Claus F. Eisenberger

Neoadjuvant Chemotherapy Compared With Surgery Alone for Locally Advanced Cancer of the Stomach and Cardia: European Organisation for Research and Treatment of Cancer Randomized Trial 40954

PURPOSE Patients with locally advanced gastric cancer benefit from combined pre- and postoperative chemotherapy, although fewer than 50% could receive postoperative chemotherapy. We examined the value of purely preoperative chemotherapy in a phase III trial with strict preoperative staging and surgical resection guidelines. PATIENTS AND METHODS Patients with locally advanced adenocarcinoma of the stomach or esophagogastric junction (AEG II and III) were randomly assigned to preoperative chemotherapy followed by surgery or to surgery alone. To detect with 80% power an improvement in median survival from 17 months with surgery alone to 24 months with neoadjuvant, 282 events were required. RESULTS This trial was stopped for poor accrual after 144 patients were randomly assigned (72:72); 52.8% patients had tumors located in the proximal third of the stomach, including AEG type II and III. The International Union Against Cancer R0 resection rate was 81.9% after neoadjuvant chemotherapy as compared with 66.7% with surgery alone (P = .036). The surgery-only group had more lymph node metastases than the neoadjuvant group (76.5% v 61.4%; P = .018). Postoperative complications were more frequent in the neoadjuvant arm (27.1% v 16.2%; P = .09). After a median follow-up of 4.4 years and 67 deaths, a survival benefit could not be shown (hazard ratio, 0.84; 95% CI, 0.52 to 1.35; P = .466). CONCLUSION This trial showed a significantly increased R0 resection rate but failed to demonstrate a survival benefit. Possible explanations are low statistical power, a high rate of proximal gastric cancer including AEG and/or a better outcome than expected after radical surgery alone due to the high quality of surgery with resections of regional lymph nodes outside the perigastic area (celiac trunc, hepatic ligament, lymph node at a. lienalis; D2).

Portal application of autologous CD133+ bone marrow cells to the liver : a novel concept to support hepatic regeneration

The liver has a large capacity for regeneration after resection. However, below a critical level of future liver remnant volume (FLRV), partial hepatectomy is accompanied by a significant increase of postoperative liver failure. There is accumulating evidence for the contribution of bone marrow stem cells (BMSCs) to participate in liver regeneration. Here we report on three patients subjected to intraportal administration of autologous CD133+ BMSCs subsequent to portal venous embolization of right liver segments, used to expand left lateral hepatic segments as FLRV. Computerized tomography scan volumetry revealed 2.5‐fold increased mean proliferation rates of left lateral segments compared with a group of three consecutive patients treated without application of BMSCs. This early experience with portovenous application of CD133+ BMSCs could suggest that this novel therapeutic approach bears the potential of enhancing and accelerating hepatic regeneration in a clinical setting.

Attenuation of sepsis-related immunoparalysis by continuous veno-venous hemofiltration in experimental porcine pancreatitis.

ObjectivesIn light of evidence suggesting that hemofiltration favorably influences septic diseases by removing sepsis mediators, the impact of different modalities of continuous veno-venous hemofiltration (CVVH) on outcome and immunologic derangements in porcine pancreatogenic sepsis was evaluated. DesignRandomized, controlled intervention trial. SubjectsForty-eight minipigs of either sex. InterventionsPancreatitis was induced by intraductal injection of sodium taurocholate (4%, 1 mL/kg body weight [BW]) and enterokinase (2 U/kg BW). Animals were allocated either to untreated controls—group 1—or to one of three treatment groups—group 2: low-volume CVVH (20 mL/kg BW), no change of hemofilters; group 3: low-volume CVVH, filters changed every 12 hrs; and group 4: high-volume CVVH (100 mL/kg BW), filters changed every 12 hrs. Survival represented the major parameter of the study. Serum cytokine levels, sepsis-related down-regulation of major histocompatibility complex II and CD14 expression on leukocytes, bacterial translocation, and endotoxemia were further parameters evaluated in the study. Measurements and Main Results High-volume CVVH combined with periodic filter change was significantly superior compared with less intensive treatment modalities (low-volume CVVH, no filter change) in sepsis protection. Long-term survival (>60 hrs) was found in 67% of group 4 and 33% of group 3 animals (p < .05), whereas in controls and group 2 no animal survived. CVVH ameliorated the initial serum tumor necrosis factor-&agr; response and prevented sepsis-induced in vitro endotoxin hyporesponsiveness. Down-regulation of major histocompatibility complex II and CD14 expression on monocytes was significantly improved by CVVH. Improved oxidative burst and phagocytosis capacity in polymorphonuclear leukocytes suggested that leukocyte function was stabilized by CVVH. Also, CVVH significantly reduced bacterial translocation and endotoxemia. ConclusionsHemofiltration reversed sepsis-induced immunoparalysis in a porcine model of bile acid–induced pancreatitis. Implications for human pancreatitis must be validated in prospective, clinical protocols.

Somatostatin-producing neuroendocrine tumors of the duodenum and pancreas: incidence, types, biological behavior, association with inherited syndromes, and functional activity

Somatostatin-producing neuroendocrine tumors (SOM-NETs) of the duodenum and pancreas appear to be heterogeneous. To determine their clinicopathological profiles, respective data were analyzed on a series of 82 duodenal and 541 pancreatic NETs. In addition, the clinical records of 821 patients with duodenal or pancreatic NETs were reviewed for evidence of a somatostatinoma syndrome. Predominant or exclusive expression of somatostatin was found in 21 (26%) duodenal and 21 (4%) pancreatic NETs. They were classified as sporadic (n=31) or neurofibromatosis type 1 (NF1)-associated duodenal NETs (n=3), gangliocytic paragangliomas (GCPGs; n=6), or poorly differentiated neuroendocrine carcinomas (pdNECs; n=2). In addition, five duodenal and four pancreatic SOM-NETs were found in five patients with multiple endocrine neoplasia type 1 (MEN1). Metastases occurred in 13 (43%) patients with sporadic or NF1-associated SOM-NETs, but in none of the duodenal or pancreatic MEN1-associated SOM-NETs or GCPGs. Sporadic advanced (stage IV) SOM-NETs were more commonly detected in the pancreas than in the duodenum. None of the patients (including the 821 patients for whom only the clinical records were reviewed) fulfilled the criteria of a somatostatinoma syndrome. Our data show that somatostatin expression is not only seen in sporadic NETs but may also occur in GCPGs, pdNECs, and hereditary NETs. Surgical treatment is effective in most duodenal and many pancreatic SOM-NETs. MEN1-associated SOM-NETs and GCPGs follow a benign course, while somatostatin-producing pdNECs are aggressive neoplasms. The occurrence of the so-called somatostatinoma syndrome appears to be extremely uncommon.

Ep-CAM expression in squamous cell carcinoma of the esophagus: a potential therapeutic target and prognostic marker

BackgroundTo 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.MethodsThe 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.ResultsEp-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.ConclusionOur 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.

Papillary urothelial hyperplasia is a clonal precursor to papillary transitional cell bladder cancer.

Papilloma and papillary hyperplasia (PH) have been proposed to be the putative precursor lesions of papillary transitional‐cell carcinoma of the urinary bladder. We examined 15 PH lesions and 4 papillomas for loss of heterozygosity (LOH) at 17 microsatellite markers on 9 chromosomal arms. Eight of 15 (53%) PHs were clonal, demonstrating LOH of at least 1 microsatellite marker. In contrast, none of the papillomas showed any genetic changes among the markers tested. In PH, chromosomal arm 9q was the most frequently lost (4/15), followed by 9p and 18q (n = 2) and, less frequently, 8p, 10q, 11p and 17p (n = 1). Furthermore, 2 hyperplastic lesions demonstrated LOH at 9q only, confirming the notion that allelic loss on chromosomal arm 9q is among the earliest events in bladder‐cancer progression. In 1 patient, identical LOH patterns were observed between PH and a recurrent transitional‐cell carcinoma. Our molecular data demonstrate that at least a proportion of PHs represent pre‐cancerous lesions of the bladder that subsequently progress to papillary bladder cancer. Moreover, chromosomal arm 9q may harbor a tumor‐suppressor gene(s) inactivated in the earliest stages of human bladder tumorigenesis. Int. J. Cancer 89:514–518, 2000.

CDC91L1 (PIG-U) is a newly discovered oncogene in human bladder cancer.

Genomic amplification at 20q11–13 is a common event in human cancers. We isolated a germline translocation breakpoint at 20q11 from a bladder cancer patient. We identified CDC91L1, the gene encoding CDC91L1 (also called phosphatidylinositol glycan class U (PIG-U), a transamidase complex unit in the glycosylphosphatidylinositol (GPI) anchoring pathway), as the only gene whose expression was affected by the translocation. CDC91L1 was amplified and overexpressed in about one-third of bladder cancer cell lines and primary tumors, as well as in oncogenic uroepithelial cells transformed with human papillomavirus (HPV) E7. Forced overexpression of CDC91L1 malignantly transformed NIH3T3 cells in vitro and in vivo. Overexpression of CDC91L1 also resulted in upregulation of the urokinase receptor (uPAR), a GPI-anchored protein, and in turn increased STAT-3 phosphorylation in bladder cancer cells. Our findings suggest that CDC91L1 is an oncogene in bladder cancer, and implicate the GPI anchoring system as a potential oncogenic pathway and therapeutic target in human cancers.

Long-term clinical and biochemical follow-up in medullary thyroid carcinoma: a single institution's experience over 20 years.

Objective:Many patients with medullary thyroid carcinomas (MTC) have reoperative surgery in different hospitals, which makes their follow-up difficult. To comprehend these complex courses and to find relevant prognostic factors we report a 20-year single center experience of 289 patients with MTC or precursor C-cell-hyperplasias. Patients and Methods:Between April 1986 and May 2006, 289 consecutive patients with MTC or MEN2 gene carriers were treated at the Department of Surgery at the University Hospital Düsseldorf. Tumor stages were documented according to the classification of the International Union against Cancer 5th edition, 1997 (Schott. Endocr Relat Cancer. 2006;13:779–795). A system to easily comprehend operative procedures is suggested. Results:There were 159 female and 130 male patients (f/m ratio 1.22). Mean age at time of diagnosis was 32 years (4–77) in the familial cases and 53 years (23–84) years in the sporadic cases. Sixty-six patients (23%) had multifocal disease. Twelve MEN2-patients had only C-cell-hyperplasia (pT0). Tumor stage was pT1 in 86 patients, pT2 in 106 patients, pT3 in 25 patients, pT4 in 52 patients and unclear in 8 patients. In the 289 patients 648 operations were performed. One hundred seventy patients had more than 1 operation (59%). Ninety-nine patients (34%) are calcitonin-negative and 91 patients (31%) live with elevated calcitonin. Median follow-up time of the surviving 211 patients was 8.9 years (range, 0.3–30.7 years). The 5- and 10-year survival of all tumor patients was 86% and 68%, respectively. Conclusion:The chance to achieve biochemical cure in MTC is clearly dependent on the primary tumor size. The chance for long-term biochemical cure in a pT4-tumor is almost nil even after multiple and extended reoperations, whereas a pT1 tumor can be cured in up to 67% of the patients. Long-term survival, however, can be achieved even in pT4 tumor patients in almost 50%.

Copy Number of Chromosome 17 but Not HER2 Amplification Predicts Clinical Outcome of Patients With Pancreatic Ductal Adenocarcinoma

PURPOSE To determine the frequency and the potential clinical use of HER2 (17q21) gene amplification and chromosome 17 aneuploidy in pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS Serial tissue sections of 50 resected PDACs were analyzed with chromogenic in situ hybridization using locus-specific HER2 probes and centromeric probes for chromosome 17. Centromeric probes for chromosome 7 and 8 were hybridized to confirm ploidy levels. Expression of HER2 protein was assessed by immunohistochemistry. Correlations of experimental findings with clinical and follow-up data were tested. RESULTS The HER2 gene locus was frequently (24%) amplified in PDAC and the rate of overexpression (2+ and 3+) was 10%, but no prognostic significance was found. Copy number analysis of chromosomes 7, 8, and 17 revealed disomic (40%), trisomic (36%), and hypertetrasomic (24%) tumors. Compared with patients with disomic tumors, patients with hypertetrasomic tumors exhibited a significantly decreased relapse-free and overall survival (5.0 v 13.0 months, P = .0144 and 7.0 v 20.0 months, P = .0099, respectively). Multivariate analysis confirmed the independent prognostic significance of hypertetrasomy. CONCLUSION Tumor ploidy levels correlate with prognosis of PDAC patients, indicating characteristic biologic properties of PDAC with high chromosomal instability. In contrast, no prognostic influence on patient outcome was found for the amplification of the HER2 oncogene or p185(HER2) overexpression. Therefore, evaluation of ploidy levels offers new opportunities for patient stratification in clinical trials and enables novel approaches to study the well-known aggressiveness of PDAC.

Microsatellite instability at AAAG repeat sequences in respiratory tract cancers

We surveyed the occurrence of novel alleles at microsatellite sequences in non‐small cell lung cancers (NSCLC) using 61 tetranucleotide repeat markers. The presence of at least one new allele, consistent with microsatellite instability (MSI), was observed in 26 of 61 (43%) markers involving 30 of 47 (64%) NSCLC. Twelve of the 26 markers detected new alleles in 2 or more tumors and 11 of these 12 markers contained an AAAG repeat sequence. Using this panel of 12 markers, MSI was detected in 24 of 47 (51%) NSCLC and 10 of 18 (56%) head and neck cancers but was only observed in 8 of 38 (21%) bladder cancers and 3 of 25 (12%) kidney cancers. Our results suggested that about 50% of respiratory tract cancers exhibited microsatellite instability predominantly at AAAG sequences. This distinct type of instability was termed EMAST for elevated microsatellite alterations at selected tetranucleotide repeats. The identification of markers with EMAST should have potential application for the molecular detection of respiratory tract cancers.