Liver Transplantation for Colorectal Liver Metastases: Current Management and Future Perspectives
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ABSTRACT:
SUBMITTER: Puia-Negulescu S
PROVIDER: S-EPMC8002956 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The liver is the commonest site of metastatic disease for patients with colorectal cancer, with at least 25% developing colorectal liver metastases (CRLM) during the course of their illness. The management of CRLM has evolved into a complex field requiring input from experienced members of a multi-disciplinary team involving radiology (cross sectional, nuclear medicine and interventional), Oncology, Liver surgery, Colorectal surgery, and Histopathology. Patient management is based on assessment of sophisticated clinical, radiological and biomarker information. Despite incomplete evidence in this very heterogeneous patient group, maximising resection of CRLM using all available techniques remains a key objective and provides the best chance of long-term survival and cure. To this end, liver resection is maximised by the use of downsizing chemotherapy, optimisation of liver remnant by portal vein embolization, associating liver partition and portal vein ligation for staged hepatectomy, and combining resection with ablation, in the context of improvements in the functional assessment of the future remnant liver. Liver resection may safely be carried out laparoscopically or open, and synchronously with, or before, colorectal surgery in selected patients. For unresectable patients, treatment options including systemic chemotherapy, targeted biological agents, intra-arterial infusion or bead delivered chemotherapy, tumour ablation, stereotactic radiotherapy, and selective internal radiotherapy contribute to improve survival and may convert initially unresectable patients to operability. Currently evolving areas include biomarker characterisation of tumours, the development of novel systemic agents targeting specific oncogenic pathways, and the potential re-emergence of radical surgical options such as liver transplantation.
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Project description:In 1967, Starzl et al performed the first successful liver transplantation for a patient diagnosed with hepatoblastoma. In the following, liver transplantation was considered ideal for complete tumor resection and potential cure from primary hepatic malignancies. Several reports of liver transplantation for primary and metastatic liver cancer however showed disappointing results and the strategy was soon dismissed. In 1996, Mazzaferro et al introduced the Milan criteria, offering liver transplantation to patients diagnosed with limited hepatocellular carcinoma. Since then, liver transplantation for malignant disease is an ongoing subject of preclinical and clinical research. In this context, several aspects must be considered: (1) Given the shortage of deceased-donor organs, long-term overall and disease free survival should be comparable with results obtained in patients transplanted for non-malignant disease; (2) In this regard, living-donor liver transplantation may in selected patients help to solve the ethical dilemma of optimal individual patient treatment vs organ allocation justice; and (3) Ongoing research focusing on perioperative therapy and anti-proliferative immunosuppressive regimens may further reduce tumor recurrence in patients transplanted for malignant disease and thus improve overall survival. The present review gives an overview of current indications and future perspectives of liver transplantation for malignant disease.
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Project description:Non-alcoholic fatty liver disease (NAFLD), specifically its progressive form non-alcoholic steatohepatitis (NASH), represents the fastest growing indication for liver transplantation in Western countries. Diabetes mellitus, morbid obesity and cardiovascular disease are frequently present in patients with NAFLD who are candidates for liver transplantation. These factors require specific evaluation, including a detailed pre-surgical risk stratification, in order to improve outcomes after liver transplantation. Moreover, in the post-transplantation setting, the incidence of cardiovascular events and metabolic complications can be amplified by immunosuppressive therapy, which is a well-known driver of metabolic alterations. Indeed, patients with NASH are more prone to developing early post-transplant complications and, in the long-term, de novo malignancy and cardiovascular events, corresponding to higher mortality rates. Therefore, a tailored multidisciplinary approach is required for these patients, both before and after liver transplantation. Appropriate candidate selection, lifestyle modifications and specific assessment in the pre-transplant setting, as well as pharmacological strategies, adjustment of immunosuppression and a healthy lifestyle in the post-transplant setting, play a key role in correct management.
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Project description:The liver is the most common site of colorectal cancer metastasis. Complete resection of the metastatic tumor is currently the only treatment modality available with a potential for cure. However, only 20% of colorectal liver metastases (CRLM) are considered resectable at the time of presentation. Liver transplantation (LT) has been proposed as an alternative oncologic treatment for patients with unresectable CRLM. This review summarizes the published experiences of LT in the setting of unresectable CRLM from the previous decades and discusses the challenges and future horizons in the field. Contemporary experiences that come mostly from countries with broader access to liver grafts are also explored and their promising findings in terms of overall survival (OS) and disease-free survival (DFS) are outlined along with their study design and methods. The rationale of establishing specific patient selection criteria and the dilemmas around immunosuppressive regimens in patients undergoing LT for CRLM are also highlighted. Additionally, this review describes the findings of studies comparing LT vs chemotherapy alone and LT vs portal vein embolization plus resection for CRLM in terms of OS and DFS. Last but not least, we present current perspectives and ongoing prospective trials that try to elucidate the role of LT for CRLM.
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Project description:More than 40% of patients with colorectal cancer present liver metastases (CRLM) during the course of their disease and up to 50% present with unresectable disease. Without surgical interventions, survival for patients treated with systemic therapies alone is dismal. In the past, liver transplantation (LT) for patients with unresectable CRLM failed to show any survival benefit due to poor selection, ineffective chemotherapeutic regimens, unbalanced immunosuppression and high perioperative mortality. Since then and for many years LT for CRLM was abandoned. The turning point occurred in 2013, when the results from the Secondary Cancer (SECA I) pilot study performed at Oslo University were published reporting a 60% 5-year overall survival after LT in patients with unresectable CRLM. These results effectively reignited the interest in LT as a potential therapy for CRLM, and several trials are undergoing. The aims of this article are to give a comprehensive overview of the available evidence on LT for CRLM, discuss the open issues in this rapidly evolving field, and highlight possible ways to address the future of this fascinating therapeutic alternative for selected patients with CRLM.
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Project description:Microglia are the tissue macrophages of the central nervous system (CNS) and the first to respond to CNS dysfunction and disease. Gene expression profiling of microglia during development, under homeostatic conditions and in the diseased CNS provided insight in microglia functions and changes thereof. Single cell sequencing studies further contributed to our understanding of microglia heterogeneity in relation to age, sex and CNS disease. Recently, single nucleus gene expression profiling was performed on (frozen) CNS tissue. Transcriptomic profiling of CNS tissues by (single) nucleus RNA-sequencing has the advantage that it can be applied to archived and well stratified frozen specimens. Here, we give an overview of the significant advances recently made in microglia transcriptional profiling. In addition, we present matched cellular and nuclear microglia RNA-seq datasets we generated from mouse and human CNS tissue to compare cellular versus nuclear transcriptomes from fresh and frozen samples. We demonstrate that microglia can be similarly profiled with cell and nucleus profiling, and importantly also with nuclei isolated from frozen tissue. Nuclear microglia transcriptomes are a reliable proxy for cellular transcriptomes. Interestingly, lipopolysaccharide- (LPS)-induced changes in gene expression were even more pronounced in the nuclear transcriptome. In addition, heterogeneity in microglia observed in fresh samples is similarly detected in frozen nuclei of the same donor. Together, these results show that microglia nuclear RNAs obtained from frozen CNS tissue are a reliable proxy for microglia gene expression and cellular heterogeneity and may prove an effective strategy to study of the role of microglia in neuropathology.
2019-08-10 | GSE135618 | GEO
Project description:Pregnancy is associated with marked physiological changes challenging the cardiovascular system. Among the more severe pregnancy associated cardiovascular complications, peripartum cardiomyopathy (PPCM) is a potentially life-threatening heart disease emerging towards the end of pregnancy or in the first postpartal months in previously healthy women. A major challenge is to distinguish the peripartum discomforts in healthy women (fatigue, shortness of breath, and oedema) from the pathological symptoms of PPCM. Moreover, pregnancy-related pathologies such as preeclampsia, myocarditis, or underlying genetic disease show overlapping symptoms with PPCM. Difficulties in diagnosis and the discrimination from other pathological conditions in pregnancy may explain why PPCM is still underestimated. Additionally, underlying pathophysiologies are poorly understood, biomarkers are scarce and treatment options in general limited. Experience in long-term prognosis and management including subsequent pregnancies is just beginning to emerge. This review focuses on novel aspects of physiological and pathophysiological changes of the maternal cardiovascular system by comparing normal conditions, hypertensive complications, genetic aspects, and infectious disease in PPCM-pregnancies. It also presents clinical and basic science data on the current state of knowledge on PPCM and brings them in context thereby highlighting promising new insights in diagnostic tools and therapeutic approaches and management.
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Project description:There is increasing incidence and prevalence of acute and chronic liver diseases (CLDs) all over the world which influence the quality of life and can give rise to life threatening complications. The burden of advanced liver disease due to hepatitis B has been controlled by antivirals but its eradication is difficult soon. Highly effective directly acting antiviral therapy has reduced the burden of hepatitis C but is partially offset by increasing IV drug abuse. Non-alcoholic fatty liver disease pandemic is on and there is recent alarming increase in alcohol related liver disease, both of which have no drug cure apart from control of the risk factors. Genetic factors have been identified in progression of all forms of CLD. Due to better management of complications of CLD, the life span of patients have increased spiking the number of hepatocellular carcinoma (HCC) and patients needing liver transplantation (LT). The present severe acute respiratory syndrome coronavirus pandemic has affected the outcome CLD including LT in addition to causing acute hepatitis. Better diagnostics and therapeutics are available for liver fibrosis, portal hypertension, HCC and post LT management and many drugs are under trial. The present review summarises the current scenario of the epidemiology and the advances in diagnosis and treatment of liver diseases including their complications like portal hypertension, HCC and LT.
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Project description:Surgical resection is the only curative modality for colorectal liver metastases (CLM) and 5-year overall survival after resection is about 40%. Nonresectable CLM is not curable and 5-year overall survival is currently about 10%. Before 1995, several liver transplantations for CLMs were performed, but outcome was poor (5-year survival rate: 18%). Liver transplantation for CLMs was abandoned and CLMs were even considered a contraindication to the procedure. Since then, the survival rate after liver transplantation in general has improved by almost 30%. In a prospective pilot study of liver transplantation for nonresectable CLM, a 5-year overall survival rate of 60% was demonstrated, however 19 of 21 patients experienced recurrence of disease. Here, current knowledge and ongoing research in this field is reviewed, and the potential role for liver transplantation as one of several treatment modalities for CLM discussed.
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