Liver Transplantation in Patients With Unresectable Colorectal Liver Metastases Treated by Chemotherapy
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ABSTRACT:
DISEASE(S): Neoplasm Metastasis,Neoplasms, Second Primary,Colorectal Cancer,Liver Metastasis,Colorectal Neoplasms,Metastasis,Liver Neoplasms
PROVIDER: 2201757 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Liver transplantation (LT) is an optimal treatment for a selected group of hepatocellular carcinoma (HCC) patients. However, about 10%-25% of LT cases develop post-transplant HCC recurrence, which drastically reduces the long-term survival of HCC patients. This study gives an analysis of the recurrent HCC after LT and the corresponding primary tumor. Results provide insight into the molecular mechanisms underlying post-LT HCC recurrence.
2021-08-27 | GSE102759 | GEO
Project description:Background: As an “immune-privileged organ”, the rate of spontaneous and operational tolerance was higher after liver transplantation (LT) compared with other solid organs. However, modern immunosuppression regimens still have multiple complications, which require a deeper understanding of the real mechanism of inducing immune tolerance. Methods: Homogenic and allogeneic rat LT models were established, and recipient tissue was collected on postoperative day 7. The degree of LT rejection was evaluated by liver pathological changes and liver function. Differentially expressed genes (DEGs) were detected by transcriptome sequencing and identified by RT-PCR. The functional properties of DEGs were characterized by the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathway analyses. The cells infiltrating the graft and recipient spleen and peripheral blood were evaluated by immunofluorescence assays and flow cytometry. Result: A total of 1465 DEGs were screened, including 1177 up-regulated genes and 288 down-regulated genes. GO enrichment and KEGG pathway analysis indicated that DEGs were involved in several immunobiological processes, including immune system process, immune response, regulation of immune response, T cell activation, cytokine-cytokine receptor interaction, allograft rejection, Th1,Th2 and Th17 cell differentiation. Reactome results showed that PD-1 signaling was also enriched. Further research confirmed that the expression of multiple immune cell markers increased, and most marker of T cell exhaustion changed significantly. Flow cytometry results showed that the proportion of Treg decreased in the allogeneic group, while CD4+PD-1+ T and CD8+PD-1+ T cells increased. Conclusion: This study, to our knowledge, was the first to reveal the impact of liver transplantation rejection on the liver at the omics level. Our results revealed that the progression of LT rejection involves multiple immune cells, activation of various immune pathways and special changes of immune checkpoints, which provides potential reference for potential risk assessment and pathogenesis. However, further clinical validation is also needed.
2022-12-09 | GSE210164 | GEO
Project description:Colorectal liver metastases (CLM) are currently considered an absolute contraindication for liver transplantation (Lt) although Lt for other primary and secondary liver malignancies show excellent outcome in selected patients. Before 1995, several Lts for CLM were performed, but the outcome was poor (18% 5-year survival) and Lt for CLM was stopped. Since then, several advances have been achieved and survival following Lt has improved by almost 30%. Thus, a 5-year survival of about 50% following Lt for CLM could be anticipated.
The investigators have previously included 21 patients in a pilot study. All patients had advanced CLM at the time of Lt. Long term overall survival (OS) exceeds by far previously reported outcome for this patient group and is comparable or better than survival following repeat Lt for non-malignant diagnoses. Development of robust selection criteria may further improve the results.
The investigators will conduct a randomized controlled trial to explore whether liver transplantation in selected patients with liver metastases from CRC can obtain significant life extension and better health related quality of life compared to patients receiving surgical resection.
The investigators will also explore if patient selection according to nomo-grams for outcome of colorectal cancer can define a subgroup of patients with a 5 year survival of at least 50% or even cure from the disease.
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Project description:Approximately 2% of heathy persons are infected with human pegivirus (HPgV). HPgV is transmitted via vertical, sexual, and blood-borne routes. Recently, the association of HPgV infection with the risk of lymphoma was reported. We examined the prevalence of chronic HPgV infection in liver transplantation (LT) recipients and hepatectomy patients and the influence of HPgV infection after LT on clinical and perioperative factors. We enrolled 313 LT recipients and 187 hepatectomy patients who received care at the Kyusyu University Hospital between May 1997 and September 2017. Total RNA was extracted from peripheral blood samples of patients/recipients collected postoperatively. HPgV RNA was measured using real-time polymerase chain reaction (RT-PCR). Of the 313 recipients and 187 patients enrolled in this study, 44 recipients (14.1%) and two patients (1.1%) had HPgV viremia. There was no significant association between HPgV infection and LT outcomes. Interestingly, one recipient was infected with HPgV during the peritransplant period, which was likely transmitted via blood transfusion as HPgV RNA was detected from the blood bag transfused to the recipient during LT. Additionally, HPgV infection induced the upregulation of interferon stimulated gene (ISG) expression in peripheral blood mononuclear cells (PBMCs). LT recipients had higher HPgV viremia compared to hepatectomy patients. Although HPgV infection was not associated with LT-related outcomes, it induced ISG expression in recipients.
2019-07-28 | GSE131504 | GEO
Project description:Natural killer (NK) cells are enriched in the liver and are main regulators in liver transplantation (LT) regarding rejection or tolerance, viral infection or tumor recurrence. Immunosuppression (IS) consists of a triple drug standard regimen, including Tacrolimus (TAC) and Corticosteroids (CS) with either Mycophenolate Mofetil (MMF) or Sirolimus (SIR)/Everolimus (EVE). In this study we simulated the immunosuppressive microenvironment in vitro. Peripheral blood mononuclear cells (PBMC) were cultured at the clinically effective plasma concentration of each drug for 3 days. CS seriously impaired the killing function of NK cells, followed by MMF and SIR/EVE. CS and TAC/CSA significantly decreased the secretion of IFN-γ. NK cell function in liver transplant (LT) recipients was most pronouncedly inhibited by a triple immunosuppressive regimen, CS playing the most prominent role compared to the other drugs. The MMF containing regimen demonstrated a significant increase in the expression of suppressive genes, especially of the Siglec7/9 family. The SIR group had stronger NK cell activity compared with the MMF group, although liver transplantation patients have lower NK cell activity and function. In conclusion, despite an overall comparable immunosuppressive efficiency in terms of prevention of acute rejection, a mTORI including regimen might be considered as having less impact on NK cell function and thus retaining their function.
2024-02-01 | GSE202224 | GEO
Project description:Multicentric prospective and observational study to assess the 5-year overall survival in a cohort of patients with unresectable liver-only colorectal metastases, well controlled by chemotherapy prior to liver transplantation.
| 2356756 | ecrin-mdr-crc
Project description:Liver transplantation (LT) is a definitive treatment for end-stage liver disease and hepatocellular cancer. As donor-recipient HLA matching is not employed, there is potential for natural killer (NK) cell-mediated alloreactivity. Here we report that recipient NK cells exhibit a downregulated phenotype with reduced expression of activating receptors NKp30 and NKp46. We found associated hypofunctionality, with impaired NK cell cytotoxicity, degranulation and IFN-gamma production. Gene expression analysis using microarray and quantitative PCR identified significant downregulation of STAT-4 in LT with associated reduction in miR-155, a microRNA target of STAT-4 and a key regulator of NK differentiation. These data indicate that LT induces recipient NK cell tolerance through altered peripheral maturation at a step prior to the acquisition of inhibitory receptors for HLA class I.
2014-02-01 | E-MTAB-2132 | biostudies-arrayexpress
Project description:MELODIC trial is an prospective, multicenter, non-randomized, open-label, parallel trial, aimed at assessing the efficacy (in terms of overall survival: OS) of liver transplantation (LT) in unresecable CRC liver-only metastases, compared with a matched cohort of patients bearing the same tumor characteristics, and treated with chemotherapy. Synthesis of Inclusion parameters: "10;10;10;100"
| 2376303 | ecrin-mdr-crc
Project description:Background: Liver transplantation (LT) for Hepatocellular carcinoma (HCC) can be offered to patients beyond Milan criteria. However, there are currently no molecular markers that can be used on HCC explant histology to predict recurrence, which arises in up to 20% of LT recipients. The goal of our study was to identify proteins on HCC explant predictive of recurrence post-transplant, thereby guiding surveillance strategies and identifying patients beyond Milan criteria who would fare well following LT. Methods: LT recipients who had been transplanted at the University Health Network for HCC beyond Milan criteria in the context of Hepatitis B cirrhosis were identified. Snap-frozen samples from the dominant tumors of recurrent (N=7) and non-recurrent (N=4) patients were analyzed using LC-MS/MS on a Q-Exactive Plus mass spectrometer to delineate a distinctive proteomic signature. These tumors were also profiled by a Human Gene 2.0 ST microarray platform to identify a transcriptomic signature predictive of recurrence and analyzed with R packages. STRING database was used to characterize the implicated pathways. Kaplan-Meier estimator was used to generate a combined proteomic/transcriptomic signature predictive of HCC recurrence in patients with HCC beyond Milan criteria at time of LT. Significantly predictive proteins were verified and internally validated by immunoblotting or immunohistochemistry. Results: A total of 79 proteins and 636 genes were significantly differentially expressed in recurrent HCC, compared to non-recurrent (p<0.05). Among these, LGALS3, LGALS3BP, HAL, THBS1, and BLMH, were significantly increased in recurrent HCC at the protein and gene expression level. In turn, ALDH1A1 protein and gene expression were significantly decreased in recurrent HCC. Univariate survival analysis depicted ALDH1A1 (HR=0.084, 95%CI 0.01-0.68, p=0.02), LGALS3BP (HR=7.14, 95%CI 1.20-42.96, p=0.03), and LGALS3 (HR=2.89, 95%CI 1.01-8.3, p=0.049) as the key dysregulated proteins and genes in the patients with HCC recurrence versus those with non-recurrence by both proteomic and transcriptomic analysis. Decreased ALDH1A1 and significantly increased LGALS3 protein expression in recurrent HCC was verified by immunoblotting. Increased LGALS3BP protein expression in recurrent HCC was orthogonally verified and validated by immunohistochemistry in 30 independent HCC samples. Conclusion: Protein and gene expression of the cancer stem cell marker ALDH1A1 was protective against cancer recurrence in patients transplanted for HCC beyond Milan criteria. Conversely, increased expression of LGALS3 and LGALS3BP on explant was significantly predictive of post-transplant recurrence. These findings were internally validated, suggesting potential utility in identifying patients with HCC beyond Milan who would clearly benefit from transplant with limited recurrence risk and guiding post-transplant surveillance.
2022-02-22 | PXD022881 | Pride
Project description:Selecting the right immunosuppressant to ensure rejection-free outcomes poses unique challenges in pediatric liver transplant (LT) recipients. A molecular predictor can comprehensively address these challenges. Although early acute cellular rejection (ACR) is mediated by cytotoxic T-cells, late rejection also includes antibody-mediated damage in addition to cell-mediated injury. Currently, there are no well-validated blood-based biomarkers for pediatric LT recipients either pre- or post- transplant. Here, we discover and validate separate pre- and post- transplant molecular signatures of LT outcome from whole blood transcriptomes. Using an integrative machine learning approach, we combine transcriptomic data with the high-quality reference human protein interactome network to identify differentially regulated functional sub-components of the network, or “network module signatures”, which drive ACR. Unlike gene signatures, our approach is inherently multivariate, more robust to replication and captures the structure of the underlying molecular network, encapsulating additive effects. We also identify, in a patient-specific manner, network module signatures that can be targeted by current anti-rejection drugs and other mechanisms that can be repurposed. Overall, our approach can enable personalized adjustment of drug regimens for the dominant targetable pathways in pre- and post- LT in children.
2022-04-11 | GSE200340 | GEO