Transarterial RAdioembolization versus ChemoEmbolization for the treatment of hepatocellular carcinoma (TRACE): study protocol for a randomized controlled trial

ABSTRACT: BACKGROUND: Hepatocellular carcinoma is a primary malignant tumor of the liver that accounts for an important health problem worldwide. Only 10 to 15% of hepatocellular carcinoma patients are suitable candidates for treatment with curative intent, such as hepatic resection and liver transplantation. A majority of patients have locally advanced, liver restricted disease (Barcelona Clinic Liver Cancer (BCLC) staging system intermediate stage). Transarterial loco regional treatment modalities offer palliative treatment options for these patients; transarterial chemoembolization (TACE) is the current standard treatment. During TACE, a catheter is advanced into the branches of the hepatic artery supplying the tumor, and a combination of embolic material and chemotherapeutics is delivered through the catheter directly into the tumor. Yttrium-90 radioembolization (90Y-RE) involves the transarterial administration of minimally embolic microspheres loaded with Yttrium-90, a beta-emitting isotope, delivering selective internal radiation to the tumor. 90Y-RE is increasingly used in clinical practice for treatment of intermediate stage hepatocellular carcinoma, but its efficacy has never been prospectively compared to that of the standard treatment (TACE). In this study, we describe the protocol of a multicenter randomized controlled trial aimed at comparing the effectiveness of TACE and 90Y-RE for treatment of patients with unresectable (BCLC intermediate stage) hepatocellular carcinoma.Methods/designIn this pragmatic randomized controlled trial, 140 patients with unresectable (BCLC intermediate stage) hepatocellular carcinoma, with Eastern Cooperative Oncology Group performance status 0 to 1 and Child-Pugh A to B will be randomly assigned to either 90Y-RE or TACE with drug eluting beads. Patients assigned to 90Y-RE will first receive a diagnostic angiography, followed by the actual transarterial treatment, which can be divided into two sessions in case of bilobar disease. Patients assigned to TACE will receive a maximum of three consecutive transarterial treatment sessions. Patients will undergo structural follow-up for a timeframe of two years post treatment. Post procedural magnetic resonance imaging (MRI) will be performed at one and three months post trial entry and at three-monthly intervals thereafter for two years to assess tumor response. Primary outcome will be time to progression. Secondary outcomes will be overall survival, tumor response according to the modified RECIST criteria, toxicities/adverse events, treatment related effect on total liver function, quality of life, treatment-related costs and cost-effectiveness.Trial registrationNCT01381211.     

The spatial origin of a perceptual transition in binocular rivalry

When the left and the right eye are simultaneously presented with incompatible images at overlapping retinal locations, an observer typically reports perceiving only one of the two images at a time. This phenomenon is called binocular rivalry. Perception during binocular rivalry is not stable; one of the images is perceptually dominant for a certain duration (typically in the order of a few seconds) after which perception switches towards the other image. This alternation between perceptual dominance and suppression will continue for as long the images are presented. A characteristic of binocular rivalry is that a perceptual transition from one image to the other generally occurs in a gradual manner: the image that was temporarily suppressed will regain perceptual dominance at isolated locations within the perceived image, after which its visibility spreads throughout the whole image. These gradual transitions from perceptual suppression to perceptual dominance have been labeled as traveling waves of perceptual dominance. In this study we investigate whether stimulus parameters affect the location at which a traveling wave starts. We varied the contrast, spatial frequency or motion speed in one of the rivaling images, while keeping the same parameter constant in the other image. We used a flash-suppression paradigm to force one of the rival images into perceptual suppression. Observers waited until the suppressed image became perceptually dominant again, and indicated the position at which this breakthrough from suppression occurred. Our results show that the starting point of a traveling wave during binocular rivalry is highly dependent on local stimulus parameters. More specifically, a traveling wave most likely started at the location where the contrast of the suppressed image was higher than that of the dominant one, the spatial frequency of the suppressed image was lower than that of the dominant one, and the motion speed of the suppressed image was higher than that of the dominant one. We suggest that a breakthrough from suppression to dominance occurs at the location where salience (the degree to which a stimulus element stands out relative to neighboring elements) of the suppressed image is higher than that of the dominant one. Our results further show that stimulus parameters affecting the temporal dynamics during continuous viewing of rival images described in other studies, also affect the spatial origin of traveling waves during binocular rivalry.     

Vasoplegia after implantation of a continuous flow left ventricular assist device: incidence,outcomes and predictors

Background

Vasoplegia after routine cardiac surgery is associated with severe postoperative complications and increased mortality. It is also prevalent in patients undergoing implantation of pulsatile flow left ventricular assist devices (LVAD). However, less is known regarding vasoplegia after implantation of newer generations of continuous flow LVADs (cfLVAD). We aim to report the incidence, impact on outcome and predictors of vasoplegia in these patients.

Methods

Adult patients scheduled for primary cfLVAD implantation were enrolled into a derivation cohort (n?=?118, 2006–2013) and a temporal validation cohort (n?=?73, 2014–2016). Vasoplegia was defined taking into consideration low mean arterial pressure and/or low systemic vascular resistance, preserved cardiac index and high vasopressor support. Vasoplegia was considered after bypass and the first 48?h of ICU stay lasting at least three consecutive hours. This concept of vasoplegia was compared to older definitions reported in the literature in terms of the incidence of postoperative vasoplegia and its association with adverse outcomes. Logistic regression was used to identify independent predictors. Their ability to discriminate patients with vasoplegia was quantified by the area under the receiver operating characteristic curve (AUC).

Results

The incidence of vasoplegia was 33.1% using the unified definition of vasoplegia. Vasoplegia was associated with increased ICU length-of-stay (10.5 [6.9–20.8] vs 6.1 [4.6–10.4] p?=?0.002), increased ICU-mortality (OR 5.8, 95% CI 1.9–18.2) and one-year-mortality (OR 3.9, 95% CI 1.5–10.2), and a higher incidence of renal failure (OR 4.3, 95% CI 1.8–10.4). Multivariable analysis identified previous cardiothoracic surgery, preoperative dopamine administration, preoperative bilirubin levels and preoperative creatinine clearance as independent preoperative predictors of vasoplegia. The resultant prediction model exhibited a good discriminative ability (AUC 0.80, 95% CI 0.71–0.89, p?<? 0.01). Temporal validation resulted in an AUC of 0.74 (95% CI 0.61–0.87, p?<? 0.01).

Conclusions

In the era of the new generation of cfLVADs, vasoplegia remains a prevalent (33%) and critical condition with worse short-term outcomes and survival. We identified previous cardiothoracic surgery, preoperative treatment with dopamine, preoperative bilirubin levels and preoperative creatinine clearance as independent predictors.

     

Susceptibility of the Coffee Leaf Miner (Perileucoptera spp.) to Bacillus thuringiensisδ-Endotoxins: A Model for Transgenic Perennial Crops Resistant to Endocarpic Insects

Binding of several Bacillus thuringiensisδ-endotoxins was studied on histological midgut sections of larvae of coffee leaf miner Perileucoptera coffeella from Brazil and Perileucoptera sp from Madagascar. CryIA(a), CryIA(b), CryIA(c), CryIB, CryIE, and CryIIA were tested for binding, and only CryIA(c), CryIB, and CryIE yielded a positive response. The toxins bound to the whole midgut, and the result was identical on both insect populations. The same toxins, to the number of which CryIC was added, were tested on larvae of P. coffeella. CryIA(c) and CryIB were toxic with an LC50 of 1.47 μg/ml and 21.93 μg/ml, respectively. CryIE was not toxic to P. coffeella. CryIA(c) and CryIB were tested for synergistic activity and were shown to act by cumulative effect when delivered to the insect larvae as a mixture. Received: 30 July 1997 / Accepted: 26 August 1997     

Smad gene expression in pulmonary fibroblasts: indications for defective ECM repair in COPD

Background

Endothelial dysfunction is a major complication of pulmonary endarterectomy (PTE) that can lead to pulmonary edema and persistent pulmonary hypertension. We hypothesized that endothelial dysfunction is related to increased endothelial-cell (EC) death.

Methods

In piglets, the left pulmonary artery (PA) was ligated to induce lung ischemia then reimplanted into the main PA to reperfuse the lung. Animals sacrificed 5 weeks after ligation (n = 5), 2 days after reperfusion (n = 5), or 5 weeks after reperfusion (n = 5) were compared to a sham-operated group (n = 5). PA vasoreactivity was studied and eNOS assayed. EC apoptosis was assessed by TUNEL in the proximal and distal PA and by caspase-3 activity assay in the proximal PA. Gene expression of pro-apoptotic factors (thrombospondin-1 (Thsp-1) and plasminogen activator inhibitor 1 (PAI-1)) and anti-apoptotic factors vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) was investigated by QRT-PCR.

Results

Endothelium-dependent relaxation was altered 5 weeks after ligation (p = 0.04). The alterations were exacerbated 2 days after reperfusion (p = 0.002) but recovered within 5 weeks after reperfusion. EC apoptosis was increased 5 weeks after PA ligation (p = 0.02), increased further within 2 days after reperfusion (p < 0.0001), and returned to normal within 5 weeks after reperfusion. Whereas VEGF and bFGF expressions remained unchanged, TSP and PAI-1 expressions peaked 5 weeks after ligation (p = 0.001) and returned to normal within 2 days after reperfusion.

Conclusion

Chronic lung ischemia induces over-expression of pro-apoptotic factors. Lung reperfusion is followed by a dramatic transient increase in EC death that may explain the development of endothelial dysfunction after PE. Anti-apoptotic agents may hold considerable potential for preventing postoperative complications.     

Nasal gene expression differentiates COPD from controls and overlaps bronchial gene expression

Background

Nasal gene expression profiling is a promising method to characterize COPD non-invasively. We aimed to identify a nasal gene expression profile to distinguish COPD patients from healthy controls. We investigated whether this COPD-associated gene expression profile in nasal epithelium is comparable with the profile observed in bronchial epithelium.

Methods

Genome wide gene expression analysis was performed on nasal epithelial brushes of 31 severe COPD patients and 22 controls, all current smokers, using Affymetrix Human Gene 1.0 ST Arrays. We repeated the gene expression analysis on bronchial epithelial brushes in 2 independent cohorts of mild-to-moderate COPD patients and controls.

Results

In nasal epithelium, 135 genes were significantly differentially expressed between severe COPD patients and controls, 21 being up- and 114 downregulated in COPD (false discovery rate?<?0.01). Gene Set Enrichment Analysis (GSEA) showed significant concordant enrichment of COPD-associated nasal and bronchial gene expression in both independent cohorts (FDR_GSEA <?0.001).

Conclusion

We identified a nasal gene expression profile that differentiates severe COPD patients from controls. Of interest, part of the nasal gene expression changes in COPD mimics differentially expressed genes in the bronchus. These findings indicate that nasal gene expression profiling is potentially useful as a non-invasive biomarker in COPD.

Trial registration

ClinicalTrials.gov registration number NCT01351792 (registration date May 10, 2011), ClinicalTrials.gov registration number NCT00848406 (registration date February 19, 2009), ClinicalTrials.gov registration number NCT00807469 (registration date December 11, 2008).

     

A Systematic Computational Analysis of Biosynthetic Gene Cluster Evolution: Lessons for Engineering Biosynthesis

Bacterial secondary metabolites are widely used as antibiotics, anticancer drugs, insecticides and food additives. Attempts to engineer their biosynthetic gene clusters (BGCs) to produce unnatural metabolites with improved properties are often frustrated by the unpredictability and complexity of the enzymes that synthesize these molecules, suggesting that genetic changes within BGCs are limited by specific constraints. Here, by performing a systematic computational analysis of BGC evolution, we derive evidence for three findings that shed light on the ways in which, despite these constraints, nature successfully invents new molecules: 1) BGCs for complex molecules often evolve through the successive merger of smaller sub-clusters, which function as independent evolutionary entities. 2) An important subset of polyketide synthases and nonribosomal peptide synthetases evolve by concerted evolution, which generates sets of sequence-homogenized domains that may hold promise for engineering efforts since they exhibit a high degree of functional interoperability, 3) Individual BGC families evolve in distinct ways, suggesting that design strategies should take into account family-specific functional constraints. These findings suggest novel strategies for using synthetic biology to rationally engineer biosynthetic pathways.