Beneficial Prognostic Effects of Aspirin in Patients Receiving Sorafenib for Hepatocellular Carcinoma: A Tale of Multiple Confounders

Case–control observational studies suggested that aspirin might prevent hepatocellular carcinoma (HCC) in high-risk patients, even if randomized clinical trials are lacking. Information regarding aspirin in subjects who already developed HCC, especially in its advanced stage, are scarce. While aspirin might be a low-cost option to improve the prognosis, multiple confounders and safety concerns are to be considered. In our retrospective analyses of a prospective dataset (n = 699), after assessing the factors associated with aspirin prescription, we applied an inverse probability treatment weight analysis to address the prescription bias. Analyses of post-sorafenib survival were also performed to reduce the influence of subsequent medications. Among the study population, 133 (19%) patients were receiving aspirin at the time of sorafenib prescription. Aspirin users had a higher platelet count and a lower prevalence of esophageal varices, macrovascular invasion, and Child–Pugh B status. The benefit of aspirin was confirmed in terms of overall survival (HR 0.702, 95% CI 0.543–0.908), progression-free survival, disease control rate (58.6 vs. 49.5%, p < 0.001), and post-sorafenib survival even after weighting. Minor bleeding events were more frequent in the aspirin group. Aspirin use was associated with better outcomes, even after the correction for confounders. While safety concerns arguably remain a problem, prospective trials for patients at low risk of bleeding are warranted.

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A Novel Epigenetic Machine Learning Model to Define Risk of Progression for Hepatocellular Carcinoma Patients

International Journal of Molecular Sciences ◽

10.3390/ijms22031075 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1075

Author(s):

Luca Bedon ◽

Michele Dal Bo ◽

Monica Mossenta ◽

Davide Busato ◽

Giuseppe Toffoli ◽

...

Keyword(s):

Machine Learning ◽

Hepatocellular Carcinoma ◽

High Risk ◽

Progression Free Survival ◽

Low Risk ◽

Functional Enrichment ◽

Free Survival ◽

High Risk Patients ◽

Risk Of Progression ◽

Risk Patients

Although extensive advancements have been made in treatment against hepatocellular carcinoma (HCC), the prognosis of HCC patients remains unsatisfied. It is now clearly established that extensive epigenetic changes act as a driver in human tumors. This study exploits HCC epigenetic deregulation to define a novel prognostic model for monitoring the progression of HCC. We analyzed the genome-wide DNA methylation profile of 374 primary tumor specimens using the Illumina 450 K array data from The Cancer Genome Atlas. We initially used a novel combination of Machine Learning algorithms (Recursive Features Selection, Boruta) to capture early tumor progression features. The subsets of probes obtained were used to train and validate Random Forest models to predict a Progression Free Survival greater or less than 6 months. The model based on 34 epigenetic probes showed the best performance, scoring 0.80 accuracy and 0.51 Matthews Correlation Coefficient on testset. Then, we generated and validated a progression signature based on 4 methylation probes capable of stratifying HCC patients at high and low risk of progression. Survival analysis showed that high risk patients are characterized by a poorer progression free survival compared to low risk patients. Moreover, decision curve analysis confirmed the strength of this predictive tool over conventional clinical parameters. Functional enrichment analysis highlighted that high risk patients differentiated themselves by the upregulation of proliferative pathways. Ultimately, we propose the oncogenic MCM2 gene as a methylation-driven gene of which the representative epigenetic markers could serve both as predictive and prognostic markers. Briefly, our work provides several potential HCC progression epigenetic biomarkers as well as a new signature that may enhance patients surveillance and advances in personalized treatment.

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Use of Non–Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation Patients with Malignancy: Clinical Practice Experience in a Single Institution and Literature Review

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-0037-1607436 ◽

2017 ◽

Vol 44 (04) ◽

pp. 370-376 ◽

Cited By ~ 13

Author(s):

Anna Rago ◽

Andrea Papa ◽

Federica Meo ◽

Emilio Attena ◽

Paolo Golino ◽

...

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Oral Anticoagulants ◽

Anticoagulation Therapy ◽

Cardiovascular Complications ◽

Vitamin K Antagonist ◽

Minor Bleeding ◽

Bleeding Events ◽

Study Population ◽

Ischemic Attack

AbstractThis observational study aimed to investigate the efficacy and safety of non–vitamin K antagonist oral anticoagulants (NOACs) in atrial fibrillation (AF) patients with malignancy. A total of 76 patients (mean age: 73.2 ± 8.9; 28 females) with AF and malignancy treated with NOAC were included in the analysis. The mean CHA2DS2-VASc and HAS-BLED scores were 3.2 ± 1.2 and 2.2 ± 0.9, respectively. The study population was taking dabigatran 150 mg (25%) twice daily (BID), apixaban 5 mg BID (25%), dabigatran 110 mg BID (24%), rivaroxaban 20 mg (18%) once a day (OD), rivaroxaban 15 mg OD (5%), or apixaban 2.5 mg OD (3%). NOAC therapy began, on average, 248 ± 238 days before malignancy diagnosis for an average duration of 1,000 ± 289 days. Stroke, transient ischemic attack, major and minor bleeding events, other adverse effects, and major cardiovascular complications during the follow-up period were collected. In our study population, no patients experienced thromboembolic events during therapy with any NOAC. We recorded a low global incidence of major bleeding (3.9%) with a mean annual incidence of 1.4%. No hemorrhagic stroke or subarachnoid hemorrhage was observed. Only nine patients (11.8%) experienced minor bleeding. According to our data, anticoagulation therapy with NOACs seems to be an effective and safe treatment strategy for nonvalvular AF patients with malignancy.

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New Drugs for Thromboembolic Prevention in Atrial Fibrillation

European Cardiology Review ◽

10.15420/ecr.2010.6.4.64 ◽

2010 ◽

Vol 6 (4) ◽

pp. 64

Author(s):

Jose L Merino ◽

Jose López-Sendón ◽

◽

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Negative Impact ◽

Vitamin K Antagonists ◽

Coagulation Factor ◽

Developed Countries ◽

New Drugs ◽

Risk Scores ◽

Bleeding Events ◽

Risk Patients

Atrial fibrillation (AF) is the most frequent sustained arrhythmia and its prevalence is increasing in developed countries. This progressive increase and the negative impact of this arrhythmia on the patient’s prognosis make AF one of the main healthcare problems faced today. This has led to intense research into the main aspects of AF, one of them being thromboembolism prevention. AF patients have a four to five times higher risk of stroke than the general population. Several factors increase thromboembolic risk in patients with AF and the use of risk scores, such as the Congestive Heart Failure, Hypertension, Age Greater than 75, Diabetes, and Prior Stroke or Transient Ischemic Attack (CHADS2), have been used to identify the best candidates for anticoagulation. Antithrombotic drugs are the mainstay of therapy for embolic prevention. The clinical use of these drugs is based on the risk–benefit ratio, where benefit is the reduction of stroke and systemic embolic events and risk is mostly driven by the increase in bleeding events. Generally, antiplatelets are indicated for low-risk patients in light of the fact anticoagulants are the drug of choice for moderate- or high-risk patients. Vitamin K antagonists have been the only option for oral anticoagulation for the last 50 years. However, these drugs have many pharmacodynamic and pharmacokinetic problems. The problems of anticoagulation with vitamin K antagonists have led to the investigation of new drugs that can be administered orally and have a better dose–response relationship, a shorter half-life and, in particular, higher efficacy and safety without the need for frequent anticoagulation controls. The drugs that have been studied most thoroughly in patients with AF are inhibitors of the activated coagulation factor X and inhibitors of coagulation factor II (thrombin), including ximelagatran and dabigatran. In addition, non-pharmacological therapies have been developed to prevent recurrent embolism in certain patient populations.

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TWILIGHT: A Randomized Trial of Ticagrelor Monotherapy Versus Ticagrelor Plus Aspirin Beginning at 3 Months in High-risk Patients Undergoing Percutaneous Coronary Intervention

US Cardiology Review ◽

10.15420/usc.2019.02 ◽

2020 ◽

Vol 14 ◽

Author(s):

Johny Nicolas ◽

Usman Baber ◽

Roxana Mehran

Keyword(s):

Percutaneous Coronary Intervention ◽

High Risk ◽

Antiplatelet Therapy ◽

Dual Antiplatelet Therapy ◽

Coronary Intervention ◽

Bleeding Events ◽

High Risk Patients ◽

Risk Of Death ◽

Percutaneous Coronary ◽

Risk Patients

A P2Y12 inhibitor-based monotherapy after a short period of dual antiplatelet therapy is emerging as a plausible strategy to decrease bleeding events in high-risk patients receiving dual antiplatelet therapy after percutaneous coronary intervention. Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention (TWILIGHT), a randomized double-blind trial, tested this approach by dropping aspirin at 3 months and continuing with ticagrelor monotherapy for an additional 12 months. The study enrolled 9,006 patients, of whom 7,119 who tolerated 3 months of dual antiplatelet therapy were randomized after 3 months into two arms: ticagrelor plus placebo and ticagrelor plus aspirin. The primary endpoint of interest, Bleeding Academic Research Consortium type 2, 3, or 5 bleeding, occurred less frequently in the experimental arm (HR 0.56; 95% CI [0.45–0.68]; p<0.001), whereas the secondary endpoint of ischemic events was similar between the two arms (HR 0.99; 95% CI [0.78–1.25]). Transition from dual antiplatelet therapy consisting of ticagrelor plus aspirin to ticagrelor-based monotherapy in high-risk patients at 3 months after percutaneous coronary intervention resulted in a lower risk of bleeding events without an increase in risk of death, MI, or stroke.

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The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma

Scientific Reports ◽

10.1038/s41598-021-84117-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hiroaki Kanzaki ◽

Tetsuhiro Chiba ◽

Junjie Ao ◽

Keisuke Koroki ◽

Kengo Kanayama ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Molecular Mechanisms ◽

Kinase Inhibitors ◽

Progression Free Survival ◽

Erk Signaling ◽

Enzyme Linked Immunosorbent Assay ◽

Antitumor Effects ◽

The Impact

AbstractFGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19high (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19low (n = 105) patients, there were no significant differences between FGF19high (n = 21) and FGF19low (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.

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The APAC Score: A Novel and Highly Performant Serological Tool for Early Diagnosis of Hepatocellular Carcinoma in Patients with Liver Cirrhosis

Journal of Clinical Medicine ◽

10.3390/jcm10153392 ◽

2021 ◽

Vol 10 (15) ◽

pp. 3392

Author(s):

Joeri Lambrecht ◽

Mustafa Porsch-Özçürümez ◽

Jan Best ◽

Fabian Jost-Brinkmann ◽

Christoph Roderburg ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

At Risk ◽

Liver Cirrhosis ◽

Early Stage ◽

Treatment Options ◽

Growth Factor Receptor ◽

Serum Samples ◽

Disease Etiology ◽

Risk Patients ◽

Scoring Tool

(1) Background: Surveillance of at-risk patients for hepatocellular carcinoma (HCC) is highly necessary, as curative treatment options are only feasible in early disease stages. However, to date, screening of patients with liver cirrhosis for HCC mostly relies on suboptimal ultrasound-mediated evaluation and α-fetoprotein (AFP) measurement. Therefore, we sought to develop a novel and blood-based scoring tool for the identification of early-stage HCC. (2) Methods: Serum samples from 267 patients with liver cirrhosis, including 122 patients with HCC and 145 without, were collected. Expression levels of soluble platelet-derived growth factor receptor beta (sPDGFRβ) and routine clinical parameters were evaluated, and then utilized in logistic regression analysis. (3) Results: We developed a novel serological scoring tool, the APAC score, consisting of the parameters age, sPDGFRβ, AFP, and creatinine, which identified patients with HCC in a cirrhotic population with an AUC of 0.9503, which was significantly better than the GALAD score (AUC: 0.9000, p = 0.0031). Moreover, the diagnostic accuracy of the APAC score was independent of disease etiology, including alcohol (AUC: 0.9317), viral infection (AUC: 0.9561), and NAFLD (AUC: 0.9545). For the detection of patients with (very) early (BCLC 0/A) HCC stage or within Milan criteria, the APAC score achieved an AUC of 0.9317 (sensitivity: 85.2%, specificity: 89.2%) and 0.9488 (sensitivity: 91.1%, specificity 85.3%), respectively. (4) Conclusions: The APAC score is a novel and highly accurate serological tool for the identification of HCC, especially for early stages. It is superior to the currently proposed blood-based algorithms, and has the potential to improve surveillance of the at-risk population.

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Efficacy and Safety of Lenvatinib Therapy for Unresectable Hepatocellular Carcinoma in a Real-World Practice in Korea

Liver Cancer ◽

10.1159/000512239 ◽

2021 ◽

pp. 1-11

Author(s):

Myung Ji Goh ◽

Joo Hyun Oh ◽

Yewan Park ◽

Jihye Kim ◽

Wonseok Kang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Prognostic Factors ◽

Disease Progression ◽

Real World ◽

Medical Center ◽

Objective Response ◽

Progression Free Survival ◽

Efficacy And Safety ◽

Eligibility Criteria ◽

Unresectable Hepatocellular Carcinoma

Background: Lenvatinib has been recently approved as a first-line treatment option for patients with unresectable hepatocellular carcinoma (HCC) in Korea. We aimed to study the efficacy and safety of lenvatinib therapy in a real-world practice and to find prognostic factors related to survival and disease progression. Methods: A hospital-based retrospective study was conducted on 111 consecutive patients who had unresectable HCC and were treated with lenvatinib at Samsung Medical Center from October 2018 to March 2020. Efficacy was determined using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria in 111 patients who completed 1st tumor assessment. Safety was evaluated in 116 HCC patients including 5 patients who discontinued lenvatinib due to adverse events (AEs) before 1st tumor assessment using Common Terminology Criteria for AEs version 5.0. Results: A total of 111 patients with a median age of 59 years were analyzed during a median follow-up duration of 6.2 (4.4–9.0) months. The Kaplan-Meier estimate of overall survival was 10.5 months, and the median progression-free survival was 6.2 months. Based on mRECIST criteria, the objective response rate was 18.9% and disease control rate was 75.7%. AEs developed in 86/116 (74.1%) patients, and grade ≥3 AEs developed in 16/116 (13.8%) patients. Diarrhea, hand-foot skin rash, abdominal pain, hypertension, and anorexia were identified as the AEs with the highest frequencies of any grade. REFLECT eligibility criteria including tumor extent ≥50% liver occupation or inadequate bone marrow function and occurrence of anorexia were prognostic factors for survival, and occurrence of diarrhea was a favorable factor for disease progression. Conclusion: Lenvatinib therapy showed a favorable efficacy and safety in a real-world practice. The REFLECT eligibility criteria and specific AEs could be one of the prognostic markers.

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Efficacy of lenvatinib for unresectable hepatocellular carcinoma based on background liver disease etiology: multi-center retrospective study

Scientific Reports ◽

10.1038/s41598-021-96089-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Atsushi Hiraoka ◽

Takashi Kumada ◽

Toshifumi Tada ◽

Joji Tani ◽

Kazuya Kariyama ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Prognostic Factors ◽

Liver Disease ◽

Hazard Analysis ◽

Progression Free Survival ◽

Significant Prognostic Factor ◽

Disease Etiology ◽

Alcoholic Fatty Liver ◽

Free Survival ◽

Significant Difference

AbstractIt was recently reported that hepatocellular carcinoma (HCC) patients with non-alcoholic steatohepatitis (NASH) are not responsive to immune-checkpoint inhibitor (ICI) treatment. The present study aimed to evaluate the therapeutic efficacy of lenvatinib in patients with non-alcoholic fatty liver disease (NAFLD)/NASH-related unresectable-HCC (u-HCC). Five hundred thirty u-HCC patients with Child–Pugh A were enrolled, and divided into the NAFLD/NASH (n = 103) and Viral/Alcohol (n = 427) groups. Clinical features were compared in a retrospective manner. Progression-free survival (PFS) was better in the NAFLD/NASH than the Viral/Alcohol group (median 9.3 vs. 7.5 months, P = 0.012), while there was no significant difference in overall survival (OS) (20.5 vs. 16.9 months, P = 0.057). In Cox-hazard analysis of prognostic factors for PFS, elevated ALT (≥ 30 U/L) (HR 1.247, P = 0.029), modified ALBI grade 2b (HR 1.236, P = 0.047), elevated AFP (≥ 400 ng/mL) (HR 1.294, P = 0.014), and NAFLD/NASH etiology (HR 0.763, P = 0.036) were significant prognostic factors. NAFLD/NASH etiology was not a significant prognostic factor in Cox-hazard analysis for OS (HR0.758, P = 0.092), whereas AFP (≥ 400 ng/mL) (HR 1.402, P = 0.009), BCLC C stage (HR 1.297, P = 0.035), later line use (HR 0.737, P = 0.014), and modified ALBI grade 2b (HR 1.875, P < 0.001) were significant. Lenvatinib can improve the prognosis of patients affected by u-HCC irrespective of HCC etiology or its line of treatment.

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Sorafenib-Regorafenib Sequential Therapy in Advanced Hepatocellular Carcinoma: A Single-Institute Experience

Digestive Diseases ◽

10.1159/000480257 ◽

2017 ◽

Vol 35 (6) ◽

pp. 611-617 ◽

Cited By ~ 9

Author(s):

Kazuomi Ueshima ◽

Naoshi Nishida ◽

Masatoshi Kudo

Keyword(s):

Hepatocellular Carcinoma ◽

Objective Response ◽

Progression Free Survival ◽

Sequential Therapy ◽

Advanced Hepatocellular Carcinoma ◽

Open Label ◽

Effective Treatment Option ◽

Sorafenib Treatment ◽

Advanced Hcc ◽

Grade 3

Objectives: Previously, no therapeutic agent has been known to improve the overall survival compared with placebo in patients with hepatocellular carcinoma (HCC), who have progressed after sorafenib. In this patient population, regorafenib was first demonstrated to confer a survival benefit in the RESORCE trial, and subsequently it was approved as a second-line treatment for patients with advanced HCC. An open-label expanded access program (EAP) of regorafenib was implemented for compassionate use. We investigated the efficacy and safety of regorafenib based on our experience of the RESORCE trial and the EAP. Methods: Data from 5 patients from the RESORCE trial and 6 from the EAP were analyzed retrospectively. All patients had tolerated prior sorafenib and were progressing during sorafenib treatment. Results: The median progression-free survival was 9.2 months (95% CI 2.3-16.1). One patient achieved a partial response and 7 achieved stable disease. The objective response rate was 9.1%, and the disease control rate was 72.7%. No treatment-associated mortalities were observed. Grade 3 hypophosphatemia was observed in 2 patients, grade 2 anorexia was observed in 5 patients, and grade 3 neutropenia was observed in 2 patients. Grade 2 and grade 3 thrombocytopenia were observed in 2 and 3 patients, respectively. All treatment-related adverse events were improved by reduction or interruption of regorafenib. Five patients showed decreased serum albumin levels. Conclusion: Sorafenib and regorafenib sequential therapy presents a safe and effective treatment option for patients with advanced HCC.

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Clinical characteristics and prognosis in patients with premature coronary artery disease of different genders after intervention

European Heart Journal ◽

10.1093/ehjci/ehaa946.1315 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

X.F Tang ◽

Y Yao ◽

S.D Jia ◽

Y Liu ◽

B Xu ◽

...

Keyword(s):

Risk Factors ◽

Risk Factor ◽

Independent Risk Factor ◽

Coronary Intervention ◽

Premature Coronary Artery Disease ◽

Minor Bleeding ◽

Bleeding Events ◽

Cerebrovascular Events ◽

Independent Risk Factors ◽

Artery Disease

Abstract Objective To investigate the clinical characteristics and long-term prognosis of coronary intervention in patients with premature coronary artery disease (PCAD) between different genders. Methods From January 2013 to December 2013, 4 744 patients diagnosed as PCAD with percutaneous coronary intervention (PCI) in our hospital were enrolled. The general clinical data, laboratory results and interventional treatment data of all patients were collected, and the occurrence of major adverse cardio-cerebrovascular events (MACCE) within 2 years after PCI was followed up. Results Of the 4 744 patients undergoing PCI, 3 390 (71.5%) were males and 1 354 (28.5%) were females. The 2-year follow-up results showed that the incidence of BARC grade 1 hemorrhage in female patients was significantly higher than that in male patients (6.9% vs. 3.7%; P<0.001); however, there was no significant difference in the incidence of major adverse cardiovascular and cerebrovascular events (MACCE), all-cause death, cardiac death, recurrent myocardial infarction, revascularization (target vessel revascularization and target lesion revascularization), stent thrombosis, stroke and BARC grade 2–5 hemorrhage between the two groups (P>0.05). Multivariate COX regression analysis showed that gender was an independent risk factor for BARC grade 1 bleeding events in PCAD patients (HR=2.180, 95% CI: 1.392–3.416, P<0.001), but it was not an independent risk factor for MACCE and BARC grade 2–5 bleeding. Hyperlipidemia, preoperative SYNTAX score, multivessel lesions and NSTE-ACS were the independent risk factors for MACCE in PCAD patients with PCI (HR=1.289, 95% CI: 1.052–1.580, P=0.014; HR=1.030, 95% CI: 1.019–1.042, P<0.001; HR=1.758, 95% CI: 1.365–2.264, P<0.001; HR=1.264, 95% CI: 1.040–1.537, P=0.019); gender, hyperlipidemia, anticoagulant drugs like low molecular weight heparin or sulfonate were the independent risk factors for bleeding events (HR=1.579,95% CI 1.085–2. 297, P=0.017; HR=1.305, 95% CI 1.005–1.695, P=0.046; HR=1.321, 95% CI 1.002–1.741, P=0.048; HR=1.659, 95% CI 1.198–2.298, P=0.002). Conclusion The incidence of minor bleeding in women with PCAD is significantly higher than that in men; After adjusting for various risk factors, gender is an independent risk factor for minor bleeding events, but not an independent risk factor for MACCE in patients with PCAD. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Science and Technology Support Program of China

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