Purpose
Portal vein tumor thrombosis is a critical complication in patients with hepatocellular carcinoma (HCC). This prospective multicenter trial assessed the efficacy of hepatic arterial infusion ...chemoembolization therapy with cisplatin suspended in lipiodol combined with 5-fluorouracil for HCC patients with portal vein tumor thrombosis.
Methods
We enrolled 52 HCC patients with portal vein tumor thrombosis. They received hepatic arterial infusion chemoembolization therapy with cisplatin suspension in lipiodol and 5-fluorouracil. The primary efficacy endpoint was progression-free survival (PFS), while the secondary endpoints were overall survival (OS), tumor response rate, safety, and tolerability. Independent factors for survival were also evaluated.
Results
The median PFS and OS were 8.6 and 27.0 months, respectively. Ten patients showed complete response, while 29 had partial response (response rate, 75.0 %). The median survival time of 10 patients with complete response and 29 with partial response was 32 months, while that of 15 patients with partial response who later showed disappearance of HCC following additional therapies was 50 months. Multivariate analysis identified response to treatment and disappearance of viable HCC as independent predictors of survival. The treatment was well tolerated, and the only encountered Grade 3 toxicities were thrombocytopenia and hyperbilirubinemia.
Conclusions
Hepatic arterial infusion chemoembolization therapy with cisplatin suspension in lipiodol combined with 5-fluorouracil is effective treatment for unresectable HCC with portal vein tumor thrombosis.
Background and Aims
Sequential therapy with molecular‐targeted agents (MTAs) is considered effective for unresectable hepatocellular carcinoma (HCC) patients. This study purposed to evaluate the ...efficacy of sequential therapy with sorafenib (SORA) as a first‐line therapy and to investigate the therapeutic impact of SORA in nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steato hepatitis (NASH)‐related HCC.
Methods
We evaluated 504 HCC patients treated with SORA (Study‐1). The times of administration for sorafenib from 2009 to 2015, 2016 to 2017, and 2018 and later were defined as the early‐, mid‐, and late‐term periods, respectively. Among them, 180 HCC patients treated with SORA in addition to MTAs in the mid‐ and late‐term periods were divided into groups based on disease etiology (NAFLD or NASH n = 37 and viral or alcohol n = 143), and outcomes were compared after inverse probability weighting (IPW) (Study‐2).
Results
Overall survival (OS) of HCC patients who received sequential MTA therapy after first‐line SORA was significantly longer. The median survival times (MST) were 12.6 versus 17.6 versus 17.4 months in the early‐term group, mid‐term group, and the later‐time group (early vs. mid, p = 0.014, early vs. later. p = 0.045), respectively. (Study‐1). In Study‐2, there was no significant differences in OS between the Virus/alcohol group and the NAFLD/NASH group in patients who received sequential therapy (MST was 23.4 and 27.0 months p = 0.173, respectively). The NAFLD or NASH, female sex, albumin‐bilirubin (ALBI) grade 2b, and major Vp (Vp3/Vp4) were significant factors for OS treated with SORA.
Conclusions
Sequential therapy with SORA as the first‐line treatment improved the prognosis of unresectable HCC patients and was effective regardless of HCC etiology.
Sequential therapy with SORA as the first‐line treatment prolonged the prognosis of unresectable HCC patients and was effective regardless of HCC etiology.
Adiponectin is shown to be inversely associated with development and progression of various cancers. We evaluated whether adiponectin level was associated with the prevalence and histological grade ...of hepatocellular carcinoma (HCC), and liver fibrosis in patients with hepatitis C virus (HCV) infection.
A case-control study was conducted on 97 HCC patients (cases) and 97 patients (controls) matched for sex, Child-Pugh grade and platelet count in patients with HCV infection. The serum total and high molecular weight (HMW) adiponectin levels were measured by enzyme-linked immunosorbent assays and examined in their association with the prevalence of HCC. In addition, the relationship between these adiponectin levels and body mass index (BMI), progression of liver fibrosis, and histological grade of HCC was also evaluated. Liver fibrosis was assessed using the aspartate aminotransferase to platelet ratio index (APRI).
There were no significant differences in the serum total and HMW adiponectin levels between cases and controls. Moreover, there were no inverse associations between serum total and HMW adiponectin levels and BMI in both cases and controls. On the other hand, serum total and HMW adiponectin levels are positively correlated with APRI in both cases (r = 0.491, P<0.001 and r = 0.485, P<0.001, respectively) and controls (r = 0.482, P<0.001 and r = 0.476, P<0.001, respectively). Interestingly, lower serum total (OR 11.76, 95% CI: 2.97-46.66 P<0.001) and HMW (OR 10.24, CI: 2.80-37.40 P<0.001 adiponectin levels were independent risk factors of worse histological grade of HCC.
Our results suggested that serum total and HMW adiponectin levels were predictors of liver fibrosis, but not prevalence of HCC in patients with HCV infection. Moreover, low these adiponectin levels were significantly associated with worse histological grades.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In 2013 and 2014, the development of microcatheters with balloons for the 4‐Fr system and new embolization materials provided various options for transarterial chemoembolization (TACE), expanding the ...range of treatment strategies. At our hospital, balloon‐occluded TACE (B‐TACE), conventional TACE (C‐TACE), and drug‐eluting bead TACE (DEB‐TACE) have been actively performed for hepatocellular carcinoma (HCC). This study compared the local recurrence‐free (LRF) periods of nodules with complete necrosis (TE4) obtained using each treatment method by extracting the nodules evaluated as complete response by the modified Response Evaluation Criteria in Solid Tumors. We performed 580 TACE procedures between June 2013 and April 2019. Among them, 58 HCC nodules in 43 patients, 33 nodules in 30 patients, and 45 nodules in 25 patients were evaluated as having complete necrosis after C‐TACE, DEB‐TACE, and B‐TACE, respectively. The time to local recurrence for each nodule was defined as the LRF period, and the quality of TE4 for each TACE was examined. Factors related to overall survival and the LRF period were determined by univariate and multivariate analyses, and overall survival and the LRF period were analyzed using the Kaplan–Meier method. Multivariate analysis of the LRF period showed that B‐TACE was an independent factor. The median LRF periods were 39.3, 13, and 9.1 months for B‐TACE, C‐TACE, and DEB‐TACE, respectively. Moreover, B‐TACE had a significantly longer LRF period than C‐TACE and DEB‐TACE. Conclusion: There was no significant difference between C‐TACE and DEB‐TACE. The LRF period of nodules with TE4 was the longest with B‐TACE, suggesting that B‐TACE should be used to achieve a radical cure in patients with HCC.
This study aimed to clarify the clinical question of whether there are differences in the quality of complete necrosis after TACE. The results showed that B‐TACE had a significantly longer LRF period than other TACEs. In addition, the factors associated with a longer LRF period were larger tumor size (> 29 mm) and choice of the B‐TACE procedure.
Background
Invasion beyond inferior vena cava (IVC) to right atrium (RA) is a rare complication in patients with advanced hepatocellular carcinoma (HCC), and results in fatal oncologic emergencies, ...including pulmonary embolism and right heart failure.
Aim
As there is no gold standard treatment for unresectable HCC with tumor thrombi involving IVC and RA, we considered it valuable to assess safety and efficacy of a combination of hepatic arterial infusion chemoembolization (HAIC) therapy and external‐beam radiation therapy (EBRT).
Methods and results
The “New FP” was chosen as the HAIC therapy, in which the enhanced permeation and retention effect was achieved using a cisplatin‐Lipiodol suspension combined with continuous infusion of 5‐fluorouracil (5‐FU). Sixteen patients with HCC with tumor thrombi in IVC, RA, and pulmonary arteries were enrolled. modified response evaluation criteria in solid tumors‐based evaluation of response to the combination treatment was as follows: complete response, 6.2% (1 patient); partial response, 81.3% (13 patients); stable disease, 12.5% (2 patients); progressive disease, 0%. The median overall survival time (MST) was 19.0 months. Notably, MST of patients receiving sequential sorafenib monotherapy (39.0 months) was significantly longer than that of the rest (15.3 months).
Conclusion
The combination of New FP and EBRT is an efficacious treatment option for unresectable HCC involving IVC and RA, complicated with pulmonary embolism. Sequential administration of molecular‐targeted drugs may prolong survival in such patients.
Background
Hepatic arterial infusion chemotherapy (HAIC) has been recognized as a useful therapeutic modality for patients with advanced hepatocellular carcinoma (HCC). The aim of this study was to ...investigate the association between serum vascular endothelial growth factor (VEGF) levels and the therapeutic effect of HAIC and the survival of patients undergoing HAIC.
Methods
Seventy-one patients with advanced HCC underwent HAIC through a subcutaneously implanted infusion port. One chemotherapy course consisted of low-dose cisplatin (10 mg/body on days 1–5) and 5-fluorouracil (250 mg/body on days 1–5), and 1 treatment cycle consisted of 2–3 courses of chemotherapy. Serum VEGF levels were measured with the Bio-Plex Suspension Array System (Bio-Rad Laboratories).
Results
The median survival time (MST) of all patients was 10.2 months, and the 1-, 2-, 3-, and 5-year survival rates were 46.5, 21.9, 12.8, and 3.7%, respectively. Of the 71 patients, 3 achieved a complete response (CR) and 22 achieved a partial response (PR) response rate (CR + PR/71) = 35%. The serum VEGF level (≥100 pg/mL,
P
= 0.026) was an independent predictor of therapeutic effect, and was positively correlated with the platelet count (
r
= 0.569,
P
< 0.001) and tumor size (
r
= 0.543,
P
< 0.001). Child–Pugh class (
P
= 0.046), serum VEGF level (
P
= 0.004), and therapeutic effect (
P
= 0.005) were identified by multivariate analysis as independent predictors of survival.
Conclusions
These results demonstrate that the serum VEGF level in patients with advanced HCC undergoing HAIC is an important predictive factor for therapeutic effect and survival.
Background
The antitumor effect of a drug is considered to be associated with a decrease in tumor blood flow.
Aims
We investigated whether the efficacy of lenvatinib (LEN) could be accurately ...assessed by measuring blood flow in hepatocellular carcinoma (HCC) during early treatment stages.
Methods and results
Blood flow changes and treatment results of 19 patients who underwent contrast‐enhanced ultrasound (CEUS), before and after LEN administration, in Kurume University Hospital from July 2018 to June 2020 were examined. Blood flow was evaluated after the intravenous administration of perflubutane (0.015 ml/kg). The vascular phase was photographed and used as RAW data, and time‐intensity curve analysis was used to obtain the region of interest (ROI) on the entire tumor nodule and quantify tumor blood flow. The evaluation was performed before and 1 and 4 weeks after LEN administration. Mean ± standard deviation (SD) values of the brightness of blood flow in the background liver before and 1 and 4 weeks after LEN administration were 2.84 × 10−4 ± 2.94 × 10−4, 3.07 × 10−4 ± 3.79 × 10−4, and 10.0 × 10−4 ± 20.8 × 10−4 dB, respectively. Blood flow in the background liver did not significantly decrease at 1 and 4 weeks compared with that before treatment. Mean ± SD values of the brightness of blood flow in HCC before and 1 and 4 weeks after administration were 3.49 × 10−3 ± 4.58 × 10−3, 1.16 × 10−3 ± 1.57 × 10−3, and 6.39 × 10−3 ± 22.8 × 10−3 dB, respectively. Blood flow in HCC after 1 week was significantly lower than that before administration (p = .0192). The therapeutic effects were significantly higher in the group with ≥50% blood flow reduction in HCC at 1 week after administration (p = .0038) and the group with reduced blood flow in HCC at 4 weeks after administration (p = .0051) than those before administration.
Conclusion
Early blood flow evaluation by CEUS may be useful in predicting the therapeutic effect of LEN for unresectable advanced HCC.
Background
Antiangiogenic tyrosine kinase inhibitors (TKIs) provide one of the few therapeutic options for effective treatment of hepatocellular carcinoma (HCC). However, patients with HCC often ...develop resistance toward antiangiogenic TKIs, and the underlying mechanisms are not understood. The aim of this study was to determine the mechanisms underlying antiangiogenic TKI resistance in HCC.
Methods
We used an unbiased proteomic approach to define proteins that were responsible for the resistance to antiangiogenic TKIs in HCC patients. We evaluated the prognosis, therapeutic response, and serum insulin‐like growth factor‐binding protein‐1 (IGFBP‐1) levels of 31 lenvatinib‐treated HCC patients. Based on the array of results, a retrospective clinical study and preclinical experiments using mouse and human hepatoma cells were conducted. Additionally, in vivo genetic and pharmacological gain‐ and loss‐of‐function experiments were performed.
Results
In the patient cohort, IGFBP‐1 was identified as the signaling molecule with the highest expression that was inversely associated with overall survival. Mechanistically, antiangiogenic TKI treatment markedly elevated tumor IGFBP‐1 levels via the hypoxia‐hypoxia inducible factor signaling. IGFBP‐1 stimulated angiogenesis through activation of the integrin α5β1‐focal adhesion kinase pathway. Consequently, loss of IGFBP‐1 and integrin α5β1 by genetic and pharmacological approaches re‐sensitized HCC to lenvatinib treatment.
Conclusions
Together, our data shed light on mechanisms underlying acquired resistance of HCC to antiangiogenic TKIs. Antiangiogenic TKIs induced an increase of tumor IGFBP‐1, which promoted angiogenesis through activating the IGFBP‐1‐integrin α5β1 pathway. These data bolster the application of a new therapeutic concept by combining antiangiogenic TKIs with IGFBP‐1 inhibitors.
The outcome of patients with hepatocellular carcinoma (HCC) is still poor. Decorin is a small leucine-rich proteoglycan, which exerts antiproliferative and antiangiogenic properties in vitro. We ...aimed to investigate the associations of decorin with physical function and prognosis in patients with HCC. We enrolled 65 patients with HCC treated with transcatheter arterial chemoembolization (median age, 75 years; female/male, 25/40). Serum decorin levels were measured using enzyme-linked immunosorbent assays; patients were classified into the High or Low decorin groups by median levels. Associations of decorin with physical function and prognosis were evaluated by multivariate correlation and Cox regression analyses, respectively. Age and skeletal muscle indices were not significantly different between the High and Low decorin groups. In the High decorin group, the 6-min walking distance was significantly longer than the Low decorin group and was significantly correlated with serum decorin levels (
= 0.2927,
= 0.0353). In multivariate analysis, the High decorin group was independently associated with overall survival (hazard ratio 2.808, 95% confidence interval 1.016-8.018,
= 0.0498). In the High decorin group, overall survival rate was significantly higher than in the Low decorin group (median 732 days vs. 463 days,
= 0.010). In conclusion, decorin may be associated with physical function and prognosis in patients with HCC.
Chemolipiodolization (CL) is less invasive than transarterial chemoembolization (TACE) for managing hepatocellular carcinoma (HCC) because it helps avoid embolization. However, the treatment outcomes ...of percutaneous radiofrequency ablation (PRFA) with or without CL for HCC remain unclear. Herein, we compared the prognostic factors for overall survival (OS) following PRFA with or without CL for HCC using propensity-score-matched analysis. A total of 221 patients with HCC treated with PRFA at Saga Central Hospital between April 2004 and October 2020, with or without CL, were enrolled. No significant difference was observed in OS between PRFA with and without CL cohorts (median survival time (MST): 4.5 vs. 5.4 years;
= 0.0806). To reduce the confounding effects of 12 variables, we performed propensity-score-matched analysis to match patients treated with PRFA with or without CL. No significant difference was observed in OS between PRFA with and without CL cohorts (MST: 4.0 vs. 3.6 years;
= 0.5474). After stratification according to tumor size, no significant difference was observed in OS for patients with tumor size ≥20 mm between PRFA with and without CL cohorts (MST: 3.5 vs. 3.4 years;
= 0.8236). PRFA with CL was not a significant prognostic factor in both univariate and multivariate analyses (
= 0.5477 and 0.9600, respectively). Our findings suggest that PRFA with CL does not demonstrate more favorable prognosis than PRFA without CL for HCC, regardless of tumor size.
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