Old technique, new use: novel use of a buddy wire to deploy a detached stent

Stent dislodgement or loss in a coronary artery carries significant risks of infarction, thrombosis and requirement for emergency bypass surgery. Even with the advent of premounted stents, stent loss can occasionally occur, especially when performing intervention in calcified and tortuous anatomy. Multiple stent retrieval/stent exclusion techniques have been described to overcome this dreaded complication. We describe the first case of deploying a dislodged stent using a buddy wire technique with both wires through the center of the dislodged stent, and subsequent use of the small balloon technique to successfully deploy a dislodged stent in a heavily calcified and tortuous circumflex artery.     

Bifurcating saphenous vein and left internal thoracic graft anatomy: treatment of a left main equivalent saphenous interposition vein graft lesion and virtual histology/grey scale IVUS characterization post-intervention

Saphenous vein graft interventions carry a significant risk of adverse events. We present a case in which a free left internal thoracic artery (LITA to the LAD) had been anastomosed to a saphenous vein graft (SVG) to an obtuse marginal (OM) as its proximal anastomosis. Due to surgical iatrogenic injury during a subsequent aortic valve replacement, the proximal portion of this dual graft was resected in error and then repaired using an interposed vein graft (vein patch). We present the first known case of percutaneous intervention to an interposition vein graft stenosis with left main equivalent anatomy. Virtual histology (VH) and grey scale intravascular ultrasound (IVUS) were utilized to visualize plaque characteristics in this novel lesion.     

Pulmonary arterial pulse pressure and mortality in pulmonary arterial hypertension

In the Framingham studies, systemic arterial pulse pressure correlated linearly with morbidity and mortality. Right ventricular (RV) systolic dysfunction and pulmonary circulation stiffening result in abnormalities of pulmonary arterial (PA) pulse pressure in PA hypertension (PAH). We investigated the prognostic potential of PA pulse pressure in 67 patients with PAH diagnosed between January 1996 and March 2004 (33 idiopathic PAH, 34 PAH-connective tissue disease). The population was arbitrarily divided into tertiles of PA pulse pressure (= systolic-diastolic PA pressure) and 5-year mortality was assessed using the Kaplan-Meier method. The extent of RV systolic dysfunction and pulmonary circulation stiffening within each tertile was assessed by comparing the mean cardiac index and alpha (a recently described measure of pulmonary circulation distensibility) in each. Independent predictors of mortality were identified by Cox regression. Five-year mortality rates in patients with low, intermediate and high pulse pressures were 40%, 91% and 54%, respectively. Pulse pressure did not independently predict mortality, but cardiac index, 6-min walk test distance and mixed venous oxygen saturation did. Pulse pressure correlated with circulation stiffening (alpha) but did not correlate with cardiac index which tended to be lower in patients with intermediate pulse pressure and high mortality. PA pulse pressure correlated with pulmonary circulation stiffening but did not predict mortality in this study. RV dysfunction provided better prognostic information and probably explains the higher mortality seen in patients with intermediate pulse pressure.     

Malignant peritoneal mesothelioma: treatment with maximal cytoreductive surgery plus intraperitoneal chemotherapy

OBJECTIVE: To report survival results in patients with diffuse malignant peritoneal mesothelioma (MPM) treated with maximal cytoreductive surgery followed by immediate intraperitoneal chemotherapy, and to compare them with the median survival of 12-24 months obtained with the standard treatment based on systemic chemotherapy. PATIENTS AND METHODS: Twenty-six patients underwent this new regional approach and a median follow-up of 55 months was achieved after this treatment. Complete cytoreductive surgery (residual disease < 2 mm) was performed in all but one patient. Intraperitoneal chemotherapy was performed with hyperthermia (4245 degrees C) and oxaliplatin in 22 patients. The last 12 patients additionally received irinotecan. Data were prospectively verified and retrospectively analyzed. RESULTS: One patient died postoperatively (4%), and morbidity attained 54%. The median survival exceeded 100 months and the overall 5-year survival rate was 63%. This small series lacks the statistical power required to conduct a well-grounded study on prognostic factors, particularly as the completeness of the surgery is not analyzable here. However, the low-grade histological types had a better disease-free survival rate that was of borderline significance compared to their high-grade counterparts. CONCLUSION: This new approach combining complete cytoreductive surgery considerably increases the survival of patients with MPM compared with the standard treatment based on systemic chemotherapy.     

Superparamagnetic iron oxides and low molecular weight gadolinium chelates are synergistic for direct visualization of advanced liver fibrosis

PURPOSE: To compare the contrast-to-noise ratio (CNR) of advanced liver fibrosis on nonenhanced (NE), gadolinium enhanced (Gd), superparamagnetic iron oxides enhanced (SPIO), and combined contrast-enhanced (CCE) spoiled gradient echoes (SGEs). MATERIALS AND METHODS: This retrospective study assessed 83 consecutive patients with cirrhosis and 10 consecutive patients without fibrosis. All patients had NE, Gd, SPIO, and CCE images at 1.5 T. A total of six breathhold SGE sequences with varying imaging parameters were assessed. MR images were evaluated qualitatively and, in 15 cirrhotics who underwent liver transplantation, compared to gross pathology. CNR of fibrosis to background liver was compared across sequences and contrast enhancement types. RESULTS: In cirrhotic patients, CCE images on all sequences showed fibrosis as a meshwork of high-signal 1-mm to 3-mm thick reticulations surrounding 2-mm to 5-mm low-signal regenerative nodules. Fibrosis was less visible on Gd and SPIO images and was barely visible on NE images. CNR was significantly higher for CCE than for NE, Gd, or SPIO images in eight of nine comparisons (P < 0.0001-0.05). The liver had a homogeneous appearance in subjects without fibrosis. CONCLUSION: CCE imaging depicts advanced liver fibrosis with higher CNR than NE, Gd, or SPIO SGEs.     

Farnesoid X Receptor Critically Determines the Fibrotic Response in Mice but Is Expressed to a Low Extent in Human Hepatic Stellate Cells and Periductal Myofibroblasts

The nuclear bile acid receptor, farnesoid X receptor (FXR), may play a pivotal role in liver fibrosis. We tested the impact of genetic FXR ablation in four different mouse models. Hepatic fibrosis was induced in wild-type and FXR knock-out mice (FXR^−/−) by CCl₄ intoxication, 3,5-diethoxycarbonyl-1,4-dihydrocollidine feeding, common bile duct ligation, or Schistosoma mansoni (S.m.)-infection. In addition, we determined nuclear receptor expression levels (FXR, pregnane X receptor (PXR), vitamin D receptor, constitutive androstane receptor (CAR), small heterodimer partner (SHP)) in mouse hepatic stellate cells (HSCs), portal myofibroblasts (MFBs), and human HSCs. Cell type-specific FXR protein expression was determined by immunohistochemistry in five mouse models and prototypic human fibrotic liver diseases. Expression of nuclear receptors was much lower in mouse and human HSCs/MFBs compared with total liver expression with the exception of vitamin D receptor. FXR protein was undetectable in mouse and human HSCs and MFBs. FXR loss had no effect in CCl₄-intoxicated and S.m.-infected mice, but significantly decreased liver fibrosis of the biliary type (common bile duct ligation, 3,5-diethoxycarbonyl-1,4-dihydrocollidine). These data suggest that FXR loss significantly reduces fibrosis of the biliary type, but has no impact on non-cholestatic liver fibrosis. Since there is no FXR expression in HSCs and MFBs in liver fibrosis, our data indicate that these cells may not represent direct therapeutic targets for FXR ligands.The farnesoid X receptor (FXR;NR1H4) is a key regulator of hepatic bile acid homeostasis, lipoprotein and glucose metabolism, bacterial colonization of the small intestine, the inflammatory response, and liver regeneration.^1,2,3 Hereditary and acquired FXR defects may contribute to cholestasis and gallstone formation in humans.^4,5,6,7 Defects in its target genes (eg, bile salt export pump/ABCB11; multidrug resistance gene 3/ABCB4 (a phosphatidylcholine floppase); multidrug related protein 2/ABCC2) cause well-characterized clinical syndromes.^8,9,10,11 Moreover, FXR knockout mice (FXR^−/−) have impaired resistance to bile acid feeding,^12,13 and show substantial differences in the cholestatic phenotype in response to common bile duct ligation,^14,15,16 have increased susceptibility for diet-induced gallstone disease,^17,18 and impaired liver regeneration following partial hepatectomy.¹⁹ FXR may also directly or indirectly (eg, by the interaction with other members of the nuclear receptor family such as PXR/NR1I2 and VDR/NR1I1) regulate the metabolism and hepatic clearance of xenobiotics.^20,21,22Recent studies also reported mRNA expression of FXR in hepatic stellate cells and FXR protein in renal proximal tubules^23,24,25 suggesting that FXR could represent a therapeutic target for the treatment of liver fibrosis and diabetic nephropathy.^23,24,25,26 Moreover, FXR ligands were claimed to repress collagen expression in HSCs in vitro via a postulated FXR/SHP-dependent mechanism.²³ It is also attractive to hypothesis that genetic FXR variants may predispose patients suffering from various forms of liver diseases to liver fibrosis as a kind of genetic disease modifier.^7,27 Taken together its pleiotrophic functions (eg, central regulator of bile acid homoeostasis, glucose and lipid metabolism, inflammation) make FXR an extremely attractive candidate for therapeutic targeting in cholestatic liver diseases and nonalcoholic fatty liver disease including their major sequel liver fibrosis.^28,30 However, little is known on hepatic cell-type FXR expression in human liver fibrosis.The aims of this study were threefold. First, we aimed to determine the impact of genetic FXR ablation on the degree of liver fibrosis in untreated mice and four different well established mouse models including CCl₄-intoxicated mice, 3,5 -diethoxycarbonyl-1,4-dihydrocollidine (DDC)-intoxicated mice and common bile duct-ligated (CBDL) mice for biliary fibrosis, and infection with Schistosoma mansoni (S.m.), which has been shown to induce “pipe-stem” fibrosis and granuloma formation.^31,32 Comparison of cholestatic (DDC, CBDL) and non-cholestatic (CCl₄, S.m.) mouse models for liver fibrosis should provide differentiated knowledge on the role of FXR in various types and etiologies of liver fibrosis. Based on previous studies reporting that pharmacological activation of FXR is antifibrotic in liver but also kidney^23,25 we hypothesized that FXR^−/− mice spontaneously develop liver fibrosis and are more susceptible to experimentally induced liver fibrosis due to the lack of a postulated FXR/SHP-dependent down-regulation of collagen mRNA expression in profibrotic states.^23,24 We therefore compared the extent of fibrosis in FXR^−/− mice and wild-type controls in a longitudinal study under baseline conditions and in response to cholestatic and non-cholestatic fibrogenic injury. Second, we aimed to determine the expression of genes involved in bile acid transport/metabolism and their regulatory nuclear receptors (including FXR, PXR, CAR/NR1I3, VDR, and SHP/NR0B2) in isolated profibrogenic rodent cells [ie, periductal myofibroblasts (MFBs), and quiescent as well as activated hepatic stellate cells (HSCs)] and to test the effects of FXR ligands on FXR target genes in vitro. Cell type-specific FXR protein expression was determined in five different in vivo models for liver fibrosis. Finally, we cross-validated these findings in isolated human HSCs and histological sections from human prototypic fibrotic liver diseases [eg, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), and alcoholic steatohepatitis (ASH)].     

c-MYC expression sensitizes medulloblastoma cells to radio- and chemotherapy and has no impact on response in medulloblastoma patients

Background

KLK15 over-expression is reported to be a significant predictor of reduced progression-free survival and overall survival in ovarian cancer. Our aim was to analyse the KLK15 gene for putative functional single nucleotide polymorphisms (SNPs) and assess the association of these and KLK15 HapMap tag SNPs with ovarian cancer survival.

Results

In silico analysis was performed to identify KLK15 regulatory elements and to classify potentially functional SNPs in these regions. After SNP validation and identification by DNA sequencing of ovarian cancer cell lines and aggressive ovarian cancer patients, 9 SNPs were shortlisted and genotyped using the Sequenom iPLEX Mass Array platform in a cohort of Australian ovarian cancer patients (N = 319). In the Australian dataset we observed significantly worse survival for the KLK15 rs266851 SNP in a dominant model (Hazard Ratio (HR) 1.42, 95% CI 1.02-1.96). This association was observed in the same direction in two independent datasets, with a combined HR for the three studies of 1.16 (1.00-1.34). This SNP lies 15bp downstream of a novel exon and is predicted to be involved in mRNA splicing. The mutant allele is also predicted to abrogate an HSF-2 binding site.

Conclusions

We provide evidence of association for the SNP rs266851 with ovarian cancer survival. Our results provide the impetus for downstream functional assays and additional independent validation studies to assess the role of KLK15 regulatory SNPs and KLK15 isoforms with alternative intracellular functional roles in ovarian cancer survival.