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The Oncologist Nov 2023The objective of this study was to investigate the impact of surgical margin and hepatic resection on prognosis and compare their importance on prognosis in patients...
OBJECTIVE
The objective of this study was to investigate the impact of surgical margin and hepatic resection on prognosis and compare their importance on prognosis in patients with hepatocellular carcinoma (HCC).
METHODS
The clinical data of 906 patients with HCC who underwent hepatic resection in our hospital from January 2013 to January 2015 were collected retrospectively. All patients were divided into anatomical resection (AR) (n = 234) and nonanatomical resection (NAR) group (n = 672) according to type of hepatic resection. The effects of AR and NAR and wide and narrow margins on overall survival (OS) and time to recurrence (TTR) were analyzed.
RESULTS
In all patients, narrow margin (1.560, 1.278-1.904; 1.387, 1.174-1.639) is an independent risk factor for OS and TTR, and NAR is not. Subgroup analysis showed that narrow margins (2.307, 1.699-3.132; 1.884, 1.439-2.468), and NAR (1.481, 1.047-2.095; 1.372, 1.012-1.860) are independent risk factors for OS and TTR in patients with microvascular invasion (MVI)-positive. Further analysis showed that for patients with MVI-positive HCC, NAR with wide margins was a protective factor for OS and TTR compared to AR with narrow margins (0.618, 0.396-0.965; 0.662, 0.448-0.978). The 1, 3, and 5 years OS and TTR rate of the two group were 81%, 49%, 29% versus 89%, 64%, 49% (P = .008) and 42%, 79%, 89% versus 32%, 58%, 74% (P = .024), respectively.
CONCLUSIONS
For patients with MVI-positive HCC, AR and wide margins were protective factors for prognosis. However, wide margins are more important than AR on prognosis. In the clinical setting, if the wide margins and AR cannot be ensured at the same time, the wide margins should be ensured first.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Retrospective Studies; Margins of Excision; Hepatectomy; Neoplasm Invasiveness; Prognosis; Neoplasm Recurrence, Local
PubMed: 37196175
DOI: 10.1093/oncolo/oyad124 -
International Journal of Biological... 2023Sorafenib is a first-line chemotherapy drug for treating advanced hepatocellular carcinoma (HCC). However, its therapeutic effect has been seriously affected by the...
Sorafenib is a first-line chemotherapy drug for treating advanced hepatocellular carcinoma (HCC). However, its therapeutic effect has been seriously affected by the emergence of sorafenib resistance in HCC patients. The underlying mechanism of sorafenib resistance is unclear. Here, we report a circular RNA, cDCBLD2, which plays an important role in sorafenib resistance in HCC. We found that cDCBLD2 was upregulated in sorafenib-resistant (SR) HCC cells, and knocking down cDCBLD2 expression could significantly increase sorafenib-related cytotoxicity. Further evidence showed that cDCBLD2 can bind to microRNA (miR)-345-5p through a competing endogenous RNA mechanism, increase type IIA topoisomerase (TOP2A) mRNA stability through a miRNA sponge mechanism, and reduce the effects of sorafenib treatment on HCC by inhibiting apoptosis. Our findings also suggest that miR-345-5p can negatively regulate TOP2A levels by binding to the coding sequence region of its mRNA. Additionally, targeting cDCBLD2 by injecting a specific small interfering RNA (siRNA) could significantly overcome sorafenib resistance in a patient-derived xenograft (PDX) mouse model of HCC. Taken together, our study provides a proof-of-concept for a potential strategy to overcome sorafenib resistance in HCC patients by targeting cDCBLD2 or TOP2A.
Topics: Animals; Humans; Mice; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Liver Neoplasms; MicroRNAs; RNA, Small Interfering; Sorafenib; RNA, Circular
PubMed: 37781045
DOI: 10.7150/ijbs.86227 -
BMC Cancer Sep 2023Studies have demonstrated that Sorting nexin 7 (SNX7) functions as an anti-apoptotic protein in liver tissue and plays a crucial role in the survival of hepatocytes...
Comprehensive analysis and validation of SNX7 as a novel biomarker for the diagnosis, prognosis, and prediction of chemotherapy and immunotherapy response in hepatocellular carcinoma.
BACKGROUND
Studies have demonstrated that Sorting nexin 7 (SNX7) functions as an anti-apoptotic protein in liver tissue and plays a crucial role in the survival of hepatocytes during early embryonic development. However, its diagnostic and prognostic value as well as the predictive value of chemotherapy and immunotherapy have not been reported in hepatocellular carcinoma (HCC).
METHODS
SNX7 mRNA expression and its diagnostic efficacy were examined in GEO datasets, and the findings were further confirmed in TCGA, ICGC cohorts, and cell lines. The protein level of SNX7 was determined using CPTAC and HPA databases, and the results were validated through immunohistochemistry (IHC). Survival analyses were performed in TCGA and ICGC cohorts, and the results were subsequently validated via Kaplan-Meier Plotter. The response to chemotherapy and immunotherapy was predicted via GDSC dataset and TIDE algorithm, respectively. R packages were employed to explore the relationship between SNX7 expression and immune infiltration, m6A modification, as well as the functional enrichment of differentially expressed genes (DEGs).
RESULTS
The expression of SNX7 at both mRNA and protein levels was significantly upregulated in HCC tissues. SNX7 exhibited superior diagnostic efficacy compared to AFP alone for HCC detection, and combining it with AFP improved the diagnostic accuracy for HCC. High SNX7 was associated with unfavorable outcomes, including poor overall survival, disease-specific survival, progression-free survival, and advanced pathological stage, in patients with HCC, and SNX7 was identified as an independent risk factor for HCC. Moreover, elevated SNX7 expression was positively correlated with increased sensitivity to various chemotherapy drugs, including sorafenib, while it was associated with resistance to immunotherapy in HCC patients. Correlation analysis revealed a relationship between SNX7 and multiple m6A-related genes and various immune cells. Finally, enrichment analysis demonstrated strong associations of SNX7 with critical biological processes, such as cell cycle regulation, cellular senescence, cell adhesion, DNA replication, and mismatch repair pathway in HCC.
CONCLUSIONS
Our study highlights the association of SNX7 with the immune microenvironment and its potential influence on HCC progression. SNX7 emerges as a promising novel biomarker for the diagnosis, prognosis, and prediction of response to chemotherapy and immunotherapy in patients with HCC.
Topics: Female; Pregnancy; Humans; Carcinoma, Hepatocellular; alpha-Fetoproteins; Liver Neoplasms; Prognosis; Biomarkers; Immunotherapy; Tumor Microenvironment
PubMed: 37743471
DOI: 10.1186/s12885-023-11405-0 -
International Journal of Molecular... Aug 2023Members of the tripartite motif (TRIM)-containing protein family have been found to be involved in the progression of hepatocellular carcinoma (HCC). TRIM14 exerts a...
Members of the tripartite motif (TRIM)-containing protein family have been found to be involved in the progression of hepatocellular carcinoma (HCC). TRIM14 exerts a promotive impact on several cancers. This study aimed to explore the function and mechanism of TRIM14 in HCC. TRIM14 expression in HCC tissues and HCC cell lines was detected. The overexpression or knockdown model of TRIM14 was established in HCC cell lines. Cell Counting Kit-8 (CCK-8) assay, flow cytometry, Transwell assay, RT-PCR, Western blot, and immunofluorescence were performed to verify the influence of TRIM14 on cell proliferation, sensitivity to chemotherapy drugs, apoptosis, migration, invasion, and autophagy. A xenograft tumor model was used to confirm the impact of TRIM14 on tumor cell growth. As shown by the data, TRIM14 level was notably higher in the tumor tissues of HCC patients than in the adjacent tissues. The overall survival rate of patients with a high TRIM14 expression was relatively lower than that of patients with a low TRIM14 expression. TRIM14 upregulation enhanced the proliferation, autophagy, migration, and invasion of HCC cells and chemoresistant HCC cells and decreased apoptosis. TRIM14 knockdown contributed to the opposite effects. In in vivo experiments, TRIM14 upregulation bolstered tumor growth. Western blot analysis revealed that TRIM14 upregulation boosted signal transducer and activator of transcription3 (STAT3) and hypoxia-inducible factor-1alpha (HIF-1α) expression, and TRIM14 knockdown suppressed their expression. Moreover, repressing STAT3 and HIF-1α could mitigate the tumor-promoting role of TRIM14 in HCC cells. Overall, TRIM14 facilitated malignant HCC development and induced chemoresistance in HCC cells by activating the STAT3/HIF-1α axis.
Topics: Humans; Animals; Carcinoma, Hepatocellular; Drug Resistance, Neoplasm; Hypoxia-Inducible Factor 1, alpha Subunit; Liver Neoplasms; Cell Line; Disease Models, Animal; Tripartite Motif Proteins; Intracellular Signaling Peptides and Proteins; STAT3 Transcription Factor
PubMed: 37628777
DOI: 10.3390/ijms241612589 -
Liver International : Official Journal... Nov 2023Surgical resection (SR) is a potentially curative treatment of hepatocellular carcinoma (HCC) hampered by high rates of recurrence. New drugs are tested in the adjuvant...
BACKGROUND
Surgical resection (SR) is a potentially curative treatment of hepatocellular carcinoma (HCC) hampered by high rates of recurrence. New drugs are tested in the adjuvant setting, but standardised risk stratification tools of HCC recurrence are lacking.
OBJECTIVES
To develop and validate a simple scoring system to predict 2-year recurrence after SR for HCC.
METHODS
2359 treatment-naïve patients who underwent SR for HCC in 17 centres in Europe and Asia between 2004 and 2017 were divided into a development (DS; n = 1558) and validation set (VS; n = 801) by random sampling of participating centres. The Early Recurrence Score (ERS) was generated using variables associated with 2-year recurrence in the DS and validated in the VS.
RESULTS
Variables associated with 2-year recurrence in the DS were (with associated points) alpha-fetoprotein (<10 ng/mL:0; 10-100: 2; >100: 3), size of largest nodule (≥40 mm: 1), multifocality (yes: 2), satellite nodules (yes: 2), vascular invasion (yes: 1) and surgical margin (positive R1: 2). The sum of points provided a score ranging from 0 to 11, allowing stratification into four levels of 2-year recurrence risk (Wolbers' C-indices 66.8% DS and 68.4% VS), with excellent calibration according to risk categories. Wolber's and Harrell's C-indices apparent values were systematically higher for ERS when compared to Early Recurrence After Surgery for Liver tumour post-operative model to predict time to early recurrence or recurrence-free survival.
CONCLUSIONS
ERS is a user-friendly staging system identifying four levels of early recurrence risk after SR and a robust tool to design personalised surveillance strategies and adjuvant therapy trials.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Prognosis; Retrospective Studies; Postoperative Period; Neoplasm Recurrence, Local; Hepatectomy
PubMed: 37577984
DOI: 10.1111/liv.15683 -
PLoS Neglected Tropical Diseases Jan 2024Extensive evidence links Clonorchis sinensis (C. sinensis) to cholangiocarcinoma; however, its association with hepatocellular carcinoma (HCC) is less acknowledged, and...
BACKGROUND
Extensive evidence links Clonorchis sinensis (C. sinensis) to cholangiocarcinoma; however, its association with hepatocellular carcinoma (HCC) is less acknowledged, and the underlying mechanism remains unclear. This study was designed to investigate the association between C. sinensis infection and HCC and reveal the relationship between C. sinensis infection and cancer stemness.
METHODS
A comprehensive analysis of 839 HCC patients categorized into C. sinensis (-) HCC and C. sinensis (+) HCC groups was conducted. Chi-square and Mann-Whitney U tests were used to assess the association between C. sinensis infection and clinical factors. Kaplan-Meier and Cox regression analyses were used to evaluate survival outcomes. Immunohistochemistry was used to determine CK19 and EpCAM expression in HCC specimens.
RESULTS
Compared to C. sinensis (-) HCC patients, C. sinensis (+) HCC patients exhibited advanced Barcelona Clinic Liver Cancer (BCLC) stage, higher male prevalence and more liver cirrhosis as well as elevated alpha-fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9), eosinophil, complement 3 (C3), and complement 4 (C4) values. C. sinensis infection correlated with shorter overall survival (OS) (p < 0.05) and recurrence-free survival (RFS) (p < 0.05). Furthermore, Cox multivariate analysis revealed that C. sinensis infection was an independent prognostic factor for OS in HCC patients. Importantly, C. sinensis infection upregulated the expression of HCC cancer stem cell markers CK19 and EpCAM.
CONCLUSION
HCC patients with C. sinensis infection exhibit a poor prognosis following hepatectomy. Moreover, C. sinensis infection promotes the acquisition of cancer stem cell-like characteristics, consequently accelerating the malignant progression of HCC.
AUTHOR SUMMARY
Clonorchis sinensis (C. sinensis) is a prominent food-borne parasite prevalent in regions such as China, particularly in Guangxi. C. sinensis has been associated with various hepatobiliary system injuries, encompassing inflammation, periductal fibrosis, cholangiocarcinoma and even hepatocellular carcinoma (HCC). A substantial body of evidence links C. sinensis to cholangiocarcinoma, However, the connection between C. sinensis and HCC and the intricate mechanisms underlying its contribution to HCC development remain incompletely elucidated. Our study demonstrates clear clinicopathological associations between C. sinensis and HCC, such as gender, BCLC stage, liver cirrhosis, MVI, AFP, CA19-9, circulating eosinophils and complements. Furthermore, we found that the co-occurrence of C. sinensis exhibited a significant association with shorter OS and RFS in patients diagnosed with HCC. A major finding was that C. sinensis infection promotes the acquisition of cancer stem cell-like characteristics, consequently accelerating the malignant progression of HCC. Our results provide a more comprehensive comprehension of the interplay between C. sinensis and HCC, shedding fresh light on the carcinogenic potential of C. sinensis.
Topics: Animals; Humans; Male; Carcinoma, Hepatocellular; Liver Neoplasms; Epithelial Cell Adhesion Molecule; Clonorchiasis; alpha-Fetoproteins; CA-19-9 Antigen; Neoplasm Staging; China; Prognosis; Clonorchis sinensis; Cholangiocarcinoma; Bile Ducts, Intrahepatic; Bile Duct Neoplasms; Liver Cirrhosis; Retrospective Studies
PubMed: 38285640
DOI: 10.1371/journal.pntd.0011906 -
Computers in Biology and Medicine May 2024Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, with an increasing incidence and poor prognosis. In the past decade, artificial... (Review)
Review
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, with an increasing incidence and poor prognosis. In the past decade, artificial intelligence (AI) technology has undergone rapid development in the field of clinical medicine, bringing the advantages of efficient data processing and accurate model construction. Promisingly, AI-based radiomics has played an increasingly important role in the clinical decision-making of HCC patients, providing new technical guarantees for prediction, diagnosis, and prognostication. In this review, we evaluated the current landscape of AI radiomics in the management of HCC, including its diagnosis, individual treatment, and survival prognosis. Furthermore, we discussed remaining challenges and future perspectives regarding the application of AI radiomics in HCC.
Topics: Humans; Carcinoma, Hepatocellular; Artificial Intelligence; Radiomics; Liver Neoplasms; Clinical Decision-Making
PubMed: 38547656
DOI: 10.1016/j.compbiomed.2024.108337 -
Annals of Palliative Medicine Jan 2024The management of hepatocellular carcinoma (HCC) and cirrhosis are closely linked. HCC most often occurs in the background of cirrhosis and can also lead to... (Review)
Review
BACKGROUND AND OBJECTIVE
The management of hepatocellular carcinoma (HCC) and cirrhosis are closely linked. HCC most often occurs in the background of cirrhosis and can also lead to decompensation of underlying liver disease. The treatment of complications of cirrhosis is important to help reduce morbidity and mortality and allow for expanded treatment options of HCC.
METHODS
We searched PubMed using search terms for cirrhosis and HCC. From this search, we selected references which appeared to be primary studies preferentially within the last 5 years, although also included select landmark studies which have shaped guidelines and recommendations.
KEY CONTENT AND FINDINGS
The development of HCC and treatment of HCC can both cause decompensation of liver disease and worsening of liver function. For most patients, the development of HCC or progression of disease are the drivers of morbidity and mortality. However, it is important to closely monitor patients for complications of liver disease that develop either as a result of HCC or as a complication of HCC treatment, and this can have important implications on treatment options. Multidisciplinary team involvement including hepatologists, surgeons, radiologists, interventional radiologists, medical oncologists, and palliative care is essential in the care of patients with cirrhosis and HCC to help guide management decisions and treatment.
CONCLUSIONS
The management of cirrhosis and HCC are both complex and interrelated. Through a multidisciplinary team approach we can best treat the complications of cirrhosis, allow for expanded treatment options, and improve quality of life through symptom management.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Quality of Life; Liver Cirrhosis; Combined Modality Therapy
PubMed: 38124474
DOI: 10.21037/apm-23-173 -
BMC Pediatrics Aug 2023Hepatocellular adenomas (HCAs) are rare benign tumors of the liver that occur predominantly in women taking oral contraceptives. In children, HCAs comprise < 5% of... (Review)
Review
BACKGROUND
Hepatocellular adenomas (HCAs) are rare benign tumors of the liver that occur predominantly in women taking oral contraceptives. In children, HCAs comprise < 5% of hepatic tumors. We report a case of HCAs in a 7-year-old girl with estrogen and glucose imbalance.
CASE PRESENTATION
A 7-year-old girl was presented to our hospital with bilateral breast enlargement for 2 months, polydipsia, polyuria, polyphagia, hyperglycemia, and significant weight gain. Computed tomography (CT) showed a 7.2 cm×6.9 cm×5.3 cm round-shaped mass in the left inner lobe of the liver, ovarian ultrasound showed multiple follicles in the ovaries bilaterally, and cranial magnetic resonance imaging (MRI) showed an enlarged superior pituitary. Hematological and biochemical results were as follows: fasting glucose was 19.7 mmol/L, estradiol was 122.9 pmol/L, follicle-stimulating hormone 10.81 IU/L, luteinizing hormone 10.99 IU/L, insulin-like growth factor 1,513 ng/mL, glutamine aminotransferase 86 U/L, and alkaline phosphatase 362 U/L. Thyroid functions, methemoglobin, fetal protein, carcinoembryonic antigen, and chorionic gonadotropin were normal. The patient had a complete surgical resection of the liver tumor, and the postoperative histopathological diagnosis was HCAs. After the surgery, insulin was injected and the glucose levels were stable. During the 36-month follow-up period, neither tumor recurrence nor significant abnormalities were detected using color Doppler ultrasound of the liver. The child's precocious puberty is currently under control.
CONCLUSIONS
HCAs are particularly rare in children with liver tumors, and risk factors for the development of HCAs in children include sex hormone imbalance, obesity, Fanconi anemia (FA), glycogen storage diseases (GSDs) type I, III, and IV, galactosemia, immunodeficiency, congenital portosystemic shunts (CPSS), cardiac hepatopathy status-post Fontan procedure, Hurler syndrome, familial adenomatous polyposis, germline HNF1A mutations, and maturity-onset diabetes of the young type 3. Most HCAs are detected during a physical examination without clinical symptoms, and some patients may present with symptoms such as abdominal pain, abdominal distension, and abdominal masse. Serum liver function tests can show increased alkaline phosphatase (ALP) and γ- glutamyl transferase (GT), whereas α-Fetoprofein (AFP) levels are normal. The definitive diagnosis relies mainly on histopathological examination. Because HCAs can rupture and bleed and become malignant. Early surgical treatment is recommended after detection.
Topics: Child; Humans; Female; Adenoma, Liver Cell; Alkaline Phosphatase; Neoplasm Recurrence, Local; Liver Neoplasms
PubMed: 37620840
DOI: 10.1186/s12887-023-04209-5 -
Cancer Letters Dec 2023Metastasis is the primary cause of death in colorectal cancer (CRC). Thyroid hormone receptor interacting protein 6 (TRIP6) is an adaptor protein that regulates cell...
Metastasis is the primary cause of death in colorectal cancer (CRC). Thyroid hormone receptor interacting protein 6 (TRIP6) is an adaptor protein that regulates cell motility. Here, we aim to elucidate the role of TRIP6 in driving CRC tumorigenesis and metastasis and evaluate its potential as a therapeutic target. TRIP6 mRNA is up-regulated in CRC compared to adjacent normal tissues in three independent cohorts (all P < 0.0001), especially in liver metastases (P < 0.001). High TRIP6 expression predicts poor prognosis of CRC patients in our cohort (P = 0.01) and TCGA cohort (P = 0.02). Colon-specific TRIP6 overexpression (Trip6Villin-Cre) in mice accelerated azoxymethane (AOM)-induced CRC (P < 0.05) and submucosal invasion (P < 0.0001). In contrast, TRIP6 knockout (Trip6 mice) slowed tumorigenesis (P < 0.05). Consistently, TRIP6 overexpression in CRC cells promoted epithelial-mesenchymal transition (EMT), cell migration/invasion in vitro, and metastases in vivo (all P < 0.05), whereas knockdown of TRIP6 exerted opposite phenotypes. Mechanistically, TRIP6 interacted PDZ domain-containing proteins such as PARD3 to impair tight junctions, evidenced by decreased tight junction markers and gut permeability dysfunction, inhibit PTEN, and activate oncogenic Akt signaling. TRIP6-induced pro-metastatic phenotypes and Akt activation depends on PARD3. Targeting TRIP6 by VNP-encapsulated TRIP6-siRNA synergized with Oxaliplatin and 5-Fluorouracil to suppress CRC liver metastases. In conclusion, TRIP6 promotes CRC metastasis by directly interacting with PARD3 to disrupt tight junctions and activating Akt signaling. Targeting of TRIP6 in combination with chemotherapy is a promising strategy for the treatment of metastatic CRC.
Topics: Animals; Humans; Mice; Carcinogenesis; Cell Line, Tumor; Cell Movement; Cell Transformation, Neoplastic; Colorectal Neoplasms; Drug Resistance; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Liver Neoplasms; Neoplasm Metastasis; Proto-Oncogene Proteins c-akt; Tight Junctions; Transcription Factors
PubMed: 37827326
DOI: 10.1016/j.canlet.2023.216438