To evaluate the effect of preoperative transarterial chemoembolization (TACE) for resectable large hepatocellular carcinoma (HCC).
Resection of HCC is potentially curative, but local recurrence is ...very common. There is currently no effective neoadjuvant or adjuvant therapy.
From July 2001 to December 2003, 108 patients (hepatitis B carrier = 98.1%) with resectable HCC (> or =5 cm) was randomly assigned to preoperative TACE treatment (n = 52) or no preoperative treatment (control group) (n = 56).
Five patients (9.6%) in the preoperative TACE group did not receive surgical therapy because of extrahepatic metastasis or liver failure. The preoperative TACE group had a lower resection rate (n = 47, 90.4% vs. n = 56, 100%; P= 0.017), and longer operative time (mean, 176.5 minutes vs. 149.3 minutes; P= 0.042). No significant difference was found between the 2 groups in operative blood loss, surgical morbidity, and hospital mortality.At a median follow-up of 57 months, 41 (78.8%) of 52 patients in the preoperative TACE group and 51 (91.1%) of 56 patients in the control group had recurrent disease (P= 0.087). The 1-, 3-, and 5-year disease-free survival rates were 48.9%, 25.5%, and 12.8%, respectively, for the preoperative TACE group and 39.2%, 21.4%, and 8.9%, respectively, for the control group (P= 0.372). The 1-, 3-, and 5-year overall survival rates were 73.1%, 40.4%, and 30.7%, respectively, for the preoperative TACE group and 69.6%, 32.1%, and 21.1%, respectively, for the control group (P= 0.679).
Preoperative TACE did not improve surgical outcome. It resulted in drop-out from definitive surgery because of progression of disease and liver failure.
Hepatocyte nuclear factor‐4α (HNF4α) is a dominant transcriptional regulator of hepatocyte differentiation and hepatocellular carcinogenesis. There is striking suppression of hepatocellular carcinoma ...(HCC) by HNF4α, although the mechanisms by which HNF4α reverses HCC malignancy are largely unknown. Herein, we demonstrate that HNF4α administration to HCC cells resulted in elevated levels of 28 mature microRNAs (miRNAs) from the miR‐379‐656 cluster, which is located in the delta‐like 1 homolog (DLK1) ‐iodothyronine deiodinase 3 (DIO3) locus on human chromosome 14q32. Consistent with the reduction of HNF4α, these miRNAs were down‐regulated in human HCC tissue. HNF4α regulated the transcription of the miR‐379‐656 cluster by directly binding to its response element in the DLK1‐DIO3 region. Interestingly, several miRNAs in this cluster inhibited proliferation and metastasis of HCC cells in vitro. As a representative miRNA in this cluster, miR‐134 exerted a dramatically suppressive effect on HCC malignancy by down‐regulating the oncoprotein, KRAS. Moreover, miR‐134 markedly diminished HCC tumorigenicity and displayed a significant antitumor effect in vivo. In addition, inhibition of endogenous miR‐134 partially reversed the suppressive effects of HNF4α on KRAS expression and HCC malignancy. Furthermore, a positive correlation between HNF4α and miR‐134 levels was observed during hepatocarcinogenesis in rats, and decreases in miR‐134 levels were significantly associated with the aggressive behavior of human HCCs. Conclusion: Our data highlight the importance of the miR‐379‐656 cluster in the inhibitory effect of HNF4α on HCC, and suggest that regulation of the HNF4α‐miRNA cascade may have beneficial effects in the treatment of HCC. (Hepatology 2013; 58:1964–1976)
Dysregulation of the neddylation pathway is related to various cancers. However, the specific role of the neddylation pathway in human hepatocellular carcinoma (HCC) remains largely unclear. In this ...study, the neddylation pathway in HCC and adjacent noncancerous liver (ANL) tissues was evaluated by immunohistochemistry (IHC), Western blotting, and qRT‐PCR (quantitative real‐time polymerase chain reaction). The results showed that the entire neddylation pathway, including NEDD8 (the IHC staining of NEDD8 represents the global‐protein neddylation), E1 NEDD8‐activating enzymes (NAE1 and UBA3), E2 NEDD8‐conjugating enzymes (UBE2F and UBE2M), E3 NEDD8‐ligases (MDM2, RBX1 and RNF7), and deneddylation enzymes (COPS5, UCHL1 and USP21), was overactivated in HCC. Furthermore, the upregulation of NEDD8 in HCC was correlated with aggressive characteristics and was an independent risk factor for overall survival (OS) and recurrence‐free survival (RFS) in patients with HCC after hepatectomy. The upregulation of NAE1, UBE2M, and UCHL1 in HCC was associated with aggressive characteristics and poor OS and RFS in patients with HCC after hepatectomy. In conclusion, our research reveals that the entire neddylation pathway is overactivated in HCC and associated with clinical characteristics and prognosis of patients with HCC.
The entire neddylation pathway is overactivated in human HCC tissues. The overactivation of neddylation pathway is associated with poor prognosis and aggressive characteristics.
Background
To develop and validate nomograms that can be used to predict outcomes in individuals suffering alpha‐fetoprotein (AFP) negative hepatocellular carcinoma (HCC) after radical resection.
...Methods
A total of 509 AFP‐negative HCC patients who received hepatectomy between January 2009 and March 2013 in our center were randomized into training and validation cohorts. Nomograms for both overall and recurrence‐free survival (OS and RFS, respectively) were established based on the predictors in the training cohort. Nomograms performance and discriminative power were assessed with concordance index (C‐index) values and decision curve analyses (DCA). The results were validated in the validation cohort.
Results
Alkaline phosphatase, liver cirrhosis, tumor size, satellite lesions, microvascular invasion, and Edmondson‐Steiner grade were significantly linked to OS and RFS. Sex and tumor number were additional predictors for RFS. The OS nomogram had a C‐index value of 0.742, which was better than that for the AJCC eighth edition (0.632), BCLC system (0.553), and JIS score (0.557) (all P < .001). The RFS nomogram C‐index was 0.669, which was also superior to that of the AJCC eighth (0.608), BCLC stage (0.554), JIS score (0.551), and model of Gan et al (0.636) (P < .05 for all). Calibration curves indicated a good agreement between observed actual outcomes and predicted values. Kaplan‐Meier curves and DCA indicated that nomograms were powerful in discrimination and clinical usefulness. These results were supported by the validation cohort.
Conclusions
These nomograms presented more accurate prognostic prediction in patients with AFP‐negative HCC after hepatectomy.
About 30% of HCC patients showed negative serum AFP and had special clinicopathologic characteristics and prognosis. We developed and validated nomograms for predicting prognosis of patients with AFP‐negative HCC after radical resection. Our novel nomograms presented superior performance and discrimination ability than conventional staging systems based on the C‐indexes, calibration curves, decision curve analysis and Kaplan‐Meier curves, which were proposed for clinical decision.
Background
The aim of this study was to compare the results of surgical resection with three-dimensional conformal radiotherapy (3D-CRT) in the treatment of resectable hepatocellular carcinoma (HCC) ...with portal vein tumor thrombus (PVTT). Transarterial chemoembolization (TACE) was given to both groups of patients when possible.
Methods
A retrospective study of 371 patients with resectable HCC with PVTT was conducted in two tertiary referral centers. The treatment of choice for these patients in one center was surgical resection. In the other center it was 3D-CRT. In the radiotherapy group (RG,
n
= 185), patients received 3D-CRT to the tumor and PVTT for a total radiation dose of 30–52 Gy (median 40 Gy). In the surgical group (SG,
n
= 186), patients underwent surgical resection. TACE was applied after surgery or 3D-CRT and then was repeated every 4–6 weeks if the patient tolerated the treatment.
Results
The median survival was 12.3 months for RG and 10.0 months for SG. The 1-, 2-, and 3-year overall survivals were 51.6, 28.4, and 19.9 %, respectively, for RG and 40.1, 17.0, and 13.6 %, respectively, for SG (
p
= 0.029). Stepwise multivariate analysis showed that the extent of PVTT and mode of treatment were independent risk factors of overall survival. The most common cause of death after treatment was liver failure as a consequence of progressive intrahepatic disease.
Conclusions
3D-CRT gave better survival than surgical resection for HCC with PVTT.
One-dimensional (1-D) metal (Ag, Au, and Pt) nanowires and their corresponding arrays have been synthesized using an ambient, surfactantless synthesis technique. The potential applicability of such ...crystalline, highly purified 1-D samples for practical uses was specifically demonstrated in their manifestation as electrocatalysts for an oxygen reduction reaction (ORR). Specifically, Pt 1-D nanostructures possessed a higher ORR activity as compared with that of Pt nanoparticles alone. Ag and Au nanowires also evinced reasonable ORR activity in alkaline solution.
MicroRNAs (miRNAs) serve an important regulatory role in carcinogenesis and cancer progression. Aberrant expression of miR-197-3p has been reported in various human malignancies. However, the role of ...miR-197-3p in the progression and prognosis of hepatocellular carcinoma (HCC) remains unknown. The present study demonstrated that miR-197-3p was downregulated in HCC tissues and that the low level of miR-197-3p expression in HCC tumours correlated with aggressive clinicopathological characteristics; thus, miR-197-3p may serve as a predictor for poor prognosis in patients with HCC. Additionally, miR-197-3p markedly inhibited the metastasis of HCC cells
and
. Bioinformatics analysis further identified zinc finger protein interacted with K protein 1 (ZIK1) as a novel target of miR-197-3p in HCC cells. These findings suggest that miR-197-3p may regulate the survival of HCC cells, partially through the downregulation of ZIK1. Therefore, the miR-197-3p/ZIK1 axis may serve as a novel therapeutic target in patients with HCC.
MicroRNA 370 (miR‐370) is located within the DLK1/DIO3 imprinting region on human chromosome 14, which has been identified as a cancer‐associated genomic region. However, the role of miR‐370 in ...malignances remains controversial. Here, we report that miR‐370 was repressed in human hepatocellular carcinoma (HCC) tissues and hepatoma cell lines. Using gain‐of‐function and loss‐of‐function experiments, we demonstrated that miR‐370 inhibited the malignant phenotype of HCC cells in vitro. Overexpression of miR‐370 inhibited growth and metastasis of HCC cells in vivo. Moreover, the RNA‐binding protein, LIN28A, was identified as a direct functional target of miR‐370, which, in turn, blocked the biogenesis of miR‐370 by binding to its precursor. LIN28A also mediated the suppressive effects of miR‐370 on migration and invasion of HCC cells by post‐transcriptionally regulating RelA/p65, which is an important effector of the canonical nuclear factor kappa B (NF‐κB) pathway. Interleukin‐6 (IL‐6), a well‐known NF‐κB downstream inflammatory molecule, reduced miR‐370 but increased LIN28A levels in HCC. Furthermore, miR‐370 levels were inversely correlated with LIN28A and IL‐6 messenger RNA (mRNA) levels, whereas LIN28A mRNA expression was positively correlated with IL‐6 expression in human HCC samples. Interestingly, reduction of miR‐370 expression was associated with the development of HCC in rats, as well as with aggressive tumor behavior and short survival in HCC patients. Conclusions: These data demonstrate the involvement of a novel regulatory circuit consisting of miR‐370, LIN28A, RelA/p65 and IL‐6 in HCC progression. Manipulating this feedback loop may have beneficial effect in HCC treatment. (Hepatology 2013; 58:1977–1991)
We previously demonstrated that interleukin‐17A (IL‐17A) is associated with the progression of hepatocellular carcinoma (HCC). However, its role in the invasion–metastasis cascade of HCC and the ...efficacy of IL‐17A‐targeting therapeutics in HCC remain largely unknown. In this study, we found that IL‐17A promoted intrahepatic and pulmonary metastasesis of HCC cells in an orthotopic implant model. Moreover, our results showed that IL‐17A induced epithelial–mesenchymal transition (EMT) and promoted HCC cell colonization in vitro and in vivo, and the role of IL‐17A in invasion–metastasis was dependent on activation of the AKT pathway. Remarkably, combined therapy using both secukinumab and sorafenib has better inhibition on tumour growth and metastasis compared to sorafenib monotherapy. Additionally, the combination of intratumoral IL‐17A+ cells and E‐cadherin predicted the outcome of patients with HCC at an early stage after hepatectomy based on tissue microarray and immunohistochemistry. In conclusion, our studies reveal that IL‐17A induces early EMT and promotes late colonization of HCC metastasis by activating AKT signalling. Secukinumab is a promising candidate for clinical development in combination with sorafenib for the management of HCC.
The role of interleukin (IL)‐17A in the invasion–metastasis cascade of hepatocellular carcinoma (HCC) and efficacy of IL‐17A targeting therapeutics in HCC remains largely unknown. Here, we reveal that IL‐17A induces early EMT and promotes late colonization of HCC metastasis by activating AKT signalling. Moreover, combined therapy using both secukinumab and sorafenib has better inhibition on tumour growth and metastasis when compared to sorafenib monotherapy.
Reports on Lenvatinib-based therapies show promising treatment outcomes for patients with unresectable hepatocellular carcinoma (uHCC). However, the effect and safety of Lenvatinib-based therapies ...still need to be further studies.
This was a retrospective, single-center study on the safety and treatment efficacy of Lenvatinib-based combination therapies for uHCC Patients. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were progressive disease (PD), stable disease (SD), partial response (PR), and complete response (CR).
Of 91 patients, there were 16 females and 75 males with uHCC who received systemic therapies based on Lenvatinib in our center. Forty-six patients (50.5%) received Lenvatinib combined with PD-1 antibody treatment. All these patients also received local therapy with the exception of 2 patients. The remaining 36 patinets received Lenvatinib combined with transcatheter arterial chemoembolization (TACE), 1 patient treated Lenvatinib combined with radiotherapy, 8 patients received Lenvatinib alone. At a median treatment time of 8 months, the objective response rate (ORR) of the entire cohort was 58.2% (53 patients), including 7 patients with CR and 46 patients with PR. 21 patients (23.1%) had SD. The disease control rate (DCR) of all patients was 81.3% (74 patients). However, 17 patients (18.7%) developed PD. The 1- and 2-year cumulative OS rates for the entire cohort were 66.8% and 39.3%, while the corresponding PFS rates were 38.0% and 17.1%, respectively. Univariate and multivariate Cox regression analysis revealed multiple tumor sites to be an independent OS risk factor for uHCC patients (HR=2.204, 95% CI=1.104-4.399,
=0.025). The most frequently reported adverse events in all patients were AST elevation (51.6%), followed by hypertension (33.0%), ALT elevation (26.4%), and decreased appetite (25.3%). After a combination treatment of Lenvatinib-based therapies, 15 patients met the criteria for salvage liver resection and underwent down-staging hepatectomy with a curative intent. The combination of PD-1 treatment was not very effective in improving the prognosis of uHCC patients treated with Lenvatinib combined with TACE.
Our study demonstrated that a proportive of patients benefited from Lenvatinib-based combination therapies with manageable safety profiles, allowing these patients to undergo downstaging surgery with curative intent.
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