Klaus L. Prenzel

Long-term results and gastroesophageal reflux in a series of laparoscopic adjustable gastric banding

During the past decade, laparoscopic adjustable gastric banding has become the most popular surgical procedure in treating morbid obesity. On the other hand, significant drawbacks such as inadequate longterm weight loss, a high prevalence of reoperations, and frequent postoperative symptoms have been reported in the literature. This analysis summarizes our Department’s experience with this operation. Thirty-one patients (27 women and 4 men) with a mean body mass index of 46.5 kg/m2 (range, 38.3-59.8 kg/m2) were operated upon laparoscopically between September 1997 and January 2003. The preoperative work-up of all patients included a psychological evaluation. Mean follow-up was 59.3 months (range, 19–84 months). Sixteen patients had esophageal pH-metry and 18 patients had upper gastrointestinal endoscopy preoperatively and postoperatively. Data were collected prospectively during the outpatient visits. Mean preoperative excess weight was 65.6 kg (range, 37.4-96.1 kg). Mean excess weight loss after 12, 24, 36, 48, 60, 72, and 84 months was 40.3%, 50.5%, 51.9%, 48.9%, 46.2%, 51.8%, and 30.2%, respectively. In total, six patients (19.4%) had an abdominal reoperation, including four patients (12.9%) for band removal. Upper gastrointestinal endoscopy was performed in 18 patients after 30.1 months (range, 5–67 months), showing a high prevalence of esophagitis (30.0%; grade 1: n = 3, grade 2: n = 3). Conversely, postoperative esophageal pH-metry performed in 16 patients was pathologic in 43.8%. Laparoscopic adjustable gastric banding produces significant weight loss even after long-term follow-up. However, the reoperation rate is high and postoperative symptoms are frequent. The high incidence of gastroesophageal reflux and esophagitis remains a matter of concern.

Inhibition of Oesophageal Squamous Cell Carcinoma Progression by in vivo Targeting of Hyaluronan Synthesis

BackgroundOesophageal cancer is a highly aggressive tumour entity with at present poor prognosis. Therefore, novel treatment options are urgently needed. Hyaluronan (HA) is a polysaccharide present in the matrix of human oesophageal squamous cell carcinoma (ESCC). Importantly, in vitro ESCC cells critically depend on HA synthesis to maintain the proliferative phenotype. The aim of the present study is (1) to study HA-synthase (HAS) expression and regulation in human ESCC, and (2) to translate the in vitro results into a mouse xenograft model of human ESCC to study the effects of systemic versus tumour targeted HAS inhibition on proliferation and distribution of tumour-bound and stromal hyaluronan.MethodsmRNA expression was investigated in human ESCC biopsies by semiquantitative real-time RT PCR. Furthermore, human ESCC were xenografted into NMRI nu/nu mice. The effects on tumour progression and morphology of 4-methylumbelliferone (4-MU), an inhibitor of HA-synthesis, and of lentiviral knock down of HA-synthase 3 (HAS3), the main HAS isoform in the human ESCC tissues and the human ESCC cell line used in this study, were determined. Tumour progression was monitored by calliper measurements and by flat-panel detector volume computed tomography (fpVCT). HA content, cellular composition and proliferation (Ki67) were determined histologically.ResultsmRNA of HAS isoform 3 (HAS3) was upregulated in human ESCC biopsies and HAS3 mRNA was positively correlated to expression of the epidermal growth factor (EGF) receptor. EGF was also proven to be a strong inductor of HAS3 mRNA expression in vitro. During the course of seven weeks, 4-MU inhibited progression of xenograft tumours. Interestingly, remodelling of the tumour into a more differentiated phenotype and inhibition of cell proliferation were observed. Lentiviral knockdown of HAS3 in human ESCC cells prior to xenografting mimicked all effects of 4-MU treatment suggesting that hyaluronan produced by ESCC is accountable for major changes in tumour environment in vivo.ConclusionsSystemic inhibition of HA-synthesis and knockdown of tumour cell HAS3 cause decreased ESCC progression accompanied by tumour stroma remodelling and may therefore be used in novel approaches to ESCC therapy.

Prognostic Relevance of Skip Metastases in Esophageal Cancer

BACKGROUND Presence of nodal skip metastasis is an established prognostic factor for patients with non-small cell lung cancer. Little is known about this form of lymphatic spread in esophageal cancer. The aim of this study was to assess nodal skip metastasis and its clinical importance for patients with cancer of the esophagus. METHODS Resected lymph nodes of 128 patients with esophageal cancer and pN1 status (adenocarcinoma, n = 67; squamous cell cancer, n = 61) were mapped according to the Japanese lymph-node classification for esophageal cancer. Skip metastases were defined as tumor-free N1 lymph nodes, whereas N2 through N4 lymph nodes harbor metastases. RESULTS Skip metastases were present in 26 of 128 (20%) patients. There was a higher rate of skip metastasis in early tumors (39% versus 23% versus 14% for T1, T2, and T3 tumors; p = 0.032) and tumors in the middle and upper third of the esophagus (37% versus 15% for upper- and middle-third and lower-third tumors; p = 0.022). Patients with skip metastasis had a significantly better 5-year survival rate than patients with continuous metastasis (53% versus 15%; p < 0.0001). Multivariate analysis revealed skip metastasis as an independent prognostic factor. CONCLUSIONS Skip metastasis is a common form of lymphatic spread in esophageal cancer, which is associated with a favorable prognosis.

Variable 18F-fluorodeoxyglucose uptake in gastric cancer is associated with different levels of GLUT-1 expression.

ObjectivesDetection rates of gastric cancer in 18F-fluorodeoxyglucose (FDG)-PET depend on the histopathological characteristics of the primary tumor. To clarify this observation, FDG uptake in gastric carcinoma was analyzed by focusing on histopathology and on the expression of the glucose transporter (GLUT-1) in the primary tumor. MethodsThirty-five patients with the diagnosis of gastric cancer underwent FDG-PET with visual image analysis and measurement of maximum standardized uptake value (SUVmax) before surgical treatment. Resected tumor samples were categorized according to Union internationale contre le cancer, WHO, and Laurén classification and tumor differentiation. GLUT-1 expression was graded semiquantitatively by immunohistochemistry. Statistical analysis was done for the correlation of histology, different classifications, and tumor grading with SUVmax and GLUT-1 expression. ResultsSUVmax significantly correlated with histopathological classifications according to the WHO (P=0.009) and Laurén classification (P=0.034). Signet-ring cell carcinoma had a median SUVmax of only 3.0 (range, 1.0–11.5). Median SUVmax for papillary and tubular carcinoma was 7.8 (range, 1.8–14.4). In 21 (60%) cases, GLUT-1 expression in the primary tumor was positive. GLUT-1 expression correlated significantly with tumor differentiation (P=0.018) and the classification according to Laurén (P=0.023) and WHO (P<0.001). Thirteen (76%) of 17 signet-ring cell carcinoma cases did not show any GLUT-1 expression. SUVmax in relation to GLUT-1 expression showed a significant correlation (P=0.002). For cases with detectable GLUT-1 expression the median SUVmax was 6.9 (range, 2.3–14.1) versus a median of 3.1 (range, 1–8.8) for cases without GLUT-1 expression. ConclusionFDG uptake in gastric cancer depends on GLUT-1 expression. One major reason for low FDG uptake in signet-ring cell carcinoma is the low GLUT-1 expression in this histological subtype of gastric cancer.

Reduced Incidence of Nodal Micrometastasis after Major Response to Neoadjuvant Chemoradiation in Locally Advanced Esophageal Cancer

BackgroundNeoadjuvant treatment modalities for esophageal cancer were developed to improve local tumor control as well as to reduce lymph node metastases and distant metastases in patients with locally advanced esophageal cancer. The influence on nodal micrometastasis has not yet been evaluated.MethodsThis study includes 52 patients with localized (cT2-4, Nx, M0) esophageal cancers (21 adenocarcinomas, 31 squamous cell cancers) who received neoadjuvant chemoradiation (36Gy, 5-FU, cisplatin) followed by transthoracic en bloc esophagectomy with two field lymphadenectomy. The extent of histomorphologic regression was categorized into major (< 10%) and minor response (>10% vital residual tumor cells) as recently reported. A total of 1186 lymph nodes were diagnosed as negative for metastases by routine histopathological analysis and were further examined for the presence of isolated tumor cells with the monoclonal anti-epithelial antibody AE1/AE3.ResultsTwenty-two tumors (42.3%) showed a major histopathologic response whereas in 30 tumors (57.7%) only a minor response was present.Of 32 patients with a pN0 category, major response was present in 19 (59.4%) tumors, whereas 13 (40.6%) tumors showed minor response. Nine (69%) out of 13 patients with minor response had AE1/AE3-positive cells in their lymph nodes, whereas only four (21%) out of 19 pN0-patients with major response showed nodal micrometastasis (P = 0.013, χ2-test).ConclusionsIf tumors show a major histomorphologic response following neoadjuvant chemoradiation, the presence of nodal micrometastasis is significantly reduced compared to those with minor response.

High Expression of Heparanase is Significantly Associated with Dedifferentiation and Lymph Node Metastasis in Patients with Pancreatic Ductal Adenocarcinomas and Correlated to PDGFA and Via HIF1a to HB-EGF and bFGF

BackgroundPancreatic cancer still has one of the worst prognoses of all cancers with a 5-year survival rate of 5%, making it necessary to find markers or gene sets that would further classify patients into different risk categories and thus allow more individually adapted multimodality treatment regimens. Especially heparanase (HPSE) has recently been discussed as a key factor in pancreatic cancer.Materials and MethodsParaffin-embedded tissue samples were obtained from 41 patients with pancreatic adenocarcinoma who were scheduled for primary surgical resection. Direct quantitative real-time reverse transcriptase polymerase chain reaction (TaqMan™) assays were performed in triplicates to determine HPSE, hypoxia inducible factor-1 alpha (HIF1a), platelet-derived growth factor alpha (PDGFA), heparin-binding EGF-like growth factor (HB-EGF), and basic fibroblast growth factor (bFGF) gene expression levels.ResultsHPSE was significantly correlated to PDGFA (p = 0.04) and HIF1a (p = 0.04). The correlation of HIF1a to bFGF and HB-EGF was significant (p = 0.04, p = 0.02). Stepwise multiple linear regression models showed a significant independent association of HPSE with lymph node metastasis (p = 0.025) and with dedifferentiation (p = 0.042).ConclusionsHeparanase seems to be significantly associated with lymph node metastasis (p = 0.025) as well as dedifferentiation (p = 0.042). We assume that HPSE plays a crucial role for the aggressiveness of pancreatic cancer. Larger studies including more patients seem to be warranted.

Prognostic impact of nodal micrometastasis in early esophageal cancer.

INTRODUCTION Nodal micrometastasis is a negative prognosticator for esophageal cancer. There is a trend toward endoscopic resection for early cancer of the esophagus without lymphadenectomy. Frequency and prognostic impact of nodal micrometastasis in early cancer of the esophagus have not been investigated so far. PATIENTS AND METHODS This study includes 69 patients with a pT1-stage cancer of the esophagus (SCC: n = 26, AC: n = 43), who underwent transthoracic en-bloc esophagectomy with D2-lympadenectomy between 1996 and 2004. On routine histopathological analysis 48 patients were diagnosed as pN0. Lymph nodes (n = 1344) of these patients were further examined for the presence of isolated tumor cells with the monoclonal anti-epithelial antibody AE1/AE3. RESULTS In lymph nodes of 7 (14.6%) out of 48 pN0-patients a positive staining for AE1/AE3 as a sign for nodal micrometastasis was found. In these patients the tumor has infiltrated the submucosal layer. In patients with tumors restricted to mucosal layer (n = 20) no nodal micrometastasis was present. 5-year survival of pN0-patients with nodal micrometastasis was inferior compared to pN0-patients (57% vs. 82%; p = 0.002). CONCLUSION Almost 15% of patients with pT1 N0 M0 carcinoma of the esophagus and only those with submucosal infiltration show nodal micrometastasis. It has a significant negative impact on survival already in early esophageal cancer.

Preoperative survivin mRNA detection in peripheral blood is an independent predictor of outcome in esophageal carcinoma.

AIMS Survivin (SVV) mRNA expression levels in peripheral blood of patients with gastrointestinal malignancies change significantly during the course of treatment. We wanted to scrutinize these findings in patients with esophageal carcinoma and furthermore evaluate whether the detection of mRNA and the change in detecting ability have an association with overall survival. MATERIALS & METHODS Whole blood was drawn 1 day pre- and 10 days post-operatively from 62 patients with esophageal carcinoma. Tumor cells were enriched from whole blood by density-gradient centrifugation prior to extraction of total cellular RNA and subsequent direct quantitative reverse transcriptase-PCR assays. RESULTS SVV was detectable in 48 out of 62 patients (77%). Stepwise multivariate Cox linear regression models demonstrated a significant and independent association of measured SVV with overall survival (6.6 exp[b]; 95% CI: 1.97-22.12; p = 0.002). Increased SVV levels after the operation were linked to shorter overall survival (p = 0.04). CONCLUSION Preoperative SVV expression levels appear to be associated with overall survival in patients with esophageal cancers. Increasing levels could potentially indicate a higher risk for shorter overall survival and therefore demand adapted treatment modalities.

Expression and prognostic significance of HLA class I, ICAM-1, and tumor-infiltrating lymphocytes in esophageal cancer

Most solid malignancies show some degree of lymphoid infiltration suggesting a specific immunologic host vs. tumor reaction. Tumor-infiltrating lymphocytes (i.e., CD3+T-lymphocyte subsets), the human leukocyte antigen (HLA) class I molecules, and the intercellular adhesion molecule-1 (ICAM-1) are key factors involved in T-cell-mediated immune surveillance. The present study was designed to assess the expression pattern of intratumoral lymphocyte infiltrates and their relationship to HLA class I and ICAM-1 expression with regard to primary esophageal carcinoma and to evaluate their prognostic influence. Representative samples of primary tumors were obtained from 55 patients who had undergone radical en bloc esophagectomy. Frozen sections of these tumors were stained with monoclonal antibodies directed against CD3 for the assessment of tumor-infiltrating lymphocytes, HLA class I, and ICAM-1. The mean postoperative observation period was 19.5 months (range 5 to 45 months). Lymphocyte infiltration was absent in four tumors (8%), whereas 31 tumors (64%) showed moderate and 13 (27%) showed strong infiltration. HLA class I expression was deficient in 24 tumors (45%). Coexpression of HLA class I and ICAM-1 was significantly associated with lymphocyte infiltration of the tumor. Kaplan-Meier analyses revealed a significant beneficial influence on relapse-free survival for patients with lymphocyte infiltration of primary tumors compared to those with no lymphocyte infiltration of tumors (median 4 months vs. 18 months;P<0.002) and for HLA class I+ tumors compared to HLA class I− tumors (median survival >18 months vs. 7 months;P=0.0081). The present data support the hypothesis that T-cell-mediated immunity may influence the fate of patients with esophageal cancer.

Portal Vein Arterialization Increases Hepatocellular Apoptosis and Inhibits Liver Regeneration

BACKGROUND Portal vein arterialization is performed in particular situations to guarantee sufficient blood flow in the portal vein. In addition, some authors have postulated a proliferation-promoting influence of portal vein arterialization on the liver tissue. However, portal vein arterialization is an unphysiological procedure: It increases portal blood flow and blood pressure as well as oxygenation of the liver tissue. On the other hand, it reduces the influx of hepatotrophic factors from the portal venous blood. The aim of these experiments was to investigate apoptosis and proliferation of hepatocytes during various conditions of the portal perfusion. MATERIALS AND METHODS After 70% liver resection in Lewis rats, the following four experimental groups were formed differing in portal perfusion: (I) hyperperfused, nonarterialized; (II) flow-regulated, nonarterialized; (III) hyperperfused, arterialized; (IV) flow-regulated, arterialized. A warm ischemia of 30 min was kept in all groups. RESULTS Portal vein arterialization of 70% reduced rat livers significantly reduced liver regeneration as shown by a significant reduction in liver weight, body weight, and liver function after 6 wk, in contrast to the group with 70% liver mass reduction and portal venous inflow of the portal vein. Furthermore, we found a significantly elevated number of apoptotic hepatocytes after portal vein arterialization. These results were independent from blood flow regulation of the arterialized portal vein, which caused no improvement of the results. CONCLUSIONS Portal vein arterialization should be performed only temporarily and is clinically not recommended as a permanent option, because of the increased hepatocellular apoptosis and the very distinctive, negative long-term effects on liver weight.