Integrin expression in esophageal squamous cell carcinoma: loss of the physiological integrin expression pattern correlates with disease progression.

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 α2ß1, α3ß1, α6ß1, and α6ß4 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, ß1, and ß4 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 α6ß4 and α6ß1 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.

EGFR intron-1 CA repeat polymorphism is a predictor of relapse and survival in complete resected only surgically treated esophageal cancer.

Basal transcription regulation of the epidermal growth factor receptor is dependent upon a CA simple sequence repeat polymorphism in the intron-1 (CA-SSR-1). Here, we evaluate the role of CA-SSR-1 in complete resected esophageal cancer (EC) patients without neoadjuvant or adjuvant treatment. Genomic DNA was extracted from peripheral blood leukocytes of 241 patients. To determine the number of the CA repeats in the CA-SSR-1, DNA was amplified by polymerase chain reaction and sequenced. The results were correlated with clinicopathological parameters and clinical outcome. Three genotypes were defined based on cut-off points for short allele (S) with ≤18 and long allele (L) >18 CA repeats. A steadily increasing risk was evident between LL, SL, and SS genotype for larger tumor size, presence of lymph node metastases, and disseminated tumor cells in bone marrow as well as tumor recurrence (P < 0.001, chi-square test). A gradual decrease in disease-free and overall survival (OS) was present among LL, SL, and SS patients (P < 0.001, log-rank test). The different outcomes were also evident in nodal status and histological type adjusted subgroup analyses. CA-SSR-1 was identified as the strongest independent prognosticator of tumor recurrence and OS (P < 0.001, Cox regression analysis). CA-SSR-1 is a strong predictive factor for tumor recurrence and overall survival in patients with complete resected esophageal cancer without neoadjuvant or adjuvant therapy.

Stapled hemorrhoidopexy versus Milligan-Morgan hemorrhoidectomy in circumferential third-degree hemorrhoids: long-term results of a randomized controlled trial.

BACKGROUND: The literature indicates higher recurrence rates for stapled hemorrhoidopexy than for conventional techniques. This could be due to inappropriate patient selection. OBJECTIVE: The aim of this study was to evaluate the short- and long-term outcome after stapled hemorrhoidopexy compared with the Milligan-Morgan procedure in a homogeneous patient population with circumferential third-degree hemorrhoids. DESIGN AND PATIENTS: One hundred thirty patients were enrolled into a randomized controlled study, of which 122 were clinically evaluated at weeks 1, 2, and 4, and thereafter each year for a minimum of 3 years. Patients completed a questionnaire for symptoms, function, and pain. Pain was assessed using a visual analog scale. Recurrences were determined by anoscopy and self-report. SETTINGS: The study was performed at the University Hospital Hamburg. MAIN OUTCOME MEASURES: Endpoints were pain, recurrence, bleeding, itching/burning, urinary retention, incontinence symptoms, and prolonged rate of wound healing. RESULTS: The cumulative recurrence rates after 5 years were 18 % (n = 11) in the stapled hemorrhoidopexy group and 23 % (n = 14) in the Milligan-Morgan group (p = 0.65). Patients who underwent stapled hemorrhoidopexy had significantly less postoperative pain with mean VAS scores at week 1: 3.1 vs. 6.2; week 2: 0.5 vs. 3; week 4: 0.05 vs. 0.6 (p < 0.001), and demonstrated less burning/itching sensation 4 weeks after surgery compared with the Milligan-Morgan group (4.9 vs. 19.7 %; p < 0.001). The postoperative bleeding rate was 4.9 % in both groups and the rate of urinary retention did not differ significantly (4.9 % vs. 1.6 %; p = 0.309). Postoperative incontinence symptoms (6.6 % versus 3.3 %; p = 0.40) resolved within the first 6 months. LIMITATIONS: Detailed measurement of incontinence was not possible because postoperative symptoms resolved between consultations, and pathological results were examined retrospectively. CONCLUSIONS: The results show a similar rate of recurrence in the long term and suggest increased patient comfort in the early postoperative course after stapled hemorrhoidopexy. In patients with circumferential third-degree hemorrhoids, stapled hemorrhoidopexy is as effective as the Milligan-Morgan procedure.

The "North German Tumor Bank of Colorectal Cancer": status report after the first 2 years of support by the German Cancer Aid Foundation.

PURPOSE: Research projects and clinical trials strongly rely on high-quality biospecimens which are provided by biobanks. Since differences in sample processing and storage can strongly affect the outcome of such studies, standardization between biobanks is necessary to guarantee reliable results of large, multicenter studies. The German Cancer Aid Foundation (Deutsche Krebshilfe e.V.) has therefore initiated the priority program "tumor tissue banks" in 2010 by funding four biobank networks focusing on central nervous system tumors, melanomas, breast carcinomas, and colorectal carcinomas. The latter one, the North German Tumor Bank of Colorectal Cancer (ColoNet) is managed by surgeons, pathologists, gastroenterologists, oncologists, scientists, and medical computer scientists. METHODS AND RESULTS: The ColoNet consortium has developed and harmonized standard operating procedures concerning all biobanking aspects. Crucial steps for quality assurance have been implemented and resulted in certification according to DIN EN ISO 9001. A further achievement is the construction of a web-based database for exploring available samples. In addition, common scientific projects have been initiated. Thus, ColoNet's repository will be used for research projects in order to improve early diagnosis, therapy, follow-up, and prognosis of colorectal cancer patients. Apart from the routine sample storage at -170 °C, the tumor banks' unique characteristic is the participation of outpatient clinics and private practices to further expand the sample and clinical data collection. CONCLUSION: The first 2 years of funding by the German Cancer Aid Foundation have already led to a closer scientific connection between the participating institutions and to a substantial collection of biospecimens obtained under highly standardized conditions.

Management of the difficult duodenal stump in penetrating duodenal ulcer disease: a comparative analysis of duodenojejunostomy with "classical" stump closure (Nissen-Bsteh).

BACKGROUND: Duodenal stump insufficiency after surgery for penetrating gastroduodenal ulcer is associated with substantial mortality. "Classical" technique of closing a difficult duodenal stump (Nissen-Bsteh) has, up to now, not been compared with duodenojejunostomy (DJ) in larger patient sets. This also refers to the potential benefit of a gastric and biliary diversion under such conditions. The aim of the present study was to compare classical duodenal closure (CC) with DJ and to evaluate the impact of gastric and biliary diversion on postoperative outcome after surgery for penetrating, high-risk duodenal ulcer in a matched control study. METHODS: Out of 321 patients, treated for penetrating duodenal ulcer disease, the perioperative outcome of 62 DJ patients was compared with 62 patients undergoing CC matched for age, gender, biliary diversion, and the operating surgeon collective. A total of 70 patients, equally distributed between DJ and CC subsets, received temporary biliary diversion. RESULTS: Overall perioperative mortality was 10.5%. However, DJ significantly reduced the mortality rate (4.8%) associated with penetrating duodenal ulcer compared to CC (16.1%, P < 0.04). The overall morbidity in DJ patients nearly equalled that in the CC group (P = 0.4). Differences in the prevalence of duodenal leakage rate between DJ (14.5%) and CC (29%) patients were of borderline significance (P = 0.05). Temporary biliary diversion was identified as a prognostic factor for closure consistency with lower duodenal leakage rates in both DJ (odds ratio 0.05, 95% confidence interval 0.005-0.42) and CC patients (odds ratio 0.2, 95% confidence interval 0.05-0.6). In contrast, gastric diversion performed in a subset of 35 DJ patients had no protective effect. CONCLUSION: Duodenojejunostomy combined with temporary biliary diversion substantially improves perioperative outcome in management of penetrating duodenal ulcer.

Disseminated tumor cells in bone marrow and the natural course of resected esophageal cancer.

OBJECTIVE: To assess the impact of disseminated tumor cells (DTC) in bone marrow on recurrence and survival in complete resected esophageal cancer (EC). BACKGROUND: Current modalities to predict tumor recurrence and survival in EC are insufficient. Here, we evaluated in a prospective study the prognostic relevance of DTC in bone marrow for the natural postoperative course of EC. METHODS: We enrolled 370 consecutive EC patients (1995-2009). All tumors, 189 squamous cell carcinomas and 181 adenocarcinomas, were completely surgically resected (R0), and patients received neither neoadjuvant nor adjuvant therapy. Disseminated tumor cells were detected by an immunocytochemical cytokeratin assay in preoperatively taken bone marrow aspirates. The results were correlated with clinic-pathological parameters and clinical outcome. RESULTS: Overall 120 (32.4%) patients harbored DTC in their bone marrow. Presence of DTC significantly correlated with aggressive tumor biology as indicated by increased tumor size (P = 0.026), regional (P = 0.002) and distant (P = 0.012) lymph node metastases, and higher relapse rate (P < 0.001, χ test). A gradual decrease in disease-free (P < 0.001) and overall (P < 0.001, log-rank test) survival was observed between DTC-negative and DTC-positive patients and was evident in subgroup analysis stratified for nodal status, lymph node yield, lymph node ratio, and tumor subtypes. Disseminated tumor cells were identified as a strong independent prognosticator of tumor recurrence (hazard ratio [HR] 4.0, 95% confidence interval [CI]: 2.96-5.45, P < 0.001) and overall survival (HR 3.1, 95% CI: 2.37-4.09, P < 0.001, Cox regression analysis). CONCLUSIONS: The presence of DTC in bone marrow is a strong and independent prognostic factor in patients with resectable EC.

Heme oxygenase-1 germ line GTn promoter polymorphism is an independent prognosticator of tumor recurrence and survival in pancreatic cancer.

BACKGROUND: Heme oxygenase-1 (HO-1) correlates with aggressive tumor behavior and chemotherapy resistance in pancreatic cancer (PC). We evaluated the prognostic value of the basal transcription controlling germ line GTn repeat polymorphism (GTn) in the promoter region of the HO-1 gene in PC. PATIENTS AND METHODS: We determined the GTn in 100 controls and 150 PC patients. DNA was extracted from blood leukocytes and GTn determined by PCR, electrophoresis, and sequencing. Clinicopathological parameters, disease-free, and overall survival (DFS, OS) were correlated with GTn. RESULTS: Three genotypes were defined based on short (S) <25 and long (L) ≥25 GTn repeat alleles. In PC patients, a steadily increasing risk was evident between LL, SL, and SS genotype patients for larger tumor size, presence of lymph node metastasis, poor tumor differentiation and higher recurrence rate (P < 0.001 each). The SS genotype displayed the most aggressive tumor biology. The LL genotype had the best and the SS genotype the worst DFS and OS (P < 0.001 each). The GTn genotype was the strongest prognostic factor for recurrence and survival (P < 0.001 each). CONCLUSION: The GTn repeat polymorphism is a strong prognostic marker for recurrence and survival in PC patients.

The GNAS1 T393C single nucleotide polymorphism predicts the natural postoperative course of complete resected esophageal cancer.

BACKGROUND: Genetic variations in cancer patients may serve as important prognostic indicators of clinical outcome. The GNAS1 T393C single nucleotide polymorphism (SNP) diversely correlates with the clinical outcome in cancer. The aim of this study was to evaluate the potential prognostic value of T393C-SNP in complete resected only surgically treated esophageal cancer (EC). METHODS: Genomic DNA was extracted from peripheral blood leucocytes of 190 patients who underwent only complete surgical resection for EC. T393C-SNP was correlated with clinic-pathological parameters, tumor cell dissemination in bone marrow (DTC) and clinical outcome. RESULTS: T-allele carriers had more advanced disease due to presence of lymph node metastasis (P < 0.0001) and DTC (P = 0.01) and higher recurrence rate (P = 0.01) compared to CC genotype. The disease-free (P < 0.001) and overall survival (P < 0.001) was better in CC compared to TT and TC patients. In the multivariate Cox regression disease-stage adjusted analysis the T393C-SNP was identified as a strong independent prognostic factor for recurrence (hazard ratio 1.8, P = 0.01) and survival (hazard ratio 2.5, P < 0.001) in EC patients. CONCLUSION: Determination of T393C-SNP preoperatively will allow allocation of EC patients into different risk profiles which may help to stratify patients eligible for neoadjuvant and or adjuvant therapy.

Heme oxygenase-1 promoter polymorphism is a predictor of disease relapse in pancreatic neuroendocrine tumors.

BACKGROUND: Current available preoperative diagnostic workup is insufficient to differentiate between benign and malignant pancreatic neuroendocrine tumors (PNET). The aim of the present study was to evaluate the potential prognostic role of the promoter GTn repeat polymorphism (GTn) of the heme oxygenase-1 gene in PNET. METHODS: Tumor, metastasis, corresponding healthy tissue, and peripheral blood leukocyte DNA of 46 patients who underwent surgical resection for PNET were analyzed for GTn by PCR, capillary electrophoresis, and DNA-sequencing. The GTn was correlated to clinicopathologic parameters and clinical outcome. RESULTS: GTn was classified into short (<25) and long (≥ 25) alleles and three (SS, SL, and LL) genotypes were defined. There was no difference in GTn genotype among tumor, healthy tissue, metastasis, and peripheral blood leukocyte DNA. The SS and SL genotype displayed significantly more poor differentiated tumors (P = 0.001) and higher tumor recurrence rate (P = 0.0001) compared with LL patients. The LL genotype patients presented predominantly benign PNET (P < 0.001). The LL genotype had the longest disease-free (P < 0.001) and overall survival (P = 0.006). Besides the WHO classification the GTn was identified as a strong predictor of tumor recurrence (hazard ratio 3.1, 95% confidence interval 1.3-7.3) in PNET. CONCLUSION: GTn differentiates between benign and malignant PNET and is a strong predictor of tumor recurrence.

Glasgow Prognostic Score is a predictor of perioperative and long-term outcome in patients with only surgically treated esophageal cancer.

BACKGROUND: Systemic inflammation (SI) plays a pivotal role in cancer. C-reactive protein (CRP) and albumin as parameters of SI form the Glasgow Prognostic Score (GPS). The purpose of the study was to evaluate the potential prognostic role of GPS in a homogeneous population of esophageal cancer (EC) patients undergoing only resection. METHODS: GPS was evaluated on the basis of admission blood sample taken before surgery. Patients with a CRP < 10 mg/L and albumin > 35 g/L were allocated to GPS0 group. If only CRP was increased or albumin decreased patients were allocated to the GPS1 and patients in whom CRP was ≥10 mg/L and albumin level ≤35 g/L were classified as GPS2. GPS was correlated to clinicopathological parameters and clinical outcome. RESULTS: Increasing GPS significantly correlated with more aggressive tumor biology in terms of tumor size (P < 0.001), presence of regional (P = 0.01) and nonregional lymph node metastasis (P = 0.02), and higher tumor recurrence rate (P < 0.001). Furthermore, GPS was identified as an independent prognosticator of perioperative morbidity (odds ratio 1.9; P = 0.03). In addition, a gradual decrease in disease-free and overall survival was evident between the three GPS subgroups. Survival differences between the GPS groups remained apparent even after stratification of the study population to underlying tumor type and nodal status. GPS was identified as a strong prognosticator of tumor recurrence (hazard ratio 2.5; P < 0.001) and survival (hazard ratio 3.0; P < 0.001) in EC. CONCLUSIONS: GPS represents a strong prognosticator of perioperative morbidity and long-term outcome in resected EC patients without neoadjuvant or adjuvant treatment.

Chronic pancreatitis: modern surgical management.

INTRODUCTION: Chronic pancreatitis (CP) is a disease with enormous social and personal impact. It is most commonly caused by the abuse of alcohol combined with nicotine. CP is usually characterised by an inflammatory mass located in the pancreatic head. Its natural course is characterised by persistent or recurrent painful attacks as well as progressive loss of pancreatic function due to fibrosis of the parenchyma with consecutive endocrine and exocrine insufficiency. CONCLUSIONS: The only success parameter of any treatment is the effective long-lasting pain relief and improvement in the quality of life. The surgical armamentarium includes simple drainage procedures, resections of different extents or a combination of both. Duodenum-preserving resection of the pancreas offers the best short-term outcome according to trials conducted so far. It has the benefit of combining the highest safety with the highest efficiency. Additionally, the extent of the operation can be adapted to the morphology of the individual patient.

Chronic pancreatitis complicated by cavernous transformation of the portal vein: contraindication to surgery?

BACKGROUND: A subgroup of patients with chronic pancreatitis and severe incapacitating pain develop mesentericoportal vascular complications with extrahepatic portal hypertension (EPH) and subsequent cavernous transformation. The purpose of this study was to address the question of whether a noninterventional approach regarding surgery is justified. METHODS: A total of 702 patients with chronic pancreatitis underwent major pancreatic surgery. EPH with cavernous transformation was diagnosed in 21 (3%; group C) and EPH without cavernous transformation in 60 (9%; group B). The remaining 621 patients (88%; group A) showed no evidence for extrahepatic hypertension or cavernous transformation. Prospectively collected data were analyzed with respect to perioperative parameters, outcomes, quality of life, and our previously established pain score. RESULTS: Patients in groups C and B had longer history and greater severity of pain (P = .0001). Group C had the longest operative times (P > .05) and greatest requirements of intraoperatively transfused packed red blood cells (P < .05). Morbidity was greater in group C compared with groups B and A (88% vs 55% vs 35%; P < .001). Mortality was 10% (2/21) in group C, compared with 1.3% (8/621) in group A and 0% in group B (P = .008). Quality of life as well as pain scores significantly improved postoperatively in group C, and were comparable to those in groups A and B (P < .001). CONCLUSION: Concomitant cavernous transformation in patients with chronic pancreatitis increases the operative risk significantly. Alternative treatment modalities should be evaluated thoroughly in every individual patient to offer every patient the best available treatment. Nevertheless, operative intervention is often the only treatment possible and improvements in quality of life and pain alleviation justify operative interventions.

Current diagnosis and future impact of micrometastases for therapeutic strategies in adenocarcinoma of the esophagus, gastric cardia, and upper gastric third.

Esophageal and gastric cancers are aggressive neoplasms with a poor prognosis. Although postoperative mortality has declined and rates of complete resection have improved considerably, 5 year survival rates are still very low. Early metastatic relapse after complete resection of an apparently localized primary lesion indicates that disseminated tumor cells, undetectable by current methods, may already have been present at the time of surgery, even in patients with seemingly early tumor stages. Occult residual tumor disease is suggested when either bone marrow or lymph nodes from which tumor relapse may originate are affected by micrometastatic lesions undetectable by conventional histopathology. The presence of single tumor cells detected by immunohistological methods is increasingly regarded as a clinically relevant prognostic factor. The use of antibodies against tumor-associated targets enables detection of individual epithelial tumor cells in lymph nodes and in bone marrow in various tumor entities. The potential role and -benefit of an antibody-based treatment as a therapeutic target would be of particular interest in tumors with a notoriously poor prognosis such as esophageal cancer and cardia cancer.

Quo vadis STARR? A prospective long-term follow-up of stapled transanal rectal resection for obstructed defecation syndrome.

INTRODUCTION: Functional and clinical long-term outcome after stapled transanal rectal resection (STARR) in patients with an isolated symptomatic rectocele are investigated. Short-term results after 1 year are comparable with the functional outcome even after 5 years. Eighty per cent of the patients were still satisfied. STARR is an alternative procedure to the conventional surgical approaches for patients with an obstructed defecation syndrome and rectocele. Several studies have reported short-term outcome after STARR, but long-term results are still missing. The objective of this study was to evaluate long-term clinical outcome after STARR with a follow-up of 5 years. MATERIALS AND METHODS: Twenty patients with only an isolated symptomatic rectocele due to obstructed defecation syndrome were subjected to STARR. Functional and clinical outcome was assessed by Outlet Obstruction Syndrome score (OOS score), Wexner score (WS), and Symptom Severity score (SSS score). Data were prospectively collected over 7 years. RESULTS: The perioperative morbidity after STARR accounted for 20% (n = 4). One patient was subjected to reoperation due to perforation, two postoperative bleedings occurred, and one patient developed an increasing local granulomatous reaction at the stapler line. The median follow-up accounted for 66 months (range 60-84). Sixteen patients (80%) were satisfied with the functional outcome. The median OOS, SSS and WS score improved significantly already after 1 year in these patients and remained stable at 5-year follow-up. In contrast, four patients were classified as treatment failures since the OOS score and the SSS score showed no improvement. At 5-year follow-up, these patients remained symptomatic without improvement in OOS and SSS scores. CONCLUSIONS: The STARR procedure is an effective operation in isolated symptomatic rectoceles with regard to relief of the obstructed defecation syndrome. The short-term improvement after STARR predicts long-term outcome in obstructed defecation syndrome caused by a rectocele.

Establishment and characterization of a new human pancreatic adenocarcinoma cell line with high metastatic potential to the lung.

BACKGROUND: Pancreatic cancer is still associated with devastating prognosis. Real progress in treatment options has still not been achieved. Therefore new models are urgently needed to investigate this deadly disease. As a part of this process we have established and characterized a new human pancreatic cancer cell line. METHODS: The newly established pancreatic cancer cell line PaCa 5061 was characterized for its morphology, growth rate, chromosomal analysis and mutational analysis of the K-ras, EGFR and p53 genes. Gene-amplification and RNA expression profiles were obtained using an Affymetrix microarray, and overexpression was validated by IHC analysis. Tumorigenicity and spontaneous metastasis formation of PaCa 5061 cells were analyzed in pfp-/-/rag2-/- mice. Sensitivity towards chemotherapy was analysed by MTT assay. RESULTS: PaCa 5061 cells grew as an adhering monolayer with a doubling time ranging from 30 to 48 hours. M-FISH analyses showed a hypertriploid complex karyotype with multiple numerical and unbalanced structural aberrations. Numerous genes were overexpressed, some of which have previously been implicated in pancreatic adenocarcinoma (GATA6, IGFBP3, IGFBP6), while others were detected for the first time (MEMO1, RIOK3). Specifically highly overexpressed genes (fold change > 10) were identified as EGFR, MUC4, CEACAM1, CEACAM5 and CEACAM6. Subcutaneous transplantation of PaCa 5061 into pfp-/-/rag2-/- mice resulted in formation of primary tumors and spontaneous lung metastasis. CONCLUSION: The established PaCa 5061 cell line and its injection into pfp-/-/rag2-/- mice can be used as a new model for studying various aspects of the biology of human pancreatic cancer and potential treatment approaches for the disease.

Insulin-like growth factor-1 receptor as a novel prognostic marker and its implication as a cotarget in the treatment of human adenocarcinoma of the esophagus.

Insulin-like growth factor-1 receptor (IGF-1R) and human epidermal growth factor receptor-2 (HER2) receptor expression has been found to be a key regulator of tumorigenesis. The purpose of our study was to establish the prognostic significance of IGF-1R in esophageal cancer and to determine the effect of IGF-1R and HER2 targeting with alpha-IR3 and Herceptin antibodies on the proliferation of esophageal cancer cells in vitro. IGF-1R expression and clinicopathological correlations were analyzed with a tissue microarray containing 234 esophageal cancer specimens (133 adenocarcinomas and 101 squamous cell carcinomas). Proliferation changes associated with Herceptin and alpha-IR3 blockage were evaluated with the unique human esophageal cancer cell lines Pt1590 and LN1590. IGF-1R and HER2 expression levels, activation and phosphorylation status of downstream signaling proteins involved in the activation pathways were analyzed by Western blotting. IGF-1R overexpression was detected in 121 (52%) of the 234 esophageal tumors examined. In the subgroup of 87 HER2-positive tumors, 93.1% showed concordant overexpression for IGF-1R. IGF-1R was identified as a variable associated with reduced overall survival for adenocarcinoma (p = 0.05), but not for squamous cell carcinoma. The combination of Herceptin and alpha-IR3 was more effective in inhibiting in vitro proliferation than treatment with either agent alone (p < 0.01). This was associated with a decrease in HER2 and IGF-1R protein levels and suppression of Akt- and MAP kinase phosphorylation. IGF-1R expression can be used as a novel prognostic marker for adenocarcinomas of the esophagus. Cotreatment with IGF-1R and HER2 antibodies might become a valuable and effective treatment option in esophageal adenocarcinoma.

NY-CO-58/KIF2C is overexpressed in a variety of solid tumors and induces frequent T cell responses in patients with colorectal cancer.

NY-CO-58/KIF2C has been identified as a tumor antigen by screening antibody responses in patients with colorectal cancer. However, expression had not consequently been examined, and nothing was known about its ability to induce spontaneous T cell responses, which have been suggested to play a role in the development of colorectal cancer. We analyzed 5 colorectal cancer cell lines, and tumor samples and adjacent healthy tissues from 176 patients with epithelial cancers for the expression of NY-CO-58/KIF2C by RT-PCR and Western Blot. T cell responses of 43 colorectal cancer patients and 35 healthy donors were evaluated by ELISpot following stimulation with 30mer peptides or full-length protein. All cell lines and tumor samples from colorectal cancer patients expressed NY-CO-58/KIF2C on the protein and RNA level, and expression levels correlated strongly with Ki-67 expression (r = 0.69; p = 0.0003). Investigating NY-CO-58/KIF2C-specific T cell responses, CD8(+) T cells directed against 1 or more peptides were found in less than 10% of patients, whereas specific CD4(+) T cells were detected in close to 50% of patients. These T cells were of high avidity, recognized the naturally processed antigen and secreted IFN-gamma and TNF-alpha. Depletion of CD4(+)CD25(+) T cells before stimulation significantly increased the intensity of the preexisting response. NY-CO-58/KIF2C is significantly overexpressed in colorectal and other epithelial cancers and expression levels correlate with the proliferative activity of the tumor. Importantly, NY-CO-58/KIF2C was able to induce spontaneous CD4(+) T cell responses of the Th1-type, which were tightly controlled by peripheral T regulatory cells.

For which type of chronic pancreatitis is the "Hamburg procedure" indicated?

BACKGROUND: A pancreatic duct diameter (PDD) ranging from 4 to 5 mm is regarded as "normal". The "large duct" form of chronic pancreatitis (CP) with a PDD > 7 mm is considered a classical indication for drainage procedures. In contrast, in patients with so-called "small duct pancreatitis" (SDP) with a PDD < 3 mm, extended resectional procedures are suggested including, as an "ultima ratio", even total pancreatectomy. METHODS: Between 1992 and 2008, among a total of 978 patients who were treated for CP, 51 suffered from SDP and underwent longitudinal "V-shaped excision" of the anterior aspect of the pancreas. The interval between symptoms and surgery varied from 12 to 123 months. Median follow-up was 87 months (range 32-131 months). A pain score was used as well as a multidimensional psychometric quality-of-life questionnaire. RESULTS: Hospital mortality was 0%. The perioperative morbidity (30 days) was 19.1%. Median pain score decreased by 95.5%. Global quality of life index increased in median by 53.6% (range 37.5-80%). In 35 patients (75%), complete pain relief was achieved. The impairment of exocrine and endocrine pancreatic function after surgery was statistically not significant. CONCLUSIONS: Longitudinal "V-shaped excision" of the ventral pancreas is a secure and effective approach for SDP, achieving significant improvement in quality of life and pain relief. While sparing patients from unnecessary, extended resectional procedures, it appears not to result in substantial deterioration of exocrine and endocrine pancreatic function.

Extended central pancreatic resection as an alternative for extended left or extended right resection for appropriate pancreatic neoplasms.

BACKGROUND: Whether patients with focal pancreatic lesions of benign or borderline pathology should be treated by extended central pancreatectomy rather than by extended classic resectional procedures, such as extended right and left resections, is controversial. METHODS: Between 1992 and 2007, 105 patients underwent operation for focal pancreatic lesions of borderline or benign neuroendocrine neoplasms, cystadenoma, intraductal papillary mucinous neoplasia (IPMN), and secondary metastasis. In all, 35 patients were subjected to extended central pancreatectomy, whereas the remaining 70 patients were treated by an extended classic right resection or an extended classic left resection. Groups were matched according to age, sex, and histopathology. RESULTS: No peri-operative mortality occurred after extended central pancreatectomy and extended classic left resection (n = 35, each). Two (6%) patients died after extended classic right resection. Overall, in-hospital morbidity was 26% after extended central pancreatectomy, 43% after extended classic right resection, and 37% after extended classic left resection. After a median follow-up of 48 months, a local recurrence rate of 17% after extended central pancreatectomy was similar to the corresponding rates of 9% after extended classic left resection and 14% after extended classic right resection. Endocrine and exocrine impairment was less pronounced after extended central pancreatectomy (6% and 9%) than after extended classic left resection (34% and 29%) and extended classic right resection (28% and 24%; P < .05). CONCLUSION: Extended central pancreatectomy for appropriate pancreatic neoplasms is associated with less peri-operative morbidity and mortality than after extended classic left and extended classic right resection. Long-term local recurrence after extended central pancreatectomy is similar to the recurrence rates after extended classic right and classic left resection. Our results suggest that appropriately selected patients will benefit from extended central pancreatectomy because of the maintenance of endocrine and exocrine function.

Subset of esophageal adenocarcinoma expresses adhesion molecule l1 in contrast to squamous cell carcinoma.

BACKGROUND: Esophageal adenocarcinoma is currently the most rapidly increasing cancer in Western populations. L1 (CD171), a neural cell adhesion molecule, has an essential function in tumor progression and has been shown to be expressed in the proliferating cells of the intestinal crypts in mice. The aim of the current study was to determine L1 expression in esophageal cancer and to evaluate whether L1 could serve as a potential marker and therapeutic target for this tumor type. MATERIALS AND METHODS: L1 expression was assessed on a tissue microarray with 257 surgically resected esophageal cancer samples by immunohistochemistry with a monoclonal antibody (Clone UJ127). L1 expression was correlated with clinicopathological data. RESULTS: L1 was detected in 22 (9%) of 257 esophageal cases, whereas 235 (91%) were L1 negative. Nineteen (86%) of the 22 L1-positive cases were adenocarcinoma. Cross table analysis showed a significant association between L1 expression and adenocarcinoma subtype (p<0.001), but not squamous cell carcinoma. CONCLUSION: L1 expression in a subgroup of esophageal cancer is specifically prevalent in adenocarcinoma. Data suggest L1 as a potential target for biological therapy in L1-positive esophageal adenocarcinoma patients.