[Show abstract][Hide abstract] ABSTRACT: The integrins are a family of heterodimeric transmembrane signaling receptors that mediate the adhesive properties of epithelial cells affecting cell growth and differentiation. In many epithelial malignancies, altered integrin expression is associated with tumor progression and often correlates with unfavorable prognosis. However, only few studies have investigated the role of integrin expression in esophageal squamous cell carcinoma (ESCC). Using a novel quantifying immunofluorescence-staining assay, we investigated the expression of the integrins α2β1, α3β1, α6β1, and α6β4 in primary ESCC of 36 patients who underwent surgical resection. Magnitude and distribution of expression were analyzed in primary tumor samples and autologous esophageal squamous epithelium. The persistence of the physiologically polarized expression of the subunits α6, β1, and β4 in the tumor tissue was significantly associated with prolonged relapse-free survival (p = 0.028, p = 0.034, p = 0.006). In contrast, patients with reduced focal α6 expression at the tumor invasion front shared a significantly shortened relapse-free survival compared to patients with strong α6 expression at their stromal surfaces, as it was regularly observed in normal esophageal epithelium (p = 0.001). Multivariate regression analysis identified the maintenance of strong α6 immunoreactivity at the invasion front as an independent prognostic factor for increased relapse-free and disease-specific survival (p = 0.003; p = 0.003). Our findings suggest that alterations in both pattern and magnitude of integrin expression may play a major role in the disease progression of ESCC patients. Particularly, the distinct expression of the integrins α6β4 and α6β1 at the invasion front as well as the maintenance of a polarized integrin expression pattern in the tumor tissue may serve as valuable new markers to assess the aggressiveness of ESCC.
PLoS ONE 11/2014; 9(11):e109026. DOI:10.1371/journal.pone.0109026 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Here we tested the prognostic impact of genomic alterations in operable localized pancreatic ductal adenocarcinoma (PDAC). Fifty-two formalin-fixed and paraffin-embedded primary PDAC were laser micro-dissected and were investigated by comparative genomic hybridization after whole genome amplification using an adapter-linker PCR. Chromosomal gains and losses were correlated to clinico-pathological parameters and clinical follow-up data. The most frequent aberration was loss on chromosome 17p (65%) while the most frequent gains were detected at 2q (41%) and 8q (41%), respectively. The concomitant occurrence of losses at 9p and 17p was found to be statistically significant. Higher rates of chromosomal losses were associated with a more advanced primary tumor stage and losses at 9p and 18q were significantly associated with presence of lymphatic metastasis (chi-square: p = 0.03, p = 0.05, respectively). Deletions on chromosome 4 were of prognostic significance for overall survival and tumor recurrence (Cox-multivariate analysis: p = 0.026 and p = 0.021, respectively). In conclusion our data suggest the common alterations at chromosome 8q, 9p, 17p and 18q as well as the prognostic relevant deletions on chromosome 4q as relevant for PDAC progression. Our comprehensive data from 52 PDAC should provide a basis for future studies with a higher resolution to discover the relevant genes located within the chromosomal aberrations identified.
[Show abstract][Hide abstract] ABSTRACT: Fistulae between an ileal pouch and the vagina are an uncommon complication of ileal pouch-anal anastomosis following proctocolectomy and mucosectomy in patients with familial adenomatous polyposis coli. Several reports describe the successful use of muscle flaps to close recurrent pouch-vaginal-fistulae (PVF). However, series only contain small numbers and an optimal management has not yet been determined. We report the case of a 26-year old woman with a third recurrence of a PVF after proctocolectomy for treatment of familial adenomatous polyposis in October 2005. Because local approaches failed, definitive closure of the fistula was achieved by interposition of a gracilis muscle flap between the pouch-anal anastomosis and the vagina. The postoperative course was uneventful; the patient was discharged 7 days after surgery and remained free of recurrence and symptomatic complaints for 22 months now. The gracilis muscle flap proved to be an effective method in the treatment of recurrent PVF.
Case Reports in Medicine 02/2009; 2009:676392. DOI:10.1155/2009/676392
[Show abstract][Hide abstract] ABSTRACT: In gastric cancer, regional lymph node metastasis verified by histopathological examination is the most important prognostic factor after complete surgical tumor resection (R0). However, the prognostic value of immunohistochemically identifiable disseminated tumor cells in lymph nodes without histopathological tumor burden in patients with gastric cancer is still controversially discussed. The aim of the study was to assess the frequency and prognostic impact of minimal tumor cell spread to lymph nodes in these patients.
One hundred sixty lymph nodes judged as "tumor free" on routine histopathology obtained from 58 patients with gastric adenocarcinoma were analyzed immunohistochemically using the monoclonal anti-EpCAM antibody Ber-EP4 for occult disseminated tumor cells.
Tumor cells in lymph nodes were detected in 62 (38.8%) of the 160 "tumor-free" lymph nodes obtained from 39 (67.2%) patients. Multivariate Cox regression analysis confirmed the presence of disseminated tumor cells in "tumor-free" lymph nodes as an independent prognostic factor for both a significantly reduced relapse-free survival (p = 0.008) and overall survival (p = 0.009).
The frequent occurrence and prognostic impact of minimal disseminated tumor cells in lymph nodes of patients with gastric carcinoma support the need for a refined staging system of excised lymph nodes, which should include immunohistochemical examination.
Langenbeck s Archives of Surgery 08/2008; 394(1):105-13. DOI:10.1007/s00423-008-0369-4 · 2.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The increasing use of primary tumors as surrogate markers for prognosis and therapeutic decisions neglects evolutionary aspects of cancer progression. To address this problem, we studied the precursor cells of metastases directly for the identification of prognostic and therapeutic markers and prospectively analyzed single disseminated cancer cells from lymph nodes and bone marrow of 107 consecutive esophageal cancer patients. Whole-genome screening revealed that primary tumors and lymphatically and hematogenously disseminated cancer cells diverged for most genetic aberrations. However, we identified chromosome 17q12-21, the region comprising HER2, as the most frequent gain in disseminated tumor cells that were isolated from both ectopic sites. Survival analysis demonstrated that HER2 gain in a single disseminated tumor cell but not in primary tumors conferred high risk for early death.
Cancer cell 06/2008; 13(5):441-53. DOI:10.1016/j.ccr.2008.04.005 · 23.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Occurrence of tumor relapse is frequent in patients with pancreatic cancer despite the absence of residual tumor detectable at primary surgery and in histopathological examination. Therefore, it has to be assumed that current tumor staging procedures fail to identify minimal amounts of disseminated tumor cells, which might be precursors of subsequent metastatic relapse. The aim of this study was to assess the prognostic impact of minimal tumor cell spread detected in lymph nodes classified as "tumor-free" in routine histopathologic evaluation.
A total of 154 "tumor-free" lymph nodes from 59 patients with pancreatic cancer who underwent intentionally curative tumor resection were examined by immunohistochemistry for disseminated tumor cells.
Fifty (32.5%) of the "tumor-free" lymph nodes obtained from 36 (61%) patients displayed disseminated tumor cells. Multivariate survival analysis revealed that the presence of disseminated tumor cells in "tumor-free" lymph nodes is an independent prognostic factor for both a significantly reduced relapse-free survival (p = 0.03) and overall survival (p = 0.02).
The frequent occurrence and prognostic impact of immunohistochemically identifiable disseminated tumor cells in lymph nodes of patients with operable pancreatic cancer supports the need for a refined staging system of excised lymph nodes, which should include immunohistochemical examination.
Langenbeck s Archives of Surgery 06/2008; 393(3):359-65. DOI:10.1007/s00423-007-0215-0 · 2.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To prospectively evaluate the effectiveness of portal vein embolization (PVE) and CD133(+) bone marrow stem cell (BMSC) administration to the liver, compared with PVE alone, to augment hepatic regeneration in patients with large hepatic malignancies.
The study was approved by the institutional ethics committee; informed consent was obtained. Thirteen patients underwent PVE of liver segments I and IV-VIII to stimulate hepatic regeneration prior to extended right hepatectomy. In six patients (three men, three women; mean age, 61 years; range, 46-72 years) with a future liver remnant volume (FLRV) below 25% and/or limited quality of hepatic parenchyma, PVE alone did not promise adequate proliferation. These patients underwent BMSC administration to segments II and III (group I). In seven patients (three men, four women; mean age, 69 years; range, 63-75 years) with an FLRV below 25%, PVE alone was performed (group II). Two radiologists blinded to patients' identity and each other's results measured liver and tumor volumes with helical computed tomography. Absolute, relative, and daily FLRV gains were compared by using the t test or the Wilcoxon test.
The increase of the mean absolute FLRV in group I from 239.3 mL +/- 103.5 (standard deviation) to 417.1 mL +/- 150.4 was significantly higher than that from 286.3 mL +/- 77.1 to 395.9 mL +/- 94.1 in group II (P = .049). The relative gain of FLRV after PVE in group I (77.3% +/- 38.2) was significantly higher than that in group II (39.1% +/- 20.4) (P = .039). The daily hepatic growth rate in group I (9.5 mL/d +/- 4.3) was significantly superior to that in group II (4.1 mL/d +/- 1.9) (P = .03). Time to surgery was 27 days +/- 11 in group I and 45 days +/- 21 in group II (P = .057).
In patients with malignant liver lesions, the combination of PVE with CD133(+) BMSC administration substantially increased hepatic regeneration compared with PVE alone.
[Show abstract][Hide abstract] ABSTRACT: Pancreatic cancer is the fourth most common cause of death in malignancies with an incidence of 8-12 cases per 100000 in western world. In spite of numerous modifications in therapeutical approaches, prognosis has not improved.
In the last few years numerous studies have been performed to reduce tumor mortality with more radical surgical procedures. Several articles of the last 15 years have been investigated to objectivate the benefit of extended lymphadenectomy in pancreatic surgery. Staging of the cancers, prognostic factors, technique and interpretation of lymphadenectomy have been analysed
All studies document a lowered perioperative mortality in pancreatic resections. The procedure is counted as a standardized and safe one. However, several controversies exist. The distinct staging systems in Japan and the western world aggravate the comparison in all studies. Japanese authors in mostly retrospective analyses seem to document a survival benefit by radical surgery. Similar results could not be achieved by western authors.
Over all, a significant benefit in extreme radical surgery could not bee found. However, there are indications of subgroups of patients in whom extended lymphadenectomy might be beneficial. This subgroup should be defined only by large multicentric, prospective, randomized studies.
European journal of medical research 03/2007; 12(2):47-53. · 1.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This is a report about a patient who had a complete remission of a metastatic pancreatic adenocarcinoma after a modified G-FLIP therapy administered in an outpatient setting. The patient underwent surgery and the complete remission could be proven histologically. The administered chemotherapy was very effective and is even more attractive since it could be administered without admission to hospital.
[Show abstract][Hide abstract] ABSTRACT: Patients with pulmonary metastatic soft tissue sarcoma benefit from resection, with long-term cure possible.
Retrospective medical records review.
Academic tertiary care center.
Between January 1, 1991, and December 31, 2002, 61 patients (33 men and 28 women; median age at initial diagnosis, 42 years [age range, 18-74 years]) were surgically treated for pulmonary metastases of soft tissue sarcoma at University Hospital, Hamburg-Eppendorf, Germany.
Sternotomy or anterior lateral thoracotomy was performed for metastasectomy, including wedge resection or lobectomy.
The effects of clinical and pathologic factors on disease-specific survival were analyzed using the log rank test and a multivariate Cox proportional hazards model.
Primary tumor size was pT1 in 13 patients and pT2 in 48 patients. The differentiation was high in 7 patients, intermediate in 19 patients, and low in 35 patients. The mean number of resected pulmonary metastatic lesions was 5 (range, 1-48). An anterolateral thoracotomy was performed in 39 patients, and sternotomy in 22 patients. There were no significant postoperative complications that required surgical revision. The perioperative mortality was 0%. At a mean follow-up of 60 months, the mean survival time after metastasectomy was 33 months (range, 2-125 months). The 5-year survival was 25%. The number of resected lung metastatic lesions had no prognostic relevance (P = .37).
Patients with lung metastasis from soft tissue sarcomas benefit from surgical excision. This treatment has low complication rates and has a favorable influence on the course of the disease. Long-term survival is possible even when recurrent pulmonary disease is resected.
Archives of Surgery 02/2007; 142(1):70-5; discission 76. DOI:10.1001/archsurg.142.1.70 · 4.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Occurrence of tumor relapse is frequent in patients with carcinoma of the papilla of Vater despite the absence of residual tumor detectable at primary surgery. Therefore it has to be assumed that current tumor staging procedures fail to identify minimal amounts of tumor cells disseminated to secondary organs, which might be precursors of subsequent metastatic relapse. The aim of the study was to assess the frequency and prognostic impact of minimal tumor cell spread in lymph nodes classified as 'tumor-free' in routine histopathologic evaluation.
A total of 41 'tumor-free' lymph nodes from 23 patients with adenocarcinoma of the papilla of Vater who underwent curative tumor resection (R0) were examined by immunohistochemistry with the monoclonal anti-EpCAM antibody Ber-EP4 for minimal disseminated tumor cells.
Twelve (29.3%) of the 41 'tumor-free' lymph nodes obtained from 9 (39.1%) of the 23 patients displayed EpCAM-positive cells. Kaplan-Meier survival analysis revealed that patients with EpCAM-positive cells in lymph showed a clearly reduced relapse-free and overall survival compared with patients without such cells. However, these differences were not statistically significant (p = 0.13 for relapse-free survival, p = 0.11 for overall survival).
Immunohistochemical assessment may refine the staging of resected lymph nodes in patients with carcinoma of the papilla of Vater. However, the presence of minimal disseminated tumor cells in lymph nodes had no significant impact on the prognosis in these patients.
[Show abstract][Hide abstract] ABSTRACT: The prognostic relevance of disseminated nodal tumor cells has been demonstrated by several groups. However, their biological behaviour still remains unclear. The aim of the study. Analyse the phenotypic characteristics of disseminated tumor cells in lymph nodes. Material and methods. We established an immuno-enzymatic immuno-gold double-staining technique to simultaneously identify an epithelial antigen as well as the co-expression of plakoglobin, HLA class-I, ICAM-I and Ki-67 on isolated tumor cells. Epithelial cells were marked by the monoclonal antibody Ber-EP4. These results were compared with the corresponding primary tumors. Results. Loss of HLA elass-I expression on Ber-EP4+ cells was observed in 33.3% of the patients. ICAM-I neo-expression was detected in 46%, whereas 54% of the cases were ICAM-1 negative. Plakoglobin was expressed in 16% while Ki-67 was detectable only in 5% of the patients. Comparison with the corresponding primary tumors revealed phenotypic alterations of the disseminated cells. In 20% of the cases HLA class-I down-regulation was found, while in 38% plakoglobin was not detectable. In contrast to the primary tumors with a proliferation index of 39%, the nodal Ber-EP4+ cells appeared to be Ki-67 negative in 95% of the patients. Conclusions. Our phenotypic analysis demonstrates that Ber-EP4+ cells in lymph nodes not only display characteristics typical of malignant cells but also phenotypic alterations, in comparison with primary tumors. This is indicative of a selective process which might result in adapted metastatic phenotypes.
Polish Journal of Surgery 01/2007; 79(3):173-181. DOI:10.2478/v10035-007-0027-5
[Show abstract][Hide abstract] ABSTRACT: Organ-confined oesophageal cancer in an early stage can be cured in many patients, whereas more extensive lesions have a poor prognosis. We sought to develop a non-invasive test for cancer detection and evaluation of the prognosis of the patients by using a novel molecular approach.
Matched normal-, tumour- and serum-samples were obtained from 32 patients with adenocarcinoma of the oesophagus. DNA was extracted and the samples were subjected to microsatellite analysis using 12 markers. Serum and normal samples from 10 healthy individuals served as controls.
Twenty-seven of the 32 patients (84.4%) with malignant tumours were found to have one or more microsatellite DNA alterations in their primary tumour. Twenty-six of the 32 patients (81.3%) had alterations in the serum by microsatellite analysis. Interestingly, all patients without lymphatic metastasis and three early carcinomas (pT1pN0) already displayed LOH alteration in the serum, while all serum DNA of samples from normal control subjects were negative. Survival was not significantly correlated with either LOH in the tumour or LOH in the serum.
These data suggest that microsatellite DNA analysis in serum specimens might provide a potentially valuable tool for early detection of oesophageal cancer. The evidence of circulating tumour DNA reflects the propensity of these tumours to spread to distant sites. Up to now the follow-up is still too short to draw further conclusions on the prognostic impact of this finding.
European Journal of Surgical Oncology 12/2006; 32(9):954-60. DOI:10.1016/j.ejso.2006.02.015 · 3.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Transcriptional modification by alternative splicing is known to be involved in the regulation of programmed cell death. Recently, alternative splice variants of the TNF-related apoptosis inducing ligand (TRAIL/APO2L) and of the death receptor TRAIL-R2/DR5 have been identified. In this study, we report the identification of a novel alternative splice variant of the decoy receptor with a truncated death domain TRAIL-R4 lacking exon 3, which we designated TRAIL-R4-beta. As revealed by BLAST search we identified the genomic organisation of the TRAIL-R4 gene which consists of 9 exons. Loss of exon 3 resulted in the truncation of the first complete cysteine rich domain 1 which is known to be involved in ligand-receptor-complex. In conclusion, alternative splicing might be involved in functional fine-tuning of TRAIL-induced programmed cell death.
Biochemical and Biophysical Research Communications 11/2006; 349(1):115-21. DOI:10.1016/j.bbrc.2006.08.031 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A substantial proportion of patients (40% to 50%) with supposedly localized esophageal cancer who had undergone curative surgical
treatment with complete tumour removal suffer from a metastatic tumour relapse within 24 months after surgery. A reason for
such an early tumour relapse in these patients might be a minimal tumour cell dissemination (minimal residual disease, MRD)
present at the time of operation, which cannot be detected by clinical and routine histopathological tumour staging procedures.
Over the past 10 years, more sensitive immunohisto-/-cytochemical and nucleic acid based assays have been developed that are
based on the detection of epithelial cell-or tumour-associated marker proteins and are able to detect single tumour cells
or small tumour cell clusters present in lymph nodes classified as tumour-free by conventional histopathologic analysis, bone
marrow or blood. Here we present an overview of recent studies concerning the prevalence and prognostic value of occult tumour
cells in lymph nodes and bone marrow of patients with esophageal cancer identified by antibody or nucleic acid based assays.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the expression and test the clinical significance of the epithelial cellular adhesion molecule (Ep-CAM) in esophageal squamous cell carcinoma (SCC) to check the suitability of esophageal SCC patients for Ep-CAM directed targeted therapies.
The Ep-CAM expression was immunohistochemically investigated in 70 primary esophageal SCCs using the monoclonal antibody Ber-EP4. For the interpretation of the staining results, we used a standardized scoring system ranging from 0 to 3+. The survival analysis was calculated from 53 patients without distant metastasis, with R0 resection and at least 2 months of clinical follow-up.
Ep-CAM neo-expression was observed in 79% of the tumors with three expression levels, 1+ (26%), 2+ (11%) and 3+ (41%). Heterogeneous expression was observed at all expression levels. Interestingly, tumors with 3+ Ep-CAM expression conferred a significantly decreased median relapse-free survival period (log rank, p = 0.0001) and median overall survival (log rank, p = 0.0003). Multivariate survival analysis disclosed Ep-CAM 3+ expression as independent prognostic factor.
Our results suggest Ep-CAM as an attractive molecule for targeted therapy in esophageal SCC. Considering the discontenting results of the current adjuvant concepts for esophageal SCC patients, Ep-CAM might provide a promising target for an adjuvant immunotherapeutic intervention.
BMC Cancer 02/2006; 6(1):165. DOI:10.1186/1471-2407-6-165 · 3.36 Impact Factor