCV)related disease (cyclosporine in 20, tacrolimus in 40). Mean (±SEM) follow-up was 23.6 ± 22.5 and 22.3 ± 13.7 months in patients receiving cyclosporine or tacrolimus, respectively. Clinically indicated biopsies were performed in 15/20 cyclosporine patients (75%) and 22/40 tacrolimus patients (55%; P = .17). The Ishak fibrosis score was significantly lower in cyclosporine-treated patients versus tacrolimus-treated patients (mean 1.7 ± 0.4 vs 3.1 ± 0.4; P = .023), as was percentage of fibrosis grade Ishak <4 (7% vs 41%; P = .028). The mean time to moderate fibrosis (Ishak score <3) was 38.2 ± 15.1 months in cyclosporine patients (4/15) and 23.5 ± 12.6 months in tacrolimus patients (14/22); the difference was not statistically significant (P = .09). This retrospective study suggests that cyclosporine-based immunosuppression is associated with less severe hepatic fibrosis in HCV-positive liver transplant recipients compared with tacrolimus-based regimens, but a larger prospective comparative trial is necessary to confirm these findings.

Lymphatic micrometastases in patients with early esophageal adenocarcinoma (Article)

2010-12-01T00:00:00Z

Background: Both endoscopic and surgical treatments are recommended for m3- or sm1-adenocarcinomas of the esophagus, depending on patients' lymph nodal status. Lymphatic dissemination is related to tumor infiltration depth, but varying incidences have been reported in m3- and sm1-adenocarcinomas. The study aim was to investigate whether the presence of occult tumor cells in lymph nodes could explain this variation. Methods Sixty-three node-negative (N0) patients with early esophageal adenocarcinoma (m2/m3/sm1-tumors) were included. Multilevel-sectioning of lymph nodes was performed; sections were stained by means of immunohistochemistry with cytokeratin marker CAM5.2. Two pathologists searched for micrometastases (0.2-2.0 mm) and isolated tumor cells (ITCs, <0.2 mm). Results Positive CAM5.2 staining in lymph nodes was not seen in any of the 18 m2-patients. In 2/25 m3-tumors (8.0%) an ITC was found, but no micrometastases. Tumor cells were identified in 4/20 sm1-tumors (20.0%): three micrometastases and one ITC. Median follow-up was 121 months. Two m3-patients (3.2%) died due to disease recurrence, including one patient in whom an ITC was detected. Conclusions Lymphatic migration of tumor cells was found in node-negative m3- and sm1-adenocarcinomas of the esophagus (8.0% and 20.0%, respectively). However, the clinical relevance of these occult tumor cells should become apparent from large series of endoscopically treated patients.

Effects of a rehabilitation programme on daily functioning, participation, health-related quality of life, anxiety and depression in liver transplant recipients (Article)

2010-11-19T00:00:00Z

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.

Dysphagia after an L-shaped reconstruction technique of the free jejunum graft (Article)

2010-11-01T00:00:00Z

Background: The free jejunum graft is a well-established reconstruction technique after total laryngopharyngectomy. However, besides necrosis of the jejunum graft, the two most important complications are pharyngocutaneous fistula formation and dysphagia due to stricture formation. Objectives: This study aims to develop an L-shaped reconstruction technique of the free jejunum graft to decrease pharyngocutaneous fistula formation and long-term stricture formation after total laryngopharyngectomy. Methods: An L-shaped side-to-end anastomosis was performed at the proximal end of the jejunum graft in six patients treated for piriform sinus carcinoma. Patient and operation characteristics and follow-up were recorded. Results: A successful jejunum transfer was performed in all six patients. No pharyngocutaneous fistula or stricture formation occurred during a median follow-up of 23 months (range: 18-30 months). Swallowing rehabilitation started at the median 12th postoperative day (range: 5-150 days). Four patients developed dysphagia at a median of 2 months (range: 1-6 months) after oral intake was started. X-barium swallow revealed a redundant pouch of the transferred jejunum graft, which resulted in compression on the jejunum interposition during swallowing. In three patients, an operation was required to resolve these problems. After the revision operation, no dysphagia occurred during a median follow-up of 12 months (range: 7-13 months). Conclusions: Because of dysphagia complaints in the majority of our patients, we cannot recommend the described technique and should find other means to improve direct postoperative results and long-term quality of life in this difficult-to-treat group of patients.

Inter- and intraobserver variation in the histopathological evaluation of early oesophageal adenocarcinoma (Article)

2010-11-01T00:00:00Z

Aims: According to the classification established by the Japanese Society for Oesophageal Disease, early oesophageal cancer can be subdivided into six successive layers of the mucosa or submucosa, which influences the treatment strategy and prognosis of the individual patient. However, the reproducibility of this classification in terms of inter- and intraobserver variability is unclear. Methods: Histological slides from 105 surgical resection specimens of patients who had undergone oesophagectomy for early oesophageal adenocarcinoma were reviewed independently by three gastrointestinal pathologists, andwere classified according to the Japanese criteria (m1/m2/m3/sm1/sm2/sm3 tumours). Inter- and intraobserver variation was determined by κ-statistics. Results: The interobserver reproducibility was good between pathologist 1 and 2 (κ=0.61, 95% CI 0.55 to 0.67), and moderate between pathologist 1 and 3 (κ=0.51, 95% CI 0.45 to 0.57) and between pathologist 2 and 3 (κ=0.50, 95% CI 0.38 to 0.61). The intraobserver agreement as assessed by the expert pathologist was good (κ=0.76), with a 95% CI that was interpreted as good to very good (0.67 to 0.85). Most agreement was achieved at the lower (m1) and upper site (sm2, sm3) of the spectrum, whereas the m2 tumours reflected the most discrepant stage. The majority of the observed discrepancy included the variation in one substage only. Conclusions: The reproducibility of the Japanese classification is good in terms of inter- and intraobserver variability when grading early oesophageal adenocarcinoma on surgical resection specimens. The present data confirm that dedicated gastrointestinal pathologists with broad experience are preferred when grading the resection specimens of patients with early oesophageal adenocarcinoma.

Long-Term Esophageal Cancer Risk in Patients With Primary Achalasia: A Prospective Study (Article)

2010-10-01T00:00:00Z

OBJECTIVES:Achalasia patients are considered at increased risk for esophageal cancer, but the reported relative risks vary. Identification of this risk is relevant for patient management. We performed a prospective evaluation of the esophageal cancer risk in a large cohort of achalasia patients with long-term follow-up.METHODS:Between 1975 and 2006, all patients diagnosed with primary achalasia in our hospital were treated and followed by the same protocol. After graded pneumatic dilatation, all patients were offered a fixed surveillance protocol including gastrointestinal endoscopy with esophageal biopsy sampling.RESULTS:We surveyed a cohort of 448 achalasia patients (218 men, mean age 51 years at diagnosis, range 4-92 years) for a mean follow-up of 9.6 years (range 0.1-32). Overall, 15 (3.3%) patients (10 men) developed esophageal cancer (annual incidence 0.34 (95% confidence interval 0.20-0.56)). The mean age at cancer diagnosis was 71 years (range 36-90) after a mean of 11 years (range 2-23) following initial presentation, and a mean of 24 years (range 10-43) after symptom onset. The relative hazard rate of esophageal cancer was 28 (confidence interval 17-46) compared with an age- and sex-identical population in the same timeframe. Five patients received a potential curative treatment.CONCLUSIONS:Although the gastro-esophageal cancer risk in patients with longstanding achalasia is much higher than in the general population, the absolute risk is rather low. Despite structured endoscopical surveillance, most neoplastic lesions remain undetected until an advanced stage. Efforts should be made to identify high-risk groups and develop adequate surveillance strategies.Am J Gastroenterol advance online publication, 29 June 2010; doi:10.1038/ajg.2010.263.

Early and long-term morbidity after total laryngopharyngectomy (Article)

2010-09-01T00:00:00Z

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.

Outcome of esophagectomy for cancer in elderly patients (Article)

2010-09-01T00:00:00Z

Background: This study analyzes the outcome of esophageal resection in patients 70 or more years of age, compared with patients aged less than 70 years and identifies risk factors for worse outcome in the elderly. Methods: Comorbidity, postoperative morbidity, in-hospital mortality and survival rates were compared between 811 patients aged less than 70 years and 250 patients aged 70 years or more who underwent esophagectomy for esophageal cancer in a single high-volume center from 1985 to 2005. Results: Groups were similar regarding surgical approach, resectability, and tumor stage. More patients aged 70 years or more had cardiovascular and respiratory concomitant disease. Among patients aged 70 years or more, the prevalence of adenocarcinoma and Barrett's transformation was higher (67% versus 53% for patients aged less than 70 years, and 22% versus 15%, respectively). There were no differences in surgical complications (20% versus 17%). Nonsurgical complications occurred more in patients aged 70 years or more (35% versus 27%) and operative mortality was higher among elderly patients (8.4 versus 3.8%), as was in-hospital mortality (11.6% versus 5.4%). The disease-specific 5-year survival was lower for patients aged 70 years or more (27% versus 34%). The 1-year survival, reflecting the impact of operative morbidity and mortality, was 58% for patients aged 70 years or more and 68% for the patients aged less than 70 years (p = 0.002). Among patients aged 70 years or more, respiratory comorbidity and thoracoabdominal resection were risk factors for the occurrence of nonsurgical complications and respiratory comorbidity for in-hospital mortality. Conclusions: Older patients have increased operative and in-hospital mortality and decreased 5-year survival after esophageal resection for cancer. Our results indicate that especially thoracoabdominal resection for esophageal carcinoma should be carefully considered for patients older than 70 years who suffer from respiratory disease.

Validation of a nomogram predicting complications after esophagectomy for cancer (Article)

2010-09-01T00:00:00Z

Background: A nomogram has been developed recently in order to predict the occurrence and severity of postoperative complications after esophagectomy for cancer. In the present study, we externally validated this nomogram in a new cohort of patients who underwent esophagectomy for cancer in a different high-volume center. Methods: An independent dataset of 777 patients who underwent esophagectomy for cancer was used for validation. The discriminatory capability of the nomogram was determined by using the concordance index (C statistic). Calibration was evaluated by comparing the observed with the expected number of patients with complications, as predicted by the original nomogram across patients with different risk profiles. We also examined whether adjusting the value of the original coefficients of the predictors or adding new predictors would improve the fit of the nomogram. Results: Discrimination of the original nomogram was similar in the validation cohort: the C statistic hardly decreased from 0.65 in the original cohort to 0.64 in the validation cohort. Observed and expected number of patients with complications were in close agreement, reflecting a good calibration (p = 0.84). Reestimation of the coefficients in the validation cohort did not lead to any significant changes of the original nomogram values. Conclusions: External validation of a nomogram predicting the occurrence and severity of complications after esophagectomy showed that the model is applicable in other high-volume hospitals. Nevertheless, preoperative prediction of complications in individual patients remains difficult, most likely due to the complexity of mechanisms causing these complications.

Prognostic Value of Body Mass Index on Short-Term and Long-Term Outcome after Resection of Esophageal Cancer (Article)

2010-07-05T00:00:00Z

Introduction: Cachexia and obesity have been suggested to be risk factors for postoperative complications. However, high body mass index (BMI) might result in a higher R0-resection rate because of the presence of more fatty tissue surrounding the tumor. The purpose of this study was to investigate whether BMI is of prognostic value with regard to short-term and long-term outcome in patients who undergo esophagectomy for cancer. Methods: In 556 patients who underwent esophagectomy (1991-2007), clinical and pathological outcome were compared between different BMI classes (underweight, normal weight, overweight, obesity). Results: Overall morbidity, mortality, and reoperation rate did not differ in underweight and obese patients. However, severe complications seemed to occur more often in obese patients (p = 0.06), and the risk for anastomotic leakage increased with higher BMI (12.5% in underweight patients compared with 27.6% in obese patients, p = 0.04). Histopathological assessment showed comparable pTNM stages, although an advanced pT stage was seen more often in patients with low/normal BMI (p = 0.02). A linear association between BMI and R0-resection rate was detected (p = 0.02): 60% in underweight patients compared with 81% in obese patients. However, unlike pT-stage (p < 0.001), BMI was not an independent predictor for R0 resection (p = 0.12). There was no significant difference in overall or disease-free 5-year survival between the BMI classes (p = 0.25 and p = 0.6, respectively). Conclusions: BMI is not of prognostic value with regard to short-term and long-term outcome in patients who undergo esophagectomy for cancer and is not an independent predictor for radical R0 resection. Patients oncologically eligible for esophagectomy should not be denied surgery on the basis of their BMI class.

Liver grafts contain a unique subset of natural killer cells that are transferred into the recipient after liver transplantation (Article)

2010-07-01T00:00:00Z

In contrast to other solid organ transplantations, liver grafts have tolerogenic properties. Animal models indicate that donor leukocytes transferred into the recipient after liver transplantation (LTX) play a relevant role in this tolerogenic phenomenon. However, the specific donor cell types involved in modulation of the recipient alloresponse are not yet defined. We hypothesized that this unique property of liver grafts may be related to their high content of organ-specific natural killer (NK) and CD56+ T cells. Here, we show that a high proportion of hepatic NK cells that detach from human liver grafts during pretransplant perfusion belong to the CD56bright subset, and are in an activated state (CD69+). Liver NK cells contained perforin and granzymes, exerted stronger cytotoxicity against K562 target cells when compared with blood NK cells, and secreted interferon-γ, but no interleukin-10 or T helper 2 cytokines, upon stimulation with monokines. Interestingly, whereas the CD56bright subset is classically considered as noncytolytic, liver CD56bright NK cells showed a high content of cytolytic molecules and degranulated in response to K562 cells. After LTX, but not after renal transplantation, significant numbers of donor CD56dim NK and CD56+ T cells were detected in the recipient circulation for approximately 2 weeks. In conclusion, during clinical LTX, activated and highly cytotoxic NK cells of donor origin are transferred into the recipient, and a subset of them mixes with the recirculating recipient NK cell pool. The unique properties of the transferred hepatic NK cells may enable them to play a role in regulating the immunological response of the recipient against the graft and therefore contribute to liver tolerogenicity.

Increased incidence of early de novo cancer in liver graft recipients treated with cyclosporine: An association with C2 monitoring and recipient age (Article)

2010-07-01T00:00:00Z

The goal of this study was to determine the risk factors for de novo cancer after liver transplantation (LTx). Retrospective analyses were performed in 385 LTx patients who underwent transplantation between 1986 and 2007. In total, 50 (13.0%) recipients developed de novo malignancy. The cumulative incidence of de novo cancer at 1, 5, 10, and 15 years after LTx was 2.9% ± 0.9%, 10.5% ± 1.8%, 19.4% ± 3.0%, and 33.6% ± 6.8%, respectively. The standardized incidence ratio of malignancy in LTx patients compared to the general population was 2.2 (95% confidence interval: 1.6-2.8). After excluding posttransplant lymphoproliferative disorder and skin cancer, patients with de novo cancer had a significantly lower survival rate compared to recipients who remained cancer-free. The identified univariate risk factors for de novo cancer were cyclosporine A (CsA) treatment, time period of LTx, and recipient age. In multivariate analysis, only CsA treatment emerged as an independent risk factor for de novo cancer, which was attributed to more aggressive cancer types. A surprising finding was that CsA treatment specifically enhanced cancer risk in patients who underwent transplantation after 2004, when C2 monitoring (blood concentration at 2 hours postdose) was introduced. In addition, these patients showed a significantly lower acute rejection rate, which might reflect a more robust immunosuppressive status caused by the CsA-C2 regimen. When age was considered, only patients ≤50 years had a higher cancer rate when treated with CsA compared to treatment with tacrolimus. Our data suggest that, compared to tacrolimus treatment, CsA treatment with C2 monitoring or in younger patients of ≤50 years is associated with a higher early de novo cancer risk after LTx.

Liver grafts contain a unique subset of natural killer cells that are transferred into the recipient after liver transplantation (Article)

2010-07-01T00:00:00Z

Salvage or what follows the failure of a free jejunum transfer for reconstruction of the hypopharynx? (Article)

2010-06-01T00:00:00Z

Aim: To analyse the cases of failure of free jejunum transfer with subsequent secondary reconstruction methods after ablative surgery for malignant tumours of the laryngopharyngeal region and the cervical oesophagus with reconstruction using a jejunum interposition. Materials and methods: Four cases in which failure of the jejunum interposition was managed with a second free or pedicle transfer were identified. The electronic files of patients were studied and analysed for patient characteristics and failure of reconstruction; type of salvage surgery and outcome; swallowing function and rehabilitation; postoperative complications; recurrence of tumour; patient survival and cause of death. Results: Failure of the interposition occurred within 11 days in all patients, with oral bleeding being the most prominent sign. To replace the failed jejunum transfer, two new free jejunum transfers, two gastric pull-ups and one colon interposition after the second failure of a jejunum transfer were used. Three patients started swallowing rehabilitation, of which two achieved complete oral intake, defined as the redundancy of a feeding tube. The median disease-free period and overall survival was 28 and 42 months, respectively. Conclusion: Failure of a free jejunum transfer is a rare but inevitable complication when performed in a high-risk patient population, with oral bleeding being the most important sign of necrosis. Salvage of the buried jejunum interposition is hardly ever possible and secondary reconstruction can be performed using a new jejunum interposition or gastric pull-up procedure with considerable early postoperative complications, but relatively good results regarding swallowing rehabilitation and patient survival.

Calcineurin inhibitor tacrolimus does not interfere with the suppression of hepatitis C virus infection by interferon-α (Article)

2010-04-01T00:00:00Z

Immunosuppression considerably affects hepatitis C virus (HCV) recurrence and the outcome of antiviral treatment after liver transplantation. Recent findings have suggested that the calcineurin inhibitor tacrolimus (Tac), unlike cyclosporine A (CsA), interferes with the antiviral activity of interferon-α (IFN-α) in vitro. The aim of this study was to more extensively investigate the effects of calcineurin inhibitors on IFN-α signaling and antiviral activity in subgenomic and infectious HCV models. Treatment with Tac and CsA did not affect Huh7 cell proliferation at doses of 10 to 500 ng/mL; however, it completely inhibited T cell proliferation. In contrast to previous reports, Tac had no effect on IFN-α-stimulated reporter gene expression, even at the dose of 5 μg/mL. Furthermore, in Huh7 subgenomic HCV replicon cells, treatment with Tac had no significant effect on the suppression of viral replication by IFN-α. In the infectious HCV model, treatment with IFN-α effectively inhibited both viral RNA replication and de novo production of virus particles, and neither was attenuated at any concentration of Tac. CsA had no significant effect on IFN-α-stimulated reporter gene expression; however, as shown previously, a combination of CsA (at 500 ng/mL and higher) and IFN-α resulted in enhanced inhibition of viral replication in both the subgenomic and infectious HCV models. In conclusion, our study shows no evidence that Tac or CsA interferes with IFN-α-mediated inhibition of HCV replication and virion production in vitro. Therefore, no further mechanistic arguments have been found to break the clinical controversy about the choice of calcineurin inhibitors during posttransplantation antiviral therapy.

Preoperative risk assessment and prevention of complications in patients with esophageal cancer (Article)

2010-03-01T00:00:00Z

In this review the preoperative risk assessment and prevention of complications in patients undergoing esophagectomy for cancer is discussed. Age, pulmonary and cardiovascular condition, nutritional status, and neoadjuvant chemo(radio)therapy are known predictive factors. None of these factors is a valid exclusion criterion for esophagectomy, but may help in careful patient selection. Both anesthetists and surgeons play an important role in intraoperative risk reduction by means of appropriate fluid management and application of optimal surgical techniques.

Abundant numbers of regulatory T cells localize to the liver of chronic hepatitis C infected patients and limit the extent of fibrosis (Article)

2010-03-01T00:00:00Z

Background & Aims: Weak hepatitis C virus (HCV) specific immunity in peripheral blood has been shown to be partially controlled by regulatory T cells (Treg). However, little is known about Treg present in livers of HCV-infected patients, their association with clinical parameters, and immunopathology resulting in disease progression. Methods: The frequency and phenotype of CD4+FoxP3+ Treg, conventional CD4+ T cells, and the distribution of lymphocytes and leukocytes were studied by multi-color flowcytometry in liver and peripheral blood of 43 chronic HCV patients at different phases of liver disease. Comparisons between healthy blood and liver and correlations with disease parameters were made. Results: An extensive lymphocyte infiltration containing abundant numbers of CD4+FoxP3+ Treg was present in HCV-infected livers, while absent from healthy liver. Moreover, in all patients, intrahepatic CD4+FoxP3+ Treg showed a fully differentiated and highly activated phenotype on the basis of the surface markers CD45RO, CCR7, CTLA-4 and HLA-DR. These Treg were more numerous in those HCV-infected livers showing only limited fibrosis. However, HCV RNA loads or alanine transaminase levels did not correlate with CD4+FoxP3+ Treg frequencies. Conclusions: Our data demonstrate that large numbers of highly activated and differentiated CD4+FoxP3+ Treg localize to the infiltrated chronic HCV-infected liver and may result in limiting the extent of fibrosis. This suggests that CD4+FoxP3+ Treg play a pivotal role in limiting collateral damage by suppressing excessive HCV-induced immune activation.

Delay in diagnostic workup and treatment of esophageal cancer (Article)

2010-03-01T00:00:00Z

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.

Noninvasive functional liver blood flow measurement: Comparison between bolus dose and steady-state clearance of sorbitol in a small-rodent model (Article)

2010-02-01T00:00:00Z

Plasma clearance of D-sorbitol, a nontoxic polyol, occurs predominantly in the liver and has been used to measure functional liver blood flow after bolus and steady- state intravenous administration. However, it is not known which of these two administration methods is superior. Therefore, plasma D-sorbitol clearance was studied in an animal model both after a bolus dose and under steady-state (SS) conditions and compared directly with liver blood flow, under normal conditions, and after the induction of endotoxin (LPS) sepsis. Adult male Wistar rats (526 ± 38 g body wt; n = 27) were anesthetized and mechanically ventilated. Hemodynamics, hepatic arterial flow, and portal venous flow were measured. Two groups were studied, namely healthy animals that served as controls and a sepsis group that received 5 mg/kg LPS intravenously (Escherichia coli O127:B8). Each animal received either a SS infusion (0.1 mg/100 g body wt per min) or a bolus (3 mg/100 g body wt) of a 5% D-sorbitol solution intravenously in a randomized order. After the initial measurements and a 60-min pause time in between (T1/2,sorbitol = 9 min), a crossover was done. The hepatic clearance of D-sorbitol in the control group showed a good correlation between bolus and SS (Spearman's r = 0.7681, P = 0.0004), and both techniques correlated well with total liver blood flow (TLBF) (r = 0.7239, P = 0.0023 and r = 0.7226, P = 0.0023, respectively). Also in the sepsis group there was a good correlation between bolus and SS sorbitol clearance (r = 0.6655, P = 0.0182). In the sepsis group, only the SS clearance correlated with TLBF (r = 0.6434, P = 0.024). In conclusion, in normal and under septic conditions, hepatic clearance of D-sorbitol either by bolus or a SS infusion is comparable. In healthy animals, this also correlated well with TLBF but not in septic conditions. However, this is expected because of the changes in the liver microcirculation, shunting, and decreased hepatocyte function in sepsis.

Verification and unmasking of widely used human esophageal adenocarcinoma cell lines (Article)

2010-02-01T00:00:00Z

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.

Persistent fatigue in liver transplant recipients: A two-year follow-up study (Article)

2010-01-01T00:00:00Z

Background: Fatigue after liver transplantation (LTx) is a major problem that is associated with lower daily functioning and health-related quality of life (HRQoL). This study aimed to assess changes over time in fatigue following LTx. We also examined daily functioning and HRQoL changes over time and assessed the influence of fatigue and changes in fatigue on daily functioning and HRQoL. We determined whether sleep quality, anxiety, and depression were associated with fatigue. Methods: We identified 70 LTx recipients who had previously participated in a cross-sectional study and reassessed them after two yr to determine changes in level of fatigue, daily functioning, and HRQoL. We also assessed sleep quality, anxiety, and depression after two yr. Results: Level of fatigue and level of daily functioning were unchanged at follow-up. HRQoL domains remained stable or worsened. Fatigue was a significant predictor of daily functioning and all HRQoL domains (p < 0.01). Change in fatigue was a significant predictor of daily functioning and the HRQoL domains of " physical functioning," " vitality," and " pain" (p < 0.05). Sleep quality, anxiety, and depression were associated with fatigue severity (r = 0.35 to r = 0.60, p < 0.05). Conclusion: This longitudinal study shows that fatigue is a chronic problem after LTx and that daily functioning and HRQoL do not improve over time. This study supports the need for intervention programs to address fatigue after LTx.

Migration of allosensitizing donor myeloid dendritic cells into recipients after liver transplantation (Article)

2010-01-01T00:00:00Z

It is thought, but there is no evidence, that myeloid dendritic cells (MDCs) of donor origin migrate into the recipient after clinical organ transplantation and sensitize the recipient's immune system by the direct presentation of donor allo-antigens. Here we show prominent MDC chimerism in the recipient's circulation early after clinical liver transplantation (LTx) but not after renal transplantation (RTx). MDCs that detach from human liver grafts produce large amounts of pro-inflammatory [tumor necrosis factor alpha and interleukin 6 (IL-6)] and anti-inflammatory (IL-10) cytokines upon activation with various stimuli, express higher levels of toll-like receptor 4 than blood or splenic MDCs, and are sensitive to stimulation with a physiological concentration of lipopolysaccharide (LPS). Upon stimulation with LPS, MDCs detaching from liver grafts prime allogeneic T cell proliferation and production of interferon gamma but not of IL-10. Soluble factors secreted by liver graft MDCs amplify allogeneic T helper 1 responses. In conclusion, after clinical LTx, but not after RTx, prominent numbers of donor-derived MDCs migrate into the recipient's circulation. MDCs detaching from liver grafts produce pro-inflammatory and anti-inflammatory cytokines and are capable of stimulating allogeneic T helper 1 responses, and this suggests that MDC chimerism after clinical LTx may contribute to liver graft rejection rather than acceptance.

Neoadjuvant Chemoradiotherapy for Esophageal Cancer: A Review of Meta-Analyses (Article)

2009-12-01T00:00:00Z

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.

Chemotherapy followed by surgery in patients with carcinoma of the distal esophagus and celiac lymph node involvement. (Article)

2009-10-01T00:00:00Z

BACKGROUND: Patients with carcinoma of the distal esophagus and metastatic celiac lymph nodes (M1a) have a poor prognosis and are often denied surgery. In this study, we evaluated our treatment strategy of chemotherapy followed by surgery in patients with M1a disease. METHODS: Thirty-eight patients who received chemotherapy for carcinoma of the distal esophagus with celiac lymph node involvement between 2000 and 2007 were identified from a prospective database. Clinical and histopathological responses to chemotherapy were analyzed and follow-up comprised review of medical charts. RESULTS: Twelve non-responding patients were not eligible for surgery. Twenty-six patients with partial responses or stable disease were operated on. The resectability rate was 96% (25/26) and tumor-free resection margins (R0) were achieved in 68% (17/25). The overall survival of patients with M1a disease was 16 months. Patients who received chemotherapy alone had a median survival of 10 months; patients who underwent additional surgery had a median survival of 26 months (log-rank P < 0.001). CONCLUSION: The overall survival of patients with carcinoma of the distal esophagus and clinical celiac lymph node involvement is poor. Tumor-free resection margins (R0) in M1a patients with clinical response to chemotherapy are likely to be achieved and contributes to prolonged survival. (c) 2009 Wiley-Liss, Inc.

The sentinel node concept in adenocarcinomas of the distal esophagus and gastroesophageal junction (Article)

2009-09-01T00:00:00Z

Objective: The sentinel node concept is of great value in the treatment of various malignancies. In this study we investigated whether the application of the sentinel node procedure is feasible in esophageal adenocarcinoma and whether it can tailor surgical treatment of the individual patient. Methods: In 40 patients with an adenocarcinoma of the distal esophagus or gastroesophageal junction, blue dye was injected around the tumor intraoperatively. Sentinel nodes (blue-stained) and nonsentinel nodes were identified and dissected during transhiatal esophagectomy. In sentinel nodes negative for tumor cells on routine hematoxylin-eosin examination, multilevel sectioning and immunohistochemical staining were performed to search for micrometastases. Results: The sentinel node procedure was technically successful in 39 of 40 patients (98%). The median number of sentinel nodes identified was 4. Sentinel nodes were present in more than 1 nodal station in 8 patients (21%). In 6 patients in whom the sentinel node was negative for metastasis, nonsentinel nodes were positive for tumor cells (false-negative rate 6/39 = 15%). Micrometastases and isolated tumor cells were detected in 7 of 19 patients (37%) with sentinel nodes, but this finding did not affect the false-negative rate. Conclusion: Detection of sentinel nodes is technically feasible during esophagectomy for cancer. However, given the relatively high false-negative rate of 15% and the high frequency of sentinel nodes in more than 1 nodal station, the clinical relevance of the sentinel node concept (through application of the blue dye technique) in the current treatment of patients with an adenocarcinoma of the distal esophagus or gastroesophageal junction seems limited.

Two-Lung High-Frequency Jet Ventilation as an Alternative Ventilation Technique During Transthoracic Esophagectomy (Article)

2009-08-01T00:00:00Z

Objective: The aim of this study was to evaluate two-lung high-frequency jet ventilation during esophagectomy and evaluate the influence of high-frequency jet ventilation on pulmonary complications as compared with one-lung ventilation. Design: A retrospective study. Settings: A single-center study in a university hospital. Participants: The authors analyzed the data of patients who had undergone an elective esophagectomy by transthoracic esophagectomy between January 2000 and December 2006. Intervention: The patients had undergone a cervicothoracoabdominal subtotal esophagectomy via a right-sided thoracotomy. Patients with high-frequency jet ventilation were intubated with a single-lumen endotracheal tube, and an oxygen insufflation catheter was placed inside the endotracheal tube and connected to a high-frequency jet ventilator. Measurements and Main Results: Eighty-seven patients were enrolled, 30 with high-frequency jet ventilation and 57 with 1-lung ventilation. Both groups were adequately oxygenated, but patients in the one-lung ventilation group had a higher PaCO2(42.75 ± 7.5 mm Hg) compared with that for the high-frequency jet ventilation group (35.25 ± 8.25 mm Hg) (p < 0.05). There were no differences in postoperative respiratory complications between the 2 groups. Mean blood loss was significantly lower for patients in the high-frequency jet ventilation group (1,243 ± 787 mL). Conclusions: High-frequency jet ventilation to 2 lungs, using a single-lumen tube, is a safe and adequate ventilation technique for use during esophagectomy. High-frequency jet ventilation had no influence on the incidence of postoperative pulmonary complications but reduced perioperative blood loss and led to a decreased need for fluid replacement.

Centralization of Esophageal Cancer Surgery: Does It Improve Clinical Outcome? (Article)

2009-07-01T00:00:00Z

Background: The volume-outcome relationship for complex surgical procedures has been extensively studied. Most studies are based on administrative data and use in-hospital mortality as the sole outcome measure. It is still unknown if concentration of these procedures leads to improvement of clinical outcome. The aim of our study was to audit the process and effect of centralizing oesophageal resections for cancer by using detailed clinical data. Methods: From January 1990 until December 2004, 555 esophagectomies for cancer were performed in 11 hospitals in the region of the Comprehensive Cancer Center West (CCCW); 342 patients were operated on before and 213 patients after the introduction of a centralization project. In this project patients were referred to the hospitals which showed superior outcomes in a regional audit. In this audit patient, tumor, and operative details as well as clinical outcome were compared between hospitals. The outcome of both cohorts, patients operated on before and after the start of the project, were evaluated. Results: Despite the more severe comorbidity of the patient group, outcome improved after centralizing esophageal resections. Along with a reduction in postoperative morbidity and length of stay, mortality fell from 12% to 4% and survival improved significantly (P = 0.001). The hospitals with the highest procedural volume showed the biggest improvement in outcome. Conclusion: Volume is an important determinant of quality of care in esophageal cancer surgery. Referral of patients with esophageal cancer to surgical units with adequate experience and superior outcomes (outcome-based referral) improves quality of care.

Pathological analysis after neoadjuvant chemoradiotherapy for esophageal carcinoma: The Rotterdam experience (Article)

2009-07-01T00:00:00Z

Multimodality treatment is increasingly used in the treatment for esophageal cancer. We determined the tumor regression grade after preoperative chemoradiation and correlated the effect of specific pathologic and clinical findings to overall survival. For this purpose esophageal biopsies and surgical specimens of 67 patients treated with neoadjuvant paclitaxel and carboplatin concurrent with radiotherapy were reviewed. Neoadjuvant chemoradiotherapy led to a significant downstaging. Complete tumor regression was found in 24% of the patients resulting in a trend towards better survival. It was found more frequently in poorly differentiated tumors. Patients with pre-treatment nodal involvement, assessed by endoscopic ultrasound, had a significantly worse survival compared to patients without. Contrastingly, this was not found for post-treatment nodal involvement, as determined by pathological examination, speculating that survival is more determined by (submicroscopic) distant disease, than by locoregional tumor cells.

Combined antiviral activity of interferon-α and RNA interference directed against hepatitis C without affecting vector delivery and gene silencing (Article)

2009-07-01T00:00:00Z

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.

Prospects of RNAi and microRNA-based therapies for hepatitis C (Article)

2009-06-01T00:00:00Z

Background: RNA interference (RNAi) represents a promising new approach to combat viral infections, and recent developments in the field of gene therapy have increased the feasibility of clinical applications. Objective: to explore the utility of RNAi for the treatment of the ultimately life-threatening liver disease caused by hepatitis C virus (HCV), which affects approximately 170 million people worldwide. Methods: A review of current developments in liver-directed gene delivery and the potential application of RNAi for the treatment of HCV. In addition, the involvement of microRNAs (miRNA) in HCV infection and the potential therapeutic implications are emphasized. Conclusions: RNAi technologies have fuelled rapid progress in the basic understanding of HCV biology and revealed numerous new viral and host-cell factors as potential targets for therapy. Together with the improvement of gene delivery technology and the discovery of the critical role of miRNA in HCV infection, RNAi and miRNA-based antiviral strategies hold great promise for the future.

The effect of rabbit anti-thymocyte globulin induction therapy on regulatory T cells in kidney transplant patients (Article)

2009-05-01T00:00:00Z

Background. Prevention of alloreactivity by rabbit anti-thymocyte globulins (rATG) may not only result from immunodepletion but also from the induction of T cells that control allogeneic immune responses. In the present prospective and controlled study, we investigated the effect of rATG on the frequency, function and phenotype of peripheral immunoregulatory CD4+ T cells in kidney transplant (KTx) patients.Methods. After transplantation, 16 patients received ATG-induction therapy and triple therapy consisting of tacrolimus, MMF and steroids. The control group (n = 18) received triple therapy only. By flow cytometry, T cells were analysed for CD25, FoxP3, CD127, CD45RO and CCR7. To study their suppressive capacities, CD25bright T cells were co-cultured with CD25-dim effector T cells (Teff) in mixed lymphocyte reactions (MLR), stimulated with donor and third party (3P) antigens.Results. Pre-transplant levels of FoxP3+CD127-low T cells were 6 of CD4+ T cells. One week post-ATG treatment, no measurable numbers of regulatory T cells were present (P < 0.01). After 4 weeks, the cell numbers of CD4+FoxP3+CD127-low T cells slowly reappeared and thereafter remained low (P < 0.01). At 14 weeks, a significant shift towards the CD45RO+CCR7+ (central memory) phenotype within CD4+FoxP3+ T cells was observed (P < 0.01). At 26 weeks, the proliferative alloresponses of the PBMC and CD25-dim Teff profoundly decreased compared to pre-transplant (P = 0.01 and P = 0.02 respectively), while the regulatory capacity of the CD25bright T cells, of which 90 consisted of FoxP3+CD127-low T cells, remained unaffected. The CD25bright T cells suppressed the anti-donor (94) and 3P responses (93).Conclusion. Our findings show that rATG therapy does not spare peripheral immunoregulatory T cells in vivo, but after regeneration preserves their suppressive activity.

Conversion from calcineurin inhibitor to mycophenolate mofetil-based immunosuppression changes the frequency and phenotype of CD4+FOXP3+ regulatory T cells (Article)

2009-04-15T00:00:00Z

BACKGROUND.: CD4Foxp3 regulatory T cells (Treg) depend on interleukin (IL)-2 for their function and survival. By interfering with the IL-2 production, calcineurin inhibitors (CNI) may negatively affect Treg. Here, we describe the effects of conversion from CNI to mycophenolate mofetil (MMF) monotherapy on renal function, and on Treg frequency and phenotype in liver transplant recipients. METHODS.: Patients (=16) with renal impairment on CNI were converted to MMF and received a single dose of IL-2-receptor blocking antibody (Daclizumab). Control patients (=8) continued CNI treatment. RESULTS.: Renal function rapidly and significantly improved after conversion. Daclizumab treatment resulted in a 75% blocking of CD25 at 1 month causing a significant reduction in the percentage of CD4CD25 cells but not affecting the percentage of CD4CD25Foxp3 cells. Six months after conversion to MMF, the percentage of CD4CD25Foxp3 cells increased significantly by 125%. FOXP3 mRNA analysis of mononuclear cells confirmed the enrichment of Foxp3 in peripheral blood. Interestingly, the CD25 expression level on CD4Foxp3, but not CD4Foxp3, cells significantly increased compared with preconversion. CONCLUSION.: Conversion to MMF increases the percentage and CD25 expression of CD4Foxp3 cells indicating that MMF therapy can overturn the repressive effect of CNI on circulating Treg levels and therefore may promote Treg-mediated suppression of alloreactivity.

Array comparative genomic hybridization, expression array, and protein analysis of critical regions on chromosome arms 1q, 7q, and 8p in adenocarcinomas of the gastroesophageal junction (Article)

2009-02-01T00:00:00Z

Survival rates of adenocarcinomas of the gastroesophageal junction (GEJ) are low, because these tumors are generally in an advanced stage by the time they are detected. Chromosomal regions 1q32, 7q21, and 8p22 display critical alterations in GEJ cancers; however, the genes underlying alterations in these genomic areas are largely unknown. To delineate overexpressed genes, we performed array comparative genomic hybridization (aCGH) and mRNA expression analysis of 15 GEJ adenocarcinoma samples using a fine-tiling cDNA array covering chromosome segments 1q31.3∼q41 (193.9-215.8 Mb: 21.9 Mb), 7q11.23∼q22.1 (72.3-103.0 Mb: 30.7 Mb), and 8p23.1∼p21.3 (11.1-20.7 Mb: 9.6 Mb). Based on a mRNA overexpression criterion, 11 genes were selected: ELF3 and SLC45A3 on 1q; CLDN12, CDK6, SMURF1, ARPC1B, ZKSCAN1, MCM7, and COPS6 on 7q; and FDFT1 and CTSB on 8p. The protein expression levels were subsequently determined by immunohistochemical analysis of the cancer samples. There was a significant correlation between genomic amplification, mRNA, and protein expression or overexpression for CDK6, a cell cycle regulator on 7q21.2 (92.1 Mb; P < 0.01); other genes showed less stringent associations. In conclusion, using a straightforward approach we constructed a targeted gene profile for GEJ adenocarcinomas.

Nurse-led follow-up of patients after oesophageal or gastric cardia cancer surgery: A randomised trial (Article)

2009-01-13T00:00:00Z

Between January 2004 and February 2006, 109 patients after intentionally curative surgery for oesophageal or gastric cardia cancer were randomised to standard follow-up of surgeons at the outpatient clinic (standard follow-up; n=55) or by regular home visits of a specialist nurse (nurse-led follow-up; n=54). Longitudinal data on generic (EuroQuol-5D, European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30) and disease-specific quality of life (EORTC QLQ-OES18), patient satisfaction and costs were collected at baseline and at 6 weeks and 4, 7 and 13 months afterwards. We found largely similar quality-of-life scores in the two follow-up groups over time. At 4 and 7 months, slightly more improvement on the EQ-VAS was noted in the nurse-led compared with the standard follow-up group (P=0.13 and 0.12, respectively). Small differences were also found in patient satisfaction between the two groups (P=0.14), with spouses being more satisfied with nurse-led follow-up (P=0.03). No differences were found in most medical outcomes. However, body weight of patients of the standard follow-up group deteriorated slightly (P=0.04), whereas body weight of patients of the nurse-led follow-up group remained stable. Medical costs were lower in the nurse-led follow-up group (\[euro]2600 vs \[euro]3800), however, due to the large variation between patients, this was not statistically significant (P=0.11). A cost effectiveness acceptability curve showed that the probability of being cost effective for costs per one point gain in general quality-of-life exceeded 90 and 75% after 4 and 13 months of follow-up, respectively. Nurse-led follow-up at home does not adversely affect quality of life or satisfaction of patients compared with standard follow-up by clinicians at the outpatient clinic. This type of care is very likely to be more cost effective than physician-led follow-up.

Preoperative and Early Postoperative Quality of Life Predict Survival in Potentially Curable Patients with Esophageal Cancer (Article)

2009-01-01T00:00:00Z

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.

A J-shaped subcostal incision reduces the incidence of abdominal wall complications in liver transplantation (Article)

2008-12-29T00:00:00Z

A novel J-shaped incision for liver transplantation was introduced in attempt to reduce the wound-related complication rate while maintaining comparable access. Some 58 consecutive patients with the classic Mercedes incision were compared with the following 60 consecutive patients with a J-shaped incision. Nine of 60 patients (15%) with a J-shaped incision were converted to an extensive incision. The duration of surgery did not differ between both groups, and relaparotomy rates were comparable in both groups (45% versus 31%, P = 0.487) whereas the early wound-related morbidity was significantly reduced in the J-shaped incision group (3% versus 19%, P = 0.009), as well as incisional hernia rate (7% versus 24%, P = 0.002, corrected for different length of follow-up). Other factors such as previous surgery, ascites, abdominal drainage, retransplantation, and indications for transplantation did not differ between both groups and were not predictive of wound-related morbidity or incisional hernia. We therefore conclude that a J-shaped incision should be the incision of choice in liver transplantation. This new, seemingly minor modification reduces wound infections, fascial dehiscence, and incisional hernia.

Neoadjuvant chemoradiation followed by surgery versus surgery alone for patients with adenocarcinoma or squamous cell carcinoma of the esophagus (CROSS) (Article)

2008-12-01T00:00:00Z

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.

Immunohistochemical evaluation of a panel of tumor cell markers during malignant progression in Barrett esophagus (Article)

2008-11-01T00:00:00Z

Histopathologic grading of dysplasia in Barrett esophagus (BE) shows substantial interobserver and intraobserver variation. We used immunohistochemical analysis with a set of tumor cell markers, ie, epidermal growth factor receptor (EGFR), ERBB2 (HER2/neu), MYC, CDKN2A (p16), SMAD4, MET, CCND1 (cyclin D1), CTNNB1 (β-catenin), and TP53 (p53), in histologic sections of endoscopic biopsies of 86 patients with BE in various stages of neoplastic progression. The markers, except SMAD4, were scored as 0 (<1% of cells stained), 1 (1%-25%), 2 (26%-50%), or 3 (>50%). All markers, except EGFR, showed a significant trend for immunohistochemical protein overexpression during malignant progression in BE (P < .01). When the successive stages along the metaplasia-low-grade dysplasia (LGD)-high-grade dysplasia (HGD)-adenocarcinoma axis were compared, protein overexpression of β-catenin separated LGD from metaplasia, whereas protein overexpression of cyclin D1 and p53 discriminated HGD from LGD (all P < .001). β-Catenin can be helpful for a diagnosis of LGD in BE, although it stains positively in a subset only, whereas p53 remains an appropriate marker to define HGD. In case of doubt, cyclin D1 can be added to separate LGD from HGD in BE.

Patient preferences for the disclosure of prognosis after esophagectomy for cancer with curative intent (Article)

2008-11-01T00:00:00Z

Introduction: The aim of this study was to determine the preferences for content, style, and format of prognostic information of patients after potentially curative esophagectomy for cancer and to explore predictors of these preferences. Patients and Methods: This multicenter study included a consecutive series of patients who underwent surgical resection for cancer in the past 2 years and who did not have evidence of cancer recurrence. A questionnaire was used to elicit patient preferences for the content, style, and format of prognostic information. Sociodemographic characteristics, clinicopathological factors, and quality of life (EORTC QLQ-30 and OES18) were explored as predictors for certain preferences. Results: Of the 204 eligible patients, 176 patients (86%) returned the questionnaire. The majority of patients desired prognostic information. Information preferences declined when information became more specific and more negative. Married patients and higher-educated patients were more likely to want all prognostic information. The majority of patients wanted their specialist to start the discussion about prognosis. However, a significant proportion of these patients wanted their specialist to first ask if they want to have prognostic information. The percentage of patients wanted a realistic and individualistic approach was 97%. Words and numbers were preferred over visual presentations. Conclusion: After potentially curative esophagectomy for cancer, the majority of patients want detailed prognostic information and want their specialist to begin the prognostic discussion. Patients prefer their doctor to be realistic; words and numbers are preferred over figures and graphs.

Functional analysis of CD4+ CD25 bright T cells in kidney transplant patients: Improving suppression of donor-directed responses after transplantation (Article)

2008-10-01T00:00:00Z

Background: The role of CD4+ CD25bright regulatory T cells (Treg) in controlling alloreactivity is established, but little is known whether antigen-specific Treg are induced in fully immunosuppressed kidney transplant patients. Methods: The frequency and function of CD25bright T cells of nine stable kidney transplant patients before and 0.5-2yr after transplantation were measured. Patients received triple therapy consisting of cyclosporine, mycophenolate mofetil and prednisone. To investigate the influence of transplantation and immunosuppression on Treg function, we compared their suppressive capacities pre- and post-transplantation using mixed lymphocyte reactions and kept the CD25-/dim effector T-cell (Teff) population constant. Results: After transplantation, the percentage of CD4+ CD25bright T cells significantly decreased from 8.5% pre-transplant to 6.9% post-transplant (median, p=0.05). However, the lower percentage of post-transplant CD4+ CD25bright T cells was not associated with reduced, but rather improved suppressor function of these cells. The proliferative response of pre-transplant Teff to donor-antigens was more profoundly suppressed by post-transplant Treg than by pre-transplant Treg (pre-transplant 18% vs. post-transplant 55% median, p=0.03) and was comparable against third party antigens at a CD25bright:CD25-/dim ratio of 1:20. Conclusions: In immunosuppressed kidney transplant patients, the donor-directed suppressive capacity of CD4+ CD25bright regulatory T cells improved, which may contribute to the development of donor-specific hyporesponsiveness against the graft.

Molecular dissection of the chromosome band 7q21 amplicon in gastroesophageal junction adenocarcinomas identifies cyclin-dependent kinase 6 at both genomic and protein expression levels (Article)

2008-08-01T00:00:00Z

Amplification of chromosome band 7q21 has been frequently detected in various types of cancer including gastroesophageal junction (GEJ) adenocarcinomas. At present, no gene has been disclosed that can explain this frequent amplification of 7q21 in GEJ carcinomas. Therefore, a detailed genomic analysis of the 7q21 region was performed on a selected series of GEJ adenocarcinomas, i.e., 14 primary adenocarcinomas and 10 cell lines, by array comparative genomic hybridization (aCGH) with a 7q11.22-q31.2 contig array. A distinct peak of amplification was identified at 92.1 Mb in 7q21.2, precisely comprising cyclin-dependent kinase 6 (CDK6), a gene involved in cell cycle regulation. A smaller peak was seen at 116.2 Mb in 7q31.2, the locus of the MET proto-oncogene. No distinct peak was detected for the hepatocyte growth factor (HGF) at 81.3 Mb in 7q21.11. An immunoprofile of HGF, CDK6 and MET revealed a strong correlation between aCGH and immunohistochemical protein expression for CDK6 (P = 0.002). Furthermore, immunohistochemistry did not show expression of CDK6 in Barrett's dysplasia and carcinoma in situ, correlating expression of CDK6 with a malignant phenotype. We conclude that high-resolution genomic analysis and immunoprofiling identify CDK6 as the main candidate target for the recurrent amplification of 7q21 in GEJ adenocarcinomas.

Quality of Life During Neoadjuvant Treatment and After Surgery for Resectable Esophageal Carcinoma (Article)

2008-05-01T00:00:00Z

Purpose: Because of the trade-off between the potentially negative quality-of-life (QoL) effects and uncertain favorable survival effect of neoadjuvant chemoradiotherapy (CRT) in patients with resectable esophageal cancer, we assessed heath-related QoL (HRQoL) for up to 1 year postoperatively in these patients treated with preoperative CRT with a non-platinum-based outpatient regimen followed by esophagectomy. Methods and Materials: Patients undergoing neoadjuvant paclitaxel and carboplatin therapy concurrent with radiotherapy followed by surgery completed standardized HRQoL questionnaires before and after CRT and at regular times up to 1 year postoperatively. We analyzed differences in generic Qol core questionnaire [QLQ-C30] and condition-specific (esophageal site-specific [OES-18]) HRQoL scores over time by using a linear mixed-effects model. Results: Mean scores of most HRQoL scales deteriorated significantly during neoadjuvant CRT. The largest deterioration was observed for physical and role-functioning scales. All except two symptom scores worsened significantly. Postoperatively, most mean HRQoL scores improved until recovery to baseline level. Speed of improvement varied. Average taste score returned to baseline 3 months postoperatively, whereas it took 1 year for the average role-functioning score to restore. The emotional-functioning score showed a different pattern; it was worst at baseline and increased over time during CRT and postoperatively. Dysphagia and pain scores worsened considerably during CRT, restored to baseline 3 months postoperatively, and were even significantly better 1 year postoperatively. Conclusions: Preoperative CRT with paclitaxel and carboplatin for patients with resectable esophageal cancer had a considerable temporary negative effect on most aspects of HRQoL. Nonetheless, all HRQoL scores were restored or even improved 1 year postoperatively.

Vascular anatomy of the stomach related to gastric tube construction (Article)

2008-05-01T00:00:00Z

In view of constructing a gastric tube after esophagus resection, the vascular anatomy of the greater curvature of the stomach, especially the connection between the left and right gastro-epiploic arteries, was investigated. The vascular anatomy was studied in 20 embalmed human specimens. After dissection a gastric tube of 4 cm wide was constructed, using the greater gastric curvature. Various lengths of the arterial arcades were measured. In 70% an anastomosis between the right and left gastro-epiploic arteries was present. With the construction of an isoperistaltic gastric tube, in which the left gastro-epiploic artery is left in situ (ligating it at the splenic hilus), there is an 18.7% increase of length of arterial arcade along the gastric tube. Leaving the left gastro-epiploic artery in situ increases the feeding arterial arcaded-length along the gastric tube with 5.0 cm (19%). © 2007 The Authors Journal compilation

Optimizing intensive care capacity using individual length-of-stay prediction models (Article)

2008-03-14T00:00:00Z

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

Hydroxyethyl starch-based preservation solutions enhance gene therapy vector delivery under hypothermic conditions. (Article)

2008-01-01T00:00:00Z

Isolated liver perfusion offers a unique prospect for safe, effective targeting of gene therapies that can be directed against allograft rejection or recurrent diseases such as reinfection by hepatitis C virus (HCV). We aimed to examine the effect of organ preservation solutions on vector-based gene therapy delivery under hypothermic conditions. University of Wisconsin (UW) solution, histidine tryptophan ketoglutarate (HTK), EloHaes, sodium-poly(ethylene glycol)-UW solution [Institut Georges Lopez 1 solution (IGL-1)], and Dulbecco's modified Eagle's medium (DMEM) culture medium (control) were tested at 2 degrees C or 37 degrees C for lentiviral vector transduction efficiencies to the hepatoma cell line Huh-7 and primary human or mouse hepatocytes. Lentiviral vectors expressing short hairpin RNA were used to target HCV replication. With a potent short hairpin RNA vector, transductions were directly correlated to the therapeutic effect, with low transduction yielding low knockdown and vice versa. Green fluorescent protein (GFP) reporter gene expression was observed with vector incubation times as short as 10 minutes. The highest transductions were seen, after 2-hour 37 degrees C incubation, in UW (62% +/- 6 SEM); they were significantly higher than those in HTK (21% +/- 7 SEM). Neither adenosine nor glutathione, present in UW, provided any increase in transduction when supplemented to HTK, although the addition of hydroxyethyl starch (HES) significantly improved transductions. To rule out size exclusion as a mechanism of HES, IGL-1 was tested but did not result in better transductions than HTK or DMEM. When supplemented to UW, anionic compounds reduced transduction, and this indicated a charge interaction mechanism of HES. In conclusion, this study demonstrates that effective vector delivery can be achieved under conditions of hypothermic liver perfusion. UW provides superior transduction to hepatocytes over nonstarch solutions.

Thiopurine-methyltransferase and inosine triphosphate pyrophosphatase polymorphism in a liver transplant recipient developing nodular regenerative hyperplasia on low-dose azathioprine (Article)

2008-01-01T00:00:00Z

The enzymes thiopurine-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) are involved in thiopurine metabolism. We describe a liver transplant recipient who presented with liver enzyme abnormalities after 78 months of low-dose azathioprine (AZA) therapy (less than 1 mg/kg). No underlying etiology of these abnormalities was identified after extensive analysis including repeated liver biopsy. Fifteen years after transplantation, the patient presented with variceal bleeding, liver biopsy showed nodular regenerative hyperplasia (NRH). TPMT*3C genotype was found in the patient's lymphocytes and heterozygous ITPA (94C>A) genotype was found in both patient and donor liver. These findings further emphasize the importance of pharmacogenetics in predicting NRH and other adverse events during AZA therapy. Furthermore, a high index of suspicion with early detection of NRH is crucial, as improvement seems only to occur in patients with compensated liver disease. Liver biopsy and discontinuation of AZA are recommended in case of liver enzyme abnormalities or signs of portal hypertension.

High-volume versus low-volume for esophageal resections for cancer: The essential role of case-mix adjustments based on clinical data (Article)

2008-01-01T00:00:00Z

Background: Most studies addressing the volume-outcome relationship in complex surgical procedures use hospital mortality as the sole outcome measure and are rarely based on detailed clinical data. The lack of reliable information about comorbidities and tumor stages makes the conclusions of these studies debatable. The purpose of this study was to compare outcomes for esophageal resections for cancer in low- versus high-volume hospitals, using an extensive set of variables concerning case-mix and outcome measures, including long-term survival. Methods: Clinical data, from 903 esophageal resections performed between January 1990 and December 1999, were retrieved from the original patients' files. Three hundred and forty-two patients were operated on in 11 low-volume hospitals (<7 resections/year) and 561 in a single high-volume center. Results: Mortality and morbidity rates were significantly lower in the high-volume center, which had an in-hospital mortality of 5 vs 13% (P < .001). On multivariate analysis, hospital volume, but also the presence of comorbidity proved to be strong prognostic factors predicting in-hospital mortality (ORs 3.05 and 2.34). For stage I and II disease, there was a significantly better 5-year survival in the high-volume center. (P = .04). Conclusions: Hospital volume and comorbidity patterns are important determinants of outcome in esophageal cancer surgery. Strong clinical endpoints such as in-hospital mortality and survival can be used as performance indicators, only if they are joined by reliable case-mix information.

Intravenous immunoglobulins suppress T-cell priming by modulating the bidirectional interaction between dendritic cells and natural killer cells (Article)

2007-11-01T00:00:00Z

The modes of action of intravenous immunoglobulins (IVIgs) in exerting their immunomodulatory properties are broad and not fully understood. IVIgs can modulate the function of various immune cells, including suppressing the capacity of dendritic cells (DCs) to stimulate T cells. In the present study, we showed that DCs matured in the presence of IVIgs (IVIg-DCs) activated NK cells, and increased their interferon-γ production and degranulation. The activated NK cells induced apoptosis of the majority of IVIg-DCs. In consequence, only in the presence of NK cells, IVIg-DCs were 4-fold impaired in their T-cell priming capacity. This was due to NK-cell-mediated antibody-dependent cellular cytotoxicity (ADCC) to IVIg-DCs, probably induced by IgG multimers, which could be abrogated by blockade of CD16 on NK cells. Furthermore, IVIg-DCs downregulated the expression of NKp30 and KIR receptors, and induced the generation of CD56brightCD16-CCR7+lymph node-type NK cells. Our results identify a novel pathway, in which IVIgs induce ADCC of mature DCs by NK cells, which down-sizes the antigen-presenting pool and inhibits T-cell priming. By influencing the interaction between DCs and NK cells, IVIgs modulate the ability of the innate immunity to trigger T-cell activation, a mechanism that can "cool down" the immune system at times of activation.

High-resolution array comparative genomic hybridization of chromosome 8q: Evaluation of putative progression markers for gastroesophageal junction adenocarcinomas (Article)

2007-11-01T00:00:00Z

Amplification of 8q is frequently found in gastroesophageal junction (GEJ) cancer. It is usually detected in high-grade, high-stage GEJ adenocarcinomas. Moreover, it has been implicated in tumor progression in other cancer types. In this study, a detailed genomic analysis of 8q was performed on a series of GEJ adenocarcinomas, including 22 primary adenocarcinomas, 13 cell lines and two xenografts, by array comparative genomic hybridization (aCGH) with a whole chromosome 8q contig array. Of the 37 specimens, 21 originated from the esophagus and 16 were derived from the gastric cardia. Commonly overrepresented regions were identified at distal 8q, i.e. 124-125 Mb (8q24.13), at 127-128 Mb (8q24.21), and at 141-142 Mb (8q24.3). From these regions six genes were selected with putative relevance to cancer: ANXA13, MTSS1, FAM84B (alias NSE2), MYC, C8orf17 (alias MOST-1) and PTK2 (alias FAK). In addition, the gene EXT1 was selected since it was found in a specific amplification in cell line SK-GT-5. Quantitative RT-PCR analysis of these seven genes was subsequently performed on a panel of 24 gastroesophageal samples, including 13 cell lines, two xenografts and nine normal stomach controls. Significant overexpression was found for MYC and EXT1 in GEJ adenocarcinoma cell lines and xenografts compared to normal controls. Expression of the genes MTSS1, FAM84B and C8orf17 was found to be significantly decreased in this set of cell lines and xenografts. We conclude that, firstly, there are other genes than MYC involved in the 8q amplification in GEJ cancer. Secondly, the differential expression of these genes contributes to unravel the biology of GEJ adenocarcinomas. Copyright

Ultrasound, computed tomography, or the combination for the detection of supraclavicular lymph nodes in patients with esophageal or gastric cardia cancer: A comparative study (Article)

2007-09-01T00:00:00Z

Background and Objectives: Both ultrasound (US) and computed tomography (CT) can be used to detect supraclavicular lymph node metastases. Aim was to compare US, US plus fine-needle aspiration (US-FNA), CT, US + CT, and US-FNA + CT for the detection of these metastases in esophageal or gastric cardia cancer patients. Methods: Between 1994 and 2004, 567 patients underwent US and CT for esophageal or gastric cardia cancer staging. Gold standard was postoperative detection of lymph nodes in the resected specimen, FNA, or a radiological result with follow-up. Results: Sensitivities of US (75%), US-FNA (72%), US + CT (80%), and US-FNA + CT (79%) were higher than sensitivity of CT alone (25%) (P < 0.001). Specificities were high for US-FNA (100%), CT (99%), and US-FNA + CT (99%), whereas those of US alone (91%) and US + CT (91%) were lower (P < 0.001). In 4/65 (6%) patients with true-positive malignant lymph nodes, CT was positive with US and/or US-FNA being negative. However, in 36/65 (55%) patients, US and/or US-FNA were positive with CT being negative. Conclusion: US-FNA seems the preferred diagnostic modality for the detection of supraclavicular lymph node metastases in patients with esophageal or gastric cardia cancer. Sensitivity of metastases detection only slightly improves if US-FNA is combined with CT. A prospective, comparative study is however needed.

Management in patients with liver cirrhosis and an umbilical hernia (Article)

2007-09-01T00:00:00Z

Background: Optimal management in patients with umbilical hernias and liver cirrhosis with ascites is still under debate. The objective of this study was to compare the outcome in our series of operative versus conservative treatment of these patients. Methods: In the period between 1990 and 2004, 34 patients with an umbilical hernia combined with liver cirrhosis and ascites were identified from our hospital database. In 17 patients, treatment consisted of elective hernia repair, and 13 were managed conservatively. Four patients underwent hernia repair during liver transplantation. Results: Elective hernia repair was successful without complications and recurrence in 12 out of 17 patients. Complications occurred in 3 of these 17 patients, consisting of wound-related problems and recurrence in 4 out 17. Success rate of the initial conservative management was only 23%; hospital admittance for incarcerations occurred in 10 of 13 patients, of which 6 required hernia repair in an emergency setting. Two patients of the initially conservative managed group died from complications of the umbilical hernia. In the 4 patients that underwent hernia correction during liver transplantation, no complications occurred and 1 patient had a recurrence. Conclusions: Conservative management of umbilical hernias in patients with liver cirrhosis and ascites leads to a high rate of incarcerations with subsequent hernia repair in an emergency setting, whereas elective repair can be performed with less morbidity and is therefore advocated.

Mistaken identity of widely used esophageal adenocarcinoma cell line TE-7 (Article)

2007-09-01T00:00:00Z

Cancer of the esophagus is the seventh leading cause of cancer death worldwide. Esophageal carcinoma cell lines are useful models to study the biological and genetic alterations in these tumors. An important prerequisite of cell line research is the authenticity of the used cell lines because the mistaken identity of a cell line may lead to invalid conclusions. Estimates indicate that up to 36% of the cell lines are of a different origin or species than supposed. The TE series, established in late 1970s and early 1980s by Nishihira et al. in Japan, is one of the first esophageal cancer cell line series that was used throughout the world. Fourteen TE cell lines were derived from human esophageal squamous cell carcinomas and one, TE-7, was derived from a primary esophageal adenocarcinoma. In numerous studies, this TE-7 cell line was used as a model for esophageal adenocarcinoma because it is one of the few esophageal adenocarcinoma cell lines existing. We investigated the authenticity of the esophageal adenocarcinoma cell line TE-7 by xenografting, short tandem repeat profiling, mutation analyses, and array-comparative genomic hybridization and showed that cell line TE-7 shared the same genotype as the esophageal squamous cell carcinoma cell lines TE-2, TE-3, TE-12, and T E-13. In addition, for more than a decade, independent TE-7 cultures from Japan, United States, United Kingdom, France, and the Netherlands had the same genotype. Examination of the TE-7 cell line xenograft revealed the histology of a squamous cell carcinoma. We conclude that the TE-7 cell line, used in several laboratories throughout the world, is not an adenocarcinoma, but a squamous cell carcinoma cell line. Furthermore, the cell lines TE-2, TE-3, TE-7, TE-12, and TE-13 should be regarded as one single squamous cell carcinoma cell line.

Impact of steroids on hepatitis C virus replication in vivo and in vitro (Article)

2007-09-01T00:00:00Z

Chronic hepatitis C virus (HCV) infection is the leading indication for liver transplantation. Transplantation outcome is often compromised by a rapid re-infection of the graft. Several factors have been implicated in the increased severity of recurrence, including steroid-based immunosuppression. Evidence suggests that steroid boluses used to treat acute rejection are associated with an increase in HCV viral load and the severity of recurrence. Two possible mechanisms for a steroid-mediated effect on HCV viral loads can be postulated, the first being a direct effect of steroids on the virus by enhancing its replication. The second, an indirect effect due to the suppression of the HCV immune response, allows unrestricted HCV replication. To investigate the direct effect of steroids on HCV replication, dexamethasone (Dex) and prednisolone (Pred) were tested in an in vitro replicon model. HCV replication was assessed on the basis of luciferase reporter expression (luminescence) and HCV RNA (RT-PCR). At clinically relevant concentrations (1-10 nM), treatment with both Dex and Pred did not enhance, but resulted in a slight reduction of relative luciferase activity (HCV replication), which was independent of increased cellular protein content and reduced cell proliferation. This minor reduction of HCV replication was confirmed by RT-PCR showing more than 41% reduction in HCV RNA levels. In conclusion, despite clinical evidence that the use of steroids aggravates recurrence of HCV, our in vitro study suggests that there is no direct stimulatory effect of steroids on the replication of HCV. As such, the increased viral loads after high-dose steroid treatment are more likely due to a downregulation of the immune response. In such patients, a dampened immune response allows viruses like HCV to replicate free of immune-mediated killing of their host cells. When a change occurs, such as a tapering or an alteration of immunosuppressant drugs, the immune system reinitiates and vigorously attempts to control the virus, resulting in acceleration of liver damage. Therefore, either steroid avoidance or maintaining low levels, coupled with a slow tapering of corticosteroids, may be beneficial to HCV-infected transplantation recipients.

Impairment of circulating myeloid dendritic cells in immunosuppressed liver transplant recipients (Article)

2007-09-01T00:00:00Z

The aim of the present study was to elucidate the impact of liver transplantation (LTX) on myeloid dendritic cell (MDC) homeostasis. We observed a threefold reduction of circulating CD1c+MDC immediately after LTX (n = 16; P < 0.01), and normalization between 3 and 12 months after LTX. This decline was not due to recruitment of MDC into the liver graft, as numbers of MDC in post-LTX liver graft biopsies were not increased compared to pre-LTX biopsies (n = 7). Moreover, no change in chemokine receptor expression on circulating MDC was observed, suggesting that their homing properties were not altered. Normalization of circulating MDC was associated with withdrawal of corticosteroid therapy, and not with changes in calcineurin inhibitor intake, indicating that corticosteroids are responsible for the observed changes in numbers of circulating MDC. During high-dose corticosteroid treatment early after LTX, circulating MDC showed a lowered maturation status with decreased expression of human leucocyte antigen D-related (HLA-DR) and CD86 compared to pre-LTX values (P < 0.01). However, when MDC from blood of LTX recipients were matured ex vivo, they up-regulated HLA-DR and co-stimulatory molecules to a comparable extent as MDC from healthy individuals. In addition, ex vivo matured MDC from both groups had equal allogeneic T cell stimulatory capacity. In conclusion, during the first months after LTX numbers and maturational status of circulating MDC are impaired significantly, probably due to a suppressive effect of corticosteroids on MDC. However, corticosteroid therapy does not imprint MDC with an intrinsic resistance to maturation stimuli.

Flowcytometric quantitation of hepatitis B viral antigens in hepatocytes from regular and fine-needle biopsies (Article)

2007-06-01T00:00:00Z

The aim of the study was to investigate the use of flow cytometry, as an alternative for immunohistochemistry, for the detection of viral antigens in the liver of patients with chronic hepatitis B virus (HBV) infection. Hepatocytes were obtained from regular- and fine-needle biopsy from HBV positive (n = 17) and negative (n = 7) patients and quantified by flow cytometry for intracellular hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg). Number of HBsAg positive hepatocytes ranged from 0 to 83%. A significant correlation was found between the percentage of infected hepatocytes and the intracellular expression level of HBsAg (R = 0.841, p < 0.001). The specificity and sensitivity of flow cytometry was similar to immunohistochemistry. Of the patients on anti-viral treatment with undetectable serum HBV DNA (<400 copies/ml), two had high HBsAg expression in the liver. HBcAg staining was found in 3 out of 15 patients, with 2-3% positive hepatocytes. The results obtained with fine-needle aspiration biopsy (n = 12) were comparable to regular biopsy. In conclusion, flowcytometric quantitation of HBV antigens is sensitive and provides relevant information on the course of infection. The minimally invasive fine-needle biopsy provides a useful alternative for regular-needle biopsy for monitoring intrahepatic antiviral responses during therapy.

Physical fitness, fatigue, and quality of life after liver transplantation (Article)

2007-06-01T00:00:00Z

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.

An evaluation of prognostic factors and tumor staging of resected carcinoma of the esophagus (Article)

2007-05-01T00:00:00Z

OBJECTIVE: To evaluate prognostic factors and tumor staging in patients after esophagectomy for cancer. SUMMARY BACKGROUND DATA: Several reports have questioned the appropriateness of the sixth edition of the International Union Against Cancer (UICC) TNM guidelines for staging esophageal cancer. Additional pathologic characteristics, besides the 3 basic facets of anatomic spread (tumor, node, metastases), might also have prognostic value. METHODS: All patients who underwent resection of the esophagus for carcinoma between January 1995 and March 2003 were extracted from a prospective database. Univariate and multivariate analysis was performed to identify prognostic factors for survival. The goodness of fit and accuracy of 3 staging models (UICC-TNM, Korst classification, Rice classification) predicting survival were assessed. RESULTS: A total of 292 patients (mean age, 63 years) underwent esophagectomy. The 5-year overall survival rate was 29% (median, 21 months). pT-, pN-, pm-stage, and radicality of the resection were independent prognostic factors. Subdivision of T1 tumors into mucosal and submucosal showed significant differences in 5-year survival between both groups: 90% versus 47%, respectively (P = 0.01). Subdivision of pN-stage into 3 groups based on the number of positive nodes (0, 1-2, and >3 nodes positive) or the lymph node ratio (0, 0.01-0.2, and >0.2) also refined staging (P = 0.001 and P < 0.001, respectively). The current subclassification of M1 (M1a and M1b) is not warranted (P = 0.41). The staging model of Rice was more accurate than the UICC-TNM classification in predicting survival. CONCLUSION: This study supports the view that the current (6th edition) UICC-TNM staging model for esophageal cancer needs to be revised.

Authors' reply: Randomized clinical trial comparing feeding jejunostomy with nasoduodenal tube placement in patients undergoing oesophagectomy [5] (Article)

2007-04-01T00:00:00Z

Authors' reply: Randomized clinical trial comparing feeding jejunostomy with nasoduodenal tube placement in patients undergoing oesophagectomy [3] (Article)

2007-04-01T00:00:00Z

CDX2 expression in columnar metaplasia of the remnant esophagus in patients who underwent esophagectomy (Article)

2007-04-01T00:00:00Z

BACKGROUND: Patients who have undergone esophagectomy with gastric tube reconstruction often have complaints of gastro-esophageal reflux. A subset of these patients will develop columnar epithelium in the remnant esophagus, which can be of the gastric or intestinal type (Barrett esophagus). GOALS: To determine whether gastric-type mucosa (GM) in the esophagus is a precursor stage of intestinal metaplasia (IM). STUDY: The medical records of 613 patients having undergone esophagectomy were reviewed for the endoscopic presence of segments with columnar mucosa in the remnant esophagus. Of them, 45 patients underwent endoscopic follow-up at least 6 months after resection. The presence of IM in the remnant esophagus was determined histologically in archival biopsy samples. Intestinal characteristics were identified by immunohistochemistry for CDX2, MUC2, and cytokeratins 7 and 20. CDX2 transcription was assessed by reverse transcription polymerase chain reaction. RESULTS: In 18 of 45 patients (40%) GM was identified, and 7 of these patients also had foci of IM. CDX2 and MUC2 expression was observed in IM, and in 2 patients, CDX2 expression was also observed in gastric-type glands at a distance from intestinal glands. CDX2 transcription was identified in 2 patients without IM. CONCLUSIONS: In the majority of patients after esophageal resection, expression of CDX2 and MUC2 in the remnant esophagus was only detectable in IM, but CDX2 was also observed in 4 cases with only GM. This could indicate that induction of formation of GM and IM may share a common pathway, eventually leading to the development of specialized intestinal epithelium.

Down syndrome and esophageal cancer (Article)

2007-04-01T00:00:00Z

We present two cases of Down syndrome with inoperable esophageal cancer at a relatively young age. The first patient had a locally advanced squamous cell carcinoma of the distal esophagus. The second had a short circular adenocarcinoma of the distal esophagus with peritoneal and liver metastases. The cases are discussed with regard to the current literature on Down syndrome and esophageal cancer. © 2007 The Authors. Journal compilation

Intrahepatic detection of FOXP3 gene expression after liver transplantation using minimally invasive aspiration biopsy (Article)

2007-03-01T00:00:00Z

Intragraft accumulation of Forkhead box P3 (FOXP3)-positive regulatory T cells (Treg) is associated with local suppression of alloresponses in transplantation models. In the current study, the utility of the minimally invasive fine needle aspiration biopsy for the intragraft detection of FOXP3 and interferon (IFN)-γ mRNA expression was investigated in clinical liver transplantation (LTx). Intragraft FOXP3 increased within the first year after LTx, but not in blood. Elevated FOXP3, but not IFN-γ expression, in the liver was observed after hepatitis C virus (HCV) reinfection and after a previous episode of acute rejection. These data show the feasibility of aspiration biopsy for intragraft monitoring of gene expression. Intrahepatic FOXP3 levels are associated with HCV reinfection, a history of acute rejection, and increased within the first year after LTx. Differences in gene expression between the graft and blood underline the importance of local immune monitoring.

Randomized clinical trial comparing feeding jejunostomy with nasoduodenal tube placement in patients undergoing oesophagectomy (Article)

2007-01-01T00:00:00Z

Background: Feeding jejunostomy is frequently performed in patients undergoing oesophageal surgery, but can lead to serious complications. This prospective randomized trial compared the efficacy and complications of feeding jejunostomy with those of nasoduodenal tube feeding in oesophageal surgery. Methods: Over an 18-month period, 150 consecutive patients undergoing oesophageal resection were randomized to participate in the trial. Enteral access was by jejunostomy in 79 patients and by nasoduodenal tube in 71. Enteral feeding was started on the first day after surgery. Results: Full enteral feeding took 3 days to be established in both groups. Minor catheter-related complications occurred in 28 patients (35 per cent) in the jejunostomy group, and in 21 (30 per cent) in the nasoduodenal group (P = 0.488). One patient had jejunostomy leakage that required reoperation. Enteral nutrition was given for a median of 11 days in the jejunostomy group and for 10 days in the nasoduodenal group. Nine patients who had a jejunostomy and five with a nasoduodenal tube did not tolerate full enteral feeding (P = 0.411). Conclusion: Nasoduodenal tube feeding is safe and efficient after oesophageal resection. Copyright

Phase II study of neo-adjuvant chemotherapy with paclitaxel and cisplatin given every 2 weeks for patients with a resectable squamous cell carcinoma of the esophagus (Article)

2003-01-01T00:00:00Z

BACKGROUND: We have previously reported a favourable response rate in patients with advanced esophageal cancer after treatment with a biweekly regimen of paclitaxel and cisplatin. In this study we investigate the feasibility and efficacy of this regimen in a neo-adjuvant setting. PATIENTS AND METHODS: Patients with resectable squamous cell carcinoma of the esophagus received paclit-axel 180 mg/m(2) and cisplatin 60 mg/m(2) every 2 weeks. Patients received three courses and responding patients received three additional courses; thereafter, patients were referred for surgery. Patient characteristics of 50 eligible patients were as follows: male, 60%; median age, 62 years (range 45-78); median World Health Organization performance status of 1 (range 0-2). RESULTS: Ninety-four per cent of patients received at least three courses of chemotherapy. Haematological toxicity consisted of National Cancer Institute-Common Toxicity Criteria grade 3 or 4 neutropenia in 71% of patients, with neutropenic fever occurring in only two patients (4%). The overall response rate was 59%. Pathological examination showed tumour-free margins in 38 patients. In seven patients no residual tumour was found. The median overall survival was 20 months and the 1- and 3-year survival rates were 68% and 30%, respectively. CONCLUSIONS: This dose-dense schedule of paclitaxel and cisplatin administered biweekly is well tolerated and the observed overall and complete response rates are promising.

Allelic imbalance of 7q32.3-q36.1 during tumorigenesis in Barrett's esophagus (Article)

2002-01-01T00:00:00Z

Malignant transformation of Barrett's esophagus is characterized by three distinct premalignant stages: intestinal metaplasia (MET), low- (LGD), and high-grade dysplasia (HGD). We reported recently an increase in the frequency of loss of 7q33-q35 between LGD and HGD as determined by comparative genomic hybridization (P. H. J. Riegman et al., Cancer Res., 61: 3164-3170, 2001). Now the 7q32.3-q36.1 region was additionally characterized by allelotype analysis with 11 polymorphic markers in 15 METs, 20 LGDs, 20 HGDs, and 20 Barrett's adenocarcinomas from different patients. Low percentages of imbalance were determined in METs and LGDs, 7% and 10%, respectively, whereas HGDs and Barrett's adenocarcinomas revealed high percentages of loss, 75% and 65%, respectively. This difference in frequency between LGDs and HGDs appeared highly significant: P = 0.00007. The majority of imbalances were found at D7S2439 and D7S483, located on 7q36.1. These data suggest that markers from this area can be used as a diagnostic tool in Barrett's esophagus, i.e., to distinguish between watchful waiting and active treatment.

Fibrinolysis during liver transplantation is enhanced by using solvent/detergent virus-inactivated plasma (ESDEP) (Article)

2002-01-01T00:00:00Z

After the introduction of solvent/detergent-treated plasma (ESDEP) in our hospital, an increased incidence of hyperfibrinolysis was observed (75% vs 29%; P = 0.005) compared with the use of fresh frozen plasma for liver transplantation. To clarify this increased incidence, intraoperative plasma samples of patients treated with fresh frozen plasma or ESDEP were analyzed in a retrospective observational study. During the anhepatic phase, plasma levels of D-dimer (6.58 vs 1.53 microg/mL; P = 0.02) and fibrinogen degradation products (60 vs 23 mg/L; P = 0.018) were significantly higher in patients treated with ESDEP. After reperfusion, differences increased to 23.5 vs 4.7 microg/mL (D-dimer, P = 0.002) and 161 vs 57 mg/L (fibrinogen degradation products, P = 0.001). The amount of plasma received per packed red blood cell concentrate, clotting tests, and levels of individual clotting factors did not show significant differences between the groups. alpha(2)-Antiplasmin levels, however, were significantly lower in patients receiving ESDEP during the anhepatic phase (0.37 vs 0.65 IU/mL; P < 0.001) and after reperfusion (0.27 vs 0.58 IU/mL; P = 0.001). Analysis of alpha(2)-antiplasmin levels in ESDEP alone showed a reduction to 0.28 IU/mL (normal >0.95 IU/mL) because of the solvent/detergent process. Therapeutic consequences for the use of ESDEP in orthotopic liver transplantation are discussed in view of an increased incidence of hyperfibrinolysis caused by reduced levels of alpha(2)-antiplasmin in the solvent/detergent-treated plasma. IMPLICATIONS: The use of solvent/detergent virus-inactivated plasma is of increasing importance in the prevention of human immunodeficiency virus and hepatitis C virus transmission. Since the use of this plasma during orthotopic liver transplantation has increased, the incidence of hyperfibrinolysis was observed. Clotting analysis of the patients revealed small alpha(2)-antiplasmin concentrations because of the solvent/detergent process.

Molecular biology of Barrett's adenocarcinoma (Article)

2001-01-01T00:00:00Z

OBJECTIVE: To review the current knowledge on the genetic alterations involved in the development and progression of Barrett's esophagus-associated neoplastic lesions. SUMMARY BACKGROUND DATA: Barrett's esophagus (BE) is a premalignant condition in which the normal squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium. BE predisposes patients to the development of esophageal adenocarcinoma. Endoscopic surveillance can detect esophageal adenocarcinomas when they are early and curable, but most of the adenocarcinomas are detected at an advanced stage. Despite advances in multimodal therapy, the prognosis for invasive esophageal adenocarcinoma is poor. A better understanding of the molecular evolution of the Barrett's metaplasia to dysplasia to adenocarcinoma sequence may allow improved diagnosis, therapy, and prognosis. METHODS: The authors reviewed data from the published literature to address what is known about the molecular changes thought to be important in the pathogenesis of BE-associated neoplastic lesions. RESULTS: The progression of Barrett's metaplasia to adenocarcinoma is associated with several changes in gene structure, gene expression, and protein structure. Some of the molecular alterations already showed promise as markers for early cancer detection or prognostication. Among these, alterations in the p53 and p16 genes and cell cycle abnormalities or aneuploidy appear to be the most important and well-characterized molecular changes. However, the exact sequence of events is not known, and probably multiple molecular pathways interact and are involved in the progression of BE to adenocarcinoma. CONCLUSIONS: Further research into the molecular biology of BE-associated adenocarcinoma will enhance our understanding of the genetic events critical for the initiation and progression of Barrett's adenocarcinoma, leading to more effective surveillance and treatment.

Genomic alterations in malignant transformation of Barrett's esophagus (Article)

2001-01-01T00:00:00Z

The incidence of adenocarcinoma in Barrett's esophagus has been increasing rapidly over the past decades. Neoplastic progression is characterized by three well-defined premalignant stages: metaplasia, low-grade dysplasia, and high-grade dysplasia. A genome-wide overview, based on comparative genomic hybridization, was performed, evaluating 30 Barrett's adenocarcinomas and 25 adjacent precursors, i.e., 6 metaplasias, 9 low-grade dysplasias, and 10 high-grade dysplasias. The frequency of losses and gains significantly increased in the subsequent stages of malignant transformation. Losses of 5q21-q23, 9p21, 17p12-13.1, 18q21, and Y were revealed in low-grade dysplasias. This was followed by loss of 7q33-q35 and gains of 7p12-p15, 7q21-q22, and 17q21 in high-grade dysplasias along with high-level amplification (HLA) of 7q21 and 17q21. In the invasive cancers, additional losses of 3p14-p21, 4p, 4q, 8p21, 13q14-q31, 14q24.3-q31, 16q21-q22, and 22q as well as gains of 3q25-q27, 8q23-24.1, 12p11.2-12, 15q22-q24, and 20q11.2-q13.1 were distinguished along with HLAs of 8p12-p22 and 20q11.2-q13.1. Approximately one-third of the alterations in the dysplasias were also found in the adjacent adenocarcinomas, illustrating that multiple clonal lineages can be present in Barrett's esophagus. Novel findings include loss on 7q, gain on 12p, and the observation of several HLAs in high-grade dysplasias. Furthermore, loss of 7q33-q35 was found to represent a significant distinction between low-grade and high-grade dysplasia (P = 0.01), whereas loss of 16q21-q22 and gain of 20q11.2-q13.1 were disclosed to significantly discriminate between high-grade dysplasia and adenocarcinoma (P = 0.02 and P = 0.03, respectively). This inventory of genetic aberrations increases our understanding of malignant transformation in Barrett's esophagus and might provide useful biomarkers for disease progression.

Molecular cytogenetic evaluation of gastric cardia adenocarcinoma and precursor lesions (Article)

2001-01-01T00:00:00Z

Analyses of cancer incidence data in the United States and Western Europe revealed steadily rising rates over the past decades of adenocarcinomas of the esophagus and gastric cardia. Genetic information on gastric cardia adenocarcinoma and its preneoplasias is sparse. We have used comparative genomic hybridization to obtain a genome-wide overview of 20 archival gastric cardia adenocarcinomas and 10 adjacent preneoplastic lesions (4 metaplasias, 1 low-grade dysplasia, 5 high-grade dysplasias). Multiple genetic alterations were discriminated in all adenocarcinomas. Frequent loss (> or =25% of all tumors) was detected, in decreasing order of frequency, on 5q, 18q, 4q, 3p, 9p, 2q, 11q, 14q, 21q, 4p, 9q, 16q, 1p, and 8p. Frequent gain (> or =25% of all tumors) was disclosed, in decreasing order of frequency, on 20q, 7p, 8q, 1q, 7q, 20p, 17q, 13q, Xp, 6q, 8p, 19q, 5p, 6p, and Xq. Loss of the Y chromosome was found in 60% of male cases. High level amplification was frequently (>10% of all tumors) detected on 7q21, 8p22, 12p11.2, 17q12-q21, and 19q13.1-q13.2. The precursor lesions showed multiple aberrations in all high-grade dysplasias, whereas few genetic changes were discerned in LGD and metaplasias. High level amplifications were also found in high-grade dysplasias, ie, on 7q21, 8p22, and 17q12-q21. Moreover, the percentage of aberrations was not significantly different for invasive carcinomas or high-grade dysplasias. Approximately 70% of the precursor aberrations were also present in the adjacent carcinoma. Minimal overlapping regions in the preneoplasias included loss on 18q12-q21 and gains on 8q23 and 17q12-q21, suggesting involvement of genes residing in these regions. In conclusion, we have (i) created a map of genetic alterations in gastric cardia adenocarcinomas and (ii) provided evidence for the presence of a metaplasia-dysplasia-carcinoma sequence in this poorly understood type of cancer.

Efficacy of influenza vaccination in adult liver transplant recipients. (Article)

2000-01-01T00:00:00Z

To assess the efficacy of influenza vaccination in immunocompromised adult liver transplant (LTx) recipients, the serum antibody responses of 61 of these patients and 35 liver cirrhosis patients with those of 45 of their healthy spouses were compared, after one and two vaccinations with a commercial trivalent subunit influenza vaccine. In addition, virus-specific proliferative T-cell responses were measured in LTx recipients and their healthy spouses. In all three study groups, significant rises in geometric mean antibody titers were observed for all three antigens after one vaccination. These titers did not continue to increase significantly after the second vaccination in patients with cirrhosis and control subjects but did rise for LTx recipients. The overall antibody response to all three influenza virus strains proved to be significantly lower in the LTx recipients than in the group of healthy subjects after both one and two vaccinations. More than 68% of the LTx recipients developed hemagglutination-inhibiting serum antibody titers >/=40 against all three vaccine strains after the first vaccination and more than 80% after the second vaccination. These findings correlated with the T-cell responses determined for the group of LTx recipients and healthy control individuals. Testing of the respective serum samples against influenza virus A/Sydney/5/97, which circulated in the 1997-1998 influenza season and showed a considerable mismatch with the vaccine strain A/Nanchang/933/95, indicated that such a mismatch may have significant consequences for vaccine efficacy, especially for LTx recipients. Collectively the data show that LTx recipients can be vaccinated effectively against influenza despite immunosuppressive therapy. A two-dose vaccination regimen improved vaccination efficacy in LTx recipients. Whether transplant patients generally benefit from a two-dose vaccination regimen should be evaluated further.

Comparative genomic hybridization of cancer of the gastroesophageal junction: deletion of 14Q31-32.1 discriminates between esophageal (Barrett's) and gastric cardia adenocarcinomas (Article)

1999-01-01T00:00:00Z

Incidence rates have risen rapidly for esophageal and gastric cardia adenocarcinomas. These cancers, arising at and around the gastroesophageal junction (GEJ), share a poor prognosis. In contrast, there is no consensus with respect to clinical staging resulting in possible adverse effects on treatment and survival. The goal of this study was to provide more insight into the genetic changes underlying esophageal and gastric cardia adenocarcinomas. We have used comparative genomic hybridization for a genetic analysis of 28 adenocarcinomas of the GEJ. Eleven tumors were localized in the distal esophagus and related to Barrett's esophagus, and 10 tumors were situated in the gastric cardia. The remaining seven tumors were located at the junction and could not be classified as either Barrett-related, or gastric cardia. We found alterations in all 28 neoplasms. Gains and losses were distinguished in comparable numbers. Frequent loss (> or = 25% of all tumors) was detected, in decreasing order of frequency, on 4pq (54%), 14q (46%), 18q (43%), 5q (36%), 16q (36%), 9p (29%), 17p (29%), and 21q (29%). Frequent gain (> or = 25% of all tumors) was observed, in decreasing order of frequency, on 20pq (86%), 8q (79%), 7p (61%), 13q (46%), 12q (39%), 15q (39%), 1q (36%), 3q (32%), 5p (32%), 6p (32%), 19q (32%), Xpq (32%), 17q (29%), and 18p (25%). Nearly all patients were male, and loss of chromosome Y was frequently noted (64%). Recurrent high-level amplifications (> 10% of all tumors) were seen at 8q23-24.1, 15q25, 17q12-21, and 19q13.1. Minimal overlapping regions could be determined at multiple locations (candidate genes are in parentheses): minimal regions of overlap for deletions were assigned to 3p14 (FHIT, RCA1), 5q14-21 (APC, MCC), 9p21 (MTS1/CDKN2), 14q31-32.1 (TSHR), 16q23, 18q21 (DCC, P15) and 21q21. Minimal overlapping amplified sites could be seen at 5p14 (MLVI2), 6p12-21.1 (NRASL3), 7p12 (EGFR), 8q23-24.1 (MYC), 12q21.1, 15q25 (IGF1R), 17q12-21 (ERBB2/HER2-neu), 19q13.1 (TGFB1, BCL3, AKT2), 20p12 (PCNA), 20q12-13 (MYBL2, PTPN1), and Xq25. The distribution of the imbalances revealed similar genetic patterns in the three GEJ tumor groups. However, loss of 14q31-32.1 occurred significantly more frequent in Barrett-related adenocarcinomas of the distal esophagus, than in gastric cardia cancers (P = 0.02). The unclassified, "pure junction" group displayed an intermediate position, suggesting that these may be in part gastric cardia tumors, whereas the others may be related to (short-segment) Barrett's esophagus. In conclusion, this study has, fist, provided a detailed comparative genomic hybridization-map of GEJ adenocarcinomas documenting new genetic changes, as well as candidate genes involved. Second, genetic divergence was revealed in this poorly understood group of cancers.

Heterotopic ossification induced by hypoxia in a retrosternal gastric tube following transhiatal oesophagectomy (Article)

1995-01-01T00:00:00Z

A 71 year old man underwent retrosternal gastric tube reconstruction following transhiatal oesophagectomy for squamous cell carcinoma. On the second post-operative day, the patient developed a cardiac arythmia with secondary hypotension followed by hypoxaemia necessitating artificial ventilation. Two weeks after surgery, endoscopy revealed massive necrosis of the proximal segment of the gastric tube extending from the anastomosis in the neck to the watershed area. Three weeks later, the patient died and a necropsy was performed. Macroscopic evaluation of the gastric tube revealed a sharply demarcated and fully ossificated proximal segment. Heterotopic ossification was present on histological examination. This condition has only been described in conjunction with primary or metastatic gastric adenocarcinoma. The location of the ossification and the presence of temporary systemic hypoxia suggest that the latter was the main factor responsible for the ossificative response.

De femoropopliteale overbruggingsplastiek (Doctoral Thesis)

1983-09-02T00:00:00Z

This prospective randomised trial obtain an answer to polytetrafluorethylene can be was performed in order to question whether expanded applied as an equivalent to saphenous vein as a femoropopliteal bypass in patients with a symptomatic acelusion of the superficial femoral artery. Chapter 1 deals with the thrornbogenicity of vascular prostheses as well as its prevention.The development of a complete neeintimal lining is one of the most important conditions for the prevention of tbrambosis of vascular prestheses In the human body this lining is never complete. The parts of the prosthesis which are not covered by neointima are highly thrombogenic. This thrombogenicity may probably be reduced by medication which inhibits the aggregation of thrombocytes. Intimal fibrous hyperplasia is responsible for part of the delayed occlusions of srnall vascular prostheses A number of conditions as there are: operative trauma, hemadynamie and mechanic factors play their part in the development of intimal fibrous hyperplasia.