Publications by authors named "Rheun-Chuan Lee"

98 Publications

The feasibility of medial segment graft in pediatric liver transplantation revisited by three-dimensional printing.

J Pediatr Surg 2021 Mar 26. Epub 2021 Mar 26.

Division of Transplantation Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.

Background: The medial segment as a mono-segmental graft was proposed to increase the donor pool for pediatric liver transplantation, but to date, there has been no published case. This study aims to revisit the feasibility of procuring the medial segment graft (MSG) by three-dimensional (3D) printing and ex vivo procedures performed on explanted diseased livers to overcome the gap between theory and clinical implementation.

Methods: From October 2004 to December 2016, we retrospectively analyzed preoperative computed tomography, magnetic resonance cholangiopancreatography, and intraoperative cholangiography images of our previous live liver donors and identified the indicated anatomy for the MSG, then materialized by 3D printing models to simulate the engraftment. Furthermore, we practiced the procurement procedures on selected explanted diseased livers.

Results: Among 291 analyzed livers, 96 livers (33%) met the arterial criteria for MSG, and two-thirds of them had ideal portal branches for reconstruction. The proposed right border of the MSG was the Cantlie's line, and the left edge was the right side of the umbilical fissure. The mean estimated volume of the MSG was 234 ± 54 ml. Besides, we suggest implanting the MSG as an auxiliary partial graft in an inverted vertical position or a standalone graft with right-side rotation in the right subphrenic space.

Conclusion: The procurement of the MSG is feasible based on our results. However, due to the novelty of the procedure, we suggest that the first attempted case of MSG should be implanted as an auxiliary partial graft to maximize patient safety.

Level Of Evidence: Type of study: Case series with no comparison groups EVIDENCE LEVEL: Level IV.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.03.026DOI Listing
March 2021

Early prediction of 1-year tumor response of hepatocellular carcinoma with lipiodol deposition pattern through post-embolization cone-beam computed tomography during conventional transarterial chemoembolization.

Eur Radiol 2021 Mar 25. Epub 2021 Mar 25.

Department of Radiology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei, Taiwan.

Objective: To evaluate whether parenchyma-to-lipiodol ratio (PLR) and lesion-to-lipiodol ratio (LLR) on C-arm cone-beam computed tomography (CBCT) can predict 1-year tumor response in patients with hepatocellular carcinoma (HCC) treated with conventional transcatheter arterial chemoembolization (cTACE).

Methods: This retrospective analysis included 221 HCC target lesions within up-to-seven criteria in 80 patients who underwent cTACE with arterial-phase CBCT and unenhanced CBCT after cTACE from 2015 to 2018. PLR and LLR of every tumor slice were obtained through mean density division of liver parenchyma and tumor enhancement with intratumoral lipiodol deposition. The cutoff values (COVs) of maximal PLR and LLR of every tumor were analyzed using Youden's index. The reliability of COV, correlations between the related parameters, and 1-year progression were assessed through interobserver agreement and multivariate analysis. COV validity was verified using the chi-square test and Cramer's V coefficient (V) in the validation cohort.

Results: Standard COVs of PLR and LLR were 0.149 and 1.4872, respectively. Interobserver agreement of COV for PLR and LLR was near perfect (kappa > 0.9). Multivariate analysis suggested that COV of PLR is an independent predictor (odds ratio = 1.23532×10, p = 4.37×10). COV of PLR showed strong consistency, correlation with 1-year progression in prediction model (V = 0.829-0.776; p < 0.0001), and presented as an effective predictor in the validation cohort (V = 0.766; p < 0.0001).

Conclusion: The COV of PLR (0.149) assessed through immediate post-embolization CBCT is an objective, effective, and approachable predictor of 1-year HCC progression after cTACE.

Key Points: • The maximal PLR value indicates the least lipiodol-distributed region in an HCC tumor. The maximal LLR value indicates the least lipiodol-deposited region in the tumor due to incomplete lipiodol delivery. PLR and LLR are concepts like signal-to-noise ratio to characterize the lipiodol retention pattern objectively to predict 1-year tumor progression immediately without any quantification software for 3D image analysis immediately after cTACE treatment. • COV of PLR can facilitate the early prediction of tumor progression/recurrence and indicate the section of embolized HCC, providing the operator's good targets for sequential cTACE or combined ablation. • The validation cohort in our study verified standard COVs of PLR and LLR. The validation process was more convincing and delicate than that of previous retrospective studies.
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http://dx.doi.org/10.1007/s00330-021-07843-8DOI Listing
March 2021

The role of albumin-bilirubin grade in determining the outcomes of patients with very early-stage hepatocellular carcinoma.

J Chin Med Assoc 2021 Feb;84(2):136-143

Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.

Background: Patients with hepatocellular carcinoma (HCC) and with a single tumor <2 cm in size are classified as having Barcelona Clinic Liver Cancer (BCLC) stage 0 HCC. We aimed to investigate the role of the albumin-bilirubin (ALBI) grade in predicting outcomes in patients with BCLC stage 0 HCC.

Methods: We retrospectively enrolled patients with BCLC stage 0 HCC in Taipei Veterans General Hospital from 2007 to 2015. Prognostic factors were analyzed using a Cox proportional hazards model and propensity score matching (PSM) analysis.

Results: There were 420 patients enrolled, including 207 with ALBI grade 1, and 213 with ALBI grade 2 or 3. After a median follow-up of 60.0 months (interquartile range, 37.2-84.6 months), 179 patients died. The cumulative 5-year overall survival (OS) rates were 80.6% in patients with ALBI grade 1 and 53.7% in those with ALBI grade 2 or 3, respectively (p < 0.001). Multivariate analysis showed that age >65 years, negative hepatitis B surface in serum, creatinine >1.0 mg/dL, platelet count ≤105/mm3, tumor size >1.5 cm, nonsurgical resection (SR) therapy, and higher ALBI grade were independent risk factors related to poor OS. Patients who underwent SR had a better OS and recurrence-free survival than those who received radiofrequency ablation, which was confirmed by a multivariate analysis and PSM analysis.

Conclusion: The ALBI grade can determine OS for patients with BCLC stage 0 HCC. SR can also provide a better outcome than nonsurgical treatment.
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http://dx.doi.org/10.1097/JCMA.0000000000000482DOI Listing
February 2021

Author Correction: Evolution of etiology, presentation, management and prognostic tool in hepatocellular carcinoma.

Sci Rep 2020 Oct 23;10(1):18482. Epub 2020 Oct 23.

Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-75523-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582971PMC
October 2020

Prediction of survival according to kinetic changes of cytokines and hepatitis status following radioembolization with yttrium-90 microspheres.

J Formos Med Assoc 2021 Apr 23;120(4):1127-1136. Epub 2020 Sep 23.

Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan. Electronic address:

Background/purpose: Yttrium-90 radioembolization (Y90-RE) may exert an immunomodulatory effect on the tumor microenvironment of hepatocellular carcinoma (HCC). Whether the host immune alterations after Y90-RE correlated with outcomes and whether Y90-RE affects viral hepatitis reactivation remains unclear.

Methods: Between July 2014 and July 2015, 18 patients undergoing Y90-RE for HCC were prospectively enrolled. Serum levels of virological markers, cytokines and chemokines were measured at baseline, 2, 4, and 12 weeks after Y90-RE. Factors associated with the clinical outcomes were evaluated.

Results: The disease control rate of Y90-RE was 44.4% (8 of 18) at 12 weeks, including 1 case with complete response, 4 cases with partial response, and 3 cases with stable disease. Significant elevation from baseline to week 2 and week 4 were noted in IL-10 level (8.4 ± 33.8, 15.7 ± 31.6, and 16.0 ± 41.7 pg/mL, P = 0.041 and 0.013, respectively) and IP-10 level (113.5 ± 97.8, 189.1 ± 164.4, and 168.6 ± 150.5 pg/mL, P = 0.027 and 0.026, respectively). After Y90-RE, transient HBV reactivation occurred in 2 patients, and 1 out of 3 HCV-infected patients exhibited HCV reactivation. Univariate analysis revealed that lower baseline IP-10 (≤200 pg/mL) and alanine aminotransferase (ALT) (≤50 U/L) levels were associated with better overall survival. Multivariate analysis identified an IP-10 level of 200 pg/mL (HR = 4.374, P = 0.045) as a predictor of overall survival.

Conclusion: Baseline serum IP-10 level is a predictor of survival for HCC patients undergoing Y90-RE. HBV and HCV reactivation may develop after Y90-RE treatment.
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http://dx.doi.org/10.1016/j.jfma.2020.09.005DOI Listing
April 2021

A clinical trial with valproic acid and hydralazine in combination with gemcitabine and cisplatin followed by doxorubicin and dacarbazine for advanced hepatocellular carcinoma.

Asia Pac J Clin Oncol 2020 Sep 22. Epub 2020 Sep 22.

School of Medicine, National Yang-Ming University, Taipei, Taiwan.

Background: Survival benefit from chemotherapy in advanced hepatocellular carcinoma (HCC) was limited till now. New chemoregimens with cytotoxicity modulators were explored to improve efficacy. Chemotherapy modulated with valproic acid (VA) as a deacetylation inhibitor of histone and DNA damage response proteins, and hydralazine (HZ) as a DNA hypomethylating agent, hypothetically suppressing DNA repair, were used in phase II trial here for advanced HCC.

Methods: Between July 2008 and March 2016, patients with chemo-naive advanced HCC, regardless of previous sorafenib treatment, not amenable to local therapy and with Child Pugh score ≤7, were treated with VA (200 mg thrice per day) and HZ (12.5 mg twice per day) in conjunction with gemcitabine and cisplatin (GCGG): gemcitabine (1000 mg/m , D1; 800 mg/m D8, 15) and cisplatin (70 mg/m , D1) every 28 days till disease progression and then with Dox-DTIC: doxorubicin (45 mg/m ) and dacarbazine (450 mg/m ) every 28 days. The primary endpoint was overall survival (OS); the secondary endpoints were safety, progression-free survival (PFS) and response rate (RR).

Results: Thirty-seven patients with 16 sorafenib-experienced, underwent GCGG treatment, and 30 of them underwent the following Dox-DTIC treatment. The median OS was 14.6 months (95% confidence interval: 6.0-23.1). The median PFSs for patients treated with VA- and HZ-combined GCGG and Dox-DTIC were 3.7 and 4.2 months, respectively; the RRs were 10/37 (27.0%) and 7/30 (23.3%); and grade 3/4 neutropenia were 54% and 51%. However, there were no chemotherapy-related deaths.

Conclusion: VA- and HZ-combined sequential chemotherapy was effective in advanced HCC with manageable toxicities.
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http://dx.doi.org/10.1111/ajco.13443DOI Listing
September 2020

Albumin-Bilirubin (ALBI) Grade-Based Nomogram for Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization.

Dig Dis Sci 2021 May 16;66(5):1730-1738. Epub 2020 Jun 16.

Department of Medical Research, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Taipei, 11217, Taiwan.

Background/aim: The prognosis of patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE) is highly heterogeneous because of variable characteristics of tumor burden and liver dysfunction. We aimed to propose and validate an albumin-bilirubin (ALBI) grade-based prognostic nomogram for HCC patients undergoing TACE.

Methods: A total of 1051 patients with HCC undergoing TACE were randomly assigned to derivation (n = 525) and validation (n = 526) set in this retrospective study based on prospective data. The multivariate Cox proportional hazards model in derivation set was used to generate the nomogram. The predictive accuracy of the nomogram was evaluated by discrimination and calibration tests.

Results: In multivariate analysis, presence of ascites, ALBI grade 2-3, serum ɑ-fetoprotein level ≥ 400 ng/mL, total tumor volume ≥ 396 cm, presence of vascular invasion, and poor performance status were independently associated with decreased survival of patients in the derivation set. Each patient had an individualized score from 0 to 41 by adding up the points from these six prognostic predictors. The nomogram generated from the derivation set had a concordance index of 0.72 (95% confidence interval [CI] 0.63-0.82). Discrimination test in the validation set provided a good concordance index 0.72 (95% CI 0.62-0.81), and the calibration plots consistently matched the ideal 45-degree reference line for 3- and 5-year survival prediction.

Conclusions: The ALBI grade-based prognostic model can well discriminate the survival in HCC patients undergoing TACE. The proposed easy-to-use nomogram may accurately predict the survival at 3 and 5 years for individual HCC patient in the precision medicine era.
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http://dx.doi.org/10.1007/s10620-020-06384-2DOI Listing
May 2021

Survival of Patients with Hepatocellular Carcinoma in Renal Insufficiency: Prognostic Role of Albumin-Bilirubin Grade.

Cancers (Basel) 2020 Apr 30;12(5). Epub 2020 Apr 30.

Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11221, Taiwan.

Renal insufficiency (RI) is commonly seen in patients with hepatocellular carcinoma (HCC). The prognostic role of albumin-bilirubin (ALBI) grade in this special setting is unclear. We aimed to investigate the role of ALBI grade associated with the impact of RI on HCC. A prospective cohort of 3690 HCC patients between 2002 and 2016 were retrospectively analyzed. The Kaplan-Meier method and multivariate Cox proportional hazards model were used to determine survival and independent prognostic predictors. Of all patients, RI was an independent predictor associated with decreased survival. In multivariate Cox analysis for patients with RI, α-fetoprotein level ≥20 ng/mL, tumor size >3 cm, vascular invasion, distant metastasis, presence of ascites, performance status 1-2, performance status 3-4, and ALBI grade 2 and grade 3 were independent predictors of decreased survival (all < 0.05). In subgroup analysis of patients with RI undergoing curative and non-curative treatments, the ALBI grade remained a significant prognostic predictor associated with decreased survival ( < 0.001). In summary, HCC patients with RI have decreased survival compared to those without RI. The ALBI grade can discriminate the survival in patients with RI independent of treatment strategy and is a feasible prognostic tool in this special patient population.
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http://dx.doi.org/10.3390/cancers12051130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281166PMC
April 2020

Comparison of prognosis between surgical resection and transarterial chemoembolization for patients with solitary huge hepatocellular carcinoma.

Ann Transl Med 2020 Mar;8(5):238

Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei.

Background: For patients with solitary huge (>10 cm in size) hepatocellular carcinoma (HCC) and without major vascular invasion, the treatment efficacy between surgical resection (SR) and transarterial chemoembolization (TACE) is not well studied. We aimed to compare the prognoses between SR and TACE for patients with solitary huge HCC.

Methods: We enrolled 143 patients with treatment-naïve, solitary HCC (>10 cm) who had received either SR or TACE treatment between 2007-2016. Factors of overall survival (OS) were analyzed by multivariate analysis. Propensity scores matching (PSM) method was adopted to adjust baseline demographic differences for further analysis.

Results: Ninety patients underwent SR and 53 patients received TACE. After a median follow-up of 17.0 (interquartile range 7.7-45.6) months, 83 patients had died. The cumulative 5-year OS rate was 44.7% and 11.7% for the SR group and the TACE group, respectively (P<0.001). A multivariate analysis showed that TACE [hazard ratio (HR): 3.515, 95% confidence interval (CI): 2.202-5.610, P<0.001], and albumin-bilirubin (ALBI) grade >1 (HR: 2.181, 95% CI: 1.343-3.543, P=0.002) were the independent risk factors associated with poorer OS. After PSM, 37 pairs of matched patients were selected from each treatment arm. After matching, patients who underwent SR still evinced a significantly higher OS than did those who underwent TACE (P=0.010).

Conclusions: SR provided a better OS than did TACE for patients with solitary huge (≥10 cm) HCC. As such, SR is recommended as the therapeutic priority for these patients.
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http://dx.doi.org/10.21037/atm.2019.12.157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154415PMC
March 2020

A Multicenter Phase II Study of Second-Line Axitinib for Patients with Advanced Hepatocellular Carcinoma Failing First-Line Sorafenib Monotherapy.

Oncologist 2020 09 9;25(9):e1280-e1285. Epub 2020 Apr 9.

Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.

Lessons Learned: For patients with advanced hepatocellular carcinoma after failure of first-line sorafenib monotherapy, second-line axitinib provides modest efficacy with tolerable toxicity. The discrepant tumor responses and survival outcomes in trials using axitinib as salvage therapy highlight the importance of optimal patient selection with the aid of clinical biomarkers.

Background: Multikinase inhibitors have been effective treatment for hepatocellular carcinoma (HCC). This multicenter phase II study explored the efficacy and safety of second-line axitinib for advanced HCC.

Methods: Patients with advanced HCC and Child-Pugh A liver function, experiencing progression on first-line sorafenib monotherapy, were eligible. Axitinib 5 mg twice daily was given continuously with allowed dose escalation. Tumor assessment was performed according to RECIST version 1.1. The primary endpoint was rate of disease control.

Results: From April 2011 to March 2016, 45 patients were enrolled. Thirty-seven patients (82%) tested positive for hepatitis B surface antigen. The disease control rate was 62.2%, and the response rate was 6.7%, according to RECIST criteria. Median progression-free survival (PFS) and overall survival (OS) were 2.2 months and 10.1 months, respectively. Treatment-related adverse events were compatible with previous reports of axitinib.

Conclusion: Second-line axitinib has moderate activity and acceptable toxicity for patients with advanced HCC after failing the first-line sorafenib monotherapy.
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http://dx.doi.org/10.1634/theoncologist.2020-0143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485356PMC
September 2020

Specific liver volume parameters in cirrhotic patients with peribiliary cysts.

J Chin Med Assoc 2020 Jun;83(6):571-576

Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.

Background: The presence of peribiliary cysts and morphological changes in the volumes of lobes in the livers of patients with cirrhosis are both related to the alteration of portal flow. Our study explored the relationship between these two features in patients with cirrhosis.

Methods: We retrospectively selected 150 computed tomography (CT) images of cirrhotic livers and 105 CT images of healthy livers. The cirrhotic livers were further classified according to the presence of peribiliary cysts (peribiliary cysts group) or the absence of peribiliary cysts (control cirrhotic group). The characteristic features of liver cirrhosis, including modified caudate-right lobe ratio (mCR ratio), splenomegaly, ascites, and collateral shunts, were reviewed. Liver volume calculations included the sum of the left hepatic volume (LHV) and right hepatic volume (RHV; LHV + RHV) and the ratio of LHV to RHV (LHV/RHV).

Results: The two groups did not differ in the presence of splenomegaly, ascites, or collateral shunts. The control cirrhotic group exhibited a significantly higher mCR ratio and LHV/RHV ratio than the peribiliary cysts group did (p < 0.001). The healthy liver group exhibited a significantly higher LHV + RHV value than either the peribiliary cysts group or the control cirrhotic group did (p < 0.001). The peribiliary cysts group and the control cirrhotic group did not differ significantly for LHV + RHV (p > 0.05).

Conclusion: The control cirrhotic group exhibited a significantly higher mCR ratio and LHV/RHV ratio than the peribiliary cysts group did, but the two groups were similar for most measurements. Peribiliary cysts might result in reduction of portal flow, causing cirrhotic liver with peribiliary cysts with left-sided dominance not to demonstrate the typical morphological appearance of the common cirrhotic liver.
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http://dx.doi.org/10.1097/JCMA.0000000000000284DOI Listing
June 2020

Evolution of etiology, presentation, management and prognostic tool in hepatocellular carcinoma.

Sci Rep 2020 03 3;10(1):3925. Epub 2020 Mar 3.

Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide, but its current status is unclear. We aimed to investigate the evolution of etiology, presentation, management and prognostic tool in HCC over the past 12 years. A total of 3349 newly diagnosed HCC patients were enrolled and retrospectively analyzed. The comparison of survival was performed by the Kaplan-Meier method with the log-rank test. Hepatitis B and C virus infection in HCC were continuously declining over the three time periods (2004-2007, 2008-2011, 2012-2015; p < 0.001). At diagnosis, single tumor detection rate increased to 73% (p < 0.001), whereas vascular invasion gradually decreased to 20% in 2012-2015 (p < 0.001). Early stage HCC gradually increased from 2004-2007 to 2012-2015 (p < 0.001). The probability of patients receiving curative treatment and long-term survival increased from 2004-2007 to 2012-2015 (p < 0.001). The Cancer of Liver Italian Program (CLIP) and Taipei Integrated Scoring (TIS) system were two more accurate staging systems among all. In conclusion, the clinical presentations of HCC have significantly changed over the past 12 years. Hepatitis B and C virus-associated HCC became less common, and more patients were diagnosed at early cancer stage. Patient survival increased due to early cancer detection that results in increased probability to undergo curative therapies.
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http://dx.doi.org/10.1038/s41598-020-61028-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054529PMC
March 2020

Differential Survival Impact of Diabetes Mellitus on Hepatocellular Carcinoma: Role of Staging Determinants.

Dig Dis Sci 2020 11 18;65(11):3389-3402. Epub 2020 Jan 18.

Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.

Background: Diabetes mellitus (DM) is common in patients with hepatocellular carcinoma (HCC) and may impact survival. Very few studies focused on the influence of DM in different clinical scenarios. We evaluated the prognostic impact of DM on HCC patients stratified by liver dysfunction, Milan criteria, and performance status defined in the Barcelona Clínic Liver Cancer staging parameters.

Methods: A prospective dataset of 3573 HCC patients between 2002 and 2016 was retrospectively analyzed. The multivariate Cox proportional hazards model was used to identify independent prognostic predictors. The Kaplan-Meier method with a log-rank test was applied to compare the survival distributions between different patient groups.

Results: Among all, DM was not an independent prognostic predictor in the Cox multivariate analysis (p = 0.1044). In the subgroup analysis, DM was not a significant prognostic predictor in Child-Turcotte-Pugh class A or class B/C patients. However, DM was associated with a decreased survival in patients within the Milan criteria (hazard ratio [HR] 1.36, 95% confidence interval [CI] 1.155-1.601, p = 0.0002) and in those with the performance status 0 (HR 1.213, 95% CI 1.055-1.394, p = 0.0067) in the multivariate Cox analysis, but not in those beyond the Milan criteria and poor performance status.

Conclusions: DM is highly prevalent in HCC patients and has a distinct survival impact. DM is an independent survival predictor among patients within the Milan criteria and good performance status. These high-risk patients should be closely monitored, and aggressive anticancer treatment should be considered.
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http://dx.doi.org/10.1007/s10620-020-06053-4DOI Listing
November 2020

Simultaneous Time-of-Flight PET/MR Identifies the Hepatic 90Y-Resin Distribution After Radioembolization.

Clin Nucl Med 2020 Feb;45(2):e92-e93

From the Department of Nuclear Medicine, Taipei Veterans General Hospital.

A 61-year-old woman with multiple hepatic metastases from uterus cervical cancer received Y radioembolization. The simultaneous time-of-flight (TOF) PET/MR clearly identified the untreated tumor parts on the posttherapeutic Y internal pair-production imaging. After another boosted Y injection, the metastatic hepatic tumors were well covered. The follow-up PET/MR revealed tumor shrinkage. The one-stop-shop TOF PET/MR provided useful follow-up information in patients receiving Y radioembolization.
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http://dx.doi.org/10.1097/RLU.0000000000002850DOI Listing
February 2020

Initial clinical radiological findings and staging to predict prognosis of primary hepatic angiosarcoma: A retrospective analysis.

PLoS One 2019 11;14(11):e0225043. Epub 2019 Nov 11.

School of Medicine, National Yang Ming University, Taipei, Taiwan, Republic of China.

Objective: Primary hepatic angiosarcoma (PHA) is extremely rare and most patients die within 12 months of diagnosis. The object of the study is to determine the association of initial clinical-radiological features and staging with outcomes in patients with PHA.

Methods: The medical records of adult patients with PHA were retrieved from an electronic medical record database and a pathology database and retrospectively reviewed. During 10 years, 22 eligible patients were included. Data extracted focused on the information before the first formal treatment with a pathological proof, including demographic characteristics, medical history, laboratory data, preliminary images, histopathological records, treatment, and follow-up survival period. Two radiologists blindly re-analyzed preliminary images of all 22 patients together and recorded tumor features and imaging stage based on the American Joint Committee on Cancer (AJCC) 8th edition tumor-node-metastasis (TNM) Staging System for hepatocellular carcinoma. A radiologist compiled the initial clinical data and preliminary image stage to analyze the association with patients' survival outcome.

Results: Higher aspartate aminotransferase (AST), higher total bilirubin (TB), lower albumin (ALB), longer prothrombin time (PT) and lower platelet count of serum relative to the normal reference range were more common in patients who survived ≤ 90 days (all P < 0.05). Overall survival was much better in patients with single PHA than in those with other tumor patterns of multiple PHA (all P < 0.05). Overall survival determined by preliminary imaging showed significant differences between stage I and stage III (P = 0.044), stage I and stage IV (P = 0.011), and stage III and IV (P = 0.047). No patients were at stage II.

Conclusions: Initial serum levels of ALT, TB, ALB, and PT, platelet count, single mass in liver, and preliminary imaging staging could help predict survival outcomes of patients with PHA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225043PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844487PMC
March 2020

A New Prognostic Model Based on Albumin-Bilirubin Grade for Hepatocellular Carcinoma Beyond the Milan Criteria.

Dig Dis Sci 2020 02 28;65(2):658-667. Epub 2019 Oct 28.

Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.

Background: The survival of patients with advanced hepatocellular carcinoma (HCC) is highly variable due to heterogeneous tumoral characteristics. We proposed and validated an albumin-bilirubin (ALBI)-based model for HCC beyond Milan criteria, the ALBI-HOME, for these patients.

Methods: A total of 2186 patients were enrolled and randomly assigned to the derivation cohort (n = 1093) and validation cohort (n = 1093). Multivariate Cox proportional hazards model was used to determine significant prognostic factors in the derivation cohort. The performance of ALBI-HOME was evaluated in the validation cohort.

Results: In the Cox model, six factors were identified as independent predictors of poor survival: ALBI grade 2 [hazard ratio (HR) 1.848, 95% confidence incidence (CI) 1.556-2.195, p < 0.001], ALBI grade 3 (HR 3.266, 95% CI 2.531-4.215, p < 0.001), serum AFP ≥ 100 ng/ml (HR 1.482, 95% CI 1.279-1.717, p < 0.001), total tumor volume ≥ 250 cm (HR 1.503, 95% CI 1.294-1.746, p < 0.001), ascites (HR 1.400, 95% CI 1.187-1.561, p < 0.001), performance status 0-1 (HR 1.756, 95% CI 1.485-2.076 p < 0.001), and vascular invasion or metastasis (HR 2.110, 95% CI 1.809-2.0, p < 0.001). The ALBI-HOME is based on these six parameters, and the score ranges from 0 to 7. This model was associated with the best prognostic ability among different HCC staging systems to predict survival in patients beyond Milan criteria; its ability remained consistently stable in different treatment subgroups and viral etiologies.

Conclusions: The proposed ALBI-HOME is a simple and feasible predictive model for HCC beyond Milan criteria. It demonstrates superior prognostic performance among the currently used staging systems and may help identify at-risk patients to undergo more aggressive treatments.
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http://dx.doi.org/10.1007/s10620-019-05813-1DOI Listing
February 2020

Association between esophagogastric varices in hepatocellular carcinoma and poor prognosis after transarterial chemoembolization: A propensity score matching analysis.

J Formos Med Assoc 2020 Feb 19;119(2):610-620. Epub 2019 Sep 19.

Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.

Background/purpose: Whether esophagogastric varices (EGV) can determine the outcome of patients with hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE) remains unknown. This study aimed to assess the impact of EGV on the prognosis of HCC patients after TACE.

Methods: From 2007 to 2012, we retrospectively enrolled 251 treatment-naïve HCC patients who underwent TACE and received esophagogastroduodenoscopy when HCC was diagnosed. The prognostic factors were analyzed using a Cox proportional hazards model and propensity score-matching analysis.

Results: There were 120 (47.8%) patients with EGV. Compared to those without EGV, patients with EGV had worse liver functional reserve. After a median follow-up of 14.7 months (25th-75th percentiles, 6.4-35.6 months), 152 patients died. The cumulative 5-year overall survival (OS) rates were 11.2% and 38.8% in patients with and without EGV, respectively (p < 0.001). Multivariate analysis showed that presence of EGV, presence of ascites, tumor size >5 cm, serum alpha-fetoprotein >20 ng/mL, progressive disease by modified Response Evaluation Criteria in Solid Tumors, Assessment for Retreatment with TACE score ≥2.5, and higher albumin-bilirubin grades were the independent predictors of poor OS. Subgroup analysis also demonstrated that EGV was associated with poor OS in most of the subgroups. After propensity score matching, the EGV group still had a lower OS rate than their counterparts (p = 0.004).

Conclusion: HCC patients with EGV had worse liver functional reserve compared to those without EGV. Moreover, EGV was an independent risk factor to predict poor prognosis in patients with HCC after TACE.
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http://dx.doi.org/10.1016/j.jfma.2019.09.003DOI Listing
February 2020

Albumin-bilirubin grade-based nomogram of the BCLC system for personalized prognostic prediction in hepatocellular carcinoma.

Liver Int 2020 01 20;40(1):205-214. Epub 2019 Sep 20.

Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.

Background & Aims: The prognostic accuracy of individual hepatocellular carcinoma (HCC) patient in each Barcelona Clinic Liver Cancer (BCLC) stage is unclear. We aimed to develop and validate an albumin-bilirubin (ALBI) grade-based nomogram of BCLC to estimate survival for individual HCC patient.

Methods: Between 2002 and 2016, 3690 patients with newly diagnosed HCC were prospectively enrolled and retrospectively analysed. Patients were randomly split into derivation and validation cohort by 1:1 ratio. Multivariate Cox proportional hazards model was used to generate the nomogram from tumour burden, ALBI grade and performance status (PS). The concordance index and calibration plot were determined to evaluate the performance of this nomogram.

Results: Beta coefficients from the Cox model were used to assign nomogram points to different degrees of tumour burden, ALBI grade and PS. The scores of the nomogram ranged from 0 to 24, and were used to predict 3- and 5-year patient survival. The concordance index of this nomogram was 0.77 (95% confidence interval [CI]: 0.71-0.81) in the derivation cohort and 0.76 (95% CI: 0.71-0.81) in the validation cohort. The calibration plots to predict both 3- and 5-year survival rate well matched with the 45-degree ideal line for both cohorts, except for ALBI-based BCLC stage 0 in the validation cohort.

Conclusions: The proposed ALBI-based nomogram of BCLC system is a simple and feasible strategy in the precision medicine era. Our data indicate it is a straightforward and user-friendly prognostic tool to estimate the survival of individual HCC patient except for very early stage patients.
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http://dx.doi.org/10.1111/liv.14249DOI Listing
January 2020

A new ALBI-based model to predict survival after transarterial chemoembolization for BCLC stage B hepatocellular carcinoma.

Liver Int 2019 09 30;39(9):1704-1712. Epub 2019 Jul 30.

Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.

Background & Aims: Transarterial chemoembolization (TACE) is a standard treatment for Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC), but the outcome varied. This study aimed to develop a model to predict the outcome of TACE in HCC patients.

Methods: Consecutive 570 treatment-naïve BCLC stage B HCC patients undergoing TACE as the initial treatment from 2007 to 2016 were retrospectively enrolled. Factors associated with survival were analysed. Patients undergoing TACE from 2007 to 2011 constituted the training cohort (n = 293), while patients undergoing TACE from 2012 to 2016 constituted the validation cohort (n = 277). Homogeneity and corrected Akaike information criterion (AICc) were compared between each prognostic model.

Results: A total of 1796 TACE sessions were performed for the 570 patients during the median follow-up period of 18.3 months. By multivariate analysis, beyond up-to-11 criteria (hazard ratio [HR] = 1.694, P < .001), alpha-foetoprotein >200 ng/mL (HR = 1.771, P < .001) and albumin-bilirubin (ALBI) grade 2 or 3 (HR = 1.817, P < .001) were independent predictors of overall survival (OS) in the training cohort. An ALBI-TAE model based on the three independent predictors of OS from the training cohort was developed to classify HCC patients into four subgroups. The performance of the ALBI-TAE model was superior to other prognostic models with lowest AICc values and highest homogeneity in both the training and validation datasets as well as the overall cohort.

Conclusions: Albumin-bilirubin grade is an important factor associated with survival in BCLC stage B HCC patients undergoing TACE. ALBI-TAE model can be applied to select patients who can get most benefit from TACE.
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http://dx.doi.org/10.1111/liv.14194DOI Listing
September 2019

Nuclear Theranostics in Taiwan.

Nucl Med Mol Imaging 2019 Apr 1;53(2):86-91. Epub 2019 Feb 1.

1Department of Nuclear Medicine, Taipei Veterans General Hospital, No.201, Section 2, Shipai Rd., Beitou Dist., Taipei City, Taiwan Republic of China.

Boron neutron capture therapy and Y-90 radioembolization are emerging therapeutic methods for uncontrolled brain cancers and hepatic cancers, respectively. These advanced radiation therapies are heavily relied on theranostic nuclear medicine imaging before the therapy for the eligibility of patients and the prescribed-dose simulation, as well as the post-therapy scanning for assessing the treatment efficacy. In Taiwan, the Taipei Veterans General Hospital is the only institute performing the BNCT and also the leading institute performing Y-90 radioembolization. In this article, we present our single institute experiences and associated theranostic nuclear medicine approaches for these therapies.
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http://dx.doi.org/10.1007/s13139-019-00576-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473010PMC
April 2019

Radiological features and outcomes of combined hepatocellular-cholangiocarcinoma in patients undergoing surgical resection.

J Formos Med Assoc 2020 Jan 12;119(1 Pt 1):125-133. Epub 2019 Mar 12.

Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan. Electronic address:

Background/purpose: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer. Preoperative diagnosis of cHCC-CCA is difficult, and outcome of cHCC-CCA is obscured. Our study aimed to investigate the clinicopathological and radiological features of cHCC-CCA and compare their outcomes with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC).

Methods: From August 2010 to December 2017, 891 patients undergoing liver tumor resection in Taipei Veterans General Hospital, including 30 patients with pathology-proven cHCC-CCA, 819 HCC, and 42 ICC were retrospectively reviewed. Radiological features of contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) in patients with cHCC-CCA were reevaluated by a radiologist. Factors association with disease-free survival (DFS) and overall survival (OS) were analyzed.

Results: The mean age of cHCC-CCA, HCC and ICC was similar. Hepatitis B virus infection was prevalent in patients with cHCC-CCA (22/30, 73.3%). Most (70%) of the cHCC-CCA had atypical radiological pattern of HCC and belonged to classic type in pathological features. cHCC-CCA and ICC had worse DFS, but the 5-year OS of cHCC-CCA was substantial adequate after surgery. Of the 891 patients, male gender, advanced T stage, multiple tumor number, alpha-fetoprotein (AFP) level >20 ng/ml, cHCC-CCA, and ICC were factors associated with poor DFS in multivariable analysis. Older age, T stage 3 or 4, presence of macrovascular invasion, AFP >20 ng/mL, cHCC-CCA, and ICC were factors significantly associated with OS.

Conclusion: cHCC-CCA is associated with high risk of recurrence following surgical resection as compared with HCC. Closely post-operative monitoring is highly recommended.
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http://dx.doi.org/10.1016/j.jfma.2019.02.012DOI Listing
January 2020

Less barium enema, more colonoscopy: A 12-year nationwide population-based study in Taiwan.

J Chin Med Assoc 2019 Apr;82(4):312-317

Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.

Background: Colorectal cancer (CRC) is the second most common and third most fatal cancer in Taiwan. To reduce incidence and mortality rates from cancer, including CRC, the Health Promotion Administration in Taiwan initiated the National Program on Cancer Prevention in 2005. For patients who have a positive fecal occult blood test, colonoscopy is recommended, and double-contrast barium enema (BE) is reserved as an alternative for those who cannot receive colonoscopy. In addition, single-contrast BE is sometimes used in pediatrics to evaluate colonic condition. This study evaluated the usage trends of BE and colonoscopy in Taiwan.

Methods: Data from the National Health Insurance Research Database from 2001 to 2013 were used in this study. Patients who received BE and colonoscopy were identified using the procedure codes of the National Health Insurance program. Age-standardized, yearly rates of BE and colonoscopy procedures were calculated.

Results: According to the data, the total number of colonoscopies increased 3.7-fold from 2001 to 2013. The compound annual growth rates for BE and colonoscopy were -5.36% and 10.47%, respectively, during the same period. The compound annual growth rates for BE and colonoscopy were -3.89% and 11.64% from 2005 to 2009, and -11.36% and 9.82% from 2010 to 2013, respectively. BE was conducted significantly more frequently than colonoscopy in patients who were aged <12 years and in female patients.

Conclusion: Professional association guidelines, national cancer prevention programs, patient and physician preferences, and increasing awareness and knowledge of CRC may all contribute to the increasing use of colonoscopy and the dramatic decline in the use of BE in Taiwan.
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http://dx.doi.org/10.1097/JCMA.0000000000000074DOI Listing
April 2019

Multidisciplinary Taiwan Consensus Recommendations for the Use of DEBDOX-TACE in Hepatocellular Carcinoma Treatment.

Liver Cancer 2018 Oct 29;7(4):312-322. Epub 2018 Mar 29.

Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch and National Taiwan University College of Medicine, Douliu City, Taiwan.

Transarterial chemoembolization (TACE) is the first-line treatment in patients with unresectable hepatocellular carcinoma (HCC). In recent years, there has been increasing clinical evidence that drug-eluting beads provide a combined ischemic and cytotoxic effect that may be superior to conventional TACE, with low systemic toxicity. The therapeutic value of TACE performed using the embolic microsphere DC Bead loaded with doxorubicin (drug-eluting bead doxorubicin [DEBDOX]) has been shown by several randomized controlled trials. Since Lencioni et al. [Cardiovasc Intervent Radiol 2012; 35: 980-985] published the first widely accepted technical recommendations on HCC embolization with DEBDOX-TACE in 2012, new studies have contributed to a better understanding of when and how to apply this new therapeutic modality, and they have yet to be incorporated into an updated guideline. Additionally, differences in the underlying liver pathology and practice of transcatheter embolization between Asian and Western populations have not been adequately addressed, and there remain significant variations in the TACE protocols adopted in different parts of the world. These mainly revolve around the number and type of chemotherapeutic agents used, type of embolic material, reliance on Lipiodol, and selectivity of catheter positioning. As a result of these issues, it has been difficult to interpret and compare results obtained from different centers in a systematic fashion. To address these concerns, we convened a panel of experts specializing in different aspects of HCC treatment to craft an updated set of recommendations that better reflect recent clinical experiences and are tailored to the use of DEBDOX-TACE in Taiwan. The conclusions of this expert panel are described in the following article.
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http://dx.doi.org/10.1159/000487608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249590PMC
October 2018

Is right-sided ligamentum teres hepatis always accompanied by left-sided gallbladder? Case reports and literature review.

Insights Imaging 2018 Dec 19;9(6):955-960. Epub 2018 Nov 19.

Department of Radiology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei, 112, Taiwan, Republic of China.

Right-sided ligamentum teres (RSLT) hepatis is a rare anatomical variant in which the fetal umbilical vein is connected to the right paramedian trunk of the portal vein. Despite its rarity, it is crucial for surgeons and intervention specialists because of its frequent association with intrahepatic vascular and biliary anomalies. Inattention to these anomalies before intervention, especially living-donor liver transplantation, can have life-threatening consequences. The relationship between gallbladder location and RSLT is still controversial, with RSLT regarded as one of the critical features of left-sided gallbladder in most studies. According to these hypotheses, once RSLT is present, left-sided gallbladder must be found as well. Here, we report three cases in which RSLT was associated with intrahepatic portal vein anomalies. In one case, the gallbladder was left-sided, but in the other two cases, it had a normal cholecystic axis to the right of the umbilical fissure. Therefore, the relationship between RSLT and gallbladder location may require redefinition, and surgeons should be aware of vascular anomalies once RSLT has been detected, even in the absence of left-sided gallbladder or biliary anomalies. TEACHING POINTS: • Right-sided ligamentum teres (RSLT) hepatis is a rare anatomical variant, which is frequently associated with intrahepatic vascular and biliary anomalies. Previous studies had discussed the vascular anomalies in livers with RSLT. • However, no predictable correlation exists between portal vein anomalies and anomalous biliary confluences in patients with RSLT. Moreover, we found that RSLT does not always coexist with left-sided gallbladder. • Unawareness of these vascular and biliary anomalies in liver with RSLT before intervention can have life-threatening consequences. • Thus, the vascular and biliary variations should be surveyed in multimodality imaging studies such as dynamic CT, 3D magnetic resonance cholangiopancreatography, or digital subtraction angiography once the RSLT is detected before intervention.
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http://dx.doi.org/10.1007/s13244-018-0671-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269334PMC
December 2018

Three-Dimensional Quantitative Color-Coding Analysis of Hepatic Arterial Flow Change during Chemoembolization of Hepatocellular Carcinoma.

J Vasc Interv Radiol 2018 10 28;29(10):1362-1368. Epub 2018 Aug 28.

Advanced Therapies, Siemens Healthcare GmbH, Forchheim, Germany.

Purpose: To evaluate feasibility of using three-dimensional (3D) quantitative color-coding analysis (QCA) to quantify substasis endpoints after transcatheter arterial chemoembolization of hepatocellular carcinoma (HCC).

Materials And Methods: This single-institution prospective study included 20 patients with HCC who had undergone segmental or subsegmental transcatheter arterial chemoembolization between December 2015 and March 2017. The chemoembolization endpoint was a sluggish anterograde tumor-feeding arterial flow without residual tumor stains. Contrast medium bolus arrival time (BAT) was used as an indicator of arterial flow. BAT of the proper hepatic artery was obtained as a reference point. BATs of the proximal right lobar artery, proximal left lobar artery, and segmental artery that received embolization were analyzed before and after chemoembolization. Wilcoxon signed rank test was used to evaluate the difference between BATs before and after chemoembolization.

Results: BATs before and after chemoembolization of the segmental artery that received embolization were 0.47 seconds (interquartile range [IQR], 0.31-0.70 s) and 1.04 seconds (IQR, 0.78-2.01 s; P < .001), respectively. BATs before and after chemoembolization of the proximal left lobar hepatic artery (0.35 s [IQR, 0.11-0.55] and 0.13 s [IQR, 0.05-0.32], P = .025) and right lobar hepatic artery (0.23 s [IQR, 0.13-0.65] and 0.22 s [IQR, 0.08-0.39], P = .027) exhibited no significant change.

Conclusions: 3D QCA is a feasible method for quantifying sluggish segmental arterial flow after transcatheter arterial chemoembolization in patients with HCC.
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http://dx.doi.org/10.1016/j.jvir.2018.04.012DOI Listing
October 2018

Metastasis in patients with hepatocellular carcinoma: Prevalence, determinants, prognostic impact and ability to improve the Barcelona Clinic Liver Cancer system.

Liver Int 2018 10 24;38(10):1803-1811. Epub 2018 Apr 24.

Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.

Background & Aim: Patients with hepatocellular carcinoma and metastasis are classified as advanced or terminal stage by the Barcelona Clinic Liver Cancer system. This study investigates the prevalence, determinants, and prognostic effect of metastasis and its ability to improve the Barcelona Clinic Liver Cancer system.

Methods: A total of 3414 patients were enrolled. The Kaplan-Meier and Cox regression methods were used to determine survival predictors. Akaike information criterion was used to compare the prognostic performance of staging systems.

Results: There were 357 (10%) patients having extrahepatic metastasis at the time of diagnosis. Metastases were associated with old age, alcoholism, hepatitis B, poorer liver function, higher α-foetoprotein level and larger tumour burden (all P < .05). Vascular invasion was associated with metastasis regardless of total tumour volume, and higher α-foetoprotein level and multiple tumours were associated with metastasis in patients with smaller tumour volume (all P < .05). Patients with both vascular invasion and metastasis had significantly worse outcome compared to patients with either vascular invasion or metastasis (P < .05). In the Cox proportional model, the co-existence of vascular invasion and metastasis was an independent predictor of decreased survival (P < .05). Re-allocating 181 Barcelona Clinic Liver Cancer stage C patients with both vascular invasion and metastasis into stage D was associated with lower Akaike information criterion, indicating enhanced prognostic power of the Barcelona Clinic Liver Cancer.

Conclusions: Metastasis is not uncommon, and is strongly associated with tumoural factors and poor long-term survival in hepatocellular carcinoma. Modification of the Barcelona Clinic Liver Cancer system based on vascular invasion and metastasis may further improve its predictive accuracy in advanced stage patients.
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http://dx.doi.org/10.1111/liv.13748DOI Listing
October 2018

SIRveNIB: Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients With Hepatocellular Carcinoma.

J Clin Oncol 2018 07 2;36(19):1913-1921. Epub 2018 Mar 2.

Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia.

Purpose Selective internal radiation therapy or radioembolization (RE) shows efficacy in unresectable hepatocellular carcinoma (HCC) limited to the liver. This study compared the safety and efficacy of RE and sorafenib in patients with locally advanced HCC. Patients and Methods SIRveNIB (selective internal radiation therapy v sorafenib), an open-label, investigator-initiated, phase III trial, compared yttrium-90 (Y) resin microspheres RE with sorafenib 800 mg/d in patients with locally advanced HCC in a two-tailed study designed for superiority/detriment. Patients were randomly assigned 1:1 and stratified by center and presence of portal vein thrombosis. Primary end point was overall survival (OS). Efficacy analyses were performed in the intention-to-treat population and safety analyses in the treated population. Results A total of 360 patients were randomly assigned (RE, 182; sorafenib, 178) from 11 countries in the Asia-Pacific region. In the RE and sorafenib groups, 28.6% and 9.0%, respectively, failed to receive assigned therapy without significant cross-over to either group. Median OS was 8.8 and 10.0 months with RE and sorafenib, respectively (hazard ratio, 1.1; 95% CI, 0.9 to 1.4; P = .36). A total of 1,468 treatment-emergent adverse events (AEs) were reported (RE, 437; sorafenib, 1,031). Significantly fewer patients in the RE than sorafenib group had grade ≥ 3 AEs (36 of 130 [27.7%]) v 82 of 162 [50.6%]; P < .001). The most common grade ≥ 3 AEs were ascites (five of 130 [3.8%] v four of 162 [2.5%] patients), abdominal pain (three [2.3%] v two [1.2%] patients), anemia (zero v four [2.5%] patients), and radiation hepatitis (two [1.5%] v zero [0%] patients). Fewer patients in the RE group (27 of 130 [20.8%]) than in the sorafenib group (57 of 162 [35.2%]) had serious AEs. Conclusion In patients with locally advanced HCC, OS did not differ significantly between RE and sorafenib. The improved toxicity profile of RE may inform treatment choice in selected patients.
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http://dx.doi.org/10.1200/JCO.2017.76.0892DOI Listing
July 2018

Combined Yttrium-90 microsphere selective internal radiation therapy and external beam radiotherapy in patients with hepatocellular carcinoma: From clinical aspects to dosimetry.

PLoS One 2018 2;13(1):e0190098. Epub 2018 Jan 2.

Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.

Purpose: Selective internal radiation therapy (SIRT) is an effective treatment strategy for unresectable hepatocellular carcinoma (HCC) patients. However, the prognoses of patients with portal vein thrombosis, extra-hepatic metastases, or residual tumors remain poor when treated with SIRT alone. In these patients, sequential external beam radiotherapy (EBRT) may offer a chance of salvage. Here, we reported the clinical outcomes and the detailed dosimetry analysis of 22 patients treated with combination therapy.

Methods: Between October 2011 and May 2015, 22 consecutive patients who underwent EBRT after yttrium-90 (90Y) SIRT were included in this study. The post-SIRT 90Y bremsstrahlung SPECT/CT of each patient was transferred to dose distribution by adopting the local deposition hypothesis. The patient-specific 3-dimensional biological effective dose distribution of combined SIRT and EBRT was generated. The overall survival and safety were evaluated. The relationship between dosimetric parameters and liver toxicity was analyzed.

Results: The mean administered activity of SIRT was 1.50 GBq (range: 0.5-2.8). The mean prescribed dose of EBRT was 42.3 Gy (range: 15-63) in 14 fractions (range: 5-15) and was targeted to the residual liver tumor in 12 patients (55%), portal vein thrombosis in 11 patients (50%), and perihilar lymphadenopathies in 4 patients (18%). The overall 1-, 2-, and 3-year survival rates were 59.8%, 47.9%, and 47.9%, respectively. Overall, 8 patients (36%) developed > grade 2 liver toxicities, and the Child-Pugh score prior to EBRT strongly affected the toxicity risk. A dosimetry analysis restricted to 18 Child-Pugh A/B patients showed that the V100 (The fraction of normal liver exposed to more than 100 Gy) to V140 significance differed between patients who did or did not experience hepatotoxicity. The V110 was the strongest predictor of hepatotoxicity (18.6±11.6% vs 29.5±5.8%; P = 0.030).

Conclusion: Combined therapy is feasible and safe if patients are carefully selected. Specifically, 3-dimensional dosimetry is crucial for the evaluation of efficacy and toxicity. The normal liver V100 to V140 values of the combined dose should be as low as possible to minimize the risk of liver toxicity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190098PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749761PMC
February 2018

A New Treatment-integrated Prognostic Nomogram of the Barcelona Clinic Liver Cancer System for Hepatocellular Carcinoma.

Sci Rep 2017 08 11;7(1):7914. Epub 2017 Aug 11.

Department of Medicine, Taipei Veterans General Hospital, Taipei: No 201, Sec. 2, Shipai Rd, Taipei, 112, Taiwan.

The nomogram of the Barcelona Clinic Liver Cancer (BCLC) has accurate outcome prediction. This study aims to propose a treatment-integrated nomogram derived from BCLC for patients with hepatocellular carcinoma (HCC). A total of 3,371 patients were randomly grouped into derivation (n = 2,247) and validation (n = 1,124) sets. Multivariate Cox proportional hazards model was used to generate the nomogram from tumor burden, cirrhosis, performance status (PS) and primary anti-cancer treatments. Concordance indices and calibration plots were used to evaluate the performance of nomogram. The derivation and validation sets had the same concordance index of 0.774 (95% confidence intervals: 0.717-0.826 and 0.656-0.874, respectively). In calibration plots, survival distributions predicted by the nomogram and observed by the Kaplan-Meier method were similar at 3- and 5-year for patients from derivation and validation sets. Validation group patients divided into 10 subgroups by the original and new treatment-integrated BCLC nomogram were used to evaluate the prognostic performance of integrating primary anti-cancer treatments. Compared to the nomogram of original BCLC system, the treatment-integrated nomogram of BCLC system had larger linear trend and likelihood ratio X. In conclusion, based on the results of concordance index tests, integrating primary anti-cancer treatments into the BCLC system provides similar discriminatory ability.
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http://dx.doi.org/10.1038/s41598-017-08382-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554253PMC
August 2017

Prognostic role of noninvasive liver reserve markers in patients with hepatocellular carcinoma undergoing transarterial chemoembolization.

PLoS One 2017 3;12(7):e0180408. Epub 2017 Jul 3.

Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.

Background: Various noninvasive liver reserve markers were proposed to indicate the severity of liver damage. However, the role and feasibility of these markers to predict the prognosis of patients with hepatocellular carcinoma (HCC) are unknown. We aimed to identify the prognostic role of the 8 currently used hepatic reserve markers in patients with HCC undergoing transarterial chemoembolization (TACE).

Methods: Between 2002 and 2013, a total of 881 patients with HCC undergoing TACE were prospectively identified and retrospectively analyzed. The baseline characteristics, tumor status and noninvasive markers were collected. Homogeneity and corrected Akaike information criteria (AICc) were compared between these markers. The Cox proportional hazards model was used to identify independent predictors of survival.

Results: Significant differences in survival distribution were found for albumin-bilirubin (ALBI) grade, Child-Turcotte-Pugh (CTP) class, Lok index, fibrosis index based on 4 factors (FIB-4), Göteborg University cirrhosis index (GUCI), cirrhosis discriminant index (CDI) and model for end-stage liver disease (MELD) score (all p values <0.05). Among these markers, the ALBI grade showed the highest homogeneity and lowest AICc value, indicating a better prognostic performance. Cox multivariate analysis confirmed that ALBI grade 2, ascites, serum alkaline phosphatase and α-fetoprotein level, tumor diameter, vascular invasion and performance status were significant independent prognostic predictors. The distribution of the ALBI score well correlated with baseline CTP and MLED scores.

Conclusions: Our data suggest that among the currently used liver reserve markers, ALBI grade may serve as an objective and feasible surrogate to predict the prognosis of HCC patients undergoing TACE.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180408PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495392PMC
October 2017