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Prognosis of patients with ascites after PleurX insertion: an observational study.
Riedel, AN, Kimer, N, Hobolth, L, Gluud, LL
Scandinavian journal of gastroenterology. 2018;(3):340-344
Abstract
OBJECTIVE To evaluate the safety of PleurX in cirrhotic patients with refractory ascites. METHODS We prospectively registered patients who received a PleurX catheter cirrhosis-associated refractory ascites at our department from July 2015 to November 2016. Our control group consisted of matched cirrhotic patients with refractory ascites treated with large volume paracentesis (LVP) and patients with malignant ascites treated with PleurX during the same period. RESULTS We included 25 patients with cirrhosis-related ascites (7 in PleurX group) and 17 with malignant ascites (14 in PleurX group). Of these, six patients had hepatocellular carcinoma and cirrhosis (5 in PleurX group). None were eligible for insertion of a TIPS or liver transplantation. The maximum duration of follow-up was (480 days) in the PleurX group and 366 days in the LVP group (median 84 and 173 days, respectively). There was no difference in mortality when comparing PleurX with LVP treatment (hazard ratios: 3.0 and 1.0, p = .23 and .96, respectively). Mortality was higher in patients with malignant ascites (p= .01). We found no significant differences in adverse events (incl. spontaneous bacterial peritonitis) or in P-albumin, P-creatinine and P-sodium between the groups. CONCLUSION PleurX insertion for the treatment of refractory ascites in cirrhotic patients appears to be safe. Prospective randomized trials are necessary in order to confirm these findings.
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Screening and clinical evaluation of dominant peptides of centromere protein F antigen for early diagnosis of hepatocellular carcinoma.
Li, S, Li, X, Xu, A, Zhang, B, He, X, Chen, H, Huang, J
Molecular medicine reports. 2018;(3):4720-4728
Abstract
Tumor-associated antigens, such as centromere protein F (CENP‑F), have been recognized as potential serological biomarkers for early diagnosis of hepatocellular carcinoma (HCC); however, the exact regions corresponding to the dominant peptides of CENP‑F antigen remain to be explored. We aimed to screen and evaluate potential dominant peptides of CENP‑F for early diagnosis of HCC. Dominant peptides of CENP‑F were predicted by BioSun version 3.0, and the corresponding recombinant proteins were prepared. Enzyme‑linked immunosorbent assays were conducted for initial screening of dominant peptides, and selected dominant peptides were subjected to further clinical evaluation. Eight dominant peptides of CENP‑F antigens were predicted at amino acids (a.a) 121‑220, 335‑416, 1100‑1265, 1670‑1791, 1759‑2093, 2075‑2210, 2485‑2592, and 2808‑2960. Initial screening of the predicted peptides in samples of 47 HCC cases showed the highest diagnostic value for 121‑220 a.a and 1670‑1791 a.a peptides with area under the curve (AUC) values of 0.795 [95% confidence interval (CI), 0.706‑0.884] and 0.809 (95% CI, 0.721‑0.896), sensitivity of 58.3 and 85.4%, and specificity of 93.9 and 65.3%, respectively. Further evaluation of the two peptides in 405 samples comprised of 153 HCC, 126 liver cirrhosis and 126 healthy controls, presenting an AUC of 0.743 (95% CI, 0.674‑0.812) for 121‑220 a.a peptide in detecting early‑stage HCCs. Specifically, the 121‑220 a.a peptide showed a complementary effect in combination with α‑fetoprotein (AFP) for the detection of early‑stage HCC with increased AUC value of 0.840 (95% CI, 0.781‑0.899), and sensitivity of 81.4% and specificity of 72.2%. In conclusion, our study identified the 121‑220 a.a dominant peptide as the region of CENP‑F antigen with the highest immunogenicity and demonstrated its value in combination with AFP for diagnosis of early-stage HCC.
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Which is the best combination of TACE and Sorafenib for advanced hepatocellular carcinoma treatment? A systematic review and network meta-analysis.
Feng, F, Jiang, Q, Jia, H, Sun, H, Chai, Y, Li, X, Rong, G, Zhang, Y, Li, Z
Pharmacological research. 2018;:89-101
Abstract
The aim of this study was to assess the comparative efficacy and safety of combination therapy with transarterial chemoembolization (TACE) and Sorafenib for patients with advanced hepatocellular carcinoma (HCC) through a systematic review and network meta-analysis and identify the best combination of TACE and Sorafenib. We searched databases for publications prior to May 2018. The prespecified efficacy outcomes were the objective response rate, overall survival rate, and time to progression. adverse effects included dermatologic, gastrointestinal, and general disorders. Subgroup analyses, meta-regression, and a network meta-analysis regarding two types of outcomes by different chemotherapy agents in TACE (5-fluorouracil, Adriamycin, Platinum, mitomycin C, hydroxycamptothecin) were included. The study is registered with PROSPERO (CRD42018098541). For efficacy outcomes, subgroups which included 5-fluorouracil and hydroxycamptothecin ranked higher than other chemotherapy agents, while mitomycin C ranked the lowest. For advanced effects, the use of mitomycin C or 5-fluorouracil as the chemotherapy agent ranked higher, while hydroxycamptothecin ranked the lowest. Therefore, we excluded 5-Fu and Mitomycin C in subsequent studies. Additionally, in the evaluation of primary adverse effects by the network meta-analysis, Platinum ranked the highest while hydroxycamptothecin ranked the lowest. Therefore, we excluded Platinum this time. Furthermore, all types of Adriamycin are not same, and some studies included two types of Adriamycin. The network meta-analysis results showed that the TACE (hydroxycamptothecin + pirarubicin) +Sorafenib arm and TACE (hydroxycamptothecin + epirubicin) +Sorafenib arm had significant efficacy differences. In conclusion, for patients with advanced HCC, combination therapy with HCPT plus THP/EPI in TACE and Sorfenib may be used as a first-line treatment.
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Evidence Supporting LI-RADS Major Features for CT- and MR Imaging-based Diagnosis of Hepatocellular Carcinoma: A Systematic Review.
Tang, A, Bashir, MR, Corwin, MT, Cruite, I, Dietrich, CF, Do, RKG, Ehman, EC, Fowler, KJ, Hussain, HK, Jha, RC, et al
Radiology. 2018;(1):29-48
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Abstract
The Liver Imaging Reporting and Data System (LI-RADS) standardizes the interpretation, reporting, and data collection for imaging examinations in patients at risk for hepatocellular carcinoma (HCC). It assigns category codes reflecting relative probability of HCC to imaging-detected liver observations based on major and ancillary imaging features. LI-RADS also includes imaging features suggesting malignancy other than HCC. Supported and endorsed by the American College of Radiology (ACR), the system has been developed by a committee of radiologists, hepatologists, pathologists, surgeons, lexicon experts, and ACR staff, with input from the American Association for the Study of Liver Diseases and the Organ Procurement Transplantation Network/United Network for Organ Sharing. Development of LI-RADS has been based on literature review, expert opinion, rounds of testing and iteration, and feedback from users. This article summarizes and assesses the quality of evidence supporting each LI-RADS major feature for diagnosis of HCC, as well as of the LI-RADS imaging features suggesting malignancy other than HCC. Based on the evidence, recommendations are provided for or against their continued inclusion in LI-RADS. © RSNA, 2017 Online supplemental material is available for this article.
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Metronomic capecitabine as second-line treatment for hepatocellular carcinoma after sorafenib discontinuation.
Trevisani, F, Brandi, G, Garuti, F, Barbera, MA, Tortora, R, Casadei Gardini, A, Granito, A, Tovoli, F, De Lorenzo, S, Inghilesi, AL, et al
Journal of cancer research and clinical oncology. 2018;(2):403-414
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Abstract
PURPOSE Metronomic capecitabine (MC) is a well-tolerated systemic treatment showing promising results in one retrospective study, as second-line therapy after sorafenib failure, in patients with hepatocellular carcinoma (HCC). METHODS 117 patients undergoing MC were compared to 112 patients, eligible for this treatment, but undergoing best supportive care (BSC) after sorafenib discontinuation for toxicity or HCC progression. The two groups were compared for demographic and clinical features. A multivariate regression analysis was conducted to detect independent prognostic factors. To balance confounding factors between the two groups, a propensity score model based on independent prognosticators (performance status, neoplastic thrombosis, causes of sorafenib discontinuation and pre-sorafenib treatment) was performed. RESULTS Patients undergoing MC showed better performance status, lower tumor burden, lower prevalence of portal vein thrombosis, and better cancer stage. Median (95% CI) post-sorafenib survival (PSS) was longer in MC than in BSC patients [9.5 (7.5-11.6) vs 5.0 (4.2-5.7) months (p < 0.001)]. Neoplastic thrombosis, cause of sorafenib discontinuation, pre-sorafenib treatment and MC were independent prognosticators. The benefit of capecitabine was confirmed in patients after matching with propensity score [PSS: 9.9 (6.8-12.9) vs. 5.8 (4.8-6.8) months, (p = 0.001)]. MC lowered the mortality risk by about 40%. MC achieved better results in patients who stopped sorafenib for adverse events than in those who progressed during it [PSS: 17.3 (10.5-24.1) vs. 7.8 (5.2-10.1) months, (p = 0.035)]. Treatment toxicity was low and easily manageable with dose modulation. CONCLUSIONS MC may be an efficient and safe second-line systemic therapy for HCC patients who discontinued sorafenib for toxicity or tumor progression.
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Sustained complete response of advanced hepatocellular carcinoma with metronomic capecitabine: a report of three cases.
Brandi, G, Venturi, M, De Lorenzo, S, Garuti, F, Frega, G, Palloni, A, Garajovà, I, Abbati, F, Saccoccio, G, Golfieri, R, et al
Cancer communications (London, England). 2018;(1):41
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Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most frequent causes of cancer-related death. Sorafenib, a multitarget angiogenesis inhibitor, is an approved frontline treatment for advanced HCC in Western countries, although a complete response (CR) to treatment is infrequently reported. Capecitabine, an oral fluoropyrimidine, has been shown to be effect in both treatment-naïve patients and those previously treated with sorafenib. To date, however, only one case of sustained CR to metronomic capecitabine has been reported. CASE PRESENTATION We describe three cases of advanced HCC treated with metronomic capecitabine where a CR was obtained. In the first case, capecitabine was administered as first line therapy; in the second case, capecitabine was used after intolerance to sorafenib; while in the third case, capecitabine was administered after sorafenib failure. CONCLUSION Capecitabine is a potentially important treatment option for patients with advanced HCC and may even represent a cure in certain cases.
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Regorafenib: A Review in Hepatocellular Carcinoma.
Heo, YA, Syed, YY
Drugs. 2018;(9):951-958
Abstract
Regorafenib (Stivarga®), a small molecule inhibitor of multiple kinases, is the first drug to be approved for the treatment of hepatocellular carcinoma (HCC) in patients who have progressed during or after sorafenib therapy. Its approval was based on the results of the randomized, double-blind, placebo-controlled, multinational, phase III RESORCE trial in patients with HCC who had progressed during sorafenib therapy. In RESORCE, regorafenib significantly prolonged overall survival (OS; primary endpoint), progression-free survival (PFS) and time to progression (TTP) compared with placebo, with the OS benefit appearing to be largely due to disease stabilization. Regorafenib had an acceptable tolerability profile. The most common treatment-related adverse events in the regorafenib group included hand-foot skin reaction, fatigue, diarrhoea and hypertension. No fatal hepatic failure was reported with regorafenib in patients with HCC in RESORCE. In conclusion, current evidence suggests that regorafenib is an important new targeted therapy option for the treatment of HCC patients who have progressed on sorafenib therapy.
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Hepatocarcinoma: genetic and epigenetic features.
Lombardi, A, Grimaldi, A, Zappavigna, S, Misso, G, Caraglia, M
Minerva gastroenterologica e dietologica. 2018;(1):14-27
Abstract
HCC is the third leading cause of cancer-related deaths worldwide, accounting for about 1 million deaths annually. The incidence of HCC is highest in Asia and Africa, where the endemic high prevalence of hepatitis B and hepatitis C strongly predisposes to the development of chronic liver disease and subsequent development of HCC. Patients with HCC generally present at an advanced stage due to compensated cirrhosis defined by the absence of pathognomonic symptoms, resulting in death within 6 to 20 months, suggesting an urgent need in treatment modalities that will dramatically decrease the mortality rate of HCC. The molecular hepatocarcinogenesis is, however, a gradual process during which genetic alterations progressively accumulate and lead to HCC through intermediate preneoplastic stages. With the advent of whole genome sequencing tools, various mutations associated with HCC have been identified, which have advanced our molecular understanding of HCC. However, the frequency of these mutations is rare, and these genetic mutations only partly explain the etiology of the disease. Better understanding and characterization of novel genetic and epigenetic alterations, which are important to hepatocarcinogenesis, may help understand the molecular pathogenesis of HCC, as well as providing novel therapeutic targets for HCC treatment. Further consideration should be given to developing more effective molecular diagnostic markers and targeted drug therapy.
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Nuclear Lipid Microdomains Regulate Daunorubicin Resistance in Hepatoma Cells.
Codini, M, Conte, C, Cataldi, S, Arcuri, C, Lazzarini, A, Ceccarini, MR, Patria, F, Floridi, A, Mecca, C, Ambesi-Impiombato, FS, et al
International journal of molecular sciences. 2018;(11)
Abstract
Daunorubicin is an anticancer drug, and cholesterol is involved in cancer progression, but their relationship has not been defined. In this study, we developed a novel experimental model that utilizes daunorubicin, cholesterol, and daunorubicin plus cholesterol in the same cells (H35) to search for the role of nuclear lipid microdomains, rich in cholesterol and sphingomyelin, in drug resistance. We find that the daunorubicin induces perturbation of nuclear lipid microdomains, localized in the inner nuclear membrane, where active chromatin is anchored. As changes of sphingomyelin species in nuclear lipid microdomains depend on neutral sphingomyelinase activity, we extended our studies to investigate whether the enzyme is modulated by daunorubicin. Indeed the drug stimulated the sphingomyelinase activity that induced reduction of saturated long chain fatty acid sphingomyelin species in nuclear lipid microdomains. Incubation of untreated-drug cells with high levels of cholesterol resulted in the inhibition of sphingomyelinase activity with increased saturated fatty acid sphingomyelin species. In daunodubicin-treated cells, incubation with cholesterol reversed the action of the drug by acting via neutral sphingomyelinase. In conclusion, we suggest that cholesterol and sphingomyelin-forming nuclear lipid microdomains are involved in the drug resistance.
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Hand-foot skin reaction is a beneficial indicator of sorafenib therapy for patients with hepatocellular carcinoma: a systemic review and meta-analysis.
Wang, P, Tan, G, Zhu, M, Li, W, Zhai, B, Sun, X
Expert review of gastroenterology & hepatology. 2018;(1):1-8
Abstract
BACKGROUND Sorafenib remains the only standard first-line drug for advanced hepatocellular carcinoma (HCC). Hand-foot skin reaction (HFSR) is a very common side-effect in patients treated with sorafenib, and also affects the treatment schedule and quality of life. However, the association of HFSR and response of HCC to sorafenib remain unclear. METHODS Databases including PubMed, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials were searched up to May 7th, 2017. Review Manager 5.3 software was adopted for performing meta-analyses, Newcastle-Ottawa Scale for assessing the bias of cohort studies, and GRADEprofler software for further assessing outcomes obtained from meta-analyses. RESULTS 1478 articles were reviewed, and 12 cohort studies with 1017 participants were included in the analyses. The pooled hazard ratio (HR) of overall survival is 0.45 (95% confidence interval (CI) 0.36, 0.55; P < 0.00001; I2 = 35%). The pooled HR of time to progression is 0.41 (95% CI 0.28, 0.60; P < 0.00001; I2 = 0%). Patients suffering HFSR had significantly better outcomes from sorafenib therapy than those without HFSR. CONCLUSIONS The results indicate that HFSR is a beneficial indicator for HCC patients receiving sorafenib therapy. However, molecular mechanisms accounting for sorafenib-induced HFSR in HCC patients remain.