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Cell Mar 2024Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases and after extended liver resections, resulting in the inability to maintain or...
Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases and after extended liver resections, resulting in the inability to maintain or restore a sufficient functional liver mass. Therapies to restore hepatocyte regeneration are lacking, making liver transplantation the only curative option for end-stage liver disease. Here, we report on the structure-based development and characterization (nuclear magnetic resonance [NMR] spectroscopy) of first-in-class small molecule inhibitors of the dual-specificity kinase MKK4 (MKK4i). MKK4i increased liver regeneration upon hepatectomy in murine and porcine models, allowed for survival of pigs in a lethal 85% hepatectomy model, and showed antisteatotic and antifibrotic effects in liver disease mouse models. A first-in-human phase I trial (European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2021-000193-28) with the clinical candidate HRX215 was conducted and revealed excellent safety and pharmacokinetics. Clinical trials to probe HRX215 for prevention/treatment of liver failure after extensive oncological liver resections or after transplantation of small grafts are warranted.
Topics: Animals; Humans; Mice; Hepatectomy; Hepatocytes; Liver; Liver Diseases; Liver Failure; Liver Regeneration; Swine; MAP Kinase Kinase 4; Enzyme Inhibitors
PubMed: 38490194
DOI: 10.1016/j.cell.2024.02.023 -
Nature Communications Nov 2023Mitochondria dysfunction contributes to acute liver injuries, and mitochondrial regulators, such as PGC-1α and MCJ, affect liver regeneration. Therefore, identification...
Mitochondria dysfunction contributes to acute liver injuries, and mitochondrial regulators, such as PGC-1α and MCJ, affect liver regeneration. Therefore, identification of mitochondrial modulators may pave the way for developing therapeutic strategies. Here, ZHX2 is identified as a mitochondrial regulator during acute liver injury. ZHX2 both transcriptionally inhibits expression of several mitochondrial electron transport chain genes and decreases PGC-1α stability, leading to reduction of mitochondrial mass and OXPHOS. Loss of Zhx2 promotes liver recovery by increasing mitochondrial OXPHOS in mice with partial hepatectomy or CCl4-induced liver injury, and inhibition of PGC-1α or electron transport chain abolishes these effects. Notably, ZHX2 expression is higher in liver tissues from patients with drug-induced liver injury and is negatively correlated with mitochondrial mass marker TOM20. Delivery of shRNA targeting Zhx2 effectively protects mice from CCl4-induced liver injury. Together, our data clarify ZHX2 as a negative regulator of mitochondrial OXPHOS and a potential target for developing strategies for improving liver recovery after acute injuries.
Topics: Humans; Mice; Animals; Oxidative Phosphorylation; Chemical and Drug Induced Liver Injury, Chronic; Mitochondria; Hepatectomy; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Transcription Factors; Homeodomain Proteins
PubMed: 37980429
DOI: 10.1038/s41467-023-43439-0 -
Translational Cancer Research Jul 2023
PubMed: 37588728
DOI: 10.21037/tcr-23-725 -
Journal of Clinical Medicine Jul 2023With advancements in minimally invasive (MIS) technology and techniques, MIS hepatectomy has evolved as an effective treatment for both benign and malignant liver tumors...
With advancements in minimally invasive (MIS) technology and techniques, MIS hepatectomy has evolved as an effective treatment for both benign and malignant liver tumors [...].
PubMed: 37510698
DOI: 10.3390/jcm12144583 -
World Journal of Gastroenterology Aug 2023The robotic liver resection (RLR) has been increasingly applied in recent years and its benefits shown in some aspects owing to the technical advancement of robotic... (Review)
Review
The robotic liver resection (RLR) has been increasingly applied in recent years and its benefits shown in some aspects owing to the technical advancement of robotic surgical system, however, controversies still exist. Based on the foundation of the previous consensus statement, this new consensus document aimed to update clinical recommendations and provide guidance to improve the outcomes of RLR clinical practice. The guideline steering group and guideline expert group were formed by 29 international experts of liver surgery and evidence-based medicine (EBM). Relevant literature was reviewed and analyzed by the evidence evaluation group. According to the WHO Handbook for Guideline Development, the Guidance Principles of Development and Amendment of the Guidelines for Clinical Diagnosis and Treatment in China 2022, a total of 14 recommendations were generated. Among them were 8 recommendations formulated by the GRADE method, and the remaining 6 recommendations were formulated based on literature review and experts' opinion due to insufficient EBM results. This international experts consensus guideline offered guidance for the safe and effective clinical practice and the research direction of RLR in future.
Topics: Humans; Robotic Surgical Procedures; Hepatectomy; China; Consensus; Liver
PubMed: 37701136
DOI: 10.3748/wjg.v29.i32.4815 -
BMC Surgery Oct 2023Laparoscopic repeat hepatectomy (LRH) has increased, but appropriate indications for LRH are unclear. This study aimed to clarify appropriate indications for LRH.
BACKGROUND
Laparoscopic repeat hepatectomy (LRH) has increased, but appropriate indications for LRH are unclear. This study aimed to clarify appropriate indications for LRH.
METHODS
We retrospectively compared surgical outcomes between open RH (ORH) (n = 57) and LRH (n = 40) groups. To detect difficult cases of complete pure LRH, we examined patients with unplanned intraoperative hand-assisted laparoscopic surgery (HALS)/open conversion (n = 6).
RESULTS
In the LRH versus ORH group, as previous hepatectomy, laparoscopic (75% vs. 12%, p < 0.001) and partial hepatectomy (Hr0) (73% vs. 37%, p = 0.002) were more frequently performed, and as RH procedure, partial hepatectomy (Hr0) (88% vs. 47%, p = 0.0002) was more frequently performed. S1 tumor cases were higher in ORH group (11% vs. 0%), but S2-6 cases were higher in LRH group (73% vs. 49%) (p = 0.02). In LRH group, compared to the pure LRH patients, HALS/open conversion patients underwent significantly more previous hepatectomy with more than lobectomy (Hr2-3) (33% vs. 2.9%, p = 0.033) and more RH procedures with segmentectomy (HrS) (33% vs. 2.9%, p = 0.03). All LRH requiring a repeat hepatic hilar approach were HALS conversions.
CONCLUSION
Appropriate indications for LRH were previous hepatectomy was laparoscopic partial hepatectomy (Hr0), and RH procedure was partial hepatectomy (Hr0) for S2-6 tumor location. When RH is more than segmentectomy (HrS) requiring a repeat hepatic hilar approach, planned HALS or ORH may be a better approach than pure LRH.
Topics: Humans; Hepatectomy; Liver Neoplasms; Retrospective Studies; Laparoscopy; Length of Stay; Treatment Outcome
PubMed: 37875912
DOI: 10.1186/s12893-023-02208-y -
BMC Genomics Sep 2023Surgical resection remains a critical treatment option for many patients with primary and secondary hepatic neoplasms. Extended hepatectomy (eHx) may be required for...
Surgical resection remains a critical treatment option for many patients with primary and secondary hepatic neoplasms. Extended hepatectomy (eHx) may be required for some patients with large tumors, which may cause liver failure and death. Partial hepatectomy (pHx) and eHx mouse models were constructed, liver tissues were sampled at 18, 36, and 72 h posthepatectomy. Transcriptome and metabolome analyses were employed to explore the different potential mechanisms in regeneration and injury between pHx and eHx. The results showed that eHx was associated with more severe liver injury and lower survival rates than pHx. Transcriptomics data showed there were 1842, 2129, and 1277 differentially expressed genes (DEGs) in eHx and 962, 1305, and 732 DEGs in pHx at 18, 36, and 72 h posthepatectomy, respectively, compared with the those in the sham groups. Compared with pHx, the number of DEGs in the eHx group reached a maximum of 230 at 18 h after surgery and decreased sequentially to 87 and 43 at 36 and 72 h. Metabolomics analysis identified a total of 1399 metabolites, and 48 significant differentially produced metabolites (DPMs) were screened between eHx and pHx. Combined analysis of DEGs and DPMs indicated that cholesterol metabolism and insulin resistance may be two important pathways for liver regeneration and mouse survival postextended hepatectomy. Our results showed the global influence of pHx and eHx on the transcriptome and metabolome in mouse liver, and revealed cholesterol metabolism and insulin resistance pathways might be involved in regeneration post-pHx and -eHx.
Topics: Animals; Mice; Hepatectomy; Insulin Resistance; Transcriptome; Metabolome; Cholesterol
PubMed: 37679685
DOI: 10.1186/s12864-023-09647-0 -
Annals of Gastroenterological Surgery Jul 2023In patients with colorectal liver metastases (CLM), surgery is potentially curative. The use of novel surgical techniques and complementary percutaneous ablation allows... (Review)
Review
In patients with colorectal liver metastases (CLM), surgery is potentially curative. The use of novel surgical techniques and complementary percutaneous ablation allows for curative-intent treatment even in marginally resectable cases. Resection is used as part of a multidisciplinary approach, which for nearly all patients will include perioperative chemotherapy. Small CLM can be treated with parenchymal-sparing hepatectomy (PSH) and/or ablation. For small CLM, PSH results in better survival and higher rates of resectability of recurrent CLM than non-PSH. For patients with extensive bilateral distribution of CLM, two-stage hepatectomy or fast-track two-stage hepatectomy is effective. Our increasing knowledge of genetic alterations allows us to use them as prognostic factors alongside traditional risk factors (e.g. tumor diameter and tumor number) to select patients with CLM for resection and guide surveillance after resection. Alteration in RAS family genes (hereafter referred to as " alteration") is an important negative prognostic factor, as are alterations in the , , , and genes. However, alteration appears to improve prognosis. alteration, increased number and diameter of CLM, and primary lymph node metastasis are well-known risk factors for recurrence after CLM resection. In patients free of recurrence 2 y after CLM resection, only alteration is associated with recurrence. Thus, surveillance intensity can be stratified by alteration status after 2 y. Novel diagnostic instruments and tools, such as circulating tumor DNA, may lead to further evolution of patient selection, prognostication, and treatment algorithms for CLM.
PubMed: 37416742
DOI: 10.1002/ags3.12689 -
Current Opinion in Organ Transplantation Feb 2024Liver transplantation has emerged as a possible treatment for selected patients with nonresectable colorectal liver metastasis, but controversy still exists regarding... (Review)
Review
PURPOSE OF REVIEW
Liver transplantation has emerged as a possible treatment for selected patients with nonresectable colorectal liver metastasis, but controversy still exists regarding optimal selection criteria and acceptable outcomes.
RECENT FINDINGS
Univariate analysis in the largest cohorts confirms that metachronous disease, Oslo score = 0-1, metabolic tumor volume (MTV) less than 70 cm 3 , and tumor burden score less than 9 are positive predictive factors for good overall survival outcomes. Some recent trials might suggest that technical resectability is not a valid exclusion criterion for patients with high tumor load and favorable prognostic scores in the transplant evaluation. Recent developments in circulation DNA technology and liquid biopsy may play a future role in the selection and monitoring of patients.
SUMMARY
Evaluation for transplant needs multidisciplinary involvement and should not be delayed until the failure of conventional oncological therapy. Larger data sets are needed to refine the selection criteria for liver transplantation in colorectal liver metastasis (CRLM).
Topics: Humans; Colorectal Neoplasms; Liver Transplantation; Liver Neoplasms; Hepatectomy
PubMed: 37995153
DOI: 10.1097/MOT.0000000000001126 -
International Journal of Surgery... Dec 2023Robotic platform has been increasingly applied in major hepatectomy. However, the role or advantage of robotic approach comparing with laparoscopic approach in major... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Robotic platform has been increasingly applied in major hepatectomy. However, the role or advantage of robotic approach comparing with laparoscopic approach in major hepatectomy remains controversial. This meta-analysis compares perioperative outcomes of robotic major hepatectomy (RMH) to laparoscopic major hepatectomy (LMH) for hepatic neoplasms.
METHODS
PubMed, Web of Science, EMBASE, and Cochrane Library were searched to identify comparative studies compared RMH versus LMH for hepatic neoplasms. The search timeframe was set before May 2023. Main outcomes were mortality, overall morbidities, serious complications, and conversion to open surgery. Secondary outcomes were operative time, intraoperative blood loss, blood transfusion, postoperative length of hospital stay, R0 resection, reoperation, and readmission. Studies were evaluated for quality by Cochrane risk of bias tool or Newcastle-Ottawa scale. Data were pooled as odds ratio (OR) or mean difference (MD). This study was registered at PROSPERO (CRD42023410951).
RESULTS
Twelve retrospective cohort studies concerning total 1657 patients (796 RMH, 861 LMH) were included. Meta-analyses showed no significant differences in mortality (OR=1.23, 95% CI=0.50-2.98, P =0.65), overall postoperative complications (OR=0.83, 95% CI=0.65-1.06, P =0.14), operative time (MD=6.47, 95% CI=-14.72 to 27.65, P =0.55), blood transfusion (OR=0.77, 95% CI=0.55-1.08, P =0.13), R0 resection (OR=1.45, 95% CI=0.91-2.31, P =0.12), reoperation (OR=0.76, 95% CI=0.31-1.88, P =0.56), and readmission (OR=0.63, 95% CI=0.28-1.44, P =0.27) between RMH and LMH. Incidence of serious complications (OR=0.60, 95% CI=0.40-0.90, P =0.01), conversion to open surgery (OR=0.41, 95% CI=0.27-0.63, P <0.0001), blood loss (MD=-91.42, 95% CI=-142.18 to -40.66, P =0.0004), and postoperative hospital stay (MD=-0.64, 95% CI=-0.78 to -0.49, P <0.00001) were reduced for RMH versus LMH.
CONCLUSIONS
RMH is associated with comparable short-term surgical outcomes and oncologic adequacy compared to LMH when performed by experienced surgeons at large centres. RMH may result in reduced major morbidities, conversion rate, blood loss, and hospital stay, but these results were volatile. Further randomized studies should address the potential advantages of RMH over LMH.
Topics: Humans; Hepatectomy; Laparoscopy; Length of Stay; Liver Neoplasms; Operative Time; Postoperative Complications; Retrospective Studies; Robotic Surgical Procedures; Treatment Outcome
PubMed: 37720925
DOI: 10.1097/JS9.0000000000000750