H. D. Saeger

Colorectal cancer (CRC) is the second leading cause of cancer deaths despite the fact that detection of this cancer in early stages results in over 90% survival rate. Currently less than 45% of at-risk individuals in the US are screened regularly, exposing a need for better screening tests. We performed two case-control studies to validate a blood-based test that identifies methylated DNA in plasma from all stages of CRC.Using a PCR assay for analysis of Septin 9 (SEPT9) hypermethylation in DNA extracted from plasma, clinical performance was optimized on 354 samples (252 CRC, 102 controls) and validated in a blinded, independent study of 309 samples (126 CRC, 183 controls). 168 polyps and 411 additional disease controls were also evaluated. Based on the training study SEPT9-based classification detected 120/252 CRCs (48%) and 7/102 controls (7%). In the test study 73/126 CRCs (58%) and 18/183 control samples (10%) were positive for SEPT9 validating the training set results. Inclusion of an additional measurement replicate increased the sensitivity of the assay in the testing set to 72% (90/125 CRCs detected) while maintaining 90% specificity (19/183 for controls). Positive rates for plasmas from the other cancers (11/96) and non-cancerous conditions (41/315) were low. The rate of polyp detection (>1 cm) was approximately 20%.Analysis of SEPT9 DNA methylation in plasma represents a straightforward, minimally invasive method to detect all stages of CRC with potential to satisfy unmet needs for increased compliance in the screening population. Further clinical testing is warranted.

Cancers originating from epithelial cells are the most common malignancies. No common expression profile of solid tumors compared to normal tissues has been described so far. Therefore we were interested if genes differentially expressed in the majority of carcinomas could be identified using bioinformatic methods. Complete data sets were downloaded for carcinomas of the prostate, breast, lung, ovary, colon, pancreas, stomach, bladder, liver, and kidney, and were subjected to an expression analysis using SAM. In each experiment, a gene was scored as differentially expressed if the q value was below 25%. Probe identifiers were unified by comparing the respective probe sequences to the Unigene build 155 using BlastN. To obtain differentially expressed genes within the set of analyzed carcinomas, the number of experiments in which differential expression was observed was counted. Differential expression was assigned to genes if they were differentially expressed in at least eight experiments of tumors from different origin. The identified candidate genes ADRM1, EBNA1BP2, FDPS, FOXM1, H2AFX, HDAC3, IRAK1, and YY1 were subjected to further validation. Using this comparative approach, 100 genes were identified as upregulated and 21 genes as downregulated in the carcinomas.

Learning Objectives Assess the basic aspects of PNET tumor biology, pathogenesis, and classification. Explain the epidemiology and evaluate the prognosis of PNET patients. Engage in rational clinical management of PNETs. This article is available for continuing medical education credit at CME.TheOncologist.com

Pancreatic ductal adenocarcinoma (PDAC) remains an important cause of malignancy-related death and is the eighth most common cancer with the lowest overall 5-year relative survival rate. To identify new molecular markers and candidates for new therapeutic regimens, we investigated the gene expression profile of microdissected cells from 11 normal pancreatic ducts, 14 samples of PDAC, and 4 well-characterized pancreatic cancer cell lines using the Affymetrix U133 GeneChip set. RNA was extracted from microdissected samples and cell lines, amplified, and labeled using a repetitive in vitro transcription protocol. Differentially expressed genes were identified using the significance analysis of microarrays program. We found 616 differentially expressed genes. Within these, 140 were also identified in PDAC by others, such as Galectin-1, Galectin-3, and MT-SP2. We validated the differential expression of several genes (e.g., CENPF, MCM2, MCM7, RAMP, IRAK1, and PTTG1) in PDAC by immunohistochemistry and reverse transcription polymerase chain reaction. We present a whole genome expression study of microdissected tissues from PDAC, from microdissected normal ductal pancreatic cells and pancreatic cancer cell lines using highdensity microarrays. Within the panel of genes, we identified novel differentially expressed genes, which have not been associated with the pathogenesis of PDAC before.

Background Arterial pseudoaneurysm formation in pancreatitis is a rare complication. The optimal treatment modality is controversial. Operative treatment and interventional treatment, either alone or as a temporizing method with a later operation, are options. Methods In this single-center, patient-based cohort study, we managed 35 patients (8 with necrotizing pancreatitis and 27 with chronic pancreatitis) with bleeding pseudoaneurysms treated over a period of 10.5 years with a median follow-up of 4.6 years. Angiography was performed depending on the patient's hemodynamic condition. Results Angiography had a sensitivity of 96% for 26 patients. Angiographic embolization as primary treatment was performed in 16 patients (61% embolization rate); there were 2 rebleeding complications. No patients required intervention for embolization complications after discharge. Nineteen patients (54%) underwent an operation, 9 urgently without angiographic evaluation. The overall mortality rate for the 35 patients was 20% (19% for embolization, 21% after an operation). For necrotizing pancreatitis, an advantage of angiographic embolization was observed (mortality in 2/5 vs 2/3 after surgery). Ligation or repair of the bleeding vessel was complicated by higher rebleeding rates (6/13) than partial pancreatectomy (1/6). Conclusions Concerns that angiographic embolization is unable to provide definitive hemostasis in both acute and chronic pancreatitis are unfounded. In the operative treatment of chronic pancreatitis, partial pancreatectomy is superior to vessel ligation, depending on the patient's general condition and degree of pancreatic inflammation. We propose an algorithm for the management of arterial pseudoaneurysms in the setting of pancreatitis. Arterial pseudoaneurysm formation in pancreatitis is a rare complication. The optimal treatment modality is controversial. Operative treatment and interventional treatment, either alone or as a temporizing method with a later operation, are options. In this single-center, patient-based cohort study, we managed 35 patients (8 with necrotizing pancreatitis and 27 with chronic pancreatitis) with bleeding pseudoaneurysms treated over a period of 10.5 years with a median follow-up of 4.6 years. Angiography was performed depending on the patient's hemodynamic condition. Angiography had a sensitivity of 96% for 26 patients. Angiographic embolization as primary treatment was performed in 16 patients (61% embolization rate); there were 2 rebleeding complications. No patients required intervention for embolization complications after discharge. Nineteen patients (54%) underwent an operation, 9 urgently without angiographic evaluation. The overall mortality rate for the 35 patients was 20% (19% for embolization, 21% after an operation). For necrotizing pancreatitis, an advantage of angiographic embolization was observed (mortality in 2/5 vs 2/3 after surgery). Ligation or repair of the bleeding vessel was complicated by higher rebleeding rates (6/13) than partial pancreatectomy (1/6). Concerns that angiographic embolization is unable to provide definitive hemostasis in both acute and chronic pancreatitis are unfounded. In the operative treatment of chronic pancreatitis, partial pancreatectomy is superior to vessel ligation, depending on the patient's general condition and degree of pancreatic inflammation. We propose an algorithm for the management of arterial pseudoaneurysms in the setting of pancreatitis.

Bei diesem Dokument handelt es sich um die aktualisierte Fassung der 2006 erstmals erstellten S3-Leitlinie zum exokrinen Pankreaskarzinom.

Pancreatic intraductal papillary mucinous neoplasms (IPMNs) rank among the most common cystic tumors of the pancreas. For a long time they were misdiagnosed as mucinous cystadenocarcinoma, ductal adenocarcinoma in situ, or chronic pancreatitis. Only in recent years have IPMNs been fully recognized as clinical and pathological entities, although their origin and molecular pathogenesis remain poorly understood. IPMNs are precursors of invasive carcinomas. When resected in a preinvasive state patient prognosis is excellent, and even when they are already invasive, patient prognosis is more favorable than with ductal adenocarcinomas. Subdivision into macroscopic and microscopic subtypes facilitates further patient risk stratification and directly impacts treatment. There are main duct and branch duct IPMNs, with the main duct type including the intestinal, pancreatobiliary, and oncocytic types and the branch duct type solely harboring the gastric type. Whereas main duct IPMNs have a high risk for malignant progression, demanding their resection, branch duct IPMNs have a much lower risk for harboring malignancy. Patients with small branch duct/gastric-type IPMNs (<2 cm) without symptoms or mural nodules can be managed by periodic surveillance.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant desmoplastic stroma. Interactions between cancer and stromal cells play a critical role in tumour invasion, metastasis and chemoresistance. Therefore, we hypothesized that gene expression profile of the stromal components of pancreatic carcinoma is different from chronic pancreatitis and reflects the interaction with the tumour. We investigated the gene expression of eleven stromal tissues from PDAC, nine from chronic pancreatitis and cell lines of stromal origin using the Affymetrix U133 GeneChip set. The tissue samples were microdissected, the RNA was extracted, amplified and labelled using a repetitive in vitro transcription protocol. Differentially expressed genes were identified and validated using quantitative RT‐PCR and immuno‐histochemistry. We found 255 genes to be overexpressed and 61 genes to be underexpressed within the stroma of pancreatic carcinoma compared to the stroma of chronic pancreatitis. Analysis of the involved signal transduction pathways revealed a number of genes associated with the Wnt pathway of which the differential expression of SFRP1 and WNT5a was confirmed using immunohistochemistry. Moreover, we could demonstrate that WNT5a expression was induced in fibroblasts during cocultivation with a pancreatic carcinoma cell line. The identified differences in the expression profile of stroma cells derived from tumour compared to cells of inflammatory origin suggest a specific response of the tissue surrounding malignant cells. The overexpression of WNT5a, a gene involved in the non canonical Wnt signalling and chondrocyte development might contribute to the strong desmoplastic reaction seen in pancreatic cancer.

Abstract Ampullary cancer represents approximately 6% of the malignant periampullary tumors. An early occurrence of symptoms leads to a 5-year survival rate after curative surgery of 30 to 67%. In addition to the tumor stage, the immunohistological subtypes appear to be important for postoperative prognosis. The aim of this study was to analyze the different subtypes regarding their prognostic relevance. A total of 170 patients with ampullary cancer were retrospectively analyzed between 1999 until 2016 after pancreatic resection. Patients were grouped according to their pathohistological subtype of ampullary cancer (pancreatobiliary, intestinal, mixed). Characteristics among the groups were analyzed using univariate and multivariate models. Survival probability was analyzed by the Kaplan-Meier method. An exact subtyping was possible in 119 patients. A pancreatobiliary subtype was diagnosed in 69 patients (58%), intestinal in 41 patients (34.5%), and a mixed subtype in 9 patients (7.6%). Survival analysis showed a significantly worse 5-year survival rate for the pancreatobiliary subtype compared with the intestinal subtype (27.5% versus 61%, p &lt; 0.001). The mean overall survival of patients with pancreatobiliary, intestinal, and mixed subtype was 52.5, 115 and 94.7 months, respectively ( p &lt; 0.001). The pathohistological subtypes of ampullary cancer allows a prediction of the postoperative prognosis.

Germline mutations in human mismatch repair (MMR) genes yield a predisposition for the hereditary nonpolyposis colon cancer (HNPCC) syndrome. In contrast to hMLH1 and hMSH2, little is known about the overall involvement of hMSH6 in colorectal cancer. We investigated 82 tumors from patients who fulfilled the Bethesda guidelines for HNPCC as well as 146 sporadic tumors, analyzing microsatellite instability and expression of the 4 MMR proteins hMSH6, hMSH2, hMLH1 and hPMS2. Four tumors with lost expression and 1 tumor with cytoplasmic expression of hMSH6 were identified. Sequence analysis revealed germline mutations in 4 of the 5 patients, including 1 patient with sporadic disease. The lost or reduced expression of hMSH2 and hMLH1 was always identical to its heterodimerization partners, hMSH6 and hPMS2, respectively. Furthermore, hMSH2 expression was reduced upon hMSH6 deficiency. Abnormal expression of 1 or more of the 4 proteins was always associated with a high level of microsatellite instability (MSI-H). Conversely, all but 1 of the 44 MSI-H tumors had abnormal expression of 1 or more of the proteins, basically excluding additional genes associated with the MSI-H phenotype. We conclude that the involvement of somatic or epigenetic hMSH6 inactivation in colorectal cancer is rare.

Abstract Aberrant DNA methylation occurs early in oncogenesis, is stable, and can be assayed in tissues and body fluids. Therefore, genes with aberrant methylation can provide clues for understanding tumor pathways and are attractive candidates for detection of early neoplastic events. Identification of sequences that optimally discriminate cancer from other diseased and healthy tissues is needed to advance both approaches. Using well-characterized specimens, genome-wide methylation techniques were used to identify candidate markers specific for colorectal neoplasia. To further validate 30 of these candidates from genome-wide analysis and 13 literature-derived genes, including genes involved in cancer and others with unknown functions, a high-throughput methylation-specific oligonucleotide microarray was used. The arrays were probed with bisulfite-converted DNA from 89 colorectal adenocarcinomas, 55 colorectal polyps, 31 inflammatory bowel disease, 115 extracolonic cancers, and 67 healthy tissues. The 20 most discriminating markers were highly methylated in colorectal neoplasia (area under the receiver operating characteristic curve &amp;gt; 0.8; P &amp;lt; 0.0001). Normal epithelium and extracolonic cancers revealed significantly lower methylation. Real-time PCR assays developed for 11 markers were tested on an independent set of 149 samples from colorectal adenocarcinomas, other diseases, and healthy tissues. Microarray results could be reproduced for 10 of 11 marker assays, including eight of the most discriminating markers (area under the receiver operating characteristic curve &amp;gt; 0.72; P &amp;lt; 0.009). The markers with high specificity for colorectal cancer have potential as blood-based screening markers whereas markers that are specific for multiple cancers could potentially be used as prognostic indicators, as biomarkers for therapeutic response monitoring or other diagnostic applications, compelling further investigation into their use in clinical testing and overall roles in tumorigenesis. (Mol Cancer Res 2007;5(2):153–63)

Background: Pancreatic cancer is one of the leading causes of cancer-related death. Using DNA gene expression analysis based on a custom made Affymetrix cancer array, we investigated the expression pattern of both primary and established pancreatic carcinoma cell lines. Methods: We analyzed the gene expression of 5 established pancreatic cancer cell lines (AsPC-1, BxPC-3, Capan-1, Capan-2 and HPAF II) and 5 primary isolates, 1 of them derived from benign pancreatic duct cells. Results: Out of 1,540 genes which were expressed in at least 3 experiments, we found 122 genes upregulated and 18 downregulated in tumor cell lines compared to benign cells with a fold change > 3. Several of the upregulated genes (like Prefoldin 5, ADAM9 and E-cadherin) have been associated with pancreatic cancer before. The other differentially regulated genes, however, play a so far unknown role in the course of human pancreatic carcinoma. By means of immunohistochemistry we could show that thymosin [β-10 (TMSB10), upregulated in tumor cell lines, is expressed in human pancreatic carcinoma, but not in non-neoplastic pancreatic tissue, suggesting a role for TMSB10 in the carcinogenesis of pancreatic carcinoma. Conclusion: Using gene expression profiling of pancreatic cell lines we were able to identify genes differentially expressed in pancreatic adenocarcinoma, which might contribute to pancreatic cancer development.

To describe a genotype-phenotype correlation in MEN2 families with germline mutations of codons 790/791 and discuss options for the therapeutic management of gene carriers.Heredity of MEN2 syndromes is caused by a heterozygous germline mutation in the protooncogene. Rare mutations of codons 790/791 associated with incomplete penetrant MEN2A/FMTC phenotype were reported in five families, contraindicating the prophylactic thyroidectomy for the genetically affected children.Forty-five patients with a putative sporadic MTC were screened for germline mutations by direct DNA sequencing. Family members of identified index cases underwent genetic analysis. Gene carriers were examined clinically and biochemically, and all gene carriers underwent prophylactic thyroidectomy.Five index patients were identified, four of whom harbored mutations in codons 790/791 and one in codon 634. In the kindreds, four L790F carriers and one Y791F carrier were detected. The thyroid gland histology of L790F carriers revealed medullary thyroid carcinoma in two patients (aged 29 and 50 years) and C-cell hyperplasia in two additional patients (aged 9 and 16 years). The Y791F carrier had a normal histology.Codon 790/791 mutations had diverse penetrance. Whereas prophylactic thyroidectomy in children is a justifiable approach for codon 790 mutation carriers, the indication for thyroidectomy should depend on the clinical course of codon 791 carriers.

To evaluate the involvement of hMSH6 in colorectal cancer, the complete coding sequence and flanking intron regions of the gene were analyzed by DNA sequencing in 10 patients fulfilling Bethesda Guidelines for colorectal tumors and 10 patients with sporadic colorectal carcinoma. In addition, 10 mono- and 10 dinucleotide repeat markers were analyzed for microsatellite instability. A protein-truncating T insertion at codon 218 was identified in the index person of a hereditary non-polyposis colorectal cancer (HNPCC)-like kindred and was accompanied by a somatic T deletion in the tumor. The tumor of this patient was positive for mono- but negative for dinucleotide repeat instability and lacked allelic losses at loci frequently affected in colorectal carcinomas. A novel amino acid change, F340S, was found in a patient with sporadic colon and breast cancer and leukemia but was not detected in 246 chromosomes from healthy anonymous blood donors. In addition, we describe 2 silent and 15 intronic sequence variants not previously reported. Although the frequency is low, we present further evidence for hMSH6 germline mutations that predispose patients to HNPCC-like phenotypes and suggest that mono- and dinucleotide repeat instability testing may be useful for distinguishing between individuals harboring an hMSH2 or hMLH1 mutation and a mutation of the hMSH6 gene.

Mononucleotide repeat sequences are particularly prone to frameshift mutations in tumors with biallelic inactivation of the mismatch repair (MMR) genes MLH1 or MSH2. In these tumors, several genes harboring mononucleotide repeats in their coding region have been proposed as targets involved in tumor progression, among which are also the MMR genes MSH3 and MSH6. We have analyzed the expression of the MSH3 and MSH6 proteins by immunohistochemistry in 31 colorectal carcinomas in which MLH1 was inactivated. Loss of MSH3 expression was identified in 15 tumors (48.5%), whereas all tumors expressed MSH6. Frameshift mutations at coding microsatellites were more frequent in MSH3 (16 of 31) than in MSH6 (3 of 31; Fisher's exact test, P < 0.001). Frameshift mutations and allelic losses of MSH3 were more frequent in MSH3-negative tumors compared with those with normal expression (22 mutations in 30 alleles versus 8 mutations in 28 alleles; chi(2), P = 0.001). Biallelic inactivation was evident or inferred for 60% of MSH3-negative tumors but none of the tumors with normal MSH3 expression. In contrast, we did not identify frameshift mutations in the (A)8 tract of MSH3 in a control group of 18 colorectal carcinomas in which the MMR deficiency was based on the inactivation of MSH2. As it has been suggested that mutations of MSH3 might play a role in tumor progression, we studied the association between MSH3 expression and disease stage assessed by lymph node and distant metastases status. Dukes stages C and D were more frequent in primary tumors with loss of MSH3 expression (9 of 13), compared with tumors with retained expression (1 of 14; Fisher's exact test, P = 0.001), suggesting that MSH3 abrogation may be a predictor of metastatic disease or even favor tumor cell spread in MLH1-deficient colorectal cancers.

Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in the folate metabolism, which affects DNA synthesis and methylation. Low enzyme activity may reduce the capacity of DNA methylation, and possibly reduce uracil misincorporation into DNA, which can result in double strand breaks. Both processes may be critical for the oncogenic transformation of human cells. Two common amino acid-changing and enzyme activity-reducing nucleotide polymorphisms (677C --> T/Ala222Val and 1298A --> C/Glu428Ala) have been described in MTHFR. We performed estimations of the relative risk associated with these two polymorphisms in samples from 287 colorectal cancer patients, compared to 346 healthy controls. Relative risk were further determined for subpopulations of cancer patients having sporadic (n = 227) or suspected/verified hereditary disease (n = 60) and tumours exhibiting high-level microsatellite instability (n = 41) or not (n = 246). No significant differences for the relative risk of colorectal cancer were observed for the MTHFR genotypes either alone or in combination in the analysed cohorts, although the frequency of the 1298AA + AC genotypes was increased among the 60 cases with hereditary disease. Whereas our results do not support an association of high enzyme activity and increased risk of colorectal cancer in general, we can not exclude an association of patients with hereditary disease and the MTHFR 1298A --> C variant.

Evaluation of b-mode and colour-duplex imaging, contrast-enhanced ultrasound (CEUS) and CT for the detection of liver lesions in comparison to intraoperative and histological findings.Before laparotomy, 100 patients with suspected liver lesions were prospectively examined with b-mode and colour-duplex imaging followed by contrast-enhanced ultrasound (SonoVue) and CT-scan. Patients with nonresectable tumours (n=44) were excluded from the analysis. The diagnostic findings of 56 patients who displayed liver lesions were compared to the intraoperative and histological findings.CEUS enhanced the sensitivity for the number of detected lesions from 53 % (b-mode) to 86 % (CEUS) (p = 0.001), while CT-scan reached 76 %. The specificity of the three methods differed only slightly (87 % to 89 %). Contrast agents lead to an improvement in the results of ultrasound, particularly in cases of nodular metastases smaller than one centimeter (n = 7), after adjuvant chemotherapy (n = 4), near the surface (n = 6) and in lesions situated around the Lig. teres (n = 6).CEUS leads to a significant improvement in the detection of liver lesions. For patients after adjuvant chemotherapy as well as for cases of small nodular metastases a CEUS should be carried out as a routine.

Background: Pancreatic métastases from renal cell carcinoma (RCC) are clinically rare but highly resectable. The aim of this article is to identify patients who profit from pancreatic resection of RCC despite the invasiveness of the surgery. Methods: Between January 1996 and December 2007, data from 744 patients were collected in a prospective pancreatic surgery database, and patients with metastasis into the pancreas from RCC were identified. Results: Resective surgery was performed in 14 patients with metastasis to the pancreas from RCC. Most patients were clinically asymptomatic. The median interval between primary treatment of RCC and occurrence of pancreatic metastasis was 94 months (range 32–158). The morbidity rate was 42.8%. Patients with a metastasis size <2.5 cm had a much better survival after resection (100 months) than those with a metastasis size >2.5 cm (44 months). Moreover, the number of métastases predicts the survival after resection. Conclusions: In patients with pancreatic métastases from RCC who have only limited disease, complete resection of all lesions can be successfully performed with a low rate of complications. Thus, patients with a history of RCC should be monitored for more than 10 years after nephrectomy to detect recurrence.

The many varieties of cystic pancreatic tumor, and especially intraductal papillary mucinous neoplasia (IPMN), have attracted increased attention recently. Their incidence may be rising, and their histopathological evaluation and classification have become more precise than before.We discuss the current diagnostic evaluation of IPMN, along with treatment and prognostication, on the basis of the current international guideline as well as pertinent literature retrieved by a selective PubMed search.The preoperative diagnostic evaluation of IPMN is often problematic. In particular, it may not be possible to differentiate main-duct disease from branch-duct disease (MD-IPMN vs. BD-IPMN) before surgery--a distinction with implications for prognosis and treatment, as MD-IPMN is more often malignant. An IPMN adenoma can develop into invasive pancreatic cancer. Because firm diagnostic criteria are still lacking, it is recommended that all MD-IPMN lesions and all large BD-IPMN lesions should be resected. Partial pancreatectomy with clean margins is the treatment of choice.As IPMN seems to be a slow-growing precursor of pancreatic cancer, it is possible that its early detection and surgical treatment can lead to a cure. No conclusion about the efficacy of surveillance and follow-up programs can be drawn from the available evidence. A better understanding of the natural course of IPMN and the biology of pancreatic cancer is needed to enable further improvements in diagnosis and treatment.

The objective of this study was to determine the long-term quality of life (QOL) in patients with an abdominal aortic aneurysm (AAA) undergoing surveillance or after operative treatment.249 patients with AAAs completed the WHO Quality of Life-BREF (WHOQOL-BREF) test and Short Form (36) Health Survey (SF-36) survey: 78 patients with small AAAs under surveillance, 26 after ruptured AAAs (rAAAs), 47 after endovascular aneurysm repair (EVAR), and 98 after elective open repair. The results were compared with WHOQOL-BREF and SF-36 standard values from a matched German population using the Student's 2-tailed t-test.Long-term results of the WHOQOL-BREF test showed that patients undergoing AAA surveillance had a significantly lower physical QOL (P = 0.04). Patients after EVAR or open repair rated their environmental QOL significantly higher than the age- and sex-matched general population (open repair: P = 0.006; EVAR: P < 0.001). Patients with rAAAs had the same QOL as the matched German population. Long-term results of the QOL SF-36 showed that patients undergoing AAA surveillance rated their QOL significantly lower in the subgroup of role-physical (P = 0.02) and role-emotional (P = 0.003). Patients with rAAAs rated lower scores for role-physical (P = 0.02) and had more bodily pain (P = 0.02). Patients who underwent elective open repair had the same high QOL as the matched German population, whereas patients who underwent EVAR reported significant improvement in vitality (P = 0.002) and mental health (P = 0.03) compared with the matched German population.Based on measurements from 2 independent QOL tests, the well-established operative treatment of AAAs provided patients with a QOL comparable to that of a matched German population. The electively treated AAA groups rated environmental QOL factors significantly higher than the control group. The impaired physical and emotional QOL of the AAA group under surveillance suggests that more intense patient education could be beneficial.

Pancreatic cancer is a disease with high resistance to most common therapies and therefore has a poor prognosis, which is partly due to a lack of reaction to apoptotic stimuli. Signal transduction of such stimuli includes a death receptor-mediated extrinsic pathway as well as an intrinsic pathway linked to the mitochondria. Defects in apoptotic pathways and the deregulation of apoptotic proteins, such as Survivin, Bcl-2, Bcl-xL and Mcl-1, play decisive roles in the development of pancreatic cancer. Investigation of the molecular mechanism allowing tumors to resist apoptotic cell death would lead to an improved understanding of the physiology and the development of new molecular strategies in pancreatic cancer.

Objectives. Quality of life as an endpoint of surgery and the long-term prognosis for patients who have survived surgery for a ruptured abdominal aortic aneurysm (RAAA) is not well-documented.Patients and methods. The records of all patients from 1993 to 2000 who underwent resection of RAAA were reviewed. Survival data were calculated from direct contact with the patients or follow-up records. All patients who were alive at the time of our study were invited to participate in follow-up investigations. They received the internationally comparable WHO-QOL-BREF-test.Results. In a period of 7 years, 80 patients underwent surgery for RAAA. The average follow-up time was 5.1 years (1–7.9 years). Our data show that 51% of our patients died within 6 months postoperatively because of the complications of the aortic rupture (in-hospital mortality 39%). Patients who survived the first 6 months after surgery died for the same reasons as the normal population. However, patients who were younger than 75 at the time of RAAA had a higher relative survival rate than a matched sample of the population. There was no significant difference in the quality of life between the study group and the general population.Conclusions. RAAA survivors had no difference in long-term survival as compared to the general population and also had very few long-term complications. The WHOQOL-BREF-test suggests that the quality of life of survivors of RAAA is similar to the general population.

Infectious agents are likely to play a role in the pathogenesis of chronic inflammatory diseases, including abdominal aortic aneurysms (AAAs). The goal of this study was to determine if Borrelia burgdorferi sensu lato (sl), a microorganism responsible for Lyme disease, is involved in the etiology of AAAs. The presence of serum antibodies against B. burgdorferi sl was measured with enzyme-linked immunosorbent assay (ELISA) and confirmed by Western blotting in 96 AAA and 108 peripheral artery disease (PAD) patients. Polymerase chain reaction (PCR) was used for the detection of Borrelia-specific DNA in the aneurysm wall. Among AAA patients 34% and among PAD patients 16% were seropositive for B. burgdorferi sl antibodies (Fisher's exact test, p = 0.003; odds ratio [OR] 2.79; 95% confidence interval [CI] 1.37-5.85). In the German general population, 3-17% are seropositive for Borrelia antibodies. No Borrelia DNA was detected in the aneurysm wall. Our findings suggest a relationship between AAAs and B. burgdorferi sl. We hypothesize that the underlying mechanism for B. burgdorferi sl in AAA formation is similar to that by the spirochete Treponema pallidum; alternatively, AAAs could develop due to induced autoimmunity via molecular mimicry due to similarities between some of the B. burgdorferi sl proteins and aortic proteins.

One impediment for a wider application of islet transplantation is the limited number of donor pancreata for islet isolation. A more efficient utilization of available organs could in part alleviate this problem. Perfluorocarbons (PFCs) have a high oxygen solubility coefficient and maintain high oxygen partial pressures for extended time. They serve also as oxygen "reservoirs" for harvested organs in pancreas organ transplantation. The aim of this study was to test whether the use of PFCs could also be beneficial for the secretory activity and overall viability of cultured purified islets before transplantation. Purified rat islets were cultured in static conditions with or without oxygen-saturated PFCs for 1 or 7 days. Cell death and apoptosis were assessed by trypan blue staining, DNA strand breaks, and caspase 3/7 activity. mRNA levels of insulin and ICA512/IA-2, a membrane marker of secretory granules (SGs), were quantitated by real-time PCR, whereas insulin content and secretion were measured by RIA. Polypyrimidine tract binding protein (PTB), which promotes SG biogenesis, was assessed by Western blotting. The number of SGs and the ultrastructural appearance of beta5-cells were analyzed by cryoimmunoelectronmicroscopy for insulin. Various parameters, including caspase activity, insulin and ICA512/IA-2 mRNA levels, PTB expression, number of secretory granules, and ultrastructural appearance did not significantly differ between control and PFC-cultured islets. On the other hand, PFC culture islets showed significantly increased DNA fragmentation and a reduced insulin stimulation index at both time points compared to control islets. While advantageous for the transport of human harvested organs, the use of PFH in the culture may be comparable to and/or not provide advantage over conventional protocols for culture of islets for transplantation.

Familial pancreatic cancer (FPC) (approximately 3% of all cases) has not been linked to defects in any specific gene. Germline inactivation of the gene LKB1/STK11 have been shown to cause Peutz-Jeghers syndrome (PJS) associated with a ∼100-fold higher risk for the development of pancreatic cancer. We have analysed 39 index patients from European FPC families for mutations of LKB1/STK11 by sequencing of their DNA. No germline mutation was found within the complete coding region. Therefore, our results indicate that LKB1/STK11 is not altered in the germline of patients with hereditary pancreatic cancer.

Symptomatic compression of the celiac trunk by crura of the diaphragm is a rare disorder. Even more infrequent external compression of renal arteries is found. Although the indication for surgical therapy is controversially discussed in the literature for celiac artery compression syndrome, it is unequivocally for renal artery entrapment. We present the case of a young woman who was assigned to our hospital with arterial hypertension and stenosis of the left renal artery. After percutaneous transluminal angioplasty was performed, immediate recoil occurred. Therefore, the suspicion of entrapment by diaphragmatic crura was expressed. Additionally performed diagnostic procedures including computed tomography (CT)-angiography verified our suspicion. Surgical decompression of both vessels was successfully performed. Symptomatic compression of the celiac trunk by crura of the diaphragm is a rare disorder. Even more infrequent external compression of renal arteries is found. Although the indication for surgical therapy is controversially discussed in the literature for celiac artery compression syndrome, it is unequivocally for renal artery entrapment. We present the case of a young woman who was assigned to our hospital with arterial hypertension and stenosis of the left renal artery. After percutaneous transluminal angioplasty was performed, immediate recoil occurred. Therefore, the suspicion of entrapment by diaphragmatic crura was expressed. Additionally performed diagnostic procedures including computed tomography (CT)-angiography verified our suspicion. Surgical decompression of both vessels was successfully performed. The celiac artery compression syndrome (CACS) is a disorder caused by extrinsic compression that the relatively inferior insertion of the median arcuate ligament (MAL) or prominent fibrous bands and ganglionic periaortic tissue of the celiac nervous plexus may exert on the celiac artery. It is a frequent finding in imaging studies performed for screening or diagnosis. Most of these patients have no symptoms related to celiac artery compression. But few patients present with a variety of symptoms.1Gloviczki P. Duncan A.A. Treatment of celiac artery compression syndrome: does it really exist?.Perspect Vasc Surg Endovasc Ther. 2007; 19: 259-263Crossref PubMed Scopus (60) Google Scholar Intermittent foregut ischemia and weight loss are the most frequently described symptoms.2Harjola P.T. A rare obstruction of the coeliac artery Report of a case.Ann Chir Gynaecol Fenn. 1963; 52: 547-550PubMed Google Scholar Occasionally, in addition to the celiac trunk, the constricting effects may also be exerted on the superior mesenteric artery and the renal arteries. These findings are even more infrequent and only a few cases have been reported in literature.3Vahdat O. Creemers E. Limet R. [Stenosis of the right renal artery caused by the crura of the diaphragm. Report of a case].[Article in French] J Mal Vasc. 1991; 16: 304-307PubMed Google Scholar, 4Bacourt F. Depondt J.L. Lacombe P. Mignon E. [Compression of the left renal artery by the diaphragm].[Article in French] J Mal Vasc. 1992; 17: 315-318PubMed Google Scholar, 5Déglise S. Corpataux J.M. Haller C. Binaghi S. Meuwly J.Y. Qanadli S.D. Bilateral renal artery entrapment by diaphragmatic crura: a rare cause of renovascular hypertension with a specific management.J Comput Assist Tomogr. 2007; 31: 481-484Crossref PubMed Scopus (11) Google Scholar, 6Kopecky K.K. Stine S.B. Dalsing M.C. Gottlieb K. Median arcuate ligament syndrome with multivessel involvement: diagnosis with spiral CT angiography.Abdom Imaging. 1997; 22: 318-320Crossref PubMed Scopus (61) Google Scholar In cases of renal artery entrapment by the MAL, the patients usually present with hypertension.5Déglise S. Corpataux J.M. Haller C. Binaghi S. Meuwly J.Y. Qanadli S.D. Bilateral renal artery entrapment by diaphragmatic crura: a rare cause of renovascular hypertension with a specific management.J Comput Assist Tomogr. 2007; 31: 481-484Crossref PubMed Scopus (11) Google Scholar, 7Baguet J.P. Thony F. Tremel F. Cracowski J.L. Sessa C. Mallion J.M. [Compression of the renal artery by a musculo-tendinous band: an unrecognised cause of renovascular hypertension].[Article in French] Arch Mal Coeur Vaiss. 1999; 92: 1767-1772PubMed Google Scholar Here we introduce a patient with entrapment of the left renal artery (LRA) and the celiac trunk by surrounding dense fibrous and ganglionic tissue originating from the diaphragmatic crura, who had to undergo open surgical decompression of both vessels. A 19-year-old woman with an unremarkable medical history presented with recurring tachycardia and hypertension (systolic pressure 200 mm Hg). Her general practitioner administered a low-dose beta-blocker therapy with limited success. The performed cardiac diagnostics were inconspicuous. For further diagnosis, a magnetic resonance imaging (MRI) scan was performed. A short ostial stenosis of the LRA was detected in the MRI scan. With the suspect of a fibromuscular dysplasia, the patient was referred to our clinic. A duplex ultrasound scan determined a severe ostial stenosis of the LRA with a peak systolic velocity (PSV) of 4.5 m/s (renal to aortic velocity ratio: 4.1; approximately 75%) with no variation in inspiration and expiration. Initially, the other visceral arteries and the right renal artery were described as normal. In accordance with these findings, stenting of the renal stenosis was planned. In the angiography, a high origin of the LRA from the aorta was seen just beneath the origin of the celiac trunk. During the same session, the patient underwent a percutaneous transluminal angioplasty (PTA). However, immediate recoil occurred. Intervention was abandoned and further diagnostic procedures were initiated. We performed a computed tomography (CT) scan, which depicted an entrapment of the LRA by bands originating from the left crura of the diaphragm (Fig 1). Additionally, the root of the celiac trunk was compressed and narrowed by the median arcuate ligament (Fig 2). Because we did not have access to the earlier external MRI pictures, we performed a magnetic resonance angiography (MRA) scan in inspiration and expiration. During inspiration, a severe stenosis of the celiac trunk was depicted which decreased in expiration (Fig 3). The LRA stenosis was high-grade and independent of respiratory action. Repeated duplex ultrasound scans of the celiac trunk revealed a PSV of 3.2 m/s in inspiration and 2.1 m/s in expiration. Therefore, we indicated a need for surgical therapy.Fig 2The celiac trunk course inferiorly from its origin, the proximal portions pulled down an in toward the aorta, causing severe narrowing (>80%; big arrow) by the median arcuate ligament (small arrows) well demonstrated in the sagittal computed tomography (CT) slices.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 3Magnetic resonance angiography performed in expiration discloses a mild ostial stenosis of the celiac artery. But, performed during inspiration, a high-grade stenosis is depicted (arrow).View Large Image Figure ViewerDownload Hi-res image Download (PPT) The abdomen was entered via a transverse epigastric incision. The left lobe of the liver was mobilized to expose the aorta. After the bursa omentalis had been opened and the gastric curvature had been reflected, cranially the suprarenal aorta was explored. During the operation we found an exceptional wide caliber of the superior mesenteric artery (SMA). We interpreted this as a sign for an increased collateral circulation from the SMA. Above the SMA we dissected pre-aortal and left side of the aorta dense fibrous and ganglionic tissue. The root of the LRA was surrounded by hypertrophic partially scarred fibers of the diaphragm. After we resected those fibers, the lumen of the LRA increased immediately (Fig 4). Afterwards, we subtly explored the celiac trunk which was also compressed and showed a narrowed lumen. After resection of those dense fibrous structures, an immediate decompression of the celiac trunk was observed. An intraoperative Doppler ultrasound scan did not show any residual stenosis of the LRA and all mesenteric arteries. In the histologic analysis of the resected tissue, ganglionic and muscular structures were seen. A postoperative Duplex ultrasound scan was repeated and revealed normal flow in both renal and all visceral arteries during inspiration (PSV aorta: 1.4 m/s; LRA: 1.4 m/s; and celiac trunk: 2.4 m/s). Bisoprolol was withdrawn postoperatively and the blood pressure remained in range between values of 125/75 mm Hg and 145/80 mm Hg. The renal function was not altered (creatinine preoperative 55 μmol/L and postoperative 53 μmol/L). The patient was discharged without any complications on postoperative day 8. Doppler ultrasound scan and clinical follow-up at 6, 12, and 18 months after surgery confirmed the normalization of renal blood flow without restenosis (resistance index: LRA 0.61; right renal artery [RRA] 0.62; and superior mesenteric artery [SMA] 0.89). At these time points, the patient was doing well without any clinical findings. Renal artery stenosis accounts for about 1% of patients with hypertension, but its incidence rises to 30% in cases of refractory hypertension.8Safian R.D. Textor S.C. Renal-artery stenosis.N Engl J Med. 2001; 344: 431-442Crossref PubMed Scopus (861) Google Scholar The two major causes are atherosclerosis and fibromuscular dysplasia. Extrinsic compression of the renal artery is a very rare cause of hypertension. Congenital abnormalities, such as abnormal musculo-tendinous fibers,3Vahdat O. Creemers E. Limet R. [Stenosis of the right renal artery caused by the crura of the diaphragm. Report of a case].[Article in French] J Mal Vasc. 1991; 16: 304-307PubMed Google Scholar, 9d'Abreu Strickland B. Developmental renal-artery stenosis.Lancet. 1962; 2: 517-521Abstract PubMed Scopus (19) Google Scholar, 10Silver D. Clements J.B. Renovascular hypertension from renal artery compression by congenital bands.Ann Surg. 1976; 183: 161-166Crossref PubMed Scopus (14) Google Scholar high ectopic renal artery origin,10Silver D. Clements J.B. Renovascular hypertension from renal artery compression by congenital bands.Ann Surg. 1976; 183: 161-166Crossref PubMed Scopus (14) Google Scholar, 11Dure-Smith P. Bloch R.D. Fymat A.L. Chang P. Hammond P.G. Renal artery entrapment by the diaphragmatic crus revealed by helical CT angiography.AJR Am J Roentgenol. 1998; 170: 1291-1292Crossref PubMed Scopus (12) Google Scholar or hypertrophic diaphragmatic crus12Martin Jr, D.C. Anomaly of the right crus of the diaphragm involving the right renal artery.Am J Surg. 1971; 121: 351-354Abstract Full Text PDF PubMed Scopus (4) Google Scholar were found to be responsible for these entrapments. The median arcuate ligament is a condensation of the medial fibrous borders of the two crura of the diaphragm as they decussate to form the ventral border of the aortic hiatus. The ligament is highly variable, with its appearance ranging from a well-defined ligamentous mass to an amorphous area of connective tissue.13Lindner H.H. Kemprud E. A clinicoanatomical study of the arcuate ligament of the diaphragm.Arch Surg. 1971; 103: 600-605Crossref PubMed Scopus (138) Google Scholar A relatively inferior insertion of the median arcuate ligament and prominent fibrous bands, or the ganglionic periaortic tissue of the celiac nervous plexus, could be the cause of the extrinsic compression on the celiac trunk.6Kopecky K.K. Stine S.B. Dalsing M.C. Gottlieb K. Median arcuate ligament syndrome with multivessel involvement: diagnosis with spiral CT angiography.Abdom Imaging. 1997; 22: 318-320Crossref PubMed Scopus (61) Google Scholar, 14Reilly L.M. Ammar A.D. Stoney R.J. Ehrenfeld W.K. Late results following operative repair for celiac artery compression syndrome.J Vasc Surg. 1985; 2: 79-91PubMed Scopus (178) Google Scholar Renal artery entrapment usually develops in a renal artery with its origin high on the aorta, as observed in the presented case where the origin of the LRA was just underneath the origin of the celiac trunk. The mechanism evoked is an anomaly of migration of the kidneys, which seems to be more common on the left side. The diaphragmatic fibers cause a verticalization of the root of the renal artery and lead to a stenosis.15Thony F. Baguet J.P. Rodiere M. Sessa C. Janbon B. Ferretti G. Renal artery entrapment by the diaphragmatic crus.Eur Radiol. 2005; 15: 1841-1849Crossref PubMed Scopus (26) Google Scholar, 16Clément C. Ruiz R. Costa-Foru B. Nicaise H. Extrinsic compression of the renal artery by diaphragmatic crus.Ann Vasc Surg. 1990; 4: 305-308Abstract Full Text PDF PubMed Scopus (11) Google Scholar Since the first report by d'Abreu and Strickland,9d'Abreu Strickland B. Developmental renal-artery stenosis.Lancet. 1962; 2: 517-521Abstract PubMed Scopus (19) Google Scholar only a few cases of renal artery entrapments have been reported in the literature.3Vahdat O. Creemers E. Limet R. [Stenosis of the right renal artery caused by the crura of the diaphragm. Report of a case].[Article in French] J Mal Vasc. 1991; 16: 304-307PubMed Google Scholar, 4Bacourt F. Depondt J.L. Lacombe P. Mignon E. [Compression of the left renal artery by the diaphragm].[Article in French] J Mal Vasc. 1992; 17: 315-318PubMed Google Scholar, 10Silver D. Clements J.B. Renovascular hypertension from renal artery compression by congenital bands.Ann Surg. 1976; 183: 161-166Crossref PubMed Scopus (14) Google Scholar, 11Dure-Smith P. Bloch R.D. Fymat A.L. Chang P. Hammond P.G. Renal artery entrapment by the diaphragmatic crus revealed by helical CT angiography.AJR Am J Roentgenol. 1998; 170: 1291-1292Crossref PubMed Scopus (12) Google Scholar, 12Martin Jr, D.C. Anomaly of the right crus of the diaphragm involving the right renal artery.Am J Surg. 1971; 121: 351-354Abstract Full Text PDF PubMed Scopus (4) Google Scholar, 16Clément C. Ruiz R. Costa-Foru B. Nicaise H. Extrinsic compression of the renal artery by diaphragmatic crus.Ann Vasc Surg. 1990; 4: 305-308Abstract Full Text PDF PubMed Scopus (11) Google Scholar, 17Spies J.B. LeQuire M.H. Robison J.G. Beckett Jr, W.C. Perkinson D.T. Vicks S.L. Renovascular hypertension caused by compression of the renal artery by the diaphragmatic crus.AJR Am J Roentgenol. 1987; 149: 1195-1196Crossref PubMed Scopus (9) Google Scholar, 18Villanueva A. Nuñez R.V. Baltar L. Ruibal G. Arterial hypertension and extrinsic renal artery compression: case report.J Cardiovasc Surg (Torino). 1972; 13: 617-619PubMed Google Scholar, 19Baguet J.P. Thony F. Sessa C. Mallion J.M. Stenting of a renal artery compressed by the diaphragm.J Hum Hypertens. 2003; 17: 213-214Crossref PubMed Scopus (29) Google Scholar Indeed these fibrous bands originating from the diaphragm are more commonly known for the celiac artery compression syndrome, also known as median arcuate ligament syndrome. It has proven to be controversial in definition and relevance. Asymptomatic extrinsic compression of the celiac artery is quite common; it has been confirmed with direct pressure measurements in 3% to 10% of patients who undergo orthotopic liver transplantation. Patients with symptomatic CACS may present in a variety of ways. Most have symptoms of chronic mesenteric ischemia and present with weight loss, postprandial abdominal pain, nausea and vomiting, or diarrhea. The diagnosis continues to be controversial, because in most patients the SMA is not affected. It has been implicated that the CACS may cause an increased collateral circulation from the SMA.1Gloviczki P. Duncan A.A. Treatment of celiac artery compression syndrome: does it really exist?.Perspect Vasc Surg Endovasc Ther. 2007; 19: 259-263Crossref PubMed Scopus (60) Google Scholar In the presented case, the patient did not show any familiar symptoms of CACS, but during the operation a wide caliber of the SMA was observed, which would confirm these implications. Combined entrapment of visceral and renal arteries has rarely been described.3Vahdat O. Creemers E. Limet R. [Stenosis of the right renal artery caused by the crura of the diaphragm. Report of a case].[Article in French] J Mal Vasc. 1991; 16: 304-307PubMed Google Scholar, 4Bacourt F. Depondt J.L. Lacombe P. Mignon E. [Compression of the left renal artery by the diaphragm].[Article in French] J Mal Vasc. 1992; 17: 315-318PubMed Google Scholar, 5Déglise S. Corpataux J.M. Haller C. Binaghi S. Meuwly J.Y. Qanadli S.D. Bilateral renal artery entrapment by diaphragmatic crura: a rare cause of renovascular hypertension with a specific management.J Comput Assist Tomogr. 2007; 31: 481-484Crossref PubMed Scopus (11) Google Scholar, 6Kopecky K.K. Stine S.B. Dalsing M.C. Gottlieb K. Median arcuate ligament syndrome with multivessel involvement: diagnosis with spiral CT angiography.Abdom Imaging. 1997; 22: 318-320Crossref PubMed Scopus (61) Google Scholar Interestingly, in every case reported, the patient presented with hypertension. In only one case, postprandial epigastric pain was described.6Kopecky K.K. Stine S.B. Dalsing M.C. Gottlieb K. Median arcuate ligament syndrome with multivessel involvement: diagnosis with spiral CT angiography.Abdom Imaging. 1997; 22: 318-320Crossref PubMed Scopus (61) Google Scholar In most of the patients, the diagnosis was initially missed and interventional or operative procedures were performed that failed. Therefore, the diagnosis of MAL compression plays a decisive role. A Doppler ultrasound scan allows the visualization of renal blood flow during a complete respiratory cycle. Indeed, during the same procedure, it permits detection of stenosis, presence of flow demodulation, and increase of flow velocities during expiration. But in cases of severe entrapment, the changes of flow velocities during the respiratory cycle can decrease or even dissolve,20Ilica A.T. Kocaoglu M. Bilici A. Ors F. Bukte Y. Senol A. et al.Median arcuate ligament syndrome: multidetector computed tomography findings.J Comput Assist Tomogr. 2007; 31: 728-731PubMed Google Scholar as experienced for the LRA in our patient. Also, an ultrasound scan is an accurate examination for screening renal artery stenoses, but it does not allow the analysis of the relationship between renal artery and muscular structures. Conventional arteriography has the same disadvantage. CT and MRI scans allow for depiction of these compressions. However, reports of visceral and renal artery entrapment with these imaging tools are few.6Kopecky K.K. Stine S.B. Dalsing M.C. Gottlieb K. Median arcuate ligament syndrome with multivessel involvement: diagnosis with spiral CT angiography.Abdom Imaging. 1997; 22: 318-320Crossref PubMed Scopus (61) Google Scholar, 11Dure-Smith P. Bloch R.D. Fymat A.L. Chang P. Hammond P.G. Renal artery entrapment by the diaphragmatic crus revealed by helical CT angiography.AJR Am J Roentgenol. 1998; 170: 1291-1292Crossref PubMed Scopus (12) Google Scholar, 15Thony F. Baguet J.P. Rodiere M. Sessa C. Janbon B. Ferretti G. Renal artery entrapment by the diaphragmatic crus.Eur Radiol. 2005; 15: 1841-1849Crossref PubMed Scopus (26) Google Scholar A great advantage of the CT scan, compared to the MRI scan, is the visualization of artherosclerotic lesions. If there are clinical and sonographic findings suggesting entrapment by the MAL, these findings should be corroborated by a CT angiography scan.6Kopecky K.K. Stine S.B. Dalsing M.C. Gottlieb K. Median arcuate ligament syndrome with multivessel involvement: diagnosis with spiral CT angiography.Abdom Imaging. 1997; 22: 318-320Crossref PubMed Scopus (61) Google Scholar, 11Dure-Smith P. Bloch R.D. Fymat A.L. Chang P. Hammond P.G. Renal artery entrapment by the diaphragmatic crus revealed by helical CT angiography.AJR Am J Roentgenol. 1998; 170: 1291-1292Crossref PubMed Scopus (12) Google Scholar It permits visualization of the diaphragm and its relationships with the aorta and its branches. Furthermore, thin fibrous bands from the diaphragm insertion are well demonstrated by CT scan. In 1995, the first diagnosis of renal artery stenosis with a CT scan was reported by Kopecky et al,6Kopecky K.K. Stine S.B. Dalsing M.C. Gottlieb K. Median arcuate ligament syndrome with multivessel involvement: diagnosis with spiral CT angiography.Abdom Imaging. 1997; 22: 318-320Crossref PubMed Scopus (61) Google Scholar since then it is considered the “gold standard” tool for diagnosing this pathology. Ilica et al20Ilica A.T. Kocaoglu M. Bilici A. Ors F. Bukte Y. Senol A. et al.Median arcuate ligament syndrome: multidetector computed tomography findings.J Comput Assist Tomogr. 2007; 31: 728-731PubMed Google Scholar recently described nicely the CT scan findings suggesting MAL compression. For the celiac trunk and SMA narrowing, kinking, and inferior displacement on sagittal views are indicative. Coursing inferior and medial of narrowed proximal renal artery adjacent to the aorta suggests MAL compression on frontal reformations. These findings can distinguish this entity from artherosclerotic stenosis. Treatment for CACS has historically involved surgical release of the celiac trunk from extrinsic compression by the MAL or division of fibrotic celiac ganglia. Mihas et al21Mihas A.A. Laws H.L. Jander H.P. Surgical treatment of the celiac axis compression syndrome.Am J Surg. 1977; 133: 688-691Abstract Full Text PDF PubMed Scopus (30) Google Scholar reported 6 patients with CACS with 4 undergoing surgical reconstruction without benefit for painful symptoms lasting greater than 20 months. Although angioplasty and stenting of visceral arteries seems to be successful in the setting of atherosclerosis, their use in the setting of CACS has been questioned because of the presence of extrinsic compression.17Spies J.B. LeQuire M.H. Robison J.G. Beckett Jr, W.C. Perkinson D.T. Vicks S.L. Renovascular hypertension caused by compression of the renal artery by the diaphragmatic crus.AJR Am J Roentgenol. 1987; 149: 1195-1196Crossref PubMed Scopus (9) Google Scholar, 22Jaik N.P. Stawicki S.P. Weger N.S. Lukaszczyk J.J. Celiac artery compression syndrome: successful utilization of robotic-assisted laparoscopic approach.J Gastrointestin Liver Dis. 2007; 16: 93-96PubMed Google Scholar The increasing applicability of stent deployment for mesenteric occlusive disease has given interventional radiologists the opportunity to expand the use of PTA and stenting to patients with CACS before primary surgical intervention. However, the few attempts of angioplasty and stenting patients with entrapment of renal arteries by diaphragmatic crura are not convincing.5Déglise S. Corpataux J.M. Haller C. Binaghi S. Meuwly J.Y. Qanadli S.D. Bilateral renal artery entrapment by diaphragmatic crura: a rare cause of renovascular hypertension with a specific management.J Comput Assist Tomogr. 2007; 31: 481-484Crossref PubMed Scopus (11) Google Scholar, 15Thony F. Baguet J.P. Rodiere M. Sessa C. Janbon B. Ferretti G. Renal artery entrapment by the diaphragmatic crus.Eur Radiol. 2005; 15: 1841-1849Crossref PubMed Scopus (26) Google Scholar, 19Baguet J.P. Thony F. Sessa C. Mallion J.M. Stenting of a renal artery compressed by the diaphragm.J Hum Hypertens. 2003; 17: 213-214Crossref PubMed Scopus (29) Google Scholar In the case presented here, renal angioplasty failed and immediate recoil occurred. A review of the literature revealed only 4 patients where renal artery entrapment was treated through stenting.5Déglise S. Corpataux J.M. Haller C. Binaghi S. Meuwly J.Y. Qanadli S.D. Bilateral renal artery entrapment by diaphragmatic crura: a rare cause of renovascular hypertension with a specific management.J Comput Assist Tomogr. 2007; 31: 481-484Crossref PubMed Scopus (11) Google Scholar, 15Thony F. Baguet J.P. Rodiere M. Sessa C. Janbon B. Ferretti G. Renal artery entrapment by the diaphragmatic crus.Eur Radiol. 2005; 15: 1841-1849Crossref PubMed Scopus (26) Google Scholar This treatment failed in 2 patients because the stent was compressed during respiratory motions and this led to stent rupture. The other patients treated with balloon-expandable stents did not collapse and remained patent on CT scan follow-up controls at 6 months. But the patients did not show any significant decrease in their blood pressure level or improvement of their impaired renal function.15Thony F. Baguet J.P. Rodiere M. Sessa C. Janbon B. Ferretti G. Renal artery entrapment by the diaphragmatic crus.Eur Radiol. 2005; 15: 1841-1849Crossref PubMed Scopus (26) Google Scholar Perhaps the potential benefits of the developing stent fabrication could have significant implications in mechanical fatigue. With current standards, primary stent deployment should be avoided in the likely occurrence of extrinsic compression or motion. We therefore indicated and successfully performed open surgery to release both vessels. All patients reported in the literature eventually were treated successfully by open surgery (Table). In every patient, the extensive dissection and resection of the musculotendinous bands surrounding the compressed vessels was performed, even though the patients were asymptomatic regarding the compression of the visceral arteries.3Vahdat O. Creemers E. Limet R. [Stenosis of the right renal artery caused by the crura of the diaphragm. Report of a case].[Article in French] J Mal Vasc. 1991; 16: 304-307PubMed Google Scholar, 4Bacourt F. Depondt J.L. Lacombe P. Mignon E. [Compression of the left renal artery by the diaphragm].[Article in French] J Mal Vasc. 1992; 17: 315-318PubMed Google Scholar, 5Déglise S. Corpataux J.M. Haller C. Binaghi S. Meuwly J.Y. Qanadli S.D. Bilateral renal artery entrapment by diaphragmatic crura: a rare cause of renovascular hypertension with a specific management.J Comput Assist Tomogr. 2007; 31: 481-484Crossref PubMed Scopus (11) Google Scholar The intention for us to perform an extended resection of the hypertrophic diaphragmatic crura with release of the celiac trunk without symptomatic CACS was the easy feasibility and the possibility that a symptomatic complication can occur in the future.TableOverview of described cases with multivessel entrapmentAuthorAgeGenderCompressed arteriesTreatmentFollow-upVahdat et al3Vahdat O. Creemers E. Limet R. [Stenosis of the right renal artery caused by the crura of the diaphragm. Report of a case].[Article in French] J Mal Vasc. 1991; 16: 304-307PubMed Google Scholar23♀SMARRA(1) Angioplasty failed(2) Double revascularization with venous graft – early thrombosis in both grafts(3) Resection of MAL6 monthsBacourt et al4Bacourt F. Depondt J.L. Lacombe P. Mignon E. [Compression of the left renal artery by the diaphragm].[Article in French] J Mal Vasc. 1992; 17: 315-318PubMed Google Scholar21♂CALRAResection of MAL4 yearsKopecky et al6Kopecky K.K. Stine S.B. Dalsing M.C. Gottlieb K. Median arcuate ligament syndrome with multivessel involvement: diagnosis with spiral CT angiography.Abdom Imaging. 1997; 22: 318-320Crossref PubMed Scopus (61) Google Scholar50♀CASMARRALRAResection of MAL and patchplasty of CA6 monthsDeglise et al5Déglise S. Corpataux J.M. Haller C. Binaghi S. Meuwly J.Y. Qanadli S.D. Bilateral renal artery entrapment by diaphragmatic crura: a rare cause of renovascular hypertension with a specific management.J Comput Assist Tomogr. 2007; 31: 481-484Crossref PubMed Scopus (11) Google Scholar39♂SMARRALRA(1) Angioplasty with balloon expandable stent (LRA) – stent rupture after 6 months(2) Resection of MAL, reinsertion of RRA and rVSM bypass to LRA6 monthsCA, Celiac artery; SMA, superior mesenteric artery; RRA, right renal artery; LRA, left renal artery; MAL, median arcuate ligament; rVSM, reversed vena saphena magna. Open table in a new tab CA, Celiac artery; SMA, superior mesenteric artery; RRA, right renal artery; LRA, left renal artery; MAL, median arcuate ligament; rVSM, reversed vena saphena magna. Combined renal artery and celiac trunk external compression by fibrous bands from the diaphragm is an extremely rare finding. Like external compression of the celiac trunk, it was demonstrated that renal artery external compression does not benefit from angioplasty or stenting because of elastic recoil or stent fracture. Therefore, primary angioplasty and stenting are not indicated for this entity. In our opinion, today the procedure of first choice is surgical decompression of the vessels by dividing or resecting the surrounding dense fibrous and ganglionic tissue. After surgery, long-term duplex ultrasound scan and clinical follow-up is necessary for these patients.

The formation of sporadic abdominal aortic aneurysm (AAA) is explained by remodeling of the extracellular matrix (ECM) and breakdown of structural components of the vascular wall. Matrix metalloproteinase 2 (MMP2) is one of the principal matrix-degrading proteases and is known to play a major role in the remodeling of the extracellular matrix in arterial vessels. Increased MMP2 expression in the extracellular matrix of the walls of AAAs has been shown in several studies. To investigate the possible impact of genetic variants of the MMP2 gene in the etiology of AAA, we conducted this case-control study.We analyzed MMP2 single-nucleotide polymorphisms (SNPs) in 51 patients with AAA and 48 controls. Differences in genotype and allele frequencies of identified polymorphisms were determined after sequencing the entire coding region and three selected parts of the promoter.Eighteen polymorphisms were identified, 6 of which are newly described, with 3 located in the introns (c.IVS1+31C>G, c.IVS7-18G>A, c.IVS10+26C>T) and 3 located in the coding region (c.124G>A, c.1368C>T, c.1860C>T). There were no statistically significant differences in genotype or allele frequencies between the two groups.Our analysis of the entire coding region and three parts of the promoter of the MMP2 gene failed to show an association between genetic polymorphisms and AAA, suggesting that variations in the MMP2 gene do not contribute to the development of AAA.

Abstract Background: Patients suffering from locally advanced esophageal carcinoma are generally treated using multimodal therapies. This prospective, non‐randomized trial was performed to evaluate the survival benefit of neoadjuvant radiochemotherapy prior to surgery in comparison with surgery only. Patients &amp; Methods: Histopathological outcomes and survival were compared between 61 patients who underwent neoadjuvant radiochemotherapy and 64 comparable control patients who had been under‐staged. After neoadjuvant therapy, tumor regression was assessed using the method described by Mandard in 1994. Survival curves for the two groups were estimated using the Kaplan‐Meier method, and compared with the log‐rank test. Results: Median and 3‐year recurrence‐free survival for the entire group were 26 months and 39.7%, respectively. The median and 3‐year overall survival reached 34 months and 48.1%. Patients who showed complete response to neoadjuvant therapy had significantly improved survival (35 months) compared to patients with residual tumor cells (28 months), patients with tumors unresponsive to radiochemotherapy (22 months), or patients who received surgery only (control group, 29 months). Patients with nodal‐negative carcinomas showed significantly longer survival after surgery only and after neoadjuvant therapy compared to patients with lymph node‐positive cancers. Conclusions: Complete response after neoadjuvant radiochemotherapy is associated with significantly improved survival. Negative nodal status is a major determinant of outcomes following primary operation or neoadjuvant treatment.

Germline mutations in mismatch repair genes are responsible for hereditary nonpolyposis colorectal cancer (HNPCC), the most common hereditary cancer-susceptibility syndrome. We report six novel germline mutations, three in MSH2 and three in MLH1. All but one mutation have been found in families fulfilling the criteria of the Bethesda guidelines; two of them additionally fulfilled the Amsterdam criteria. We identified two nonsense mutations in MSH2 (c.1764T>G [p.Y588X], c.2579C>A [p.S860X]), one duplication of four nucleotides causing premature stop codon (MLH1: c.821_824dupAAGC [p.A275fsX307]), one splice site mutation resulting in skipping of exon 8 from the MLH1 transcript (c.677+3A>G), one duplication of 18 nucleotides leading to duplication of six amino acids in the mismatch-binding domain of MSH2 (c.4_21dup [p.A2_E7dup) and one missense mutation in the PMS2 interaction domain of MLH1 (c.1756G>C [p.A586P]). The three latter mutations were not found in 73, 90 and 94 healthy control individuals, respectively. The corresponding tumors from all patients showed a high level of microsatellite instability (MSI-H). Immunohistochemistry (IH) revealed complete loss of expression of the affected protein in the tumor cells from the patients with the nonsense, splice-site and missense mutation. The tumor from the patient with the c.821_824dupAAGC mutation showed a reduced, rather than lost, expression of the MLH1-protein.

Hereditary nonpolyposis colorectal cancer (HNPCC) is one of the most common hereditary cancer-susceptibility syndromes. Germline mutations in mismatch repair genes are associated with the clinical phenotype of HNPCC. We report ten novel germline mutations, three in MSH2 and seven in MLH1. All but one mutation have been found in families fulfilling criteria of the Bethesda guidelines; four of them additionally fulfilled the Amsterdam criteria I or II. Eight mutations were considered pathogenic and predictive diagnostics in healthy family members at risk shall be undertaken; these include five frameshift mutations leading to premature stop codons, in MSH2: c.1672delT (p.S558Xfs) and c.2466_2467delTG (p.C822X) and in MLH1: c.1023delG (p.R341Xfs), c.1127_1128dupAT (p.K377Xfs) and c.1310delC (p.P437Xfs); three mutations leading to splice aberrations, in MSH2: c.1661G>C (r.1511_1661del) and in MLH1: c.677+3A>C (r.589_677del) and c.1990-2A>G predicted to result in a splice site defect. The remaining two mutations are unclassified variants with assumed pathogenicity: one missense mutation in the highly conserved ATPase domain of MLH1 (c.122A>G [p.D41G]) and one in-frame insertion of twelve nucleotides in MLH1 (c.2155_2156insATGTGTTCCACA [p.I719delinsNVFHI]). These two mutations were not found in 102 alleles of healthy control individuals. The corresponding tumors from all patients showed a high level of microsatellite instability (MSI-H). Immunohistochemistry (IHC) revealed complete loss of expression of the affected protein in the tumor cells from all but three patients. The tumors from the patients with the mutations c.1127_1128dupAT and c.1990-2A>G showed a reduction of expression of the MLH1-protein, rather than complete loss. In the tumor from the patient with the missense mutation c.122A>G [p.D41G] a normal expression of the proteins coded by MLH1 and MSH2 was noticed.

Investigations into the pathogenesis of type 2 diabetes and islets of Langerhans malfunction 1 have been hampered by the limited availability of type 2 diabetic islets from organ donors2. Here we share our protocol for isolating islets from human pancreatic tissue obtained from type 2 diabetic and non-diabetic patients who have undergone partial pancreatectomy due to different pancreatic diseases (benign or malignant pancreatic tumors, chronic pancreatitis, and common bile duct or duodenal tumors). All patients involved gave their consent to this study, which had also been approved by the local ethics committee. The surgical specimens were immediately delivered to the pathologist who selected soft and healthy appearing pancreatic tissue for islet isolation, retaining the damaged tissue for diagnostic purposes. We found that to isolate more than 1,000 islets, we had to begin with at least 2 g of pancreatic tissue. Also essential to our protocol was to visibly distend the tissue when injecting the enzyme-containing media and subsequently mince it to aid digestion by increasing the surface area. To extend the applicability of our protocol to include the occasional case in which a large amount (>15g) of human pancreatic tissue is available , we used a Ricordi chamber (50 ml) to digest the tissue. During digestion, we manually shook the Ricordi chamber3 at an intensity that varied by specimen according to its level of tissue fibrosis. A discontinous Ficoll gradient was then used to separate the islets from acinar tissue. We noted that the tissue pellet should be small enough to be homogenously resuspended in Ficoll medium with a density of 1.125 g/ml. After isolation, we cultured the islets under stress free conditions (no shaking or rotation) with 5% CO2 at 37 °C for at least 48 h in order to facilitate their functional recovery. Widespread application of our protocol and its future improvement could enable the timely harvesting of large quantities of human islets from diabetic and clinically matched non-diabetic subjects, greatly advancing type 2 diabetes research.

N-acetyltransferase (NAT) 2 is an essential polymorphic enzyme involved in the metabolism of various xenobiotics, including potential carcinogens. The individual differences in the NAT2 metabolic capacity are caused by allelic variants of the NAT2 gene which are determined by a pattern of single nucleotide polymorphisms (SNPs) resulting in slow (SA), intermediate (IA) or rapid acetylator (RA) phenotypes. Highly penetrant germline mutations in mismatch repair (MMR) genes are the cause of the disease in hereditary nonpolyposis colorectal cancer (HNPCC). There is no strict correlation between the type of germline mutation in MMR genes and the HNPCC phenotype, but age of tumor onset (AO) in HNPCC has been associated at least in part with different variants in apoptosis-related genes. To clarify the potential modifying role of the NAT2 acetylator status in HNPCC, we performed a multicenter study in 226 individuals with colorectal cancer carrying exclusively pathogenic germline mutations in MSH2 or MLH1. We did not observe any significant difference in the NAT2 acetylator status frequency between HNPCC patients and 107 healthy controls (P=0.156), and between MLH1 and MSH2 mutation carriers (P=0.198). Multivariate Cox regression analysis revealed that male patients had a significantly increased risk to develop CRC compared to females during any interval (P=0.043), while the NAT2 acetylator status (P=0.447) and the mutated gene (MLH1 or MSH2) (P=0.236) were not risk factors for AO. The median AO in HNPCC patients was 39 years in patients with RA as well as with SA status (P=0.347). In MLH1 mutation carriers, the median AO was 38 years in RA and 36 years in SA status patients (P=0.901), whereas in MSH2 mutation carriers, the median AO was 39 years in RA and 42 years in SA status patients (P=0.163). Log-rank test revealed a significantly lower age of CRC onset in male compared to female HNPCC patients (P=0.0442). These data do not support the hypothesis that the NAT2 acetylatorship acts as a modifying factor on AO in HNPCC-associated CRC.

The Value of Colour Duplex Sonography in the Assessment of Surgical Resectability of Pancreatic Tumors.The aim of this study was to evaluate the assessment by modern colour duplex imaging (CDI) concerning the relation between tumour and vessels including haemodynamic parameters in the main abdominal arteries and the portal system, and to evaluate the influence of these results on surgical decision making.From January 1997 to October 1998, 146 patients with a tumour of the pancreas were included in a prospective study. Tumour contact to vessels and to the retroperitoneum, data on the flow in the main abdominal arteries and the portal circulation (regional topography) as well as the detection of liver metastases, enlarged lymph nodes and peritoneal carcinomatosis were defined as representing criteria of resectability. The results were compared with the intraoperative situation and with the definite histological findings.In 57 resectable tumours, the portal system was found to be infiltrated by the tumour up to a length of 1.5 cm. The flow velocity reached between 4 and 53 cm/s (mean flow) and 9 to 105 cm/s (maximum flow). Out of 146 pancreatic tumours, 89 were found as being non-resectable. In these cases, the measured parameters differed depending on the degree of tumour infiltration in to the portal circulation. We measured values from 0 to 96 cm/s (mean flow) and from 0 to 201 cm/s (maximum flow) with loss of breath-dependent modulation. The contact area between tumor and portal vessel was longer than 2 cm. Pathological flow in the main abdominal arteries was only found in 2 of 13 cases. The local situation was assessed correctly in 140 out of 146 cases by CDI (sensitivity of 93.0 %, specificity of 97.8 %, positive predictive value of 96.4 %, negative predictive value of 95.6 %). Regarding the complete oncological status (local situation, metastases, lymph node involvement and peritoneal carcinomatosis), a sensitivity of 82.5 % and a specificity of 92.1 % (positive predictive value of 87.0 %, negative predictive value of 89.1 %) was found.Modern CDI can reliably assess the resectability of pancreatic tumours by the evaluation of morphological and haemodynamic parameters. There are still difficulties in the assessment of lymph node involvement as well as in the detection of small liver metastases and of peritoneal carcinomatosis without ascites.

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most frequent hereditary form of colorectal cancer and is caused by germline mutations in mismatch repair (MMR) genes. The majority of mutations occur in MLH1 and MSH2. We report hereby seven novel germline mutations in these two genes (five in MLH1 and two in MSH2). All mutations have been found in families fulfilling criteria of the Bethesda guidelines and four of which also fulfilled the Amsterdam criteria. We identified three insertions or deletions of 1 bp leading to premature stop codons (MLH1: c.341delC, c.1413-1414insA; MSH2: c.1119delG) and three nonsense mutations (MLH1: c.67G>T [E23X], c.436C>T [Q146X]; MSH2: c.1857T>G [Y619X]). The corresponding tumors showed a high level of microsatellite instability (MSI-H) and a complete loss of expression of the affected protein. In addition, a missense mutation in MLH1 was identified (c.1984A>C [T662P]). The respective tumor also showed a high level of microsatellite instability but a reduced, rather then lost, expression of the MLH1-protein. This missense mutation was not found in 107 healthy control individuals and in 54 HNPCC patients.

Vascular injuries are an uncommon finding. In times of peace vascular injuries occur in approximately 1-4 % during traffic accidents. Especially challenging is the treatment of open fractures combined with arterial lesions. These fractures are usually accompanied with severe soft tissue damage and injuries to neurological structures. The overall prognosis of these trauma patients is dependent on fast and sufficient diagnostics and therapy. In particular, for unstable patients time-consuming diagnostics can be dispensed and a primarily operative therapy should be targeted. Vascular reconstruction by direct suture is sometimes only possible with interposition and should be the primary goal. Interposition should be performed with autologous vein material because of the high risk of infection. Here we demonstrate on the basis of our patients the interdisciplinary -management of such trauma patients in our hospital.

Pancreatic cancer is a devastating disease. It is the fourth leading cause of cancer-related death in Germany. The incidence in 2003/2004 was 16 cases per 100.000 inhabitants. Of all carcinomas, pancreatic cancer has the highest mortality rate, with one- and five-year survival rates of 25% and less than 5%, respectively, regardless of the stage at diagnosis. These low survival rates demonstrate the poor prognosis of this carcinoma. Previous therapeutic approaches including surgical resection combined with adjuvant therapy or palliative chemoradiation have not achieved satisfactory results with respect to overall survival. Therefore, it is necessary to evaluate new therapeutic approaches. Neoadjuvant therapy is an interesting therapeutic option for patients with pancreatic cancer. For selected patients with borderline or unresectable disease, neoadjuvant therapy offers the potential for tumor downstaging, increasing the probability of a margin-negative resection and decreasing the occurrence of lymph node metastasis. Currently, there is no universally accepted approach for treating patients with pancreatic cancer in the neoadjuvant setting. In this review, the most common neoadjuvant strategies will be described, compared and discussed.

Hintergrund: Die Bildung von großen interdisziplinären operativen Intensiveinheiten durch Zusammenführung von mehreren fachspezifischen Intensivstationen erfolgt vorwiegend aus ökonomischen Gründen. Unter welchen Voraussetzungen ein Zusammenschluss mehrerer chirurgischer Intensivstationen wirklich kostensenkend wirkt und welchen Einfluss größere interdisziplinäre opera­tive Intensiveinheiten auf die Qualität der Patientenversorgung und auf die ärztliche Weiterbildung haben, ist Gegenstand dieser Analyse. Material und Methoden: Auf der Grundlage einer umfangreichen Literaturrecherche und der eigenen Erfahrung wurde der Einfluss der Betriebsgröße von Intensivstationen nicht nur hinsichtlich ökonomischer, sondern auch medizinischer und weiterbildungsrelevanter Aspekte analysiert. Ergebnisse: Die ökonomischen Größenvorteile limitieren sich aufgrund von Managementproblemen bei Stationsgrößen von über 10–12 Betten. Dieser Bettenumfang sichert auch eine optimale medizinische Betreuung, insbesondere wenn es sich dabei um Patienten einer chirurgischen Fachrichtung mit einem entsprechend spezialisierten Behandlungsteam handelt. Dadurch wird auch der Anspruch auf eine fachbezogene ärztliche Weiterbildung gewährleistet. Zur Sicherung von ökonomischen und medizinischen Verbundvorteilen kann ein Zusammenschluss mehrerer solcher Bettenspangen zu einer interdisziplinären operativen Intensiveinheit sinnvoll sein. Für die Koordination und Leitung sollte ein intensiv­medi­zinisch qualifizierter Facharzt aus dem operativen Bereich eingesetzt werde. Schlussfolgerung: Das Konzept einer interdisziplinären operativen Intensiveinheit ist praktikabel und sinnvoll, wenn für eine optimale krankheitsbezogene intensivmedizinische Patientenbetreuung organisatorische fachspezifische Teilbereiche von zirka 12 Betten geschaffen bzw. erhalten werden. Diese Bettenspanne gewährleistet sowohl optimale ökonomische Größen- und Verbundvorteile als auch eine effektive Logistik. Die Leitung sollte einem erfahrenen intensivmedizinisch qualifizierten Facharzt der Anästhesie oder eines chirurgischen Fachgebietes mit einer intensivmedizinischen Weiterbildungsberechtigung in diesem Fachgebiet übertragen werden. Eine Verbundweiterbildung muss alle vertretenen fachgebundenen intensivmedizinischen Weiterbildungen gewährleisten können.

Context Palliative procedures play an important role in the treatment of malignancies of the pancreatic head/distal biliary tree, as only 20-30% can be cured by surgical resection. Objective We sought to determine if surgical or non-surgical management was the most appropriate therapy for the treatment of obstructive jaundice in the palliative setting. Setting High volume center for pancreatic surgery. Patients Analysis of 342 palliatively-treated patients with adenocarcinoma of the pancreatic head or the distal biliary tree. Main outcome measures We studied the outcomes with regard to treatment, complications and survival times. Design The patients were divided into three groups. Group 1: endoscopic bile duct endoprosthesis (no. 138, 56%); Group 2: preoperative stenting followed by laparotomy (if patients were found to be unresectable, palliative hepaticojejunostomy was performed) (no. 68, 28%); Group 3: hepaticojejunostomy without preoperative stenting (no. 41, 16%). We also determined the frequency of re-hospitalization for recurrent jaundice. Results Two hundred and sixty-one (76%) patients showed obstructive jaundice. Mortality in Groups 1, 2, and 3 was 2.2%, 0%, and 2.4%, respectively and morbidity was 5.1%, 17.6%, and 14.6%, respectively. The mean interval between stent exchanges was 70.8 days. Median survival for patients treated only with an endoscopic stent (Group 1) was significantly shorter than that of patients who were first stented and subsequently treated with hepaticojejunostomy (Group 2) (5.1 vs. 9.4 months; P<0.001). Conclusions Hepaticojejunostomy can be performed with satisfactory operative results and acceptable morbidity. Considering that biliary stents can occlude, a hepaticojejunostomy may be superior to endoscopic stenting; hepaticojejunostomy should be especially favored in patients whose disease is first found to be unresectable intraoperatively.

In Westeuropa dominieren stumpfe Verletzungen des Thorax, penetrierende Verletzungen sind Raritäten. Entsprechend wenig Routine besteht in der Versorgung Letzterer, sie orientiert sich an den Erfahrungen aus den USA und Südafrika. Während penetrierende Verletzungen häufig operativ versorgt werden müssen, können die meisten stumpfen Traumen konservativ bzw. mit Thoraxdränage und maschineller Beatmung suffizient behandelt werden. Bei insgesamt niedriger Frequenz ist es umso wichtiger, die Fälle zu erkennen, bei denen eine Thorakotomie erforderlich ist. Neben der akuten Versorgung spielt insbesondere die konsequente Therapie des sich häufig entwickelnden ARDS eine wichtige Rolle. Therapiepfeiler sind die Lungen schonende maschinelle Beatmung, die nicht standardisiert, sondern individuell angepasst erfolgen muss, die Flüssigkeitsrestriktion sowie die Lagerungstherapie. Trotz vieler Versuche spielen adjuvante medikamentöse Therapien und die Lungenersatzverfahren nur eine untergeordnete Rolle.

Biomedical ChromatographyVolume 11, Issue 2 p. 77-78 Extended Abstract Interaction of NO, Endothelin and Oxalate in Patients with Systemic Inflammatory Response Syndrome (SIRS) S. Albrecht, Corresponding Author S. Albrecht Department of Gynecology and Obstetrics, The Technical University, Dresden, Ferscherstrasse 74, D-01307, Dresden, GermanyDepartment of Gynecology and Obstetrics, The Technical University, Dresden, Ferscherstrasse 74, D-01307, Dresden, GermanySearch for more papers by this authorT. Zimmermann, T. Zimmermann Department of Surgery, The Technical University Dresden, Fetscherstrasse 74, D-01307 Dresden, GermanySearch for more papers by this authorM. Freidt, M. Freidt Medical Laboratory Bautzen, Töpferstrasse 17, D-02625 Bautzen, GermanySearch for more papers by this authorT. Freidt, T. Freidt Medical Laboratory Bautzen, Töpferstrasse 17, D-02625 Bautzen, GermanySearch for more papers by this authorH.-D. Saeger, H.-D. Saeger Department of Surgery, The Technical University Dresden, Fetscherstrasse 74, D-01307 Dresden, GermanySearch for more papers by this authorW. Distler, W. Distler Department of Gynecology and Obstetrics, The Technical University, Dresden, Ferscherstrasse 74, D-01307, Dresden, GermanySearch for more papers by this author S. Albrecht, Corresponding Author S. Albrecht Department of Gynecology and Obstetrics, The Technical University, Dresden, Ferscherstrasse 74, D-01307, Dresden, GermanyDepartment of Gynecology and Obstetrics, The Technical University, Dresden, Ferscherstrasse 74, D-01307, Dresden, GermanySearch for more papers by this authorT. Zimmermann, T. Zimmermann Department of Surgery, The Technical University Dresden, Fetscherstrasse 74, D-01307 Dresden, GermanySearch for more papers by this authorM. Freidt, M. Freidt Medical Laboratory Bautzen, Töpferstrasse 17, D-02625 Bautzen, GermanySearch for more papers by this authorT. Freidt, T. Freidt Medical Laboratory Bautzen, Töpferstrasse 17, D-02625 Bautzen, GermanySearch for more papers by this authorH.-D. Saeger, H.-D. Saeger Department of Surgery, The Technical University Dresden, Fetscherstrasse 74, D-01307 Dresden, GermanySearch for more papers by this authorW. Distler, W. Distler Department of Gynecology and Obstetrics, The Technical University, Dresden, Ferscherstrasse 74, D-01307, Dresden, GermanySearch for more papers by this author First published: 04 December 1998 https://doi.org/10.1002/(SICI)1099-0801(199703)11:2<77::AID-BMC642>3.0.CO;2-MCitations: 5AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume11, Issue2March 1997Pages 77-78 RelatedInformation

About one-third of hereditary non-polyposis colorectal cancer-related mutations in the mismatch repair gene hMLH1 result in the loss of entire exons from the wild type transcripts. Here we describe quantitative differences of hMLH1 transcripts without exon 15, exon 16 or exon 17 in several members of a family with hereditary non-polyposis colorectal cancer. The transcript lacking exon 15 is caused by a G to A transition affecting the last nucleotide of the respective exon and results in a truncated protein. The transcripts lacking exon 16 or exon 17, which are in-frame deletions, were also found in all tested samples of a normal population and represent common isoforms. Reverse transcription-polymerase chain reaction-based relative quantification revealed about 50 % signal intensity for the mutation-based transcript, but less than 10% for the common isoforms, if compared to the wild type. All aberrant transcripts were detected from blood-derived cDNAs but not from samples of normal colon epithelium. Although the biological significance of the common isoforms is unknown, they might lead to false risk assessment in hereditary non-polyposis colorectal cancer cases.

Biomedical ChromatographyVolume 13, Issue 2 p. 131-134 Extended Abstract Chemiluminometric measurement of NO and 77Se-NMR studies about the redox-sensitive behaviour of sodium selenite in the presence of peroxynitrite and H2O2/O2 S. Albrecht, Corresponding Author S. Albrecht Department of Gynaecology and Obstetrics, Technical University Dresden, Fetscherstrasse 74, D-01307 Dresden, GermanyDepartment of Gynaecology and Obstetrics, Technical University of Dresden, Fetscherstrasse 74, D-01307 Dresden, Germany.Search for more papers by this authorT. Zimmermann, T. Zimmermann Department of Visceral, Thoracic and Vascular Surgery, Technical University Dresden, Fetscherstrasse 74, D-01307 Dresden, GermanySearch for more papers by this authorD. Scheller, D. Scheller Department of Analytical Chemistry, Technical University Dresden, Fetscherstrasse 74, D-01307 Dresden, GermanySearch for more papers by this authorR. Grützmann, R. Grützmann Department of Visceral, Thoracic and Vascular Surgery, Technical University Dresden, Fetscherstrasse 74, D-01307 Dresden, GermanySearch for more papers by this authorH. D. Saeger, H. D. Saeger Department of Visceral, Thoracic and Vascular Surgery, Technical University Dresden, Fetscherstrasse 74, D-01307 Dresden, GermanySearch for more papers by this authorW. Distler, W. Distler Department of Gynaecology and Obstetrics, Technical University Dresden, Fetscherstrasse 74, D-01307 Dresden, GermanySearch for more papers by this author S. Albrecht, Corresponding Author S. Albrecht Department of Gynaecology and Obstetrics, Technical University Dresden, Fetscherstrasse 74, D-01307 Dresden, GermanyDepartment of Gynaecology and Obstetrics, Technical University of Dresden, Fetscherstrasse 74, D-01307 Dresden, Germany.Search for more papers by this authorT. Zimmermann, T. Zimmermann Department of Visceral, Thoracic and Vascular Surgery, Technical University Dresden, Fetscherstrasse 74, D-01307 Dresden, GermanySearch for more papers by this authorD. Scheller, D. Scheller Department of Analytical Chemistry, Technical University Dresden, Fetscherstrasse 74, D-01307 Dresden, GermanySearch for more papers by this authorR. Grützmann, R. Grützmann Department of Visceral, Thoracic and Vascular Surgery, Technical University Dresden, Fetscherstrasse 74, D-01307 Dresden, GermanySearch for more papers by this authorH. D. Saeger, H. D. Saeger Department of Visceral, Thoracic and Vascular Surgery, Technical University Dresden, Fetscherstrasse 74, D-01307 Dresden, GermanySearch for more papers by this authorW. Distler, W. Distler Department of Gynaecology and Obstetrics, Technical University Dresden, Fetscherstrasse 74, D-01307 Dresden, GermanySearch for more papers by this author First published: 30 April 1999 https://doi.org/10.1002/(SICI)1099-0801(199904)13:2<131::AID-BMC886>3.0.CO;2-2Citations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Citing Literature Volume13, Issue2Special Issue:Extended Abstracts from VIIIth International Symposium on Luminescence Spectrometry in Biomedical and Environmental Analysis – Detection Techniques and Applications in Chromatography and Capillary Electropharesis. 26–29 May 1998. Held at University of Las Palmas de Gran Canaria, Canary Islands, SpainApril 1999Pages 131-134 RelatedInformation

An active specific immunization (ASI) procedure with two types of autologous tumor cell vaccines (ATV) is tested for adjuvant immunotherapy of resected colorectal carcinoma to provide preliminary information on local immunological skin responses, side effects and two year survival rates. For vaccine preparation, the tumor derived freshly isolated and cryopreserved cells were thawed, purified by PercolI density centrifugation and depleted of tumor infiltrating lymphocytes by immunomagnetic-beads. Atter inactivation by 200 Gy, the cells of this ATV were either infected by Newcastle Disease Virus (NDV) or they were admixed with Bacillus Calmette Guerin (BCG) organisms. Vaccination was performed in the arm beginning 6–8 weeks after operation, 3 times at two week intervals. Of 57 patients that received ASI, 48 were treated by virus infected autologous tumor cell vaccine (ATV-NDV) and 9 with the BCG admixed vaccine (ATV/BCG). The mean value of delayed hypersensitivity skin reactions (DTH) from ATV-NDV treated patients was 18 mm for the first vaccination and 26 and 29 mm for the following ones. While application of ATV-NDV was associated with only mild side effects, the ATV/BCG vaccine lead to long lasting ulcers and to more serious side-effects. The 2 year survival rates obtained with ATV-NDV was 97.9% while the survival rate with ATV/BCG was 66.7% (P < 0.01). The mean survival of 661 patients from a historical control was 73.8%. Thus, the type and quality of the tumor vaccine for ASI-treatment appears to be important. The findings with ATV-NDV necessitate corroboration in a prospective randomised controlled study An active specific immunization (ASI) procedure with two types of autologous tumor cell vaccines (ATV) is tested for adjuvant immunotherapy of resected colorectal carcinoma to provide preliminary information on local immunological skin responses, side effects and two year survival rates. For vaccine preparation, the tumor derived freshly isolated and cryopreserved cells were thawed, purified by PercolI density centrifugation and depleted of tumor infiltrating lymphocytes by immunomagnetic-beads. Atter inactivation by 200 Gy, the cells of this ATV were either infected by Newcastle Disease Virus (NDV) or they were admixed with Bacillus Calmette Guerin (BCG) organisms. Vaccination was performed in the arm beginning 6–8 weeks after operation, 3 times at two week intervals. Of 57 patients that received ASI, 48 were treated by virus infected autologous tumor cell vaccine (ATV-NDV) and 9 with the BCG admixed vaccine (ATV/BCG). The mean value of delayed hypersensitivity skin reactions (DTH) from ATV-NDV treated patients was 18 mm for the first vaccination and 26 and 29 mm for the following ones. While application of ATV-NDV was associated with only mild side effects, the ATV/BCG vaccine lead to long lasting ulcers and to more serious side-effects. The 2 year survival rates obtained with ATV-NDV was 97.9% while the survival rate with ATV/BCG was 66.7% (P < 0.01). The mean survival of 661 patients from a historical control was 73.8%. Thus, the type and quality of the tumor vaccine for ASI-treatment appears to be important. The findings with ATV-NDV necessitate corroboration in a prospective randomised controlled study

Neuron-specific enolase and beta-human chorionic gonadotropin are serum markers frequently found associated with germ cell tumors. To our knowledge, we report the first case of a malignant fibrous histiocytoma producing both markers and discuss the significance of this unusual condition in the differential diagnosis of retroperitoneal tumors.

Abstract Prognosis for patients with pancreatic carcinoma (PDAC) remains poor. Despite of increasing knowledge about the molecular basis of PDAC neither a specific marker for early diagnosis nor target proteins for a new therapeutic approach have been identified so far. However, reliable prediction of survival might help to improve the therapeutic outcome for patients with PDAC. In recent years it has become evident, that the Hedgehog (Hh) signal transduction pathway is a key regulator of pancreatic cancer development. Hedgehog interacting protein (HHIP) is a key modulator of Hh action and is overexpressed in the tumor stroma of PDACs. Reasoning that HHIP could serve as an indicator of Hh signaling activation we identified HHIP associated genes (HAG) using guilt by association (GBA) analysis in a set of PDAC gene expression profiles from microdissected tissue. Using the Affymetrix GeneChip U133 2.0 array and TNASAS we analyzed the gene expression profile of 59 PDAC samples and identified prognostic marker from HAG for survival of PDAC patients with adjuvant therapy. GBA analysis of gene expression profiles from microdissected PDAC tissue yielded 276 HAGs. TNASAS analysis using these genes revealed a prognostic gene expression signature of 50 genes, which was able to identify patients receiving adjuvant therapy with gemcitabine surviving more than 24 month with a total error of 0.087. TNASAS analysis of samples from patients treated without adjuvant therapy failed to identify a gene set with prognostic significance. Gene expression analysis is able to identify genes with prognostic significance in patients with adjuvant chemotherapy. These genes seem to be correlated with the efficacy of adjuvant gemcitabine therapy. Further analysis of those genes can reveal more insights in the signal transduction mechanisms associated with those genes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5106. doi:1538-7445.AM2012-5106

Abstract Background: Prognosis for patients with pancreatic carcinoma (PDAC) remains poor. Despite of increasing knowledge about the molecular basis of PDAC neither a specific marker for early diagnosis nor a target protein for a new therapeutic approach have been identified so far. Determination of DNA methylation events is a promising technology for the early detection and classification of cancer. We were therefore interested to elucidate the significance of DNA methylation to distinct between ductal adenocarcinoma and cancers of the ampulla vateri (AVT) of the pancreas. Methods: DNA isolation using the Qiamp mini kit and modification using the Zymo EZ DNA Methylation-Gold system was performed. Primers for methylation specific PCR (MSP) for RELN, ADAMTS8, SFRP1, BNIP3, ID4 and TFPI2 were selected from the literature and tested for their performance on bisulfite modified fully methylated human DNA. After successfully establishing the assays, DNA samples isolated from formalin fixed and paraffin embedded tissue from patients with diagnosed ductal adenocarcinoma (n = 14) and tumors of the ampulla vateri (n=7) were investigated. MSP was performed and the amount of produced fragment was scored semiquantitatively using agarose gelelectrophoresis. Results: MSP analysis of the bisulfite modified DNA showed methylation differences in RELN (PDAC: 63%, AVT: 37%), ADAMTS8 (PDAC: 37%, AVT: 14%), BNIP3 (PDAC: 85%, AVT: 50%), SFRP1 (PDAC: 84%, AVT: 100%) and ID4 (PDAC: 93%, AVT: 62,5). Interestingly, for TFPI2 both tumors types showed nearly the same incidence of methylation events (PDAC: 86%; AVT: 87%). Conclusion: Detection of DNA methylation is able to indentify differences between tumors of the pancreas. This might resemble crucial changes during tumor development, which are also reflected in gene expression and histopathologic appearance. For the establishment of a methylation-based discrimination of tumors further samples and promoters have to be tested. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 98. doi:10.1158/1538-7445.AM2011-98

Investigations into the pathogenesis of type 2 diabetes and islets of Langerhans malfunction 1 have been hampered by the limited availability of type 2 diabetic islets from organ donors2. Here we share our protocol for isolating islets from human pancreatic tissue obtained from type 2 diabetic and non-diabetic patients who have undergone partial pancreatectomy due to different pancreatic diseases (benign or malignant pancreatic tumors, chronic pancreatitis, and common bile duct or duodenal tumors). All patients involved gave their consent to this study, which had also been approved by the local ethics committee. The surgical specimens were immediately delivered to the pathologist who selected soft and healthy appearing pancreatic tissue for islet isolation, retaining the damaged tissue for diagnostic purposes. We found that to isolate more than 1,000 islets, we had to begin with at least 2 g of pancreatic tissue. Also essential to our protocol was to visibly distend the tissue when injecting the enzyme-containing media and subsequently mince it to aid digestion by increasing the surface area. To extend the applicability of our protocol to include the occasional case in which a large amount (>15g) of human pancreatic tissue is available , we used a Ricordi chamber (50 ml) to digest the tissue. During digestion, we manually shook the Ricordi chamber3 at an intensity that varied by specimen according to its level of tissue fibrosis. A discontinous Ficoll gradient was then used to separate the islets from acinar tissue. We noted that the tissue pellet should be small enough to be homogenously resuspended in Ficoll medium with a density of 1.125 g/ml. After isolation, we cultured the islets under stress free conditions (no shaking or rotation) with 5% CO2 at 37 °C for at least 48 h in order to facilitate their functional recovery. Widespread application of our protocol and its future improvement could enable the timely harvesting of large quantities of human islets from diabetic and clinically matched non-diabetic subjects, greatly advancing type 2 diabetes research.

The Wnt signaling inhibitor secreted Frizzled-related protein 1 (SFRP1) [1] is a tumour suppressor gene in several human cancerous disorders [3, 4, 5]. Recent studies have shown that independently of Wnts SFRP1 can function morphogen-like by influencing the outgrowth of vertebrate neuronal axons [2]. In this context we examined here the possible influence of SFRP1 on the migration of pancreatic cells. Immunohistochemical stainings of tissue microarrays revealed that in addition to the tumour epithel of patients with ductal adenocarcinoma of the pancreas (PDAC) also the tumour stroma clearly expresses less SFRP1 compared to samples obtained from chronic pancreatitis patients. In vitro, the invasion assay showed less migratory activity of pancreatic stroma cells as well as pancreatic carcinoma cells in presence of SFRP1 than in its absence. Woundhealing assays demonstrated lesser closure of the scratched confluent SFRP1-producing cells after 24 h than empty transfected cells. These results suggest an inhibitory influence of SFRP1 on the directed migration of pancreatic cells. We conclude that downregulation of SFRP1 in PDAC tumour tissue could promote migration of tumour cells.

Prognosis for patients with pancreatic carcinoma (PDAC) remains poor. Despite of increasing knowledge about the molecular basis of PDAC no specific marker for early diagnosis nor a target protein for a new therapeutic approach have been identified so far. Surgery is the only potentially curative option. But even after R0-resection of PDAC, the prognosis is bad and most patients suffer from recurrences and metastases. Moreover, the individual prognosis is not known. This might be of interest for indication of adjuvant therapy. We were therefore interested in the analysis of differential gene expression between PDAC with relatively good and worse prognosis.

Pancreatic cancer (PDAC) is an exceptionally devastating and incurable disease, the treatment of which has largely been unsuccessful due to higher resistance of pancreatic tumor cells to oncologic treatment. The last 10 years, many investigations were on the way to get insights into the details of drug resistance mechanisms of PDAC cells. Recent publications emphasize especially defects of the mitochondrial pathway of apoptosis signalling for the failure of oncologic treatment. Because of this, those defects came into the interest of clinicians as possible targets for new therapeutic approaches. However, there are numerous and sequential defects in the course of the cell death pathway. Therefore defects might act redundantly in inhibiting physiologic signal transduction. Because of this we followed a new approach and aimed to simultaneous inhibit expression of several overexpressed, anti-apoptotic members of the mitochondrial cell death pathway to normalize the information flow. Simultaneous transfection of siRNAs against Bcl-2, XIAP and Survivin showed knock down of the target genes. The silencing was validated by RT-PCR and Western Blot. Quantification of cell death was achieved with flow cytometrie and by caspase assay. This is to our knowledge the first report on simultaneous gene inhibition in the apoptosis pathway. We could show a significant re-sensibilisation of signal transduction in MIA PaCa-2 cells with an additive effect by simultaneous inhibition compared to single transfection of target siRNA.

Introduction The presentation and outcome of patients with acinar cell carcinoma (ACC) of the pancreas compared to the more common ductal cell adenocarcinoma (DCA) may be distinct. This study combines the experience with ACC from multiple academic institutions to better understand its natural history and outcomes. Methods This study is a multi-institutional retrospective review of patients with ACC. Results Between 1988 and 2008, 17 patients were identified with pathologically confirmed ACC. Median age at presentation was 59 years. Common presenting symptoms were abdominal pain (60%), back pain (50%), and weight loss (45%). Fifteen patients underwent 16 operations: pancreaticoduodenectomy (nine), distal pancreatectomy (four), and exploratory laparotomy (three). Mean tumor size was 5.3 cm. American Joint Commission on Cancer tumor stages were stage I (two), stage II (eight), stage III (four), and stage IV (three). Overall, 1- and 5-year survival rates were 88% and 50%, respectively. In resected cases (13), 1- and 5-year survival rates were 92% and 53%, respectively. Median survival in resected cases was 61 months. This is in contrast to 1,608 patients with ductal cell adenocarcinoma who underwent resection identified from recent literature reports where the average median survival was only 24 months. There was no discernable difference in the outcomes of patients with ACC between United States and Germany patients. Conclusion Acinar cell carcinoma of the pancreas is rare and appears to have a presentation and outcome distinct from the more common pancreatic DCA. Based upon these data, the outcome of patients with ACC is superior to that of DCA.

Background: Pancreatic ductal adenocarcinoma is characterized by an abundant desmoplastic stroma. Interactions between cancer and stromal cells play a critical role in tumour invasion, metastasis and chemoresistance. Therefore, we hypothesised that the gene expression profile of the stromal components of pancreatic carcinoma is different from chronic pancreatitis and reflects the interaction with the tumour. Methods: We investigated the gene expression of eleven stromal tissue from pancreatic ductal adenocarcinoma, nine from chronic pancreatitis and cell lines of stromal origin using the Affymetrix U133 GeneChip set. The tissue samples were microdissected, the RNA was extracted, amplified, and labelled using a repetitive in vitro transcription protocol. Differentially expressed genes were identified using the significance analysis of microarrays program. Results: We found 255 genes to be over-expressed and 61 genes to be under-expressed within the stroma of pancreatic carcinoma compared to the stroma of chronic pancreatitis. Analysis of the involved signal transduction pathways revealed a number of genes associated with the Wnt pathway. Therefore, we confirmed the differential expression of SFRP1 and WNT5a using immunohistochemistry. Moreover, we could demonstrate that WNT5a expression was induced in fibroblasts during co-cultivation with a pancreatic carcinoma cell line. Conclusion: The identified differences in the expression profile of stroma cells derived from tumour compared to cells of inflammatory origin suggest a specific response of the tissue surrounding malignant cells. The over-expression of WNT5a, a gene involved in the non canonical Wnt signalling and chondrocyte development might contribute to the strong desmoplastic reaction seen in pancreatic cancer.

Prognosis for patients with pancreatic carcinoma (PDAC) remains poor. Despite of increasing knowledge about the molecular basis of PDAC no specific marker for early diagnosis nor a target protein for a new therapeutic approach have been identified so far. Surgery is the only potentially curative option. But even after R0-resection of PDAC, the prognosis is bad and most patients suffer from recurrences and metastases. Moreover, the individual prognosis is not known. This might be of interest for indication of adjuvant therapy. We were therefore interested in the analysis of differential gene expression between PDAC with relatively good and worse prognosis. We used fresh frozen tissue from 29 patients with pancreatic ductal adenocarcinoma. From every single patient, the clinical characteristics, pathological data as well as follow up has been collected prospectively. The tissues were obtained during surgery and freshly frozen. The type of each frozen tissue sample was re evaluated pathologically. The RNA was extracted using the RNeasy Mini Kit. The quality of the RNA was assessed using the Agilent Lab on a Chip System and only samples displaying a RIN>4 were used. For hybridization we used 100 ng of total RNA, and samples were prepared according the Affymetrix two cycle amplification labelling protocol. Samples were hybridised to Affymetrix U133 2.0 plus GeneChips. The obtained data from the microarray were analysed using dCHIP. Median survival of the patients was 13 (2–53) months. Using this time point we classified the samples into two groups. Differentially gene expression analysis (FC>2, difference of means > 100; p value <0.05) revealed 21 probe sets. Hierarchical clustering using these 21 probe sets displayed two clusters of samples. One cluster contained only samples from patients with a survival time <13 months. Sensitivity and specificity calculations based on the cluster data resulted in 100% sensitivity and 73% specificity for the detection of patient samples with a survival > 13 month. In conclusion, gene expression analysis of the tumor tissue of PDAC enables prediction of prognosis with high specificity and good sensitivity. The role of adjuvant treatment has to be elucidated. Moreover, using the set of differentially expressed genes we might identify new markers and therapeutic targets for pancreatic cancer.

Background: Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the digestive tract and are characterized by constitutive activation of either the KIT or the platelet-derived growth factor receptor alpha (PDGFRA) receptor tyrosine kinase. The prognostic significance of mutually exclusive gain-of-function mutations of KIT and PDGFRA in GISTs is still controversial and poorly understood. The aim of this study was to investigate the effect of mutations and expression of KIT and PDGFRA in GISTs and their association with the clinical pathology and the prognosis of patients after curative resection of the primary tumour. Methods: Paraffin-embedded tumour tissue sections of 109 GISTs were analyzed for CD 117 (KIT receptor protein) and PDGFRA expression by immunohistochemistry. PDGFRA expression was judged using a score system subdividing tumours in negative/weak and strong immunreactivity-groups according to the results of staining. DNA was extracted from microdissected tumour tissues and sequenced for KIT mutations in exons 9, 10, 11, 13 and 17 and PDGFRA mutations in exons 10, 12, 14 and 18. Results: Of 109 GISTs, 106 (97%) showed CD-117 expression and 61% (66/109) revealed strong expression of PDGFRA. Patients with strong PDGFRA overexpression showed a significant longer disease-free survival (DFS) than patients with absent or weak PDGFRA-immunoreactivity (p<0.01). Furthermore, PDGFRA overexpression was associated with gastric location. Expression of CD117 was not related to prognosis. Simultaneous complete sequencing of KIT exons 9, 10, 11, 13 and 17 as well as PDGFRA exons 10, 12, 14 and 18 was successful in 63 of 109 tumours (58%). Overall, KIT mutations were detected in 43 of 63 (68.3%) cases. PDGFRA mutations were identified in 10 of the 63 cases (16%) solely in KIT wild-type GISTs, which all showed strong PDGFRA overexpression. Three tumours with a detected PDGFRA mutation did not express CD117. KIT and PDGFRA oncogenic mutations were mutually exclusive and did not correlate with DFS after resection of the primary GIST. Conclusions: PDGFRA overexpression in GIST is associated with a longer DFS after resection in our patients and might act as an additional prognostic marker. The higher PDFGRA expression in gastric GISTs is possibly related to the wellknown site-dependent clinical behaviour. Mutations in KIT or PDGFRA, respectively, have no obvious relationship to the clinical behavior of GISTs or the prognosis.

Cystic diseases of the adrenal glands, which were thought to be rare, are being found more frequently nowadays by means of sonography and computer tomography. Our experience of fifteen cases is reported; of these, ten were confirmed at operation. Contrary to expectations based on the relevant literature, only one of the operated cases proved to be an endothelial cyst of lymphangiomatous origin. All other patients had pseudo-cysts of the adrenals. These are due to bleeding into a normal or tumour-containing gland. About one quarter of the pseudo cysts showed circular calcification on the plain films, although the incidence of this is given as 8-15% in the literature. The cystic nature of these lesions can be readily demonstrated by ultrasound or CT. The latter also provided information concerning the wall of the cyst and of the remaining adrenal tissue. An aspiration biopsy of the cyst can be carried out under ultrasound or CT control; cytological examination will confirm the benign nature of the lesion. A benign lesion without symptoms requires no further diagnostic or therapeutic measures. If there is hypertension, as may occur with a cystic phäeochromocytoma or lymphangioma, angiography is still indicated. Hormone assays are possible following catheterisation of the vena cava combined with adrenal phlebography. The origin and extent of a malignant pseudo-cyst can be demonstrated by arteriography, if this information is lacking following CT.

True aneurysms of the epigastric artery are rare. We report a case of a 65-year-old female who was admitted for increasing upper abdominal pain. A leukocytosis, pyrexia, breathing stop on inspiration, and a palpable mass next to the right costal arch with severe local pain were suspicious for acute cholecystitis. Surprisingly, sonography and CT scan revealed a 5 x 4 cm structure limited to the abdominal wall directly above the gallbladder, which showed an arterial flow in the duplex scan. After resection and an uneventful postoperative course, the histological findings confirmed the diagnosis of a symptomatic true atherosclerotic aneurysm. True aneurysms of the epigastric artery are rare. We report a case of a 65-year-old female who was admitted for increasing upper abdominal pain. A leukocytosis, pyrexia, breathing stop on inspiration, and a palpable mass next to the right costal arch with severe local pain were suspicious for acute cholecystitis. Surprisingly, sonography and CT scan revealed a 5 x 4 cm structure limited to the abdominal wall directly above the gallbladder, which showed an arterial flow in the duplex scan. After resection and an uneventful postoperative course, the histological findings confirmed the diagnosis of a symptomatic true atherosclerotic aneurysm. Aneurysms of the epigastric arteries are rare. Systematic Medline search (key words: epigastric, aneurysm, pseudoaneurysm, false aneurysm, abdominal wall, trauma) combined with a review of the references of each article provided not a single report of a true atherosclerotic aneurysm while there are some reports of mostly traumatic pseudoaneurysms of the inferior epigastric artery. A 65-year-old female patient was admitted to the hospital because of severe pain progressing for hours in the right epigastic region. She had never had similar symptoms before. As a result of repeated vomiting, she showed signs of dehydration. Clinical examination revealed pain next to the right costal arch with signs of regional peritonitis, stop of breathing on inspiration, and a palpable swelling despite the obesity. The body temperature was increased to 38.2°C. The laboratory analysis showed a WBC-count of 14.8 GPt/l, and the CRP elevated to 17.9 mg/l. Subnormal serum potassium and a slightly increased γGT were noticed. The ECG showed a sinus rhythm with tachycardia of 115/min and a left anterior hemi blockage. Her personal history was remarkable for hypercholesterolemia, arterial hypertension, and obstructive lung disease. While excluding cholecystolithiasis, the ultrasound surprisingly revealed a 5 x 4 cm mass limited to the abdominal wall directly above the gallbladder, which had an arterial flow in the duplex scan with a cranio-caudal direction. The CT scan (Fig 1) confirmed the diagnosis of an aneurysm of the right superior epigastric artery bulging out the posterior leaflet of the rectus sheath, tangent to the surface of the gallbladder. Due to pain and signs of local inflammation operative intervention was indicated. Using a paramedian incision just above the palpable swelling, the aneurysm was displayed. The proximal and distal sections of the epigastric artery were heavily kinked (Fig 2). Surrounding tissue showed signs of inflammation. The aneurysm was resected including the kinked portions of the artery. The proximal and distal artery was ligated (Fig 3). The wound healing was uneventful, and the patient could be discharged at the fifth postoperative day. The histological examination revealed the diagnosis of a true atherosclerotic aneurysm with a diameter of 5 cm and a severe calcifying arteriosclerosis (Fig 4).Fig 3The resected and incised aneurysm.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 4Aneurysm wall and proximal artery with typical atherosclerotic changes. Freshly ruptured plaque with bleeding signs and old calcifications as well as cholesterol crystals and fibrotic and sclerotic wall thickness, no evidence for arteritis, mycotic aneurysm, or other diseases like Behcet’s disease.View Large Image Figure ViewerDownload Hi-res image Download (PPT) In the 15 reports of pseudoaneurysms of the inferior epigastric artery available, seven were caused by sutures after laparotomy, four by an incidental puncture during paracentesis or surgical drain placement, one by a laparoscopic trocar, one while implanting a catheter for continuous ambulatory peritoneal dialysis, and two were spontaneous.1Georgiodis G.S. et al.Inferior epigastric artery false aneurysms: review of the literature and case report.Eur J Vasc Endovasc Surg. 2007; 33: 182-186Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 2Ello F.V. Nunn D.B. False aneurysm of the inferior epigastric artery as a complication of abdominal retention sutures.Surgery. 1973; 74: 460-461PubMed Google Scholar, 3Gage S.G. et al.Pseudoaneurysm of the inferior epigastric artery: diagnosis and percutaneous treatment.Am J Roentgenol. 1990; 155: 529-530Crossref PubMed Scopus (25) Google Scholar, 4Ferrer J.V. et al.Pseudoaneurysm of the inferior epigastric artery: pathogenesis, diagnosis, and treatment.Arch Surg. 1996; 131: 102-103Crossref PubMed Scopus (20) Google Scholar, 5Verbist J. et al.Pseudoaneurysm of the inferior epigastric artery.Acta Belg. 1997; 97: 196-198PubMed Google Scholar Different types of treatment were reported: the resection of the aneurysm with arterial ligation, percutaneous ultrasound guided thrombin, injection, or percutaneous coil embolization.6Shabani A.G. Baxter G.M. Inferior epigastric artery pseudoaneurysm: ultrasound diagnosis and treatment with percutaneous thrombin.Br J Radiology. 2002; 75: 689-691PubMed Google Scholar In this case, we preferred the complete resection of the aneurysm due to potential complications and local inflammation. The rectus muscle is easily supplied by collaterals even if the artery is ligated or resected over a longer distance. The patient could not remember either a puncture or a trauma. The pathologist confirmed the first case of a true symptomatic atherosclerotic aneurysm of the right superior epigastric artery. There was no evidence of mycotic aneurysm or arteritis or Behcet’s disease. The local inflammation around the aneurysm and peritoneal irritation were mimicking an acute cholecystitis and were responsible for the clinical symptoms.

Pancreatic ductal adenocarcinoma (PDAC) remains an important cause of malignancy related death. Despite recent progress in understanding the molecular basis of PDAC further studies are needed to find new molecular markers for diagnostic and therapeutic purposes. Gene expression profiling revealed ADAM9 to be distinctly over-expressed in pancreatic ductal adenocarcinoma (PDAC). We examined the relevance of ADAM9 expression in PDAC diagnosis and prognosis. 59 infiltrating primary PDACs, 32 specimens from patients with chronic pancreatitis, 11 endocrine tumours and 24 acinar cell carcinomas were immunohistochemically analysed for ADAM9 expression. Staining for ADAM9 was detected in 58/59 (98.3%) PDACs and in 2/24 (8.3%) acinar cell carcinomas, but not in endocrine tumours. In the non-neoplastic pancreas, whether normal or chronically inflamed, ADAM9 was expressed in centroacinar and intralobular duct cells, but not in interlobular duct cells and their hyperplastic lesions. PDACs showing cytoplasmic ADAM9 expression showed a lower degree of tumour differentiation and correlated with shorter overall survival than in cases with only an apical membranous staining pattern (p = 0.001). Multivariate analysis identified cytoplasmic ADAM9 expression as an independent marker of shortened survival in a set of 42 curatively (R0) resected PDACs (P < 0.05, hazard ratio 2.85, 95% confidence interval: 1.21-26.71). We conclude that ADAM9 expression distinguishes PDACs from other solid pancreatic tumours. In addition, cytoplasmic ADAM9 over-expression is associated with poor differentiation and shortened survival. Therefore, ADAM9 over-expression might contribute to the aggressiveness of PDACs. Moreover cytoplasmic expression seems be a novel prognostic marker for survival in PDAC.

Variable gene expression patterns of the tissue inhibitor of metallo-proteinase 1 and 2 (TIMP1 and TIMP2) in the wall of spontaneous aortic aneurysms suggest that the phenotype may be associated with functional genetic variants of those genes. Thus, we have analyzed the coding sequences of the TIMP1- and TIMP2-gene in a group of 50 patients with abdominal aortic aneurysm and in a control group of 48 healthy individuals. We have identified 3 new single nucleotide polymorphisms (SNP). An association described by Wang et al. [1] of the SNP TIMP2 nt 573 G/A with the phenotype could not be shown in our population.

Perfluorocarbons are known for their high oxygen-solubility coefficients and for their maintenance of high-oxygen partial pressures for extended time. They serve as oxygen „reservoirs“ for harvested organs in pancreas organ transplantation.

Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study

4159 Background: Prognosis for patients with pancreatic carcinoma (PDAC) remains poor. Despite of increasing knowledge about the molecular basis of PDAC neither a specific marker for early diagnosis nor a target protein for a new therapeutic approach have been identified so far. In recent year’s gene expression profiling experiments have identified a large number of candidate genes for diagnosis and therapy. However, given the large number of differentially expressed genes in PDAC the functional characterization of those genes in a one by one approach is time consuming and biases further analysis to genes with at least some existent knowledge. With the development of the siRNA technology new approaches for functional characterization in large scale have emerged. Methods: In the last years we were able to characterize the gene expression of PDAC by different methods. All identified candidate genes were assembled in one file and we randomly selected 140 genes for functional high throughput characterization. For these genes cDNA clones were obtained from the RZPD and sequenced. We were able to confirm the sequence of 125 genes. From 103 of these we successfully generated dsRNA by in vitro transcription using the T7 Megascript kit from Ambion. The dsRNA was digested using the recombinant Dicer enzyme from Stratagene. After purification of the digested RNA by a combination of gel- and ultrafiltration the resulting dsiRNA was analyzed using PAGE. The amount was calculated based on the ethidium bromide staining intensity and compared to a chemical synthesized siRNA with known concentration. The dsiRNA was transfected into 4.000 cells of either Panc89 (30 ng dsiRNA / well) or MiaPaca-2 (50 ng dsiRNA / well) cells in 96 well format using oligofectamine. Growth inhibition of the investigated dsiRNA was analyzed via nuclear staining using DraqV and induction of apoptosis was identified using an Annexin V assay. All assays were performed in triplicate. Results: Of the transfection of 103 generated dsiRNA molecules 19 resulted in a growth inhibition in both assays and in both of the cell lines analyzed, whereas in 30 no growth inhibition could be observed in any assay or cell line. Within these 19 genes are three (∼15%) genes without a known functional characterization. These three genes might have been un-analyzed by conventional techniques and could lead to new insights in the development of this dismal disease. Conclusion: High throughput functional characterization is a new and useful tool for the further investigation of gene lists resulting from gene expression profiling experiments. It will lead to a better understanding of the development of cancer and it will provide new targets for new therapeutic approaches.

5278 Lung cancer is the leading cancer-related death in U.S. Even patients with earlier stage (I-IIIA) that undergo surgical resection have poor survival, and tumor relapse is a common scenario. The overexpression of several receptors has been postulated as a possible prognostic factor for survival. We reviewed the outcome and survival of 101 patients with an established diagnosis of small cell (SCLC) and non-small cell lung cancers (NSCLC), and attempted to demonstrate a correlation with the overexpression of c-Kit (CD117) by immunohistochemistry and gene mutation analysis. The median age of the patients was 59.5 years (range 37 –78 years). Seventy patients were males and 31 were females. The median survival of patients who had a positive c-Kit immunoreaction was 42.5 months versus 11 months for patients who were c-Kit negative. The histologic distribution was: 30 squamous cell carcinoma (SQ), 39 adenocarcinoma (ADE), 17 large cell (LC), and 15 small cell lung cancer (SCLC). According to AJCC Cancer Staging, the distribution by stage was: stage I: 30 cases, stage II: 15 cases, stage III: 31 cases (15 stage IIIA, 16 stage IIIB), and stage IV: 25 cases. The apportionment between patients who were candidates for surgical resection versus concomitant chemoradiation or chemotherapy alone was similar. Sixteen patients (15.8%) overexpressed c-Kit in their tumor cells. Only four (∼ 4%) had c-Kit gene mutations (560-CTT-GCT V-A, 586-AGA-ATA R-I, 553-TAT-TCT Y-S, and 561-GAG-GTG E-V). The c-Kit overexpression was distributed as: 8/39 ADE, 4/15 SCLC, 3/30 SQ, and 1/17 LC. The staging of these tumors was classified as follows: stage I: 8 cases, stage II: 0 cases, stage III: 3 cases, and stage IV: 5 cases. We found that the presence of c-Kit by immunohistochemistry was associated with a better survival at 2 and 3 years (p value

Colorectal cancer is the second most common cause of malignant death in industrialized countries. More accurate detection markers are needed to improve the effectiveness and efficiency of both the screening and surveillance of colorectal neoplasia. Aberrant DNA methylation occurs early in oncogenesis, is stable once initiated, and can be assayed in both primary tissues and remote clinical samples. While DNA methylation markers are attractive candidates for colorectal cancer screening, robust searches are needed to discover DNA methylation sequences that optimally discriminate colorectal neoplasia from other diseased and histologically normal tissues for accurate testing in body fluid samples.Using well-characterized normal and neoplastic specimens, a candidate methylation-based gene microarray of oligonucleotides and a genome-wide methylation discovery process was utilized to identify markers for colorectal neoplasia. To identify markers highly specific for colorectal neoplasia, 12 genes selected from the candidate gene array and 30 fragments from the discovery process were validated on a second methylation-based microarray using a larger, more diverse sample set. Sequences were probed with DNA extracted from 89 colorectal adenocarcinomas, 56 colorectal polyps, 31 inflammatory bowel disease samples, 123 extracolonic cancers, and 67 endoscopically proven normal tissues.We found markers highly methylated in colorectal neoplasia. The 16 most discriminating methylated sequences comprise both known and predicted genes including EYA4, N33, BCL6, FCGR2A, SIX6, NGFR, Q96PX8, DLX5, C14orf59, PCDH17, HVIAAT, SMAD7, CSPG2, GSK3B, CD44, and TMEFF2. Normal epithelium and extracolonic cancers revealed significantly lower or no methylation.Individual markers displayed sensitivities > 80% and specificities > 85% indicating the DNA methylation markers identified in this study can correctly classify colorectal neoplasia from other normal and diseased tissues and are attractive marker candidates for clinical testing.

Variable expression patterns of the matrix metalloproteinase-2 (MMP-2) gene in the wall of spontaneous aortic aneurysms suggest that the phenotype may be associated with functional genetic variants of this gene. Thus, we have analyzed the coding sequence of the MMP-2 gene in a group of 51 patients with abdominal aortic aneurysm and in a control group of 48 healthy individuals. We have identified ten new single nucleotide polymorphisms (SNP) and established a weak association of the SNP c.2122C > G with the phenotype. Our findings do not exclude a potential role for SNPs or haplotypes of the MMP-2 gene in the etiology of spontaneous abdominal aortic aneurysms.