Non-transplant therapies for patients with hepatocellular carcinoma and Child-Pugh-Turcotte class B cirrhosis

Granito, Alessandro; Bolondi, Luigi

doi:10.1016/s1470-2045(16)30569-1

Cited by 132 publications

(114 citation statements)

References 68 publications

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“…The mechanistic insights for how DAPK1 is regulated by b-catenin in liver cancer may result in novel therapeutic approach in treatment of liver cancer. Liver cirrhosis is commonly present in most patients with hepatocellular carcinoma with limited effective treatments, of which liver transplantation is one strategy to cure both diseases (Granito & Bolondi, 2017). As demonstrated in our China patient cohort, we found that the association between DAPK1 expression and survival was significant in liver cancer patients who had also cirrhosis implies that DAPK1 may be a potential therapeutic target for this particular group of patients.…”

Section: Discussionmentioning

confidence: 99%

DAPK1 as an independent prognostic marker in liver cancer

Guo

Wang

et al. 2017

PeerJ

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The death-associated protein kinase 1 (DAPK1) can act as an oncogene or a tumor suppressor gene depending on the cellular context as well as external stimuli. Our study aims to investigate the prognostic significance of DAPK1 in liver cancer in both mRNA and protein levels. The mRNA expression of DAPK1 was extracted from the Gene Expression Omnibus database in three independent liver cancer datasets while protein expression of DAPK1 was detected by immunohistochemistry in our Chinese liver cancer patient cohort. The associations between DAPK1 expression and clinical characteristics were tested. DAPK1 mRNA expression was down-regulated in liver cancer. Low levels of DAPK1 mRNA were associated with shorter survival in a liver cancer patient cohort (n = 115; p = 0.041), while negative staining of DAPK1 protein was significantly correlated with shorter time to progression (p = 0.002) and overall survival (p = 0.02). DAPK1 was an independent prognostic marker for both time to progression and overall survival by multivariate analysis. Liver cancer with the b-catenin mutation has a lower DAPK1 expression, suggesting that DAPK1 may be regulated under the b-catenin pathway. In addition, we also identified genes that are co-regulated with DAPK1. DAPK1 expression was positively correlated with IRF2, IL7R, PCOLCE and ZBTB16, and negatively correlated with SLC16A3 in both liver cancer datasets. Among these genes, PCOLCE and ZBTB16 were significantly down-regulated, while SLC16A3 was significantly upregulated in liver cancer. By using connectivity mapping of these co-regulated genes, we have identified amcinonide and sulpiride as potential small molecules that could potentially reverse DAPK1/PCOLCE/ZBTB16/SLC16A3 expression. Our study demonstrated for the first time that both DAPK1 mRNA and protein expression levels are important prognostic markers in liver cancer, and have identified genes that may contribute to DAPK1-mediated liver carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

DAPK1 as an independent prognostic marker in liver cancer

Guo

Wang

et al. 2017

PeerJ

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“…These patients have a grim prognosis and, at the same time, are not usually accepted in second-line trials to minimize the risk of noncancer-related death due to progressive hepatic failure [52]. In general, the opportunity of systemic treatments (including sorafenib) in Child-Pugh B patients is still a controversial issue [17,18,53]. These aspects leave Child-Pugh B patients as an orphan category (at the present time only a dedicated cohort of the nivolumab trial is enrolling these patients in a frontline and second-line setting [33]).…”

Section: Stratification Of the Patients Determinants Of Postsorafenibmentioning

confidence: 99%

“…Additionally, a number of studies suggested that a carefully selected subset of the Child-Pugh B population may benefit from sorafenib (i.e., Child-Pugh B7) [17,18]. Consequently, the search for second-line systemic treatments able to prolong life expectancy of Child-Pugh B7 patients has a scientific rationale and represents an open problem.…”

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confidence: 99%

Postsorafenib systemic treatments for hepatocellular carcinoma: questions and opportunities after the regorafenib trial

et al. 2017

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The search for systemic therapies for hepatocellular carcinoma has been characterized by difficulties and failures. Despite recent progresses, many issues are still to be settled. In particular, the development of drugs inhibiting different neoplastic pathways remains a priority for patients intolerant or resistant to antiangiogenic drugs. This task may be daunting, as previous failures extensively demonstrated. We aimed to identify the future perspective of postsorafenib trials analyzing the strengths and the critical points of past and currently undergoing studies, in the light of the most recent evidences in the field. We identified various points (including stratification, biomarkers, end points, radiologic criteria of response, treatment beyond radiologic progression) that should be considered by future trials to reduce the risks of failure.P P P P P P P P P P T cell PD-1

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“…HCC usually develops in conditions of chronic liver disease (CLD), mostly on the background of a cirrhotic liver, with liver transplantation at present being the only treatment strategy to cure both HCC and the specific CLD. All the other therapeutic strategies, because of the underlying liver cirrhosis, have to take into account, and may be limited in their feasibility, by the residual liver function of the individual patient, a critical parameter affecting the patient's prognosis 2. Indeed, even when the surgical intervention is feasible, according to current guidelines, efficient removal of the primary lesions is not often conclusive since intrahepatic recurrence, as well as extrahepatic metastasis, are very frequent and associated with poor prognosis for patients 3.…”

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confidence: 99%

“…This opens a new avenue of therapeutic intervention since the development of efficient and selective inhibitors specifically targeting SENP1, and then HIF-1α-related transcriptional activity, may result in a significant interference with HCC growth as well as intrahepatic recurrence and extrahepatic metastasis. This is an urgent need for HCC, a very aggressive tumour with associated high mortality, for which the only validated therapeutic approach relies in the administration of sorafenib, currently recommended as standard treatment for patients with advanced-stage HCC 2 12. Moreover, although effective in prolonging the survival of patients with advanced HCC, sorafenib unfortunately induces heavy side effects and multiorgan toxicity, often leading to interruption of treatment in these patients.…”

mentioning

confidence: 99%