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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.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.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 (P0.001). The LL genotype had the longest disease-free (P0.001) 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.GTn differentiates between benign and malignant PNET and is a strong predictor of tumor recurrence.

Microcirculatory disorders play a major part in the pathogenesis of acute pancreatitis. Improvement of microcirculation is hypothesized to open a therapeutic window. The aim of this study was to evaluate the effects of small-volume resuscitation in acute pancreatitis.In rats, acute pancreatitis of graded severity was induced and pancreatic microcirculation was observed in vivo with an epiluminescent microscope. Primary outcome measures were microcirculation, leukocyte adherence, concentration of trypsinogen-activating peptide, amylase activity and histopathologic tissue damage.In necrotizing pancreatitis patients receiving prophylactic intervention with 7.5% hypertonic saline the functional capillary density was 76%. Postcapillary venular leukocyte adherence was 45% of vein cross-section. The median histopathologic damage scored 8 points. In controls, a complete microcirculatory breakdown was observed, and in the group with therapeutic intervention no significant difference was detected. In intermediate pancreatitis, the number of perfused capillaries remained 55.0 versus 23.3% in controls. Leukocyte adherence was 40.0 versus 51.7%. The histopathologic damage scored 6.0 versus 9.0 points. Trypsinogen-activating peptide concentration was reduced to 164 versus 402 nM in controls. In cerulein pancreatitis, the number of perfused capillaries was equally preserved in both groups.Small-volume resuscitation preserves capillary microcirculation and prevents pancreatic injury in intermediate necrotizing pancreatitis.

Her-2 is the molecular target for antibody-based treatment of breast cancer (trastuzumab). The potential benefit of anti-Her-2 therapy is currently investigated in several other HER-2-amplified cancers including gastric cancer. Although HER-2 amplification occurs in more than 10% of gastric cancers, potential heterogeneity of HER-2 amplification and overexpression could represent a major drawback for anti-Her-2 therapy. To address the potential applicability of trastuzumab in gastric cancer, tissue microarray sections of 166 gastric adenocarcinomas and 69 lymph node metastases were analyzed for Her-2 overexpression and amplification using Food and Drug Administration-approved reagents for immunohistochemistry and fluorescence in situ hybridization. HER-2 amplification was seen in 27 (16%) of 166 gastric adenocarcinomas. Amplification was typically high level with more than 20 HER-2 copies per tumor cell and a HER-2/centromere 17 ratio >3. Amplification was associated with intestinal tumor phenotype but unrelated to survival, grading, pT, pN, or pM. Identical HER-2 status was found in primary tumor and their matched lymph node metastases. Moreover, HER-2 and Topoisomerase IIalpha coamplification analysis of 3 to 16 large sections from 8 Her-2-positive gastric cancers did not reveal any heterogeneity of the amplicon site. The high level of HER-2 amplification in combination with the homogeneity of its expression in primary and metastatic tumors argues for a possible therapeutic utility of trastuzumab in HER-2-amplified gastric adenocarcinomas.

Identification of dysplasia in inflammatory bowel disease represents a major challenge for both clinicians and pathologists. Clear diagnosis of dysplasia in inflammatory bowel disease is sometimes not possible with biopsies remaining "indefinite for dysplasia." Recent studies have identified molecular alterations in colitis-associated cancers, including increased protein levels of alpha-methylacyl coenzyme A racemase, p53, p16 and bcl-2. In order to analyze the potential diagnostic use of these parameters in biopsies from inflammatory bowel disease, a tissue microarray was manufactured from colons of 54 patients with inflammatory bowel disease composed of 622 samples with normal mucosa, 78 samples with inflammatory activity, 6 samples with low-grade dysplasia, 12 samples with high-grade dysplasia, and 66 samples with carcinoma. In addition, 69 colonoscopic biopsies from 36 patients with inflammatory bowel disease (28 low-grade dysplasia, 8 high-grade dysplasia, and 33 indefinite for dysplasia) were included in this study. Immunohistochemistry for alpha-methylacyl coenzyme A racemase, p53, p16 and bcl-2 was performed on both tissue microarray and biopsies. p53 and alpha-methylacyl coenzyme A racemase showed the most discriminating results, being positive in most cancers (77.3% and 80.3%) and dysplasias (94.4% and 94.4%) but only rarely in nonneoplastic epithelium (1.6% and 9.4%; P < .001). Through combining the best discriminators, p53 and alpha-methylacyl coenzyme A racemase, a stronger distinction between neoplastic tissues was possible. Of all neoplastic lesions, 75.8% showed a coexpression of alpha-methylacyl coenzyme A racemase and p53, whereas this was found in only 4 of 700 nonneoplastic samples (0.6%). alpha-methylacyl coenzyme A racemase/p53 coexpression was also found in 10 of 33 indefinite for dysplasia biopsies (30.3 %), suggesting a possible neoplastic transformation in these cases. Progression to dysplasia or carcinoma was observed in 3 of 10 p53/alpha-methylacyl coenzyme A racemase-positive, indefinite-for-dysplasia cases, including 1 of 7 cases without and 2 of 3 cases with p53 mutation. It is concluded that combined alpha-methylacyl coenzyme A racemase/p53 analysis may represent a helpful tool to confirm dysplasia in inflammatory bowel disease.

Background The utility of open lung biopsy (OLB) in mechanically ventilated patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) of unknown origin has been questioned because of its potentially low diagnostic yield and possibly related morbidity. To quantify possible benefits and risks, and especially so for bedside lung biopsy, we reviewed retrospectively our 8-year, single unit experience with this procedure. Methods Mechanically ventilated, critically ill patients with acute respiratory failure of unknown origin who underwent OLB were analyzed in a retrospective, single-center, cohort study in a medical intensive care unit in a university medical center. Measurements and Main Results Twenty-seven patients were analyzed (15 female, 12 male, of mean 48 years [standard deviation, 14]), 67% of whom were immunocompromised. All patients underwent bronchoscopy and bronchoalveolar lavage before OLB. Pa o 2 /Fraction of inspired oxygen at the time of biopsy was 188 ± 109 mm Hg. Biopsies were performed in the operating room on 9 patients and at bedside on 18. A specific diagnosis was obtained in 70% of biopsies. Biopsy results led to alteration in treatment in 81% of patients. Minor complications occurred in 52% of patients and major complications in 7%. The rate of complications did not appear to differ with the location of the procedure (bedside vs operating room). No deaths were attributed to the procedure. Conclusions Bedside OLB can be performed safely in selected, mechanically ventilated, critically ill patients with ALI or ARDS. Our results support the concept that lung biopsy often leads to management alterations in patients where a standardized diagnostic workup failed to yield a definitive diagnosis.

L1 is a cell adhesion molecule expressed at the invasive front of colorectal tumors with an important role in metastasis. The aim of the present study was to determine L1 protein expression in a large cohort of colorectal cancer patients and its impact on early metastatic spread and survival. A total of 375 patients that underwent surgical treatment for colorectal cancer were chosen retrospectively. A tissue microarray was constructed of 576 tissue samples from these patients and analyzed by immunohistochemistry with a monoclonal antibody against human L1 (UJ127). Lymph node and bone marrow micrometastasis were assessed with monoclonal antibodies Ber-EP4 and pancytokeratin A45-B/B3, respectively. Associations between L1 expression and lymph node, bone marrow micrometastasis and survival were investigated with Fisher's, log-rank test and Cox multivariate analysis. All statistical tests were two-sided. L1 was detected in a subset of 48 (13%) of 375 patients examined. Analysis of L1 expression and survival revealed a significantly worse outcome for L1-positive patients by log-rank test (P

Background EUS-guided pancreatic pseudocyst and abscess drainage ideally requires the insertion of both a transmural stent and nasocystic catheter to ensure continuous irrigation and effective drainage. Sequential stent and nasocystic catheter insertion may be time consuming because of the difficulty in recannulating the pseudocyst after the initial stent placement. Objective Our purpose was to describe a novel one-step simultaneous double-wire technique that facilitates effective pancreatic pseudocyst and abscess drainage. Design To solve the problem of recannulating the pseudocyst cavity after the initial transmural stent placement, we developed a prototype 3-layer puncture kit that allows the simultaneous insertion of 2 guidewires at the initial puncture in one step. This puncture kit consists of a 22-gauge needle used for FNA, a 6F inner polytetrafluoroethylene (Teflon) catheter, and an outer 8.5F Teflon catheter. Setting Tertiary referral center. Patients Eight consecutive patients were treated. Interventions With use of a therapeutic linear echoendoscope and the assembled kit with the needle protruding out distally, the pseudocyst cavity was punctured by using electrocautery. The needle and the inner catheter were then withdrawn, leaving the outer catheter within the cavity. The size of this outer catheter permitted the simultaneous insertion of two 0.035-inch guidewires. Sequential insertion of a transmural stent and nasocystic catheter was then performed without a need for recannulation of the pseudocyst or abscess cavity. Main Outcome Measurements Successful endoscopic drainage. Results All patients were successfully treated without complications. Mean procedural time was 32.5 minutes (range 25-45 minutes). Conclusions With this novel technique, establishing an irrigation system for the treatment of pancreatic pseudocysts and abscesses becomes easier, faster, and safer.

Impact of different modalities of continuous venovenous hemofiltration on sepsis-induced alterations in experimental pancreatitis. Background Continuous venovenous hemofiltration (CVVH) is assumed to attenuate systemic complications in septic diseases. The impact of different treatment intensities of CVVH on immunologic and systemic alterations in experimental pancreatitis was evaluated. Methods Eighty-four minipigs were allocated either to an untreated control group (group 1) or to one of six treatment groups (groups 2 to 7) that underwent CVVH in different modalities: ( 1 ): "late" CVVH, started after a decline of total peripheral resistance of 30% versus "prophylactic" CVVH started immediately after the induction of pancreatitis; ( 2 ) no change of hemofilters versus a periodic change of filters every 12 hours; ( 3 ) low-volume CVVH with a filtrate turnover of 20 mL/kg body weight (BW)/h versus high-volume CVVH (100 mL/kg/h). Pancreatitis was induced by intraductal injection of sodium-taurocholate (3%, 1 mL/kg BW) and enterokinase (2 U/kg BW). We focused on the occurrence of sepsis, serum cytokines, down-regulation of major histocompatibility complex II (MHC II) and the endotoxin receptor CD14 expression, bacterial translocation/endotoxemia, and pulmonary and renal histologic alterations. Results CVVH delayed or definitively prevented the occurrence of sepsis. Pancreatitis was associated with a tremendous initial tumor necrosis factor-α (TNF-α) response prior to a return to near baseline levels in the late course of sepsis. Endotoxin hyporesponsiveness, suggested by the dissociation of decreasing TNF-α levels and increasing endotoxemia in end-stage sepsis, was favorably influenced by CVVH. Down-regulation of MHC II and CD14 expression was prevented in non-septic animals. CVVH-related sepsis-protection led to a significant attenuation of histological injury in lungs and kidneys. "Prophylactic" CVVH prevented histological changes more effectively than "late" CVVH. Conclusions CVVH offers a therapeutic option for supportive treatment in severe pancreatitis. The efficiency of CVVH is associated with the duration of filter use and cumulative plasma turnover. Since CVVH may lead to sepsis-protection and long-term survival, further evaluation in controlled, clinical trials is warranted.

AIM: To evaluate the role of PET/CT as an additional staging modality in oesophageal cancer. PATIENTS AND METHODS: 46 consecutive patients with potentially curable oesophageal cancer underwent PET/CT as part of primary staging after conventional staging with CT, +/endoscopic ultrasound (EUS), +/staging laparoscopy and discussion at the regional multidisciplinary team meeting (MDT). Data was collected prospectively between 1st May and 1st November 2009. RESULTS: Patients included 32 males, 14 females, median age 68 years (range 44-86 years). 29 had adenocarcinoma, 15 squamous carcinoma and 2 undifferentiated carcinoma. All had previous CT and, 32 (68%) had EUS and 19 (41%). Staging prior to PET-CT was recorded as: T1/2 N0 = 5; T3 N0 = 7; T1/2 N1 = 9; T3 N1 = 21; T4 N0/1 = 4. Staging following these investigations was recorded and compared to findings at PET/CT. There were 8 (17%) examinations reported positive for metastatic disease. 6 (13%) patients had metastatic disease not identified on previous staging. 2 patients had confirmation of metastatic disease after suspicion was raised on previous investigation. Other previously undiagnosed cancers were seen in 2 cases: 1 confirmed breast cancer and 1 advanced oropharygeal cancer. In 13 of 31 (42%) cases, PET/CT understaged nodal disease reported as N1 on previous staging. 2/46 (4%) with negative PET/CT were later identified to have metastatic disease (false negatives). 27 patients post PET-CT proceeded to radical treatment (neo-adjuvant chemotherapy + surgery in 18; radical chemo-radiotherapy in 9). 19 patients proceeded to palliative treatment. CONCLUSION: We conclude that PET/CT is a highly important stagingmodality in oesophageal carcinoma. Treatment plans were changed from potentially curable to palliative in 10 (22%) with metastatic disease identified in 8/46 (17%) of patients previously thought possible candidates for radical treatment after conventional imaging with CT +/EUS +/laparoscopy. PET/CT showed a relatively poor correlation with conventional staging for nodal disease with 13/31 (42%) of patients with local nodal disease after conventional staging understaged as node negative.