The substantial heterogeneity and hierarchical organization in liver cancer support the theory of liver cancer stem cells (LCSCs). However, the relationship between chronic hepatic inflammation and ...LCSC generation remains obscure. Here, we observed a close correlation between aggravated inflammation and liver progenitor cell (LPC) propagation in the cirrhotic liver of rats exposed to diethylnitrosamine. LPCs isolated from the rat cirrhotic liver initiated subcutaneous liver cancers in nonobese diabetic/severe combined immunodeficient mice, suggesting the malignant transformation of LPCs toward LCSCs. Interestingly, depletion of Kupffer cells in vivo attenuated the LCSC properties of transformed LPCs and suppressed cytokeratin 19/Oval cell 6–positive tumor occurrence. Conversely, LPCs cocultured with macrophages exhibited enhanced LCSC properties. We further demonstrated that macrophage‐secreted tumor necrosis factor‐α triggered chromosomal instability in LPCs through the deregulation of ubiquitin D and checkpoint kinase 2 and enhanced the self‐renewal of LPCs through the tumor necrosis factor receptor 1/Src/signal transducer and activator of transcription 3 pathway, which synergistically contributed to the conversion of LPCs to LCSCs. Clinical investigation revealed that cytokeratin 19/Oval cell 6–positive liver cancer patients displayed a worse prognosis and exhibited superior response to sorafenib treatment. Conclusion: Our results not only clarify the cellular and molecular mechanisms underlying the inflammation‐mediated LCSC generation but also provide a molecular classification for the individualized treatment of liver cancer. (Hepatology 2017;66:1934–1951)
Background
The role of carbohydrate antigen 19‐9 (CA 19‐9) in response assessment among patients with intrahepatic cholangiocarcinoma (iCCA) remains unknown. The authors studied the association of ...the CA 19‐9 response (defined as a reduction >50% from baseline) with the radiologic response and the outcome in patients with unresectable iCCA.
Methods
A prospective cohort of 422 patients who were initially diagnosed with unresectable iCCA, had baseline CA 19‐9 levels ≥100 U/mL, and received treatment with systemic therapies at the authors' institution between January 2017 and December 2021 were enrolled in this study. The radiologic response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. A landmark assessment of the CA 19‐9 response and the radiologic response was performed. The associations between CA 19‐9 response and imaging response, progression‐free survival (PFS), and overall survival (OS) were analyzed.
Results
Two hundred sixty‐seven patients (63.3%) had a CA 19‐9 response. A CA 19‐9 response was observed in 123 of 132 (93.2%) radiologic responders and in 144 of 290 (49.7%) radiologic nonresponders (p < .001). CA 19‐9 responders outperformed nonresponders in median PFS (10.6 vs. 3.6 months; hazard ratio HR, 4.8 months; 95% confidence interval CI, 3.8–6.0 months; p < .001) and OS (21.4 vs. 6.3 months; HR, 5.3 months; 95% CI, 4.2–6.7 months; p < .001). The common independent predictors of both OS and PFS included metastasis, CA 19‐9 nonresponder status, and radiologic nonresponder status in multivariable analysis.
Conclusions
CA 19‐9 response is a valuable addition to assess tumor response and is associated with improved outcomes in patients with iCCA. Achieving a CA 19‐9 response should be one of the therapeutic objectives of patients with iCCA after systemic therapies.
Plain language summary
A decline in carbohydrate antigen 19‐9 levels from elevated baseline levels should be one of the therapeutic aims of patients with intrahepatic cholangiocarcinoma who are managed with systemic therapies.
Biomarkers for predicting treatment outcomes are an unmet need for patients with intrahepatic cholangiocarcinoma (iCCA) treated with systemic therapies. This article shows that the carbohydrate antigen 19‐9 response correlates with the radiologic response and outcome of patients with iCCA after treatment.
Background Recurrent hepatocellular carcinoma (RHCC) after curative resection is a major challenge for hepatic surgeons. A better understanding of the clonal origin of RHCC will help clinicians ...design personalized therapy and assess postoperative outcomes. The current study was performed to determine the clonal origin of RHCC and its clinical significance. Study Design Fifteen high-frequency of loss of heterozygosity of DNA microsatellites were determined on 100 tumor nodules in 60 matched pairs of RHCC from 40 patients who underwent liver re-resections. The relationships among the origin of clonal patterns of RHCC and the surgicopathologic features and clinical outcomes were analyzed. Results Of 60 pairs of RHCC, there were 2 clonal patterns with 6 subclonal types. Pattern I was multicentric occurrence (MO type) in 14 pairs (23.3%) and pattern II was intrahepatic metastasis (IM type) in 46 pairs (76.7%). The clinicopathologic features, including recurrence time, tumor size, vascular invasion, histological grading, and associated chronic liver diseases in patients with the MO type of RHCC were significantly different from those with the IM type of RHCC (p < 0.05 to 0.001). Compared with patients in the IM group, patients in the MO group had significantly better overall survival (130.8 ± 8.5 months vs 80.8 ± 8.5 months; p < 0.05) and recurrence-free survival (33.8 ± 4.5 months vs 14.2 ± 2.5 months; p < 0.001). Conclusions The MO-type RHCC was closely associated with better postoperative outcomes when compared with the IM-type RHCC. Generally, we recommend liver re-resection for MO-type RHCC, and interventional therapy for IM-type RHCC. Microdissection-based microsatellite loss of heterozygosity protocol has advantages in assessing the clonal origin, modes of personalized treatment, and clinical outcomes of RHCC.
Abstract
Background
Mindfulness-based cognitive therapy (MBCT) is a promising alternative treatment for generalized anxiety disorder (GAD). The objective of this study was to examine whether the ...efficacy of group MBCT adapted for treating GAD (MBCT-A) was noninferior to group cognitive behavioural therapy (CBT) designed to treat GAD (CBT-A), which was considered one of first-line treatments for GAD patients. We also explored the efficacy of MBCT-A in symptomatic GAD patients compared with CBT-A for a variety of outcomes of anxiety symptoms, as well as depressive symptoms, overall illness severity, quality of life and mindfulness.
Methods
This was a randomized, controlled, noninferiority trial with two arms involving symptomatic GAD patients. Adult patients with GAD (
n
= 138) were randomized to MBCT-A or CBT-A in addition to treatment as usual (TAU). The primary outcome was the anxiety response rate assessed at 8 weeks after treatment as measured using the Hamilton Anxiety Scale (HAMA). Secondary outcomes included anxiety remission rates, scores on the HAMA, the state-trait anxiety inventory (STAI), the Hamilton Depression Scale (HAMD), the Severity Subscale of the Clinical Global Impression Scale (CGI-S), and the 12-item Short-Form Health Survey (SF-12), as well as mindfulness, which was measured by the Five Facet Mindfulness Questionnaire (FFMQ). Assessments were performed at baseline, 8 weeks after treatment, and 3 months after treatment. Both intention-to-treat (ITT) and per-protocol (PP) analyses were performed for primary analyses. The χ2 test and separate two-way mixed ANOVAs were used for the secondary analyses.
Results
ITT and PP analyses showed noninferiority of MBCT-A compared with CBT-A for response rate ITT rate difference = 7.25% (95% CI: -8.16, 22.65); PP rate difference = 5.85% (95% CI: − 7.83, 19.53). The anxiety remission rate, overall illness severity and mindfulness were significantly different between the two groups at 8 weeks. There were no significant differences between the two groups at the 3-month follow-up. No severe adverse events were identified.
Conclusions
Our data indicate that MBCT-A was noninferior to CBT-A in reducing anxiety symptoms in GAD patients. Both interventions appeared to be effective for long-term benefits.
Trial registration
Registered at chictr.org.cn (registration number:
ChiCTR1800019150
, registration date: 27/10/2018).
: The existence of primary and acquired drug resistance is the main obstacle for the effect of multi-kinase inhibitor sorafenib and regorafenib in advanced hepatocellular carcinoma (HCC). However, ...plenty of patients did not significantly benefit from sorafenib treatment and little is known about the mechanism of drug resistance.
: Laser capture microdissection was used to acquire matched normal liver and tumor tissues on formalin-fixed paraffin-embedded specimens collected before sorafenib therapy from the first surgery of 119 HCC patients. Ultra-deep sequencing (~1000×) targeting whole exons of 440 genes in microdissected specimens and siRNA screen in 7 cell lines were performed to find mutations associated with differential responses to sorafenib. Patient-derived xenograft models were employed to determine the role of
in response to sorafenib. Lentiviruses harboring wild-type and c.G52C-mutant
were applied to explore the function of
in resistance to sorafenib. ChIP-PCR assay for analysis of OCT4 transcriptional activity was performed to explore the affinity with the
promoter. Statistical analyses were used to associate levels of p53 and OCT4 with tumor features and patient outcomes.
: Total 1,050 somatic mutations and 26 significant driver genes were identified. SiRNA screening in 7 HCC cell lines was further performed to identify mutations associated with differential responses to sorafenib. A recurrent nonsynonymous mutation c.G52C in
(
) was strongly associated with good response to sorafenib, whereas the stop-gain mutation in
showed the opposite outcome both in vitro and in vivo.
-induced stem cell factor (encoded by
gene, SCF) expression and cross-activation of c-KIT/FLT3-BRAF signals were identified indispensably for sorafenib resistance, which could be reversed by the combination of c-KIT tyrosine kinase inhibitors or neutralizing antibody against SCF. Mechanistically, an OCT4 binding site in upstream of
promoter was identified with a higher affinity to wildtype of OCT4 rather than G52C-mutant form, which is indispensable for OCT4-induced expression of
and sorafenib resistance.
: Our study reported a novel somatic mutation in
(c.G52C) responsible for the sorafenib effect, and also shed new light on the treatment of HCC through the combination of specific tyrosine kinase inhibitors according to individual genetic patterns.
Background:Combined hepatocellular and cholangiocarcinoma(CHC) is a unique subtype of liver cancer comprising both hepatocellular carcinoma(HCC) and intrahepatic cholangiocarcinoma(ICC);however,its ...cellular origin remains unclear.The purpose of this study was to investigate the clinicopathologic features and the clonal relationship between HCC and ICC in 34 patients with CHC.Methods:The clinicopathologic features and prognosis of the 34 CHC patients were compared with those of 29 patients with separated HCC and ICC(5HC).Loss of heterozygosity(LOH) at 10 highly polymorphic microsatellite markers was detected in 16 CHC and 10 SHC tissues for determination of the clonal origin of CHC.Expression of hepatocyte markershepatocyte paraffin 1(Hep Par 1) and glypican 3(GPC3)and cholangiocyte markerscytokeratin(CK)7 and 19in tumor tissues was examined by immuno histochemical analysis.Results:In the 16 CHC specimens,the difference in LOH patterns between HCC and ICC was less than 30%,suggesting the same clonal origin of HCC and ICC.Consistent with this finding,immunohistochemical analysis revealed that hepatocyte markers(Hep Par 1 and GPC3) and cholangiocyte markers(CK7 and CK19) were simultaneously expressed in both the HCC and ICC components in 52.9%of CHC specimens,suggesting that the two components shared a similar phenotype with hepatic progenitor cells(HPCs).On the contrary,in all 10 SHC cases,the difference in LOH patterns between the HCC and ICC components was greater than 30%,suggesting different clonal origins of HCC and ICC.Overall survival and disease-free survival were shorter for patients with CHC than for patients with SHC(P < 0.05).Conclusions:Our results suggest that the HCC and ICC components of CHC may originate from the same clone,having the potential for dual-directional differentiation similar to HPCs.CHC tended to exhibit the biological behaviors of both HCC and ICC,which may enhance the infiltrative capacity of tumor cells,leading to poor clinical outcomes for patients with CHC.
The long-term survival rate of hepatocellular carcinoma (HCC) is poor. One of the reasons for the poor rate of survival is the high rate of recurrence caused by intrahepatic metastas is that ...adversely affects long-term outcome. Many studies have indicated that microRNAs play an important role in HCC, but there has been no research of clonal origins on recurrent HCC (RHCC) by analzing microRNAs. In the present study, we found that miR-483-5p was significantly upregulated in RHCC tissues of short-term recurrence (≤ 2 years) by miRNA microarray screening, and can significantly promote migration and invasion of HCC cells
and increase intrahepatic metastasis in nude mice
. Furthermore, we demonstrated that activated leukocyte cell adhesion molecule (ALCAM), which significantly suppressed migration and invasion of HCC cells, was a direct target of miR-483-5p, and the re-introduction of ALCAM expression could antagonize the promoting effects of miR-483-5p on the capacity of HCC cells for migration and invasion. In addition, expression level of ALCAM was negatively correlated with microvascular invasion and tumor size recognized as prognostic factors. The cases which were negative for ALCAM expression had shorter time to recurrence than positive cases, and univariate and multivariate survival analyses showed that ALCAM was an independent risk factor of HCC recurrence. qRT-PCR and Western blotting showed that the expression of EMT related genes (MMP-2, MMP-9, E-caherin and vimentin) significantly changed as a result of interfering or overexpression of ALCAM, and ALCAM was significantly associated with EMT in HCC. These results suggest that the miR-483-5p/ALCAM axis is an important regulator in invasion and metastasis and biomarker for recurrence risk assessment of HCC.
Salsalate plays beneficial roles for ameliorating hyperglycemia and dyslipidemia in type 2 diabetes patients, but the underlying mechanisms are still poorly understood. In this study, by ...administering salsalate to mice fed with high fat diet and examining how salsalate rectifies metabolic dysfunction in these obese mice, we found that salsalate stimulated body temperature and attenuated body weight gain without affecting food intake. Our results showed that salsalate application decreased lipid accumulation in liver and epididymal white adipose tissue (eWAT), inhibited hepatic gluconeogenesis and improved insulin signaling transduction in eWAT. In addition, salsalate increased the expression of genes related to glucose and fatty acid transport and oxidation in skeletal muscle. Our results also showed that expression of genes in mitochondrial uncoupling and mitochondrial electron transport are strengthened by salsalate. Moreover, sarcolipin (Sln) and sarcoplasmic reticulum Ca2+ ATPase 2 (Serca2) in skeletal muscle were enhanced in salsalate-treated mice. Together, our data suggest that the beneficial metabolic effects of salsalate may depend, at least in part, on skeletal muscle thermogenesis via activation of mitochondrial uncoupling and the axis of Sln/Serca2a.
•Salsalate improves metabolic dysfunction in high-fat diet induced obese mice.•Salsalate stimulates energy expenditure by activating skeletal muscle thermogenesis.
It has been well documented that salicylate-based compounds play beneficial roles for treating obesity-related metabolic syndromes and enhanced energy expenditure was thought to be one of the underlying mechanisms. However, the tissues targeted by salicylate for energy expenditure and the involved mechanisms are still not clear. Our data show that, by activating mitochondrial uncoupling and the axis of Sln/Serca2, salsalate stimulates skeletal muscle thermogenesis in high-fat diet induced obese mice. Therefore, we suggest skeletal muscle thermogenesis may account for salsalate-induced energy expenditure and its beneficial metabolic effects in type 2 diabetes patients.
A 61‐year‐old Chinese male was found to have a lesion in the left liver during a routine body check‐up. Laboratory tests revealed no abnormalities except for a rise in C‐reactive protein. Computed ...tomography showed features suggestive of hepatocellular carcinoma. The patient underwent liver IVb segmentectomy and cholecystectomy. Histopathology showed features of hepatic inflammatory pseudotumor. The C‐reactive protein decreased to close to normal on postoperative day 9. A patient with hepatic inflammatory pseudotumor who presented with features mimicking hepatocellular carcinoma was reported. A preoperatively raised C‐reactive protein was the only hint which suggested that our patient might have had hepatic inflammatory pseudotumor instead of hepatocellular carcinoma.
A 61‐year‐old Chinese male with HIPT who presented with features mimicking HCC was reported. A preoperatively raised CRP was the only hint which suggested that our patient might have had HIPT instead of HCC.
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