Gilbert Mühlmann

Prostate-specific membrane antigen expression in the neovasculature of gastric and colorectal cancers

Prostate-specific membrane antigen (PSMA), a type II transmembrane metallo-peptidase highly overexpressed in prostate cancer cells, has been studied as a targeting molecule in prostate cancer. Recently, PSMA has also been found to be expressed in the neovasculature of multiple nonprostatic solid tumors. Because of its unique expression pattern limited to tumor-associated endothelial cells, PSMA may also be an interesting molecule for vascular targeting. In this study, PSMA expression was determined by immunohistochemistry in 119 cases of primary gastric adenocarcinoma, 130 cases of primary colorectal adenocarcinoma, and 24 metastasis of colorectal adenocarcinoma. Expression data were correlated with clinicopathologic information. PSMA expression was detected in tumor-associated neovasculature of 79 (66%) of 119 gastric and 110 (85%) of 130 colorectal carcinomas. Furthermore, the neovasculatures of 16 (84%) of 19 liver and 4 (80%) of 5 nodal metastases from colorectal carcinomas were prostate-specific membrane antigen positive. There was a trend for high-grade tumors to higher PSMA expression (Spearman r = 0.18, P = .046) in colorectal cancers. No association between PSMA expression and overall- or disease-free survival was observed in gastric or colorectal cancers. This study provides the first in-depth look at PSMA expression in gastric and colorectal cancer. Because of its highly tumor-restricted expression and its accessibility to targeted therapy, PSMA represents a promising therapeutic and diagnostic target in colorectal and gastric cancer.

GALLSTONE ILEUS: RARE AND STILL CONTROVERSIAL

Background:  Gallstone ileus is a rare disease and accounts for about 1−3% of mechanic ileus of the small bowel, but for 25% of all small bowel obstructions in patients older than 65 years. Concomitant cardiorespiratory diseases or diabetes are frequent in older patients and responsible for the high mortality rate. The aim of the present study was to evaluate and discuss different surgical approaches and to analyze the clinical outcome.

TROP2 expression as prognostic marker for gastric carcinoma

Background: In gastric cancer the recurrence rate is unacceptably high, even after R0 resection and (neo)adjuvant chemotherapy. Therefore, there is an urgent need for identification of predictive and/or prognostic biomarkers to select high-risk patients who might benefit from additional therapies. Expression of TROP2 has been shown to be associated with tumour aggressiveness and poor prognosis in patients with various epithelial cancers. Aims: To investigate TROP2 expression in gastric cancer and its correlation with clinicopathological features and disease outcome. Methods: Expression of TROP2 was investigated by immunohistochemistry of tumour specimens from 104 patients who underwent resection for gastric cancer. Parameters found to be of prognostic significance in univariate analysis were verified in a multivariate Cox regression model. Results: TROP2 was found to be overexpressed in 58 (56%) tumour samples. Significantly higher expression of TROP2 could be detected in intestinal-type carcinomas (p = 0.03). In intestinal-type gastric cancer, TROP2 overexpression was significantly correlated with shorter disease-free survival (DFS) (p = 0.03). Among the total group, TROP2 overexpression was predictive for poor disease-free (p<0.01) and overall (p = 0.03) survival in lymph node positive patients. Multivariate Cox regression analysis revealed TROP2 overexpression to be an independent prognostic marker for poor DFS in the subgroup of patients with intestinal-type gastric cancer irrespective of lymph node involvement. Conclusion: Results show that TROP2 is an independent prognostic marker for disease recurrence in intestinal type gastric cancer. Due to its wide distribution TROP2 may become an attractive therapeutic target in a subgroup of patients with gastric cancer.

SFRP2 methylation in fecal DNA—a marker for colorectal polyps

IntroductionDNA methylation of secreted frizzled-related proteins (SFRPs) can be detected in colorectal cancer (CRC) tissue, in tissue of adenomas, and in aberrant crypt foci, whereas in normal colorectal mucosa tissue, SFRP genes are unmethylated. Recently, our study group was able to demonstrate SFRP2 methylation as the most sensitive single DNA-based marker in stool for identification of CRC. The purpose of this study was to clarify whether SFRP2 methylation in fecal DNA can be found in stool of individuals with hyperplastic and adenomatous colorectal polyps.Materials and methodsPatients who were diagnosed with colorectal polyps or showed negative colonoscopy were included in this study. DNA from stool samples was isolated. SFRP2 methylation was assessed by means of MethyLight.ResultsStool samples from 68 individuals were checked for DNA content; 23% of the samples (6 of 26) from healthy controls, 46% of the samples (6 of 13) from patients with hyperplastic polyps, and 45% of the samples (13 of 29) from patients with adenomas were positive for human DNA. SFRP2 methylation in stool samples was found in none of the healthy controls, in 33% (2 of 6) patients with hyperplastic polyps, and in 46% (6 of 13) patients with adenomas. Statistical analysis revealed that the frequency of SFRP2 methylation increased significantly (P = 0.028) from healthy controls to patients with hyperplastic polyps and to patients with adenomas.ConclusionsIn the current study, we report for the first time that SFRP2 methylation in fecal DNA increases significantly from healthy controls to patients with hyperplastic polyps and to patients with adenomas. SFRP2 methylation may serve as a marker for molecular stool-based adenoma and CRC screening.

DaVinci® Robotic-Assisted Laparoscopic Bariatric Surgery: Is it Justified in a Routine Setting?

Background: Laparoscopic silicone adjustable gastric banding (SAGB) has gained popularity for the surgical treatment of morbid obesity. The implantable gastric stimulator (IGS®) system represents a novel surgical alternative. We aimed to assess the feasibility of robotic-assisted laparoscopic bariatric operations and to critically elucidate the technical and financial advantages and patient outcome. Methods: Robotic-assisted laparoscopic bariatric procedures were performed on 10 consecutive patients using the daVinci® robot system (4 SAGB, 4 IGS®, 2 SAGB revisions). 10 conventional laparoscopic-operated patients (4 SAGB, 4 IGS®, 2 SAGB revisions) during the learning curve served as controls. Equipment, operative technique and procedural time were evaluated. A cost analysis was calculated. Results: The personnel equipment, numbers of trocars and operation technique were comparable in both groups. The mean operative time was 137 min (range 110-175) and 97 min (60-140) in robotic-assisted and conventional laparoscopy, respectively (P =0.04). Establishment of the pneumoperitoneum and placement of trocars and robotic arms took a mean of 30 min (15-45) in the robotic-assisted group, compared with 5 min in the control group (P <0.001). In 1 patient, intraoperative gastric injury was suspected and led to band removal in the robotic-assisted group. There was no postoperative complication. Average procedural costs were significantly higher in the robotic-assisted group. Conclusion: Primary and revisional robotic-assisted bariatric surgery is technically simple, with the benefit of precise instrument handling. However, it is still expensive, the set-up of the system is time-consuming, and a limited variety of instruments are available presently.

Dickkopf-3 As a New Potential Marker for Neoangiogenesis in Colorectal Cancer: Expression in Cancer Tissue and Adjacent Non-Cancerous Tissue

Gene expression of Dickkopf-3 (Dkk-3) has been shown to be upregulated in tumor endothelium of colorectal cancer (CRC). For the first time, we analyzed Dkk-3 protein expression in CRC and its potential as a marker for neoangiogenesis. We used tissue microarrays (TMAs) to investigate Dkk-3 in microvessels of 403 CRC samples, 318 appropriate adjacent non-cancerous samples and 127 normal colorectal samples. Of cancer samples with CD31-positive microvessels, 67.7% were positive for Dkk-3. Dkk-3 staining was demonstrated in endothelial cells of all microvessels in nearly all cases. Dkk-3-positive samples showed a higher mean microvessel count than did Dkk-3-negative samples (P=0.001). Dkk-3 expression increased with rising numbers of microvessels per sample (P<0.0001). In adjacent samples with CD31-positive microvessels, 56% were Dkk-3-positive in all microvessels. Similar to cancer samples, Dkk-3-positive adjacent samples had a higher mean microvessel count than did Dkk-3-negative samples (P<0.0001), and Dkk-3 expression also increased with rising numbers of microvessels (P<0.0001). All microvessels in normal mucosa samples were negative for Dkk-3. Dkk-3 can be considered a putative pro-angiogenic protein in neovascularization and may possibly be a marker for neoangiogenesis in CRC. Further investigations will elucidate whether Dkk-3 is a target structure for novel therapies.

Immunohistochemically detectable dickkopf-3 expression in tumor vessels predicts survival in gastric cancer

Dickkopf-3 (Dkk-3) may act as a tumor suppressor as it is downregulated in various types of cancer. Moreover, a putative role in tumor neovascularization is discussed. Here, we investigated the expression of Dkk-3 protein in gastric cancer and its potential value as a prognostic marker. Dkk-3 expression was analyzed by immunohistochemistry in 136 tumor samples and was correlated with microvessel density (MVD), tumor stage, and grading as well as the clinical outcome of the patients. Dkk-3 expression was detected in endothelial cells of the tumor vessels in 129/136 (94.9%) and in tumor cells in 85/136 (62.5%) samples. MVD was high and low in 57 (42.9%) and 76 (57.1%) specimens respectively. In tumor cells, overexpression of Dkk-3 was found in 41 (30.1%) of all cases and was correlated significantly to pT-stage (p < 0.05) and UICC stage (p < 0.05). Survival analysis regarding Dkk-3 expression in tumor endothelial cells showed that Dkk-3 is an independent predictor of disease-free survival (p < 0.05). Dkk-3 expression in tumor vessels of patients with gastric cancer identifies a population of patients with relatively favorable prognosis.

Adjustable Gastric Banding: Assessment of Safety and Efficacy of Bolus-Filling during Follow-Up

Background: Individual band-filling on demand of the morbidly obese patient is a major advantage of adjustable gastric banding. An increasing number of patients results in an enormous amount of outpatient follow-up visits, which inspired us to compare a stepwise band-filling strategy with a single bolus injection 4 weeks after the operative procedure. Methods: 40 consecutive patients were prospectively randomized in 2 groups. 20 patients (Group A) had stepwise band-filling during 6 monthly ambulant visits. 20 patients (Group B) had a bolus-filling 4 weeks postoperatively and had the next follow-up after another 5 months. Weight loss, complications and procedural costs during follow-up were compared. Results: Patients of both groups did not differ in age, gender or preoperative BMI.There was no significant difference postoperatively in excess weight lost (EWL) after 9 months. Postoperative complications did not differ significantly.By means of bolus-filling, a 60% and 53% reduction in outpatient clinical work was achieved within the 6 and 9 months, respectively. Conclusion: Postoperative management after gastric banding takes advantage of a single bolus-filling during the first postoperative 6 months due to sufficient weight loss, low complication rate but significant reduction of personal, financial and logistic efforts.

Selection of Patients with Gastroesophageal Reflux Disease for Antireflux Surgery Based on Esophageal Manometry

Gastroesophageal reflux disease (GERD) is caused by a mechanically defective lower esophageal sphincter (LES) and may be worsened by impaired esophageal peristalsis. The aim of this study was to evaluate the efficacy of medical treatment depending on the function of the LES and esophageal peristalsis. We studied 128 GERD patients with mild esophagitis. Group 1 (N = 26) consisted of patients with a normal LES and normal esophageal peristalsis. Group 2 (N = 63) comprised patients with a defective LES but normal peristalsis. Patients of group 3 (N = 39) had a defective LES as well as impaired esophageal peristalsis. The patients were continuously treated with omeprazole. Clinical evaluation and endoscopy were repeated after 3, 6, and 12 months. Recurrence of GERD was diagnosed if there was relapse of heartburn and/or esophagitis. The recurrence rate was 7.7% in group 1, 38.1% in group 2 (P < 0.05) and 79.5% in group 3 (P < 0.05). In conclusion, in GERD patients with a mechanically defective LES, especially in those with deteriorated esophageal peristalsis, antireflux surgery should be considered since medical therapy reveals a high recurrence rate.

14-3-3 Sigma And p53 Expression in Gastric Cancer and Its Clinical Applications

14-3-3 sigma (σ) induces G2 arrest enabling the repair of damaged DNA. The function of 14-3-3 σ is frequently lost in tumor cells, indicating a potential tumor suppressor function. The purpose of this study was to evaluate the prognostic value of 14-3-3 σ expression in human gastric cancer. 14-3-3 σ expression was analyzed by immunohistochemistry in 157 tumor samples of patients, who underwent resection for gastric cancer. Since 14-3-3 σ is involved in the p53 network, p53 expression was detected in parallel and correlated with 14-3-3 σ. 14-3-3 σ was found to be overexpressed in 75 (47.8%) of 157 cases, the overexpression rate of p53 protein was 27.4%. 14-3-3 σ overexpression was statistically significantly associated with pT-stage (p=0.041) pN-stage (p=0.015) and UICC-stage (p=0.019) and showed a borderline significance with Lauren classification (p=0.057). Univariate survival calculations revealed a coexistent 14-3-3 σ and p53 overexpression as a significant predictor of disease-free survival. Multivariate analysis did not unfold 14-3-3 as an independent prognostic factor for disease-free survival and overall survival. Concomitant 14-3-3 σ and p53 overexpression in tumor cells of patients with gastric cancer identifies a population of patients with relatively unfavorable prognosis.