Multimodal Assessment of Liver Volume and Function
Ontology highlight
ABSTRACT:
DISEASE(S): Neoplasm Metastasis,Liver Metastases,Colorectal Cancer
PROVIDER: 2243438 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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The investigators conclude that it is time to perform a randomized study comparing the two surgical approaches in regard to oncological outcome.
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Project description:Brief Summary: Some colorectal liver metastases can only be resected after inducing liver regeneration by portal vein embolization (PVE) to increase size function of the future liver remnant (FLR). While PVE is standard, embolization of portal vein and hepatic veins (PVE/HVE) on one side of the liver may faster and more extensive liver size and function growth. PVE/HVE is a novel procedure and requires a safety and feasibility evaluation in a pretrial (DRAGON1) to then be compared in a randomized controlled trial (RCT) to PVE (DRAGON 2).
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Project description:Interventions: Group 1: Patients receive a therapy with yttrium-90 radioembolisation, at first only the right hepatic lobe is treated.
In case of the treatment of the whole liver, the therapy is performed sequentially starting with the right liver lobe and than with the left liver lobe 4 weeks later.
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Study Design: Allocation: ; Masking: ; Control: ; Assignment: ; Study design purpose: treatment
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Project description:Human MRI studies show that experience can lead to changes in the volume of task-specific brain regions; however, the behavioural and molecular processes driving these changes remain poorly understood. Here, we used in-vivo mouse MRI and RNA sequencing to investigate the neuroanatomical and transcriptional changes induced by environmental enrichment, exercise, and social interaction. Additionally, we asked whether the volume changes require CREB, a transcription factor critical for memory formation and neuronal plasticity. Enrichment rapidly increased cortical and hippocampal volume, and these effects were not attributable to exercise or social interaction. Instead, they likely arise from learning and sensorimotor experience. Nevertheless, the volume changes were not attenuated in mice with memory impairments caused by loss of CREB, indicating that these effects are driven by processes distinct from this canonical learning and memory pathway. Finally, within brain regions that underwent volume changes, enrichment increased the expression of genes associated with axonogenesis, dendritic spine development, synapse structural plasticity, and neurogenesis, suggesting these processes underlie the volume changes detected with MRI.
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Project description:Following parenchymal loss, the liver regenerates restoring normal mass and metabolic function. Prevailing theories on triggering events leading to regeneration include humoral, metabolic and flow-mediated mechanisms, the latter emphasizing the importance of shear stress mediated nitric oxide (NO) regulation. We aimed to investigate whether the grade of resection and hence the portal venous pressure and sinusoidal shear stress increase, would be reflected in the gene expression profiles in the liver remnant by employing a global porcine cDNA microarray chip with approximately 23 000 genes represented. Six pig livers were resected with 62% (Low Portal Pressure Resection, LPPR) and 75% (High Portal Pressure Resection) resulting in a portal venous pressure increase from a baseline of 6.1 mmHg to 8.2 and 12 mmHg respectively. By sampling consecutive biopsies from the liver remnants we found differentially expressed genes in the HPPR group to have functions related primarily to apoptosis, nitric oxide metabolism and oxidative stress, whereas differentially expressed genes in the LPPR group potentially regulate the cell cycle. Common to both groups was the upregulation of genes regulating inflammation, transport, cell proliferation and development and protein metabolism. Also common to both groups was both up- and downregulation of genes regulating cell-cell signaling, signal transduction, cell adhesion and translation. Genes regulating the metabolism of lipids, hormones, amines, and alcohol were downregulated in both groups. Conclusions: The genetic regenerative response in the liver remnant to varies according to the level of resection. Keywords: time course, treatment comparison Three pigs underwent a 62% liver resection (low-pressure resection, LPR) and three underwent a 75% resection (high-pressure resection, HPR). Biopsies from the liver remnant were taken from all animals at time points 1, 30, 90, minutes and 3, 4 and 6 hours after resection. Expression profiling was conducted by hybridising each sample against a common reference, consisting of liver RNA from an unrelated animal.
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Project description:Treatment of peripheral T-cell lymphoma is inadequate but investigation of their genetics demonstrated that some are derived from normal follicular helper (Tfh) T-cells. The sanroque mouse strain bears a mutation that increases Tfh cell number and heterozygous animals (Roquinsan/+) develop lymphomas similar to human Tfh lymphoma. We have begun to characterise the lymphomas by whole exome sequencing and gene expression profiling. Interleukin-2-inducible kinase (ITK) is expressed in Tfh lymphoma and ibrutinib is a small molecule inhibitor of mouse and human ITK and a potential therapeutic agent. A preclinical study of ibrutinib in established lymphoma was then carried out and showed lymphoma regression in 8/12 (67%) of mice. Using T2-weighted MRI to assess lymph node volume and diffusion weighted MRI scanning as a measure of function, we showed that treatment increased mean apparent diffusion coefficient (ADC) suggesting cell death, and that change in ADC following treatment correlated with change in lymphoma volume. We suggest that heterozygous sanroque mice produce genetically diverse Tfh cell derived lymphomas in an immunocompetent animal and are a useful model system for preclinical testing.
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Project description:Genome wide transcriptional profiling on liver mRNA retrieved from recombinant adenovirus A20 (rAd.A20) and rAd.bgalactosidase transduced livers, before and 24 hours after 78% extended liver resection. Overexpression of the NF-kB inhibitory protein A20 improves recovery of liver function and mass following extended liver resection and severe liver ischemia reperfusion injury in mice. In this project, we explored effects of A20 using transcriptional profiling on liver mRNA retrieved from recombinant adenovirus A20 (rAd.A20) and rAd.bgalactosidase transduced livers, before and 24 hours after 78% extended liver resection. A20 or beta-galactosidase gene expression in the mouse liver was achieved by penile vein injection of 1x109 pfu of rAd. in 100uL of normal saline, which results in optimal transgene expression 5 days after injection in 30% to 40% of hepatocytes (Longo et al, 2005). Extended (78%) LR, consisting of resection of the lateral, medial, left, and right lobes, was performed 5 days following rAd. administration in 8-week old BALB/c mice weighing 25 to 30 grams (Taconic, Germantown, NY), as described (Longo et al, 2005). RNA was extracted from the resected portion of the liver (before samples) and from the remnant liver 24 hours after resection (after samples). RNA from three animals was pooled per microarray and 2 microarrays per group were performed.
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Project description:Surgical resection remains the gold standard for liver tumor treatment, yet the emergence of post-operative liver failure, known as the small for size syndrome (SFSS), poses a significant challenge. The activation of hypoxia sensors in a SFSS liver remnant initiated early angiogenesis, improving vascular architecture, safeguarding against liver failure and reducing mortality. The study aimed to elucidate vascular remodeling mechanisms in SFSS, its impact on hepatocyte function and subsequent liver failure. Mice underwent extended partial hepatectomy to induce SFSS, with a subset exposed to hypoxia immediately after surgery. Hypoxia bolstered post-hepatectomy survival rates. Early proliferation of liver sinusoidal cells coupled with recruitment of putative endothelial progenitor cells (EPC) via the VEGF/SDF-1α pathway, increased vascular density, improved lobular perfusion, and limited hemorrhagic events in the regenerating liver under hypoxia. Administration of G-CSF in hepatectomized mice mimicked the effects of hypoxia on vascular remodeling and EPC recruitment, but failed to rescue survival. Compared to normoxia, hypoxia favored hepatocyte function over proliferation, , promoting functional preservation in the regenerating remnant. Injection of AAV8-TBG-HNF4α virus for hepatocyte-specific overexpression of HNF4α, the master regulator of hepatocyte function, enforced functionality in proliferating hepatocytes but did not rescue survival. Only the combination of HNF4α overexpression and G-CSF treatment rescued survival afterSFSS-setting hepatectomy. In summary, SFSS arises from an imbalance and desynchronized interplay between functional regeneration and vascular restructuring. To enhance survival following SFSS-hepatectomy, a two-pronged strategy is essential, addressing the preservation of function in the proliferating parenchymal cells alongside the simultaneous mitigation of vascular harm.
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