Michael F. Nentwich

What Should Be the Gold Standard for the Surgical Component in the Treatment of Locally Advanced Esophageal Cancer Transthoracic Versus Transhiatal Esophagectomy

Objective:To analyze survival differences between transthoracic esophagectomy (TTE) and limited transhiatal esophagectomy (THE) in clinically (cT3) and pathologically (pT3) staged advanced tumors without neoadjuvant treatment. Background:Debate exists whether in the type of resection in locally advanced cancer plays a role in prognosis and whether THE is a valuable alternative to TTE regarding oncological doctrine and overall survival. Methods:In a retrospective study of 2 high-volume centers, 468 patients with cT3NXM0 esophageal cancer, including 242 (51.7%) squamous cell carcinomas (SCCs) and 226 (48.3%) adenocarcinomas (ACs), were analyzed. A total of 341 (72.9%) TTE and 127 (27.1%) THE were performed. We used the propensity score matching to build comparable groups. Primary endpoint was the overall survival; secondary endpoints included resection status and lymph node yield. Results:TTE achieved a higher rate of R0 resections (86.2% vs 73.2%; P = 0.001) and a higher median lymph node yield (27.0 ± 12.4 vs 17.0 ± 6.4; P < 0.001) than THE. Thirty-day mortality rate was 6.6% (8/121) for TTE and 7.4% (9/121) for THE (P = 0.600). In the matched groups, TTE was beneficial for pT3 SCC (P = 0.004), pT3 AC (P = 0.029), cT3 SCC (P = 0.018), and cT3 AC (P = 0.028) patients. TTE was either beneficial in pN2 disease for cT3 AC + SCC or pT3 SCC but not for pT3 AC patients, without nodal stratification in pT3 and cT3 SCC node-positive patients. On multivariable analysis, TTE remained an independent factor for survival. Conclusions:Extended TTE achieved a higher rate of R0 resections, a higher lymph node yield, and resulted in a prolonged survival than THE in pT3, cT3, and node-positive patients.

Human Prostate Cancer in a Clinically Relevant Xenograft Mouse Model: Identification of β(1,6)-Branched Oligosaccharides as a Marker of Tumor Progression

Purpose: To establish xenograft mouse models of metastatic and nonmetastatic human prostate cancer and to apply these models to the search for aberrant glycosylation patterns associated with tumor progression in vivo and in patients. Experimental Design: Prostate cancer cells (LNCaP, PC-3, LuCaP 23.1, and DU-145) were xenografted subcutaneously into immunodeficient pfp−/−/rag2−/− mice. Tumor growth and metastasis formation were quantified and as altered glycosylation patterns have been associated with metastasis formation in several other malignancies, prostate cancer cells were profiled by a quantitative real-time PCR (qRT-PCR) glycosylation array and compared with normal human prostate cells. The activity of upregulated glycosyltransferases was analyzed by their sugar residues end products using lectin histochemistry on primary tumors and metastases in the animal experiments and on 2,085 clinical samples. Results: PC-3 cells produced the largest number of spontaneous lung metastases, followed by LNCaP and LuCaP 23.1, whereas DU-145 was nonmetastatic. qRT-PCR revealed an upregulation of β1,6-N-acetylglucosaminyltransferase-5b (Mgat5b) in all prostate cancer cell lines. Mgat5b products [β(1,6)-branched oligosaccharides] were predominantly detectable in metastatic xenografts as shown by increased binding of Phaseolus vulgaris leukoagglutinin (PHA-L). The percentage of prostate cancer patients who were PHA-L positive was 86.5. PHA-L intensity correlated with serum prostate-specific antigen and a cytoplasmic staining negatively affected disease-free survival. Conclusion: We show a novel xenograft mouse model for human prostate cancer respecting the complete metastatic cascade. Specific glycosylation patterns reveal Mgat5b products as relevant markers of both metastatic competence in mice and disease-free survival in patients. This is the first description of Mgat5b in prostate cancer indicating a significant biologic importance of β(1,6)-branched oligosaccharides for prostate cancer progression. Clin Cancer Res; 18(5); 1364–73. ©2012 AACR.

Preoperative Pancreatic Resection (PREPARE) score: a prospective multicenter-based morbidity risk score.

Objectives:Development of a simple preoperative risk score to predict morbidity related to pancreatic surgery. Background:Pancreatic surgery is standardized with little technical diversity among institutions and unchanging morbidity and mortality rates in recent years. Preoperative identification of high-risk patients is potentially one of the rare avenues for improving the clinical course of patients undergoing pancreatic surgery. Methods:Using a prospectively collected multicenter database of patients undergoing pancreatic surgery (n = 703), surgical complications were classified according to the Clavien-Dindo classification. A new scoring system for preoperative identification of high-risk patients that included only objective preoperatively assessable variables was developed using a multivariate regression model. Subsequently, this scoring system was prospectively validated from 2011 to 2013 (n = 429) in a multicenter setting. Results:Eight independent preoperatively assessable variables were identified and included in the scoring system: systolic blood pressure, heart rate, hemoglobin level, albumin level, ASA (American Society of Anesthesiologists) score, surgical procedure, elective surgery or not, and disease of pancreatic origin or not. On the basis of 3 subgroups (low risk, intermediate risk, high risk), the proposed scoring system reached an accuracy of 75% for correctly predicting occurrence or nonoccurrence of major surgical complications in 80% of all analyzed patients within the validation cohort (c-statistic index = 0.709, P < 0.001, 95% confidence interval = 0.657–0.760). Conclusions:We present an easily applied scoring system with convincing accuracy for identifying low-risk and high-risk patients. In contrast to other systems, the score is exclusively based on objective preoperatively assessable characteristics and can be rapidly and easily calculated.

Selectin binding is essential for peritoneal carcinomatosis in a xenograft model of human pancreatic adenocarcinoma in pfp−−/rag2−− mice

Background and objective E- and P-selectins expressed on the luminal surface of mesodermally derived endothelial cells play a crucial role in the formation of haematogenous metastases in a number of malignancies. As peritoneal mesothelial cells are also derived form the mesoderm, it was hypothesised that selectins are also of importance in peritoneal tumour spread. Methods Immunohistochemistry was used to identify selectin expression on normal human peritoneum and isolated mesothelial cells. E- and P-selectin interactions with human pancreatic adenocarcinoma cells were investigated in dynamic flow assays and flow cytometry; the latter was also used to determine the main selectin ligands on pancreatic adenocarcinoma cell lines PaCa 5061, BxPC-3 and PaCa 5072, and selectin expression on human mesothelial cells. All cell lines were xenografted into the peritoneum of E- and P-selectin-deficient pfp/rag2 mice and selectin wild-type controls. Peritoneal carcinomatosis was quantified using MRI or a scoring system. Results E- and P-selectin were constitutively expressed on human mesothelial and endothelial cells in the peritoneum. PaCa 5061 and BxPC-3 cells interacted with E- and P-selectins in dynamic flow assays and flow cytometry, with CA19-9 (Sialyl Lewis a) being the main E-selectin ligand. For xenografted PaCa 5061 and BxPC-3 cells, peritoneal metastasis was significantly reduced in E- and P-selectin double knockout mice compared with wild-type pfp/rag2 animals. In contrast, PaCa 5072 cells were almost devoid of selectin binding sites and no intraperitoneal tumour growth was observed. Conclusion Interactions of tumour cells with peritoneal selectins play an important role in the peritoneal spread of pancreatic adenocarcinoma.

Trastuzumab has anti-metastatic and anti-angiogenic activity in a spontaneous metastasis xenograft model of esophageal adenocarcinoma.

HER-2/neu over-expression occurs in 10-40% of patients with esophageal adenocarcinoma. Therefore, inhibitory effects of trastuzumab on proliferation, neoangiogenesis and metastatic spread of the esophageal adenocarcinoma cell line PT1590 were investigated (subcutaneous xenograft model). PT1590 revealed an amplified copy number of c-erbB2 and HER-2/neu over-expression occured in xenograft tumors and spontaneous lung metastases. PT1590 proliferation was significantly inhibited by trastuzumab in vitro. In vivo, tumor weight, volume, microvessel density and number of lung metastases decreased significantly after three weeks of treatment. These data suggest the importance of HER-2/neu for metastatic spread in esophageal adenocarcinoma and encourages clinical trials.

An Attempt at Validation of the Seventh Edition of the Classification by the International Union Against Cancer for Esophageal Carcinoma

BACKGROUND The aim of our study was to investigate the ability of the Seventh edition of the classification by the International Union Against Cancer (UICC) to identify patients at higher risk and to predict the overall survival in patients with esophageal carcinoma. METHODS Demographic and clinical data of 605 patients, who underwent esophagectomy for esophageal carcinoma between 1992 and 2009, were analyzed. Tumor stage and grade were classified according to the sixth and seventh editions of the UICC classification. RESULTS Tumor depth (T), lymph node affection (N), and metastasis (M) status according to the seventh edition of the UICC classification showed significant differences in survival of each single status. Kaplan-Meier analysis of overall survival by the seventh edition of the UICC classification showed poor discrimination between stages Ib and IIa (p=0.098), stages IIIa and IIIb (p=0.672), and stages IIIc and IV (p=0.799). Further, the estimated median survival time between stages IIa and IIb was discordant. CONCLUSIONS The seventh edition of the UICC TNM classification cannot satisfactorily distinguish among different risk groups of patients with resected esophageal carcinoma. The new subgroups do not unify the different TNM stages with similar survival. We strongly propose that the next revision of the UICC classification should reduce the stages to groups with similar survival, without defining complex subgroups.

Cyclin D1 is a strong prognostic factor for survival in pancreatic cancer: Analysis of CD G870A polymorphism, FISH and immunohistochemistry

Cyclin D1 is an important regulator protein for the G1‐S cell cycle phase transition. The aim of this trial was to evaluate the impact of the CCND1 polymorphism G870A and corresponding protein expression and CCND1 amplification on the survival of the patients.

Prognostic Significant or Not? The Positive Circumferential Resection Margin in Esophageal Cancer: Impact on Local Recurrence and Overall Survival in Patients Without Neoadjuvant Treatment.

Objective: The aim of this study is to investigate the impact of the circumferential resection margin (CRM) in esophageal cancer on survival and recurrence in patients without pretreatment. Background: Whereas the infiltration of the proximal or distal resection margin is associated with poor survival and higher recurrence, studies looking at the role of the circumferential resection margin on survival and local recurrence after esophagectomy are conflicting. Methods: Influence of CRM infiltration according to the College of American Pathologists (CAP) and Royal College of Pathologists (RCP) on long-term survival of 180 patients with resected pT3 tumors and without neoadjuvant therapy was analyzed. Results: A positive CRM was found in 76 (42.4%) patients according to RCP and 44 (24.4%) patients according to CAP. The CRM status had neither according to CAP nor according to RCP a significant impact on overall survival (P = 0.317 and 0.655, respectively), local recurrence (P = 0.716 and 0.900, respectively), or distant tumor relapse (P = 0.303 and 0.471, respectively). Lymphatic tumor spread found in 129 (71.7%) patients was an independent prognosticator (P = 0.002). In 137 (76.1%) patients who had a transthoracic esophagectomy a CRM infiltration was significantly lower according to CAP compared with 43 (23.9%) patients who had a transhiatal esophagectomy (P = 0.026). Conclusions: CRM was found to have no impact on survival and recurrence in esophageal cancer. Therefore, the possible impact of neoadjuvant pretreatment in locally advanced tumors should be considered with caution in terms of an improved resectability.

Expression of ICAM-1, E-cadherin, periostin and midkine in metastases of pancreatic ductal adenocarcinomas

Development and progression of malignant tumors is in part characterized by the ability of a tumor cell to overcome cell-cell and cell-matrix adhesion and to disseminate in organs distinct from that in which they originated. This study was undertaken to analyze the clinical significance of the expression of the following cell-cell and cell-matrix adhesion molecules in pancreatic ductal adenocarcinomas (PDACs) and synchronous liver metastases: intercellular adhesion molecule 1 (ICAM-1), E-cadherin, periostin, and midkine (MK). ICAM-1, E-cadherin, periostin and MK expression was analyzed by immunohistochemistry on a tissue microarray containing 34 PDACs and 12 liver metastasis specimens. ICAM-1 expression was predominantly localized in the membranes of the cells and was found in weak to moderate intensities in PDACs and liver metastases. E-cadherin expression was absent in the majority of PDACs and corresponding liver metastases. The secreted proteins periostin and MK were expressed in various intensities in primary cancers and liver metastases. Statistical analysis demonstrated that the expression levels of the analyzed markers were neither significantly associated with metastasis in PDACs nor with clinical outcome of patients. Our study shows that the expression of the cell-cell and cell-matrix adhesion molecules ICAM-1, E-cadherin, periostin and MK was not significantly linked to metastatic disease in PDACs. Moreover, our study excludes the analyzed markers as prognostic markers in PDACs.

Hamburg-Glasgow classification: preoperative staging by combination of disseminated tumour load and systemic inflammation in oesophageal carcinoma

Background:The aim of this study was to establish a new preoperative staging classification and evaluate its comparability to the post-operative tumour stage, lymph node invasion and metastasis (TNM) classification. To date, adequate, preoperative staging in patients with oesophageal carcinoma (EC) is still missing but urgently needed. Systemic inflammation and disseminated tumour load have a pivotal role in recurrence and oncological outcome. To improve the clinical staging, we merged the Glasgow Prognostic Score (GPS) and disseminated tumour cells (DTC) into a new sufficient preoperative staging classification, the Hamburg-Glasgow classification (HGC).Methods:In this prospective, single-centre study, 326 patients following curative oesophagectomy were included. From all patients preoperative bone marrow was aspirated from the iliac crest to detect DTCs by immunostaining with the pan-keratin antibody A45-B/B3. HGC was subdefined into four prognostic groups on the basis of C-reactive protein (CRP), albumin and DTC. The three prognostic groups of the GPS were supplemented by DTC detection status. Results were correlated with clinicopathological parameters and clinical outcome.Results:Increasing HGC significantly correlated with lymph node invasion (P=0.022), post-operative pathohistological TNM staging (P=0.001) and tumour recurrence (P=0.001). The four HGC prognostic groups displayed a gradual decrease in overall as well as disease-free survival (P<0.001, each). Hamburg-Glasgow classification was a strong, significant independent predictor of overall survival and disease-free survival (P<0.001, both) in multivariate analysis.Conclusions:Hamburg-Glasgow classification seems to be a promising preoperative additive staging classification for accurate and simple outcome stratification.