Serum Midkine is a clinical significant biomarker for colorectal cancer and associated with poor survival.

Colorectal carcinoma (CRC) is one of the most common carcinomas worldwide. Early detection is crucial for reducing morbidity and mortality. Several promising studies described the use of midkine (MK) as a tumor marker. This study aimed to investigate a larger collective to ascertain if the preoperative serum midkine level (S-MK) is suitable as a marker for screening and if S-MK correlates with tumor progression and localization. It was also investigated for the first time whether patients with high S-MK show poor survival. This prospective single-center study included 299 patients with CRC. The preoperative serum midkine level (S-MK) was determined using ELISA. Established tumor markers Carcinoembryonic antigen (CEA) and Carbohydrate antigen 19-9 (CA 19-9) were collected for comparison. The median follow-up period was 65 months. S-MK was significantly elevated in patients with CRC (P < .001). The receiver operation characteristic (ROC) curve has an area under the curve (AUC) of 0.868 (P < .001). A cut-off value of 56.42 pg/mL results in a sensitivity of 84.3% and a specificity of 75.4%. In the one-way analysis of variance (ANOVA), there were no significant correlations between S-MK and tumor progression, localization. Furthermore, no significant correlation to CEA und CA 19-9 could be found. Kaplan-Meier survival analysis was able to show for the first time that patients with S-MK of more than 225 pg/mL have a significantly shorter survival. Multivariate Cox regression showed that only CEA was an independent prognostic factor for survival. S-MK helps estimate the prognosis for CRC and is a valuable component for developing a multimarker panel for screening and surveillance.

Management of Intrauterine Arteriovenous Malformation (AVM) in 14 Patients by Sonographically Guided Tisseel Application.

PURPOSE: AVMs are rare tumorous vascular lesions derived from placental tissue that may present with massive post-partum hemorrhage (PPH) causing potentially life-threatening anemic shock. Current treatment options include the embolization of uterine arteries and emergency postpartum hysterectomy. We present a new form of minimally invasive, highly specific sonographically guided treatment in the form of the application of a human fibrin sealant leading to the instant cease of blood loss. MATERIALS AND METHODS: A management protocol was established and a case series of 14 patients is presented. Diagnosis by endovaginal color Doppler sonography is followed by the sonographically guided application of biological glue (TISSEEL®), thus allowing for super-selective occlusion of the feeding vessels. RESULTS: The procedure was technically successful in all 14 patients, 3 of whom (21 %) had a repeated procedure after 4 - 7 days. The mean age (yrs.) of the patients was 31 (25 - 40), the gravity was median 2 (1 - 5) and the parity was median 1 (0 - 4), the lowest Hb value was on average 9.35 ±â€Š2.25 (5.2 - 14.2) g/dl, the lowest Ht was on average 30.82 ±â€Š6.02 (18 - 41 %). Spectral Doppler analysis revealed an average of 80.71 ±â€Š11.2 (66 - 115) cm/sec for the maximal detectable PSV. In the period of 4 - 55 months after treatment, 7 patients (50 %) had 8 successful pregnancies and 2 miscarriages. CONCLUSION: In PPH there is vital interest in timely diagnosis of the underlying cause, thus allowing fertility-sparing, minimally invasive and super-selective emergency treatment. In AVMs causing PPH, a positive impact on perinatal morbidity and mortality may be achieved by sonographically guided application of this biological glue.

The misoprostol vaginal insert compared with oral misoprostol for labor induction in term pregnancies: a pair-matched case-control study.

AIM: To compare the efficacy and safety of the misoprostol vaginal insert (MVI) with an off-label use of oral misoprostol (OM). METHODS: Pair-matched case-control study comparing the induction of labor with a retrievable MVI to OM. The primary outcomes were the time from induction to delivery and the cesarean section rate. Secondary outcomes included uterine tachysystole, tocolysis, fetal scalp blood testing, meconium-stained amniotic fluid, umbilical arterial pH, and Apgar score. RESULTS: One hundred and thirty eight women ≥37/0 weeks pregnant undergoing labor induction with misoprostol were included. The mean time from application to delivery was significantly shorter and the caesarean section rate significantly higher in the MVI group (P<0.01) with an odds ratio of 2.75 (95% CI: 1.21-6.25) in favor of vaginal delivery in the OM group. The mean 5-min Apgar scores and arterial cord pH values were significantly lower in the MVI group. An arterial pH value of 7.10-7.19 was found in 26.1% and 15.9%, and a value <7.10 was found in 4.3% and 0% of MVI and OM cases, respectively. CONCLUSION: The MVI compared with OM significantly shortened the time from application to delivery at the expense of a higher cesarean section rate and negative effects on neonatal outcomes.

The multifunctional growth factor midkine promotes proliferation and migration in pancreatic cancer.

UNLABELLED: Pancreatic ductal adenocarcinoma (PDAC) has a devastating prognosis among solid tumors and despite increased knowledge of the molecular mechanisms contributing to progression and metastasis, minimal progress has been done in establishing new targeted therapies for this deadly disease. The expression of the multifunctional growth/differentiation factor midkine (MK) promotes a variety of cellular functions leading to increased angiogenesis, proliferation, migration, and survival. Moreover, MK is intensively discussed as a potential new-therapy target and as biomarker for cancer progression and chemotherapeutic resistance in multiple cancers. Therefore, the present study investigated the molecular role of MK in pancreatic cancer. It was found that MK is elevated in PDAC and differentially expressed in other histologic subtypes of pancreatic cancer, whereas normal pancreatic cells did not express MK, thus making it an attractive candidate for targeted therapies. As a secreted growth/differentiation factor, MK was investigated as a biomarker in clinical serum specimens using ELISA. In addition, knockdown studies of MK revealed a link to proliferation and migration status in vitro. Finally, upstream signaling pathways were analyzed, with TNF-α and EGF being the main inductors of MK expression in PDAC. IMPLICATIONS: This study presents novel MK functions and new upstream signaling effectors that induce its expression to promote PDAC and therefore defines an attractive new therapeutic target in pancreatic cancer.

CXCR4/SDF-1α-mediated chemotaxis in an in vivo model of metastatic esophageal carcinoma.

BACKGROUND/AIM: The chemokine receptor CXCR4 and its ligand (stromal cell-derived factor-1alpha; SDF-1α) play an important role in tumor cell chemotaxis and metastatic homing of esophageal carcinoma. Several methods are available to examine tumor cell migration in vitro. However, in vivo chemotaxis is subject to complex tumor-host interactions. The aim of this study was to establish an in vivo model of chemotaxis for esophageal carcinoma that allows the examination of tumor cell migration and metastatic homing in the complex microenvironment. MATERIALS AND METHODS: CXCR4 expression of OE19 adenocarcinoma cells was determined by immunostaining in an orthotopic esophageal model. SDF-1α-mediated migration of cells was examined in vitro. An in vivo model of chemotaxis and metastasis was established by subcutaneous injection of OE19 cells into NMRI/nu mice and by daily stimulation with SDF-1α. RESULTS: CXCR4 is expressed in the primary tumor and in the metastatic tissue. CXCR4-positive OE19 cells are susceptible to SDF-1α-mediated migration. The novel in vivo model leads to developement of metastases in liver, lung, peritoneum and retroperitoneum after stimulation with SDF-1α but not with PBS, and revealed an SDF-1α dose-dependent migratory effect. CONCLUSION: As metastasis is still the leading cause of tumor-related death, it is essential to investigate the complex tumor-host interactions involved in metastatic homing. We established an in vivo model of chemotaxis and metastasis for esophageal carcinoma, which allows investigation and inhibition of CXCR4/SDF-1α-mediated cell survival and proliferation, chemotaxis and homing, adhesion, and tumor angiogenesis.

Adhesion molecule L1 is down-regulated in malignant peripheral nerve sheath tumors versus benign neurofibromatosis type 1-associated tumors.

Type 1 neurofibromatosis (NF-1), also known as von Recklinghausen disease, is caused by a disorder of a single gene on chromosome 17 that usually restrains cell division. A sequence that is frequently associated with NF-1 is tumor progression from neurofibromas to malignant peripheral nerve sheath tumors (MPNSTs). The aim of this study was to determine the expression of the neural L1 cell adhesion molecule in dermal-diffuse neurofibromas, plexiform neurofibromas, and MPNSTs of NF-1. We retrospectively analyzed surgically resected primary tumors, including 20 dermal neurofibromas, 23 plexiform neurofibromas, and 17 MPNSTs, by immunohistochemistry in paraffin sections of NF-1 tumors with the use of the L1-specific monoclonal antibody UJ127, which does not cross-react with other members of the L1 family. Immunostainings for CD34 and S100 were included to distinguish and allocate L1-expressing Schwann cells and perineural (specialized) fibroblasts. Our data showed that L1 is highly expressed in all benign NF-1 tumors and in some but not all MPNSTs. Furthermore, we demonstrated a correlation between L1 expression and differentiation grade of MPNSTs. There was a significant trend toward lower or nondetectable expression in the poorly differentiated MPNSTs, in contrast to all other tumor entities so far investigated, in which L1 expression correlated positive with malignancy, except for juvenile but not adult-derived neuroblastomas. Future studies are warranted to elucidate the molecular basis of the varying effects of the degree of L1 expression, receptor, and signal transduction mechanisms in different tumors.

L1 is highly expressed in tumors of the nervous system: a study of over 8000 human tissues.

BACKGROUND: L1 cell adhesion molecule (CD171) has been detected in different malignant tumors and is associated with unfavorable outcome. It thus represents a target for tumor diagnosis and therapy. In this study, we assessed L1 expression in more than 8000 normal human tissues and different types of tumors, both malignant and non-malignant, and neural and non-neural. MATERIALS AND METHODS: Tissue micro-arrays, including a multi-tumor-array of 128 different tumor types, up to 50 samples of each type (approximately 5500 different samples), arrays with approximately 3000 different prostate and 600 mesenchymal tumor samples, and a normal human tissue-array were analyzed by immunohistochemistry with a monoclonal antibody using immunoperoxidase staining. RESULTS: L1 expression was detected in tumors of neural and neural crest origin and other types of non-neural tumors, but not in those of epithelial origin. In normal human tissues, L1 was detected in skin basal cells and small blood vessels, most notably in the mature placenta and peripheral nerves. CONCLUSION: This first comprehensive study of the importance of L1 expression in human demonstrates strong L1 overexpression in tumors of neuroectodermal and neural crest origin and an expression in only very few normal human tissues. L1 thus is a potentially important therapeutic target, particularly with respect to malignant melanoma, gastrointestinal stromal tumor, neuroblastoma, and certain subtypes of non-neural tumors.

ALCAM (CD166) expression as novel prognostic biomarker for pancreatic neuroendocrine tumor patients.

BACKGROUND: Activated leukocyte cell adhesion molecule (ALCAM, CD166) is a cell membrane protein that is aberrantly expressed in different tumors, including pancreatic neuroendocrine tumors (PNET). The aim of this study was to determine the expression of ALCAM in PNET to learn more about the prevalence and clinical significance of ALCAM expression in PNET. METHODS: Primary tumors (n = 38) and corresponding lymph node (n = 5) and liver metastases (n = 9) of patients with PNET, treated at the University Medical Center Hamburg-Eppendorf between 1993 and 2006, were analyzed via ALCAM immunohistochemistry in a tissue microarray format. The results were correlated with clinical and histopathologic data, including the WHO classification of PNET. RESULTS: The majority of primary (74%) and secondary (50%) lesions of PNET showed strong ALCAM expression. Immunohistochemistry of primary tumors revealed an association between high ALCAM expression and the hormone production status of the tumor (P = 0.037), and an inverse correlation with metastasis status (P = 0.041) and tumor size (cut off level 2 cm, P = 0.013). Elevated ALCAM expression was a significant positive prognostic factor for recurrence-free (P = 0.002) and disease-specific survival (P = 0.009) in Kaplan-Meier survival analysis (log rank test). CONCLUSIONS: ALCAM is abundantly expressed in PNET and decreased expression is significantly associated with poor prognosis. ALCAM may be a potential marker for risk prediction in patients diagnosed with PNET. Further studies with larger patient collectives are required to validate the results of this study and investigate the functional role of ALCAM in PNET.

Circulating levels of cell adhesion molecule L1 as a prognostic marker in gastrointestinal stromal tumor patients.

BACKGROUND: L1 cell adhesion molecule (CD171) is expressed in many malignant tumors and its expression correlates with unfavourable outcome. It thus represents a target for tumor diagnosis and therapy. An earlier study conducted by our group identified L1 expression levels in primary gastrointestinal stromal tumors (GIST) as a prognostic marker. The aim of the current study was to compare L1 serum levels of GIST patients with those of healthy controls and to determine whether levels of soluble L1 in sera could serve as a prognostic marker. METHODS: Using a sensitive enzyme-linked immunosorbent assay (ELISA), soluble L1 was measured in sera of 93 GIST patients und 151 healthy controls. Soluble L1 levels were then correlated with clinicopathological data. RESULTS: Median levels of soluble L1 were significantly higher (p < 0.001; Mann-Whitney U test) in sera of GIST patients compared to healthy individuals. Median soluble L1 levels were particularly elevated in patients with recurrence and relapse (p < 0.05; Mann Whitney U test). CONCLUSION: These results suggest that high soluble L1 levels predict poor prognosis and may thus be a promising tumor marker that can contribute to individualise therapy.

Monitoring of loss of heterozygosity in serum microsatellite DNA among patients with gastrointestinal stromal tumors indicates tumor recurrence.

BACKGROUND: Patients with gastrointestinal stromal tumors (GIST) harbor increased levels of circulating tumor DNA in their peripheral blood. In the current study, the aim was to investigate whether the frequency of loss of heterozygosity (LOH) on cell-free DNA in blood may reflect tumor stage and recurrent disease of these patients. MATERIALS AND METHODS: Serum DNA and follow-up samples of 92 patients suffering from recurrent GIST were analyzed by a PCR-based fluorescence microsatellite analysis using a panel of 12 polymorphic markers. The data were correlated with established risk factors, and patients were followed-up over 4 y. RESULTS: Microsatellite analysis demonstrated a positive LOH score on cell-free DNA of 30/92 patients. A significant correlation with recurrence in CT imaging showed that a positive LOH score (n ≥ 2) was detected in 58% (11/19) of patients with recurrent disease (P = 0.030, χ(2) test), but only in 25% of patients were clinically free of recurrence. No prognostic significance of a positive LOH score was observed after a median observation time of 48 mo. CONCLUSION: Our findings show that LOH on circulating serum DNA correlates with the tumor status and is a frequent event in GIST patients with recurrent disease.

Serum midkine correlates with tumor progression and imatinib response in gastrointestinal stromal tumors.

BACKGROUND: A previous study identified midkine (MK) expression in primary gastrointestinal stromal tumor (GIST) as a prognostic marker. The aim of the current study was to compare serum midkine (S-MK) concentrations of GIST patients with those of healthy controls and to determine if MK can serve as a prognostic serum marker for these patients. MATERIALS AND METHODS: S-MK concentrations were measured by enzyme-linked immunosorbent assay in GIST patients (n = 96) and healthy controls (n = 148). S-MK levels were then correlated with clinicopathological data and the administration of imatinib therapy. In addition, MK expression was evaluated in 39 surgically resected GIST and in 17 leiomyoma specimens on a tissue microarray. RESULTS: S-MK concentrations in GIST patients were significantly higher than in healthy controls: median (25th and 75th percentiles) S-MK concentration was 235 (139 and 376) pg/ml in the GIST patients and 99 (33 and 198) pg/ml in the controls (P < 0.001; Mann-Whitney U test). Significantly higher median S-MK concentrations were found in GIST with recurrence compared with those without (295 vs 230; P = 0.009). GIST patients with S-MK levels higher than 400 pg/ml showed a significantly worse recurrence-free survival (P = 0.026; log-rank test). Patients receiving imatinib therapy had decreased median S-MK concentrations compared with those who were not treated with imatinib (331 vs 201; P < 0.001). CONCLUSIONS: S-MK concentration is a potential marker for evaluating the progression and prognosis of GIST, especially during imatinib therapy. Further studies could focus on the role of midkine in the tumorigenesis of GIST and responsiveness toward imatinib therapy.

Impact of early or delayed elective resection in complicated diverticulitis.

AIM: To investigate the outcomes of early and delayed elective resection after initial antibiotic treatment in patients with complicated diverticulitis. METHODS: The study, a non-randomized comparison of the two approaches, included 421 consecutive patients who underwent surgical resection for complicated sigmoid diverticulitis (Hinchey classification  I-II) at the Department of Surgery, University Medical Center Hamburg-Eppendorf between 2004 and 2009. The operating procedure, duration of hospital and intensive care unit stay, outcome, complications and socioeconomic costs were analyzed, with comparison made between the early and delayed elective resection strategies. RESULTS: The severity of the diverticulitis and American Society of Anesthesiologists score were comparable for the two groups. Patients who underwent delayed elective resection had a shorter hospital stay and operating time, and the rate of successfully completed laparoscopic resections was higher (80% vs 75%). Eight patients who were scheduled for delayed elective resection required urgent surgery because of complications of the diverticulitis, which resulted in a high rate of morbidity. Analysis of the socioeconomic effects showed that hospitalization costs were significantly higher for delayed elective resection compared with early elective resection (9296 € ± 694 € vs 8423 € ± 968 €; P = 0.001). Delayed elective resection showed a trend toward lower complications, and the operation appeared simpler to perform than early elective resection. Nevertheless, delayed elective resection carries a risk of complications occurring during the period of 6-8 wk that could necessitate an urgent resection with its consequent high morbidity, which counterbalanced many of the advantages. CONCLUSION: Overall, early elective resection for complicated, non-perforated diverticulitis is shown to be a suitable alternative to delayed elective resection after 6-8 wk, with additional beneficial socioeconomic effects.

Orthotopic fluorescent peritoneal carcinomatosis model of esophageal cancer.

AIM: Orthotopic models utilizing orthotopic implantation have been used for developing cancer models of multiple tumor entities. The aim of this study was to evaluate the role of orthotopic injection in establishing a model of esophageal cancer using a human green fluorescent protein (GFP) cell line of human esophageal carcinoma. MATERIALS AND METHODS: Nude mice were orthotopically injected in the abdominal esophagus with stably transfected GFP-PT1590 cells. Tumor progression was examined by fluorescence imaging. RESULTS: Fifty percent of animals developed extensive peritoneal spread without a distinct primary tumor at the injection site. Continuous and metastatic spread to the liver, lungs, and lymph nodes was also observed. Fluorescence imaging enabled fast and specific visualization of tumor progression without the need for anesthesia. Intraperitoneal and metastatic tumor spread of GFP-PT1590 esophageal carcinoma demonstrated a highly aggressive but heterogeneous behaviour. Although injection of the esophageal carcinoma cell line GFP-PT1590 did not lead to primary esophageal tumor development at the site of injection, 50% of the mice developed extensive peritoneal spread, as well as lymph node and organ metastasis. CONCLUSION: The orthotopic cell injection model resulted in peritoneal carcinomatosis of esophageal adenocarcinoma, which could be visualized in real time using fluorescence imaging.

Y-box-binding protein-1 is a potential novel tumour marker for neuroblastoma.

BACKGROUND: The Y-box-binding protein-1 (YB-1) is a member of a family of DNA-binding proteins and an oncogenic transcription factor that is highly expressed in cancers of the breast, lung and prostate. To date, no data are available on its role in neuroblastoma. The aim of the present study was to evaluate the YB-1 expression in neuroblastoma. MATERIALS AND METHODS: A tumour tissue microarray (TMA) was constructed from 36 neuroblastoma samples which were analysed by immunohistochemistry for YB-1 expression. RESULTS: Expression of YB-1 was detected in 35 of 37 (94.6%) neuroblastoma cases examined. Nevertheless, no correlation of YB-1 expression with survival, risk factors or stage of the disease was observed. CONCLUSION: As the majority of neuroblastomas express YB-1, this protein may play an important role in tumour pathogenesis. The results of this study suggest that YB-1 may serve as a novel immune marker for neuroblastoma and may be potentially useful as a therapeutic target.

Subset of esophageal adenocarcinoma expresses adhesion molecule l1 in contrast to squamous cell carcinoma.

BACKGROUND: Esophageal adenocarcinoma is currently the most rapidly increasing cancer in Western populations. L1 (CD171), a neural cell adhesion molecule, has an essential function in tumor progression and has been shown to be expressed in the proliferating cells of the intestinal crypts in mice. The aim of the current study was to determine L1 expression in esophageal cancer and to evaluate whether L1 could serve as a potential marker and therapeutic target for this tumor type. MATERIALS AND METHODS: L1 expression was assessed on a tissue microarray with 257 surgically resected esophageal cancer samples by immunohistochemistry with a monoclonal antibody (Clone UJ127). L1 expression was correlated with clinicopathological data. RESULTS: L1 was detected in 22 (9%) of 257 esophageal cases, whereas 235 (91%) were L1 negative. Nineteen (86%) of the 22 L1-positive cases were adenocarcinoma. Cross table analysis showed a significant association between L1 expression and adenocarcinoma subtype (p<0.001), but not squamous cell carcinoma. CONCLUSION: L1 expression in a subgroup of esophageal cancer is specifically prevalent in adenocarcinoma. Data suggest L1 as a potential target for biological therapy in L1-positive esophageal adenocarcinoma patients.

Polymorphism Arg290Arg in esophageal-cancer-related gene 1 (ECRG1) is a prognostic factor for survival in esophageal cancer.

BACKGROUND: Esophageal cancer is one of the most frequent cancers worldwide and is associated with poor outcome. Besides clinicopathological data, few prognostic molecular markers exist. Esophageal-cancer-related gene1 (ECRG1) short tandem repeats are associated with higher risk for developing esophageal squamous cell carcinoma. The aim of the present study was to evaluate the impact of DNA polymorphisms in the coding region of ECRG1 in esophageal carcinoma. METHODS: Genomic DNA of 107 patients with esophageal cancer that underwent complete surgical resection between 1997 and 2005 was extracted. DNA was analyzed for ECRG1 polymorphisms Arg290Arg, Arg290Gln, and Gln290Gln by PCR and gel electrophoresis. Polymorphisms were correlated with survival data by the Kaplan-Meier method, multivariate Cox regression analysis, and odds ratio were determined. For all variables, cross tables were generated, followed by calculation of the p value by using the chi-square test/Fisher-exact test. RESULTS: Follow-up data of 102 patients with esophageal cancer were available after complete surgical resection for a median follow-up time of 24.3 months. Polymorphism Arg290Arg was found in 47 patients (46.1%), Arg290Gln in 48 patients (47.0%), and Gln290Gln in seven cases (6.9%). Arg290Arg polymorphism was significantly associated with reduced overall survival (p = 0.01) and tumor-free survival (p = 0.01) by the log-rank test. Multivariate regression analysis by Cox revealed polymorphism Arg290Arg to be a significant prognostic factor for survival (p = 0.012). CONCLUSIONS: Polymorphism Arg290Arg in ECRG1 is associated with poor clinical outcome after complete surgical resection in patients with esophageal cancer.

Universal expression of cell adhesion molecule NCAM in neuroblastoma in contrast to L1: implications for different roles in tumor biology of neuroblastoma?

PURPOSE: Neuroblastoma is a biological, genetic and morphological heterogeneous tumor with a variable clinical course. NCAM is a cell adhesion molecule belonging to the immunoglobulin superfamily with structural similarities to cell adhesion molecule L1. The aim of this study was to determine the expression of NCAM in neuroblastoma and to compare the results to the findings of a previous study which examined L1 expression in the same group of patients. MATERIALS AND METHODS: NCAM expression was investigated on a tissue array with 66 surgically resected neuroblastoma samples by immunohistochemistry with a monoclonal antibody clone 1B6 and peroxidase method. RESULTS: Strong expression of NCAM was detected in all of the 66 (100%) neuroblastoma tumors in contrast to L1 which was not expressed in all tumors. CONCLUSION: In contrast to L1, which was found to predict favorable outcome, NCAM is universally expressed in neuroblastoma. Therefore NCAM represents a marker for neuroblastomas irrespectively of their stages whereas L1 as an indicator for developing neuronal cells seems to identify more mature stages of this tumor. The high grade of NCAM expression might present a prerequisite for establishment of antibody-based therapies.

Short tandem repeat polymorphism in exon 4 of esophageal cancer-related gene 2 detected in genomic DNA is a prognostic marker for esophageal cancer.

BACKGROUND: Short tandem repeat (STR) polymorphisms in exon 4 of the esophageal cancer-related gene 2 (ECRG2) are a risk marker for esophageal carcinoma. The aim of the present study was to correlate these STRs with clinical outcome. METHODS: Genomic DNA of 86 patients who underwent complete surgical resection was analyzed for STRs TCA3/TCA3, TCA3/TCA4, and TCA4/TCA4 in exon 4 of ECRG2 by polymerase chain reaction and DNA sequencing. RESULTS: ECRG2 STR TCA3/TCA3 and TCA3/TCA4 were found in 40 (47%) patients, respectively, and TCA4/TCA4 in 6 (7%) cases. TCA3/TCA3 genotype was significantly associated with reduced survival (P < .05, log-rank test). TCA3/TCA3 STR was the strongest prognostic factor determined by multivariate Cox regression analysis. CONCLUSIONS: Genetically fixed STR polymorphism TCA3/TCA3 in exon 4 of ECRG2 is associated with poor clinical outcome in surgically treated esophageal cancer patients and might be a potential prognostic marker. The usefulness of these genetic markers to predict responsiveness toward neoadjuvant treatment of esophageal cancer patients would be of high clinical interest and should be examined in future studies.