To assess the diagnostic potential of dynamic real-time MRI for fundoplication failure in patients with persistent or recurrent GERD-like (gastroesophageal reflux disease) complaints. Twenty-two consecutive patients (male n = 11; female n = 11; median age 59 years) with recurrent or persistent GERD-like symptom after fundoplication were enrolled between 2015 and 2017. Median duration of GERD-like symptoms was 21 months. Real-time MRI (3 Tesla) was performed at 40 ms temporal resolution using undersampled radial fast low-angle shot acquisitions with nonlinear inverse image reconstruction. MRI movies dynamically visualized bolus transit of pineapple juice through the gastroesophageal junction, position of the fundoplication wrap and recurring hernia or reflux during Valsalva maneuver. MRI results were compared to endoscopic findings. Real-time MRI was successfully completed in all patients without adverse events (average examination time 15 min). Morphological correlates for GERD-like symptoms were evident in 20 patients (90.1%) with gastric reflux in 19 cases. Nine patients (40.1%) had wrap disruption and recurrent gastric hernia. Wrap migration or telescoping hernia was detected in nine patients (40.1%). One patient presented with continued reflux despite intact fundoplication wrap. Esophageal dysmotility with delayed bolus passage was observed in one case. On endoscopy, gastric hernia or wrap disruption was diagnosed in seven cases, and esophagitis or Barret’s metaplasia in nine cases. Real-time MRI is a fast and safe modality for dynamic imaging after fundoplication, without radiation exposure or administration of gadolinium-based contrast media. In a relevant number of cases, real-time MRI reveals correlates for GERD-like symptoms. • Real-time MRI reliably visualizes the gastroesophageal junction after fundoplication surgery. • Patients with recurring GERD-like symptoms have a high rate of morphological failure patterns that can be identified by real-time MRI. • Dynamic assessment of gastroesophageal junction by real-time MRI is a perspective diagnostic tool for detection of fundoplication failure.

The purpose of this study was to assess the reproducibility of functional and anatomical parameters of swallowing events as determined by real-time MRI at 40 ms temporal resolution (25 frames per second). Twenty-three consecutive patients with gastroesophageal reflux disease (GERD) underwent real-time MRI of the gastroesophageal junction at 3.0 T. Real-time MRI was based on highly undersampled radial fast low angle shot (FLASH) acquisitions with iterative image reconstruction by regularized nonlinear inversion (NLINV). MRI movies visualized the esophageal transport of a pineapple juice bolus, its passage through the gastroesophageal junction and functional responses during a Valsalva maneuver. His-angle, sphincter position, sphincter length and sphincter transit time were assessed by two radiologists. Interobserver and intraobserver intraclass correlation coefficients (ICC) were evaluated and Bland-Altman plots were constructed to assess the observer agreement. Interobserver agreement was excellent for sphincter transit time (ICC = 0.92), His-angle (ICC = 0.93), His-angle during Valsalva maneuver (ICC = 0.91) and sphincter-to-diaphragm distance (ICC = 0.98). Sphincter length and oesophageal diameter showed good interobserver agreement (ICC = 0.62 and ICC = 0.70). Intraobserver agreement was good for sphincter length (ICC = 0.80) and excellent for sphincter transit time, His-angle and His-angle during Valsalva maneuver, sphincter-to-diaphragm distance, and esophageal diameter (ICC = 0.91; ICC = 0.97; ICC = 0.97; ICC = 0.998; ICC = 0.93). All functional parameters of the gastroesophageal junction had good to excellent reproducibility. Visual assessment of Bland Altman plots did not reveal any systematic interobserver bias. In conclusion, the visualization of swallowing events by realtime MRI has a high potential for clinical application in gastroesophageal reflux disease.

The origin of gastrointestinal stromal tumors (GIST) from interstitial cells of Cajal or their precursor cells has been understood since the early 1990s. The first mutations within the KIT-gene have been described in the late 1990s. Even though these mutations were the breakthrough of small molecular therapy, we still do not know the factors responsible for their malignant transformation. Until then, we can only speak of recurrence risk. This review gives an introduction on the current understanding of GIST and highlights the remaining questions for diagnosis, tumor progression, and treatment in progressive disease.

Aims Rhabdoid morphology resembling that of the aggressive paediatric rhabdoid tumours occurs in various malignancies usually lacking characteristic SMARCB 1 ( INI 1) loss. Little is known about the clinicopathological and molecular characteristics of the rhabdoid phenotype in gastrointestinal stromal tumours ( GIST s). Methods and results Six gastric rhabdoid GIST s were examined by immunohistochemistry, KIT and platelet‐derived growth factor receptor‐α gene ( PDGFRA ) mutation analysis, and comparative genomic hybridization ( CGH ). All tumours expressed KIT , PDGFRA , DOG ‐1, and SMARCB 1 (two of six with a mosaic pattern). Five of six tumours harboured PDGFRA mutations (D842V in four; N659K in one), and one case was wild type for KIT / PDGFRA and succinate dehydrogenase ( SDH ) A‐negative and SDHB ‐negative by immunohistochemistry. CGH revealed aberrations typical of GIST s (−1p, −14, and −22q in three, five, and three cases, respectively), with a mean of 1.7 aberrations in the epithelioid component and 2.7 in the rhabdoid component. None showed progression (mean follow‐up of 25 months). Conclusions Rhabdoid gastric GIST s are associated with epithelioid morphology and PDGFRA mutations. They harbour CGH aberrations that are typical of ordinary GIST s in both tumour components. The presence of additional genetic alterations in the rhabdoid areas indicates evolution from the epithelioid components, and possible genetic and biological progression. On the basis of our series and previous reports, rhabdoid morphology in GIST s presumably does not imply aggressiveness.

The duodenum as primary site for gastrointestinal stromal tumors (GISTs) is rare and mitotic rate, tumor size, type of mutation and number of chromosomal aberrations have prognostic implications.We analyzed the outcome of 13 patients with duodenal GISTs who underwent surgical tumor resection. Either segmental duodenectomy or pylorus-preserving duodenopancreatectomy was performed. The tumors were histopathologically examined and the risk of progression was assessed based on tumor size and mitotic count. Additionally, mutation analysis of the KIT and PDGFRA receptor tyrosine kinase genes and comparative genomic hybridization (CGH) were performed in all cases.Eight patients underwent segmental duodenectomy and five patients were treated with pylorus-preserving duodenopancreatectomy. None of the five GISTs with low or no risk for malignancy according to the Miettinen classification developed tumor progress. In contrast, five of eight cases (62.5%) with high-risk tumors revealed tumor progress, and four of these patients died (50%). The median overall survival for all patients was 66 months, and the median disease-free survival 41 months. The operative procedure and type of mutation did not correlate with long-term survival. CGH analysis displayed -15q in 12/13 tumors, and -1p in 11/13 cases as characteristic chromosomal aberrations for intestinal origin. Notably, -22q was present in three of four cases with tumor progress.Both segmental duodenectomy and pylorus-preserving duodenopancreatectomy are appropriate options to treat duodenal GIST and should be implemented depending on resectability and the patient's performing state. The Miettinen classification and CGH findings correlate with the clinical course.

Basaloid squamous cell carcinoma (BSCC) and carcinosarcoma of the esophagus are rare entities, making up fewer than 2% of esophageal malignancies. Comparative genomic hybridization (CGH) in 1 case of BSCC and 2 cases of carcinosarcoma and subsequent array CGH in 1 case each of BSCC and carcinosarcoma revealed common chromosomal gains at 2p25.3-2p12, 7q21.3-7q22.3, and 11q13.2-11q13.4. Chromosomal losses at 13q31qter were observed in both carcinosarcomas. In addition, progression of genomic instability from in situ to invasive carcinosarcoma could be demonstrated by using array CGH. Our observations suggest a common genetic origin of BSCC and carcinosarcoma.

Purpose A common and serious problem after living donor liver transplantation (LDLT) of small grafts is small-for-size syndrome (SFSS). Although hyperdynamic portal inflow and portal hypertension are cornerstones in the development of SFSS, inadequate outflow may aggravate SFSS. Therefore, enlargement of the portal outflow tract by incision of the anterior rim of the orifice of the right hepatic vein (RHV) has been advocated for right lobe LDLT. But backwards tilt of a small graft into a large abdominal cavity may lead to a choking of the otherwise large anastomosis and thus we propose posterior enlargement of the orifice of the RHV. Method In this test-of-concept study, we evaluated portal vein pressure (PVP), clinical parameters, and laboratory measurements in 22 patients that underwent right lobe LDLT and either received standard end-to-end anastomosis of the RHV or posterior cavoplasty. Results In patients that underwent posterior cavoplasty, we observed significantly lower PVP and less hyperbilirubinemia. There was a non-significant trend to lower incidence of SFSS. Other laboratory measurements and clinical parameters were not significantly different. Conclusion We recommend posterior cavoplasty for enlargement of the hepatic venous outflow tract in right lobe LDLT as a method to avoid portal hypertension, hyperbilirubinemia, and possibly SFSS, especially in patients that receive small grafts.

AIM:To assess the outcome of patients, who underwent transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) and subsequently liver transplantation (OLT) irrespective of tumor size when no tumor progression was observed.METHODS:Records, imaging studies and pathology of 84 patients with HCC were reviewed. Ten patients were not treated at all, 67 patients had TACE and 35 of them were listed for OLT. Tumor progression was monitored by ultrasound and AFP level every 6 wk. Fifteen patients showed signs of tumor progression without transplantation. The remaining 20 patients underwent OLT. Further records of 7 patients with HCC seen in histological examination after OLT were included.RESULTS:The patients after TACE without tumor progression underwent transplantation and had a median survival of 92.3 mo. Patients, who did not qualify for liver transplantation or had signs of tumor progression had a median survival of 8.4 mo. The patients without treatment had a median survival of 3.8 mo. Independent of International Union Against Cancer (UICC) stages, the patients without tumor progression and subsequent OLT had longer median survival. No significant difference was seen in the OLT treated patients if they did not fulfill the Milan criteria.CONCLUSION:Selection of patients for OLT based on tumor progression results in good survival. The evaluation of HCC patients should not only be based on tumor size and number of foci but also on tumor progression and growth behavior under therapy.

AIM: To evaluate the mechanism underlying the effects of 5-Fluorouracil (5-FU) on adenoviral infection.METHODS: Low and high Coxsackievirus-Adenovirus Receptor (CAR) expressing human colon carcinoma cell lines were treated with 5-FU and two El-deleted adenoviral constructs, one transferring GFP (Ad/CMV-GFP) the other bax (Ad/CEA-bax). The number of infected cells were monitored by GFP expression. To evaluate the effects of 5-FU in a receptor free system, Ad/GFP were encapsulated in liposomes and treated with 5-FU. Ad/GFP release was estimated with PCR and infection of 293 cells with the supernatant. Electron microscopy of the Ad5-GFP-liposome complex was made to investigate morphological changes of the liposomes after 5-FU.RESULTS: Infection rates of all cell lines increased from 50% to 98% with emerging 5-FU concentrations. The enhanced viral uptake was independent of the CAR expression. Additionally, 5-FU treated liposomes released 2-2.5 times more adenoviruses. Furthermore, 5-FU-treated liposomes appeared irregular and porous-like.CONCLUSION: adenoviral uptake is enhanced in the presence of 5-FU irrespective of CAR and is associated with morphological changes in membranes making the combination of both a promising option in gene therapy. (C) 2006 The WIG Press. All rights reserved.

Effects of adenoviral therapy and reduced apoptosis on immune response were investigated in a rat liver transplantation model after prolonged ischemia-reperfusion. Liver donors were treated i.v. either with an adenoviral construct, expressing bcl-2, green-fluorescent-protein, or doxycyclin. Intrahepatic apoptosis was assessed by terminal transferase dUTP nick end labeling assay. The intrahepatic presence of CD4, CD8a, CD163, immunoglobulin (Ig)beta, tumor necrosis factor (TNF)-alpha and myeloperoxidase (MPO) was quantified by realtime polymerase chain reaction at 24 hours and seven days after transplantation. Bcl-2 expression abrogated the TNF-alpha elevation and reduced apoptosis of hepatocytes and sinusoidal endothelial cells as compared to advCMV green fluorescent protein. No effects on CD4, CD8a, CD163 and MPO expression were noticed in bcl-2 pretreated livers, whereas Igbeta was slightly enhanced compared to controls. Adenoviral infected liver grafts trigger an immune response but reduced apoptosis resulted in down-regulation of TNF-alpha. Thus, bcl-2 transfer might simultaneously reduce graft ischemia reperfusion injury and immunogenicity.

PURPOSE: In terms of functional outcome, there is evidence of the superiority of the colonic J-pouch over a straight coloanal anastomosis. Even though the colonic J-pouch was created to restore a neorectal reservoir, manometric data show that the volume of a short colonic J-pouch does not differ from a straight coloanal anastomosis. We speculate that the advantage of the colonic J-pouch is not in creating a larger neorectal reservoir, but rather related to decreased motility. Maurer and Z’graggen recently described a new colonic pouch design, performing a “transverse coloplasty” pouch. The purpose of this pilot study was to compare the feasibility and functional outcome of the 5-cm colonic J-pouch vs. the coloplasty pouch. METHODS: From February 2000 to June 2001, we randomized 40 consecutive patients with distal rectal cancer (<12 cm from the anal verge) into the J-pouch or coloplasty group. A low rectal resection and coloanal anastomosis was performed in all patients. Functional data were collected by a standardized questionnaire and anorectal manometry, preoperatively and six months postoperatively. Primary end points of the study were potentially differences of both groups regarding technical feasibility, stool frequency, and anorectal manometry. RESULTS: The construction of a coloplasty pouch was feasible in all cases of the coloplasty group, but not in 5 of 20 (25 percent) patients of the J-pouch group, because of colonic adipose tissue. Six months after operation or stoma closure, respectively, stool frequency was 2.75 ± 1 per day in the J-pouch group and 2 ± 2 per day in the coloplasty group. There was no significant difference in resting and squeeze pressure and neorectal volume between both groups, but an increased neorectal sensitivity in the coloplasty group. CONCLUSION: We found similar functional results in the coloplasty group compared to the J-pouch group. The neorectal sensitivity was increased in the coloplasty group. Therefore, the colonic coloplasty seems to be an attractive pouch design because of its feasibility, simplicity, and effectiveness.

Bcl-2 is an integral membrane oncoprotein that localizes to membranes of the mitochondria, endoplasmic reticulum, and nuclear envelope. Bcl-2 is a member of a family of cell death regulators and functions to inhibit apoptosis. Using confocal microscopy and immunoblotting we show that the ability of bcl-2 to suppress cell death following genotoxic damage can be a consequence of inhibiting nuclear import of induced wild-type p53 protein. Our data suggests that the ability of bcl-2 to modulate trafficking events is not cell type specific. These data support a `gatekeeper' mechanism for cell death suppression by bcl-2.

Compelling evidence indicates that activation of the JNK/SAPK signaling pathway is obligatory for apoptosis induction by multiple cell stresses that activate the sphingomyelin cycle. Moreover, ectopic expression of bcl-2 can impair apoptosis signaling by most of the cell stresses that activate the ceramide/JNK pathway. Here we show that enforced expression of bcl-2 protects prostate carcinoma cells against the induction of apoptosis by exogenous C2-ceramide. Moreover, enforced bcl-2 expression blocked the capacity of C2-ceramide to activate JNK1, indicating bcl-2 functions at the level of JNK1 or upstream of JNK1 in the ceramide/JNK pathway. The contribution of bcl-2 to the regulation of the arachidonate pathway for prostate carcinoma cell survival was also investigated using highly selective inhibitors of arachidonate metabolism. Our results indicate bcl-2 can protect cells against diminished availability of arachidonic acid, 12-HETE, and 15-HETE. Finally, arachidonic acid substantially suppresses the induction of apoptosis by C2-ceramide, providing evidence for the opposing influences of these lipid signaling pathways in the mediation of prostate carcinoma cell survival. These results provide evidence for opposing influences of the ceramide and arachidonate signaling pathways in the mediation of cell death and cell survival, respectively, in prostate carcinoma cells and suggest a dual role for bcl-2 in this context.