Endoscopic full-thickness resection and clip defect closure in the colon with the new FTRD system: experimental study.

BACKGROUND: The benefit of endoscopic full-thickness resection is the improved diagnostic work-up with an integral wall specimen which allows a precise determination of the tumor or its precursor and its infiltration depth into the wall. MATERIALS AND METHODS: A new endoscopic full-thickness resection device (FTRD), which is a combination of a modified over-the-scope-clip (OTSC) system with an electrocautery snare, has been tested in an experimental setting. In eleven pigs, divided into three groups, endoscopic full-thickness resection was performed in the colon at one or two sites, respectively. Seven days (n = 7) or 28 days (n = 4) after the intervention, the animals were euthanized following endoscopic examination of the resection and clip application sites. Furthermore, two different clips were tested during these animal trials in order to evaluate the most effective clip design. RESULTS: The average diameter of the tissue resected with the FTRD was 3.1, 3.6, and 5.4 cm in the three groups. On follow-up endoscopy 7 days after the intervention, fibrin coating and stool residues were found at all clips, causing minor inflammatory reactions. However, the colon wall under the clip was non-inflamed. After 28 days, the serosa had primarily healed in all cases. There were also stool residues at all clips; however, no acute inflammatory reactions were seen anymore, due to complete healing. Histological assessment did not show any signs of dehiscence in the region of the scar, or ischemia in the clip area. In addition, no wound infections, such as abscess formation, were observed. CONCLUSIONS: This study demonstrates the safety and efficacy of the clip-and-cut technique using the new FTRD system. With the device, a local full-thickness colon resection can be easily created, and the resulting wall defect is reliably sealed by the endoluminal application of a modified OTSC clip.

Concerted down-regulation of immune-system related genes predicts metastasis in colorectal carcinoma.

BACKGROUND: This study aimed at the identification of prognostic gene expression markers in early primary colorectal carcinomas without metastasis at the time point of surgery by analyzing genome-wide gene expression profiles using oligonucleotide microarrays. METHODS: Cryo-conserved tumor specimens from 45 patients with early colorectal cancers were examined, with the majority of them being UICC stage II or earlier and with a follow-up time of 41-115 months. Gene expression profiling was performed using Whole Human Genome 4x44K Oligonucleotide Microarrays. Validation of microarray data was performed on five of the genes in a smaller cohort. RESULTS: Using a novel algorithm based on the recursive application of support vector machines (SVMs), we selected a signature of 44 probes that discriminated between patients developing later metastasis and patients with a good prognosis. Interestingly, almost half of the genes was related to the patients' immune response and showed reduced expression in the metastatic cases. CONCLUSIONS: Whereas up to now gene signatures containing genes with various biological functions have been described for prediction of metastasis in CRC, in this study metastasis could be well predicted by a set of gene expression markers consisting exclusively of genes related to the MHC class II complex involved in immune response. Thus, our data emphasize that the proper function of a comprehensive network of immune response genes is of vital importance for the survival of colorectal cancer patients.

Performance of the OTSC System in the endoscopic closure of iatrogenic gastrointestinal perforations: a systematic review.

BACKGROUND: Reliable closure is a prerequisite for conventional and innovative endoscopic procedures, such as NOTES. The purpose of this study is the systematic evaluation of the procedural and clinical success rates in closure of iatrogenic gastrointestinal perforations and acute anastomotic leaks by means of the over-the-scope-clip system (OTSC(®)). DESIGN: PubMed and other sources were searched systematically for clinical and preclinical research on the evaluation of the OTSC System for closure of gastrointestinal perforations and leaks. Appraisal of studies for inclusion and data extraction was performed independently by two reviewers using an a priori determined data extraction grid. Major endpoints to be extracted were data on procedural success (successful clip application) and clinical access (durable closure of defect without secondary adjunct therapy). RESULTS: A total of 17 clinical research articles/abstracts and 22 preclinical research articles/abstracts were identified. The examined clinical studies comprised case series and clinical single-arm studies. The reviewed studies revealed a consistently high mean rate of procedural success of 80-100 % and durable clinical success of 57-100 %. An identified major drawback preventing successful clip application was occurrence of fibrotic or inflamed lesion edges. Usage of the OTSC System was accompanied by neither major clip-related nor application-related complication. In experimental settings, closure of larger perforations and gastric access sites of NOTES or endoscopic full-thickness resection were achieved with high rates of success. CONCLUSIONS: Because randomized, clinical trials are not available in this field of indication, the evaluation is based on small case series. Nevertheless, by pooling all experience gained, we conclude that endoscopic closure of iatrogenic gastrointestinal perforations and acute anastomotic leaks by means of the OTSC System is a safe and effective method.

Microarray meta-analysis defines global angiogenesis-related gene expression signatures in human carcinomas.

Angiogenesis is a prerequisite for progression of cancers. The number of genes linked to angiogenesis suggests the existence of complex gene-networks, which remain to be elucidated. To identify angiogenesis genes deregulated in carcinomas, we performed a meta-profiling analysis of published gene expression microarray studies. Own microarray and quantitative RT-PCR data were obtained from a colorectal carcinoma cohort. Applying highly stringent inclusion criteria, 15 cancer array studies were suitable for our analysis. These studies provided 789 tumor specimens and 190 samples of healthy tissues yielding a total of approx. 1,000,000 gene expression measurements. Meta-analysis on the expression of 480 angiogenesis-related genes in 10 cancer types identified a characteristic, entity-independent "global" cancer expression signature of 25 angiogenesis-related genes showing high frequency down-regulation when compared to corresponding healthy tissues. Furthermore, we characterized 25 genes displaying frequent up-regulation, yet less often than the 25 down-regulated genes. Comparative inter-study cross-validation revealed that both signatures discriminate cancers from healthy tissues with high accuracy in independent test sets. Moreover, own microarray data of colorectal carcinomas confirmed the specific and sensitive discriminating potential of both signatures. These results were validated by quantitative RT-PCR for eight genes displaying the highest differences in the microarray analysis. Our study for the first time defines global gene expression signatures linked to angiogenesis in carcinomas. Our findings suggest that gene down-regulation may represent a central aspect of tumor angiogenesis.

Performance of the OTSC System in the endoscopic closure of gastrointestinal fistulae--a meta-analysis.

BACKGROUND: Conventional endoscopic treatment options for closure of gastrointestinal fistulae are impaired by several limitations and therefore yield high rates of recurrence. Aim of the study is the evaluation of the primary-technical and secondary-clinical success rates in closure of gastrointestinal fistulae by means of the OTSC System. DESIGN/METHODS: The database Medline was systematically searched for primary research on the evaluation of the OTSC System in closure of gastrointestinal fistulae. Appraisal of studies for inclusion and data extraction were performed independently by two reviewers using an a priori determined data extraction grid. RESULTS: A total of 19 primary research articles were identified. The examined studies comprised case reports as well as case series and clinical single-arm studies (n = 7) with a limited number of participants. Reviewed studies revealed a high rate of procedural success (mean 84.6%; 95% confidence interval 66.6 to 93.8%) and durable clinical success (mean 69.0%; 95% confidence interval 51.8 to 82.2%). Failed attempts and incomplete closures were mainly ascribed to the challenging effort of treating highly fibrotic chronic fistulae. CONCLUSION: Endoscopic closure of gastrointestinal fistulae by means of the OTSC System is a safe and effective method.

Blm3 is part of nascent proteasomes and is involved in a late stage of nuclear proteasome assembly.

Proteasomes are multisubunit proteases that are responsible for regulated proteolysis. The degradation of the proteasomal maturation factor, named Ump1 in yeast, completes the autocatalytic processing of inactive precursor complexes into the proteolytically active core particle (CP) of the proteasome. We have identified Blm3, a conserved nuclear protein, as a new component of Ump1-associated precursor complexes. A lack of Blm3 resulted in an increased rate of precursor processing and an accelerated turnover of Ump1, which suggests that Blm3 prevents premature activation of proteasomal CPs. On the basis of biochemical fractionation experiments combined with in vivo localization studies, we propose that Blm3 joins nascent CPs inside the nucleus to coordinate late stages of proteasome assembly in yeast.