Publications by authors named "Chiun Hsu"

133 Publications

Adjuvant versus Neoadjuvant Immunotherapy for Hepatocellular Carcinoma: Clinical and Immunologic Perspectives.

Semin Liver Dis 2021 Aug 15;41(3):263-276. Epub 2021 Jun 15.

Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.

Advancement in systemic therapy, particularly immune checkpoint inhibitor (ICI)-based combination regimens, has transformed the treatment landscape for patients with advanced hepatocellular carcinoma (HCC). The advancement in systemic therapy also provides new opportunities of reducing recurrence after curative therapy through adjuvant therapy or improving resectability through neoadjuvant therapy. Improved recurrence-free survival by adjuvant or neoadjuvant ICI-based therapy has been reported in other cancer types. In this article, developments of systemic therapy in adjuvant and neoadjuvant settings for HCC were reviewed. The design of adjuvant and neoadjuvant therapy using ICI-based regimens and potential challenges of trial conduct and result analysis was discussed. Results from these trials may extend the therapeutic benefit of ICI-based systemic therapy beyond the advanced-stage disease and lead to a new era of multidisciplinary management for HCC.
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http://dx.doi.org/10.1055/s-0041-1730949DOI Listing
August 2021

Regorafenib enhances antitumor immunity via inhibition of p38 kinase/Creb1/Klf4 axis in tumor-associated macrophages.

J Immunother Cancer 2021 Mar;9(3)

Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan

Background: Regorafenib and other multikinase inhibitors may enhance antitumor efficacy of anti-program cell death-1 (anti-PD1) therapy in hepatocellular carcinoma (HCC). Its immunomodulatory effects, besides anti-angiogenesis, were not clearly defined.

Methods: In vivo antitumor efficacy was tested in multiple syngeneic liver cancer models. Murine bone marrow-derived macrophages (BMDMs) were tested in vitro for modulation of polarization by regorafenib and activation of cocultured T cells. Markers of M1/M2 polarization were measured by quantitative reverse transcription PCR (RT-PCR), arginase activity, flow cytometry, and ELISA. Knockdown of p38 kinase and downstream Creb1/Klf4 signaling on macrophage polarization were confirmed by using knockdown of the upstream MAPK14 kinase, chemical p38 kinase inhibitor, and chromatin immunoprecipitation.

Results: Regorafenib (5 mg/kg/day, corresponding to about half of human clinical dosage) inhibited tumor growth and angiogenesis in vivo similarly to DC-101 (anti-VEGFR2 antibody) but produced higher T cell activation and M1 macrophage polarization, increased the ratio of M1/M2 polarized BMDMs and proliferation/activation of cocultured T cells in vitro, indicating angiogenesis-independent immunomodulatory effects. Suppression of p38 kinase phosphorylation and downstream Creb1/Klf4 activity in BMDMs by regorafenib reversed M2 polarization. Regorafenib enhanced antitumor efficacy of adoptively transferred antigen-specific T cells. Synergistic antitumor efficacy between regorafenib and anti-PD1 was associated with multiple immune-related pathways in the tumor microenvironment.

Conclusion: Regorafenib may enhance antitumor immunity through modulation of macrophage polarization, independent of its anti-angiogenic effects. Optimization of regorafenib dosage for rational design of combination therapy regimen may improve the therapeutic index in the clinic.
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http://dx.doi.org/10.1136/jitc-2020-001657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986673PMC
March 2021

Spectrum of cancer patients receiving renal biopsy.

J Formos Med Assoc 2021 Feb 25. Epub 2021 Feb 25.

Renal Division, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address:

Background: The frontier of onco-nephrology, particularly renal complications of cancer and treatment, remains unexplored. We revisit the fundamental tool of diagnosing kidney disease, renal biopsy, in cancer patients with renal manifestation.

Methods: Patients who received renal biopsy from July 2015 to July 2019 were analyzed. Primary outcomes included end-stage renal disease (ESRD), mortality, and catastrophic outcome defined as either ESRD or mortality. A Cox proportional hazards model and Kaplan-Meier technique were used to assess the association with outcome measurements and survival analyses. Immunosuppression after renal biopsy and response to the treatment were evaluated.

Results: Among the 77 patients, the median age was 66 years (interquartile range [IQR] 59-73 years) and 46 (59.7%) were male. At the time of renal biopsy, 57 patients (74%) had various degrees of renal insufficiency. Tubulointerstitial damage score, quantified by renal pathology, were associated with higher hazards of ESRD (hazard ratio [HR], 1.77; 95% confidence interval [95% CI], 1.20 to 2.61; P = 0.004) and catastrophic outcome (HR, 1.30; 95% CI, 0.99 to 1.70; P = 0.058). The response rate to immunosuppression was lower in those diagnosed with tubulointerstitial nephritis (1 of 4 patients, 25%) than those with glomerulopathy (10 of 20 patients, 50%).

Conclusion: Renal biopsy may improve diagnostic accuracy and assist in treatment guidance of cancer patients with renal manifestation. Renal biopsy should be encouraged with clinical indication. Collaboration between oncologists and nephrologists is of paramount importance to provide more comprehensive care for caner patients.
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http://dx.doi.org/10.1016/j.jfma.2021.02.009DOI Listing
February 2021

Potential of circulating immune cells as biomarkers of nivolumab treatment efficacy for advanced hepatocellular carcinoma.

J Chin Med Assoc 2021 Feb;84(2):144-150

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

Background: Remarkable progress has been made in immunotherapy, specifically antibodies for programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1), for treating advanced cancers. In this study, we explored whether circulating immune cells can be used as biomarkers of the efficacy of such therapy.

Methods: We enrolled patients who received nivolumab, an anti-PD-1 antibody, for advanced hepatocellular carcinoma (HCC) in clinical trials and who consented to the collection of their peripheral blood. Using flow cytometry, we analyzed lymphocyte subclasses and the PD-1 or PD-L1 positivity of immune cells. These results were compared between patients with disease control (complete response, partial response, or stable disease) and those with disease progression.

Results: This study included 16 patients. The objective response rate was 19%, and the disease control rate was 75%. The hemogram results and the percentage of total αβ T cells or CD4 T cells did not significantly change after nivolumab treatment; moreover, they were not associated with treatment outcomes. The number of CD8 T cells significantly increased after 4 weeks (p = 0.016); however, this change was not associated with treatment outcomes. Patients with disease control exhibited peripheral B cells with significantly lower pretreatment PD-1 positivity than did patients with disease progression (p = 0.042). Patients with disease progression were more likely to exhibit monocytes with increased PD-L1 positivity after 28 (p = 0.020) or 42 (p = 0.008) days of treatment.

Conclusion: The low pretreatment PD-1 positivity of peripheral B cells and the constant posttreatment PD-L1 positivity of monocytes were associated with disease control after nivolumab treatment for advanced HCC.
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http://dx.doi.org/10.1097/JCMA.0000000000000477DOI Listing
February 2021

The unique characteristic in peripheral immune cells in patients with advanced hepatocellular carcinoma.

J Formos Med Assoc 2021 Aug 15;120(8):1581-1590. Epub 2020 Dec 15.

Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan.

Background/purpose: Recent progress in cancer immunology provides more insight in immune evasion of cancer cells. Cancer cells may achieve immune evasion through several ways including ineffective antigen presentation, T cell checkpoint utilization, immunosuppressive cytokines secretion and immunosuppressive cells recruitment. However, few literatures mentioned about the change of peripheral blood immune cells in advanced hepatocellular carcinoma (HCC) patients. To answer this question, we initiated a pilot study through detailed flow cytometry.

Methods: We enrolled patients with advanced HCC patients who had informed consent to the collection of their peripheral blood. We also recruited healthy individuals for the control group. Using flow cytometry, we analyzed lymphocyte subclasses and the PD-1 or PD-L1 positivity of immune cells in peripheral blood from HCC patients and healthy individuals.

Results: Twenty-four HCC patients were enrolled and twenty healthy individuals were enrolled. Most of the HCC patients were HBV carrier (58.3%), and the mean age was 61 years old. Among 55 immune cell parameters we examined in peripheral blood, 16 were significantly different between advanced HCC patients and healthy individuals by univariate analysis. Multivariate analysis was then conducted by fitting logistic regression model and showed that CD69CD25 Naïve CD4αβT cell percentage and dendritic cell percentage can reasonably predict the advanced HCC status from peripheral blood. By our regression model, the adjusted generalized R2 = 0.918 and the estimated area under the Receiver Operating Characteristic (ROC) curve was 0.99.

Conclusion: CD69CD25 Naïve CD4αβT cell percentage and dendritic cell percentage in peripheral blood are highly correlated with the advanced HCC status. The change may result from immune evasion initiated by hepatocellular carcinoma cells and further investigation is warranted. Validation study is ongoing and this mechanism may be utilized to treat advanced HCC patient in the future.
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http://dx.doi.org/10.1016/j.jfma.2020.11.015DOI Listing
August 2021

Safety and Preliminary Efficacy of Ramucirumab in Combination with FOLFOX4 in Patients with Advanced Hepatocellular Carcinoma: A Nonrandomized, Open-Label, Phase Ib Study.

Oncologist 2020 12 31;25(12):e1921-e1929. Epub 2020 Oct 31.

Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.

Lessons Learned: The combination of ramucirumab (8 mg/kg intravenous, day 1 every 2 weeks) and FOLFOX4 as first-line treatment in patients with advanced hepatocellular carcinoma (HCC) was not sufficiently tolerated. Preliminary efficacy data suggest that the combination may provide clinical benefit to patients with HCC. Dose modification and patient selection should be considered for the future development of ramucirumab plus FOLFOX chemotherapy for advanced HCC.

Background: The objective of this study was to investigate the safety, preliminary efficacy, pharmacokinetics, and immunogenicity of ramucirumab plus FOLFOX4 as first-line treatment in patients with advanced hepatocellular carcinoma (HCC).

Methods: Patients received ramucirumab (8 mg/kg) intravenously (IV) on day 1, followed by FOLFOX4 (oxaliplatin 85 mg/m IV on day 1, folinic acid 200 mg/m IV, bolus fluorouracil [5-FU] 400 mg/m , and a continuous infusion of 5-FU 600 mg/m over 22 hours, on days 1 and 2) every 2 weeks. The primary endpoint was to assess the safety and tolerability of the combination therapy.

Results: Eight patients (6 men, 2 women) were treated; all eight patients experienced at least one treatment-emergent adverse event (TEAE) of grade ≥3. Dose-limiting toxicities occurred in three patients (37.5%): hepatic hemorrhage (grade 4), blood bilirubin increased (grade 3), and febrile neutropenia (grade 3). Two patients discontinued study because of hepatic hemorrhage (grade 4) and blood bilirubin increase (grade 3). Six deaths occurred due to progressive disease, and no deaths due to TEAEs.

Conclusion: There were no unexpected safety findings with ramucirumab plus FOLFOX4 based on the known safety and toxicity of this regimen. The combination was not sufficiently tolerated in patients with advanced HCC at the specified dose and schedule.
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http://dx.doi.org/10.1002/onco.13550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108062PMC
December 2020

Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial.

JAMA Oncol 2020 Nov 12;6(11):e204564. Epub 2020 Nov 12.

Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.

Importance: Most patients with hepatocellular carcinoma (HCC) are diagnosed with advanced disease not eligible for potentially curative therapies; therefore, new treatment options are needed. Combining nivolumab with ipilimumab may improve clinical outcomes compared with nivolumab monotherapy.

Objective: To assess efficacy and safety of nivolumab plus ipilimumab in patients with advanced HCC who were previously treated with sorafenib.

Design, Setting, And Participants: CheckMate 040 is a multicenter, open-label, multicohort, phase 1/2 study. In the nivolumab plus ipilimumab cohort, patients were randomized between January 4 and September 26, 2016. Treatment group information was blinded after randomization. Median follow-up was 30.7 months. Data cutoff for this analysis was January 2019. Patients were recruited at 31 centers in 10 countries/territories in Asia, Europe, and North America. Eligible patients had advanced HCC (with/without hepatitis B or C) previously treated with sorafenib. A total of 148 patients were randomized (50 to arm A and 49 each to arms B and C).

Interventions: Patients were randomized 1:1:1 to either nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm A); nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm B); or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (arm C).

Main Outcomes And Measures: Coprimary end points were safety, tolerability, and objective response rate. Duration of response was also measured (investigator assessed with the Response Evaluation Criteria in Solid Tumors v1.1).

Results: Of 148 total participants, 120 were male (81%). Median (IQR) age was 60 (52.5-66.5). At data cutoff (January 2019), the median follow-up was 30.7 months (IQR, 29.9-34.7). Investigator-assessed objective response rate was 32% (95% CI, 20%-47%) in arm A, 27% (95% CI, 15%-41%) in arm B, and 29% (95% CI, 17%-43%) in arm C. Median (range) duration of response was not reached (8.3-33.7+) in arm A and was 15.2 months (4.2-29.9+) in arm B and 21.7 months (2.8-32.7+) in arm C. Any-grade treatment-related adverse events were reported in 46 of 49 patients (94%) in arm A, 35 of 49 patients (71%) in arm B, and 38 of 48 patients (79%) in arm C; there was 1 treatment-related death (arm A; grade 5 pneumonitis).

Conclusions And Relevance: In this randomized clinical trial, nivolumab plus ipilimumab had manageable safety, promising objective response rate, and durable responses. The arm A regimen (4 doses nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks then nivolumab 240 mg every 2 weeks) received accelerated approval in the US based on the results of this study.

Trial Registration: ClinicalTrials.gov Identifier: NCT01658878.
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http://dx.doi.org/10.1001/jamaoncol.2020.4564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530824PMC
November 2020

Novel systemic therapy for hepatocellular carcinoma.

Hepatol Int 2020 Sep 13;14(5):638-651. Epub 2020 Jul 13.

Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.

Systemic therapy for hepatocellular carcinoma (HCC) used to be limited to patients with advanced diseases and multi-kinase inhibitors targeting tumor angiogenesis the major approach of developing new treatment options. In the past 3 years, new data from trials of both molecular targeted therapy and immune checkpoint inhibitors (ICI) provided many new options of first- and second-line treatment for advanced HCC. Most notably, combination of ICI targeting the program cell death-1 (PD-1) pathway with other novel agents or conventional anti-cancer therapy may further improve treatment efficacy in different clinical settings. In this paper updated data of clinical trials of systemic therapy in the first- and second-line settings for advanced HCC were reviewed and the following issues were discussed: (1) lessons of trial design learned from positive and negative trials; (2) the balance between efficacy and safety in clinical practice; and (3) impact on future multi-disciplinary management of HCC.
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http://dx.doi.org/10.1007/s12072-020-10073-7DOI Listing
September 2020

Multicentre, phase II study of gemcitabine and S-1 in patients with advanced biliary tract cancer: TG1308 study.

Liver Int 2020 10 9;40(10):2535-2543. Epub 2020 Jun 9.

National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.

Background & Aims: Gemcitabine plus cisplatin (GC) remains the standard, frontline therapy for advanced biliary tract cancer (ABTC). The JCOG1113 study suggested that gemcitabine plus S-1 (GS) had noninferior median overall survival and comparable incidence of significant neutropenia as compared to GC treatments. This study evaluates the efficacy and safety of a modified GS regimen.

Methods: The eligible patients with chemonaive, measurable ABTC received 800 mg/m of gemcitabine on day 1 and 80 mg/m /day of S-1 (80/100/120 mg for patients with body surface <1.25/ ≥1.25 and <1.5/ ≥1.5 m respectively). The primary endpoint was the 12-week disease control rate (12-week DCR: objective response and stable disease ≥ 12 weeks). Per the p0 = 40% and p1 = 60% (α/β = 0.05/0.2) assumption, Simon's optimal two-stage design indicated 12-week DCR in ≥ 24 of 46 evaluable patients for significant activity. Tumour responses were assessed every 6 weeks.

Results: Fifty-one patients were enrolled and most of them had intrahepatic cholangiocarcinoma (64.7%), metastatic disease (84.3%) and disease-related symptoms (82.4%). On intention-to-treat analysis, 11 (21.6%) patients showed partial response, whereas 21 (41.2%) showed stable disease ≥ 12 weeks. The progression-free and overall survival were 5.4 months (95% confidence interval [CI]: 3.5-7.0), and 12.7 months (95% CI: 6.1-15.6) respectively. The study met its primary endpoint with a 12-week DCR of 69.6% in 46 evaluable patients. Grade 3/4 treatment-related adverse eventsoccurred in < 6% of patients of all individual items. The mean dose intensities of S-1 and gemcitabine were 87.1% and 92.5% respectively.

Conclusions: Modified GS showed moderate efficacy with a favourable safety profile in ABTC patients, thus mandating further assessment. ClinicalTrials.gov number: NCT02425137.
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http://dx.doi.org/10.1111/liv.14538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540301PMC
October 2020

Pembrolizumab for the treatment of programmed death-ligand 1-positive advanced carcinoid or pancreatic neuroendocrine tumors: Results from the KEYNOTE-028 study.

Cancer 2020 07 22;126(13):3021-3030. Epub 2020 Apr 22.

The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Despite a protracted disease course and multiple available therapies, patients with well-differentiated neuroendocrine tumors (NETs) inevitably experience disease progression. Programmed death-ligand 1 (PD-L1) has been associated with NET progression and prognosis. The multicohort, phase 1 KEYNOTE-028 study (ClinicalTrials.gov identifier NCT02054806) evaluated the activity and safety of the anti-programmed cell death protein 1 immunotherapy pembrolizumab in patients with well-differentiated or moderately-differentiated NETs.

Methods: Patients with PD-L1-positive, locally advanced or metastatic carcinoid or well-differentiated or moderately-differentiated pancreatic NETs (pNETs) were enrolled into separate cohorts and received pembrolizumab at a dose of 10 mg/kg every 2 weeks for up to 2 years. The objective response rate was the primary endpoint (as per Response Evaluation Criteria in Solid Tumors version 1.1, by investigator review). Safety was a secondary endpoint.

Results: Of 170 and 106 patients, respectively, who had evaluable samples among those screened for the carcinoid and pNET cohorts, 21% and 25%, respectively, had PD-L1-positive tumors; of these, 25 and 16 patients, respectively, were eligible and treated. The median follow-up was 20 months (range, 2-35 months) and 21 months (range, 5-32 months), respectively. The objective response rate was 12.0% (95% CI, 2.5%-31.2%) and 6.3% (95% CI, 0.2%-30.2%), respectively; 3 partial responses occurred among the carcinoid cohort and 1 among the pNET cohort. The median duration of response in the carcinoid cohort was 9.2 months (range, 6.9-11.1 months), and was not reached in the pNET cohort. No complete responses occurred. Treatment-related adverse events occurred in 68% and 69% of patients, respectively, most often diarrhea (7 patients in the carcinoid cohort and 4 patients in the pNET cohort) and fatigue (6 patients in each cohort). Hypothyroidism was the most common immune-mediated adverse event (5 patients in the carcinoid cohort and 2 patients in the pNET cohort).

Conclusions: Pembrolizumab demonstrated antitumor activity in a subset of patients with NETs and was well-tolerated.
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http://dx.doi.org/10.1002/cncr.32883DOI Listing
July 2020

Comorbid Obesity and Depressive Symptoms in Childhood Asthma: A Harmful Synergy.

J Allergy Clin Immunol Pract 2020 09 15;8(8):2689-2697. Epub 2020 Apr 15.

Neuroscience Program, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY; Child and Family Asthma Studies Center, Oishei Children's Hospital, Buffalo, NY; Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY; Department of Psychiatry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY. Electronic address:

Background: Overweight/obesity (OV/OB) and depression have each been separately associated with worsened childhood asthma severity and control. Pathways by which these factors may jointly affect childhood asthma have not been elucidated.

Objective: To examine the interrelationship of OV/OB and depressive symptoms with childhood asthma and explore associated psychobiologic pathways. The present study investigated whether comorbid OV/OB and depressive symptoms are associated with impaired baseline lung function and increased airway resistance during emotional stress, and to assess whether such effects may be mediated by autonomic nervous system (ANS) dysregulation, specifically through predominance of vagal over sympathetic reactivity (vagal bias).

Methods: A total of 250 children with asthma, aged 7 to 17, were assessed for OV/OB using body mass index, depressive symptoms using the Children's Depression Inventory (CDI), and asthma severity using National Asthma Education and Prevention Program Expert Panel Report 3 criteria. Baseline pulmonary function (forced expiratory volume in 1 second [FEV]) was assessed. The film "E.T. the Extra-Terrestrial" was used in a laboratory paradigm to evoke emotional stress/arousal. Airway resistance (R) was measured before and after the film to determine changes in airway function. ANS reactivity was assessed by measuring parasympathetic/vagal and sympathetic reactivity throughout the film.

Results: In OV/OB children with asthma, depressive symptoms predicted lower baseline FEV (β = -0.67, standard error [SE] = 0.24, P = .008), CDI predicted vagal bias under emotion stress/arousal (β = 0.27, SE = 0.09, P = .009), and vagal bias predicted increased R (β = 3.55, SE = 1.54, P = .023).

Conclusion: This study is the first to link OV/OB and depressive symptoms in their relationship to childhood asthma. In OV/OB children with asthma, depression may potentiate airway compromise, mediated by vagal bias. Use of antidepressant and anticholinergic therapies should be studied in this subgroup of patients.
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http://dx.doi.org/10.1016/j.jaip.2020.03.036DOI Listing
September 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

Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma.

J Hepatol 2020 02;72(2):307-319

Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.

Immune checkpoint inhibitor (ICI) therapy targeting anti-programmed cell death-1 (anti-PD-1) or its ligand (anti-PD-L1) is the backbone of numerous combination regimens aimed at improving the objective response and survival of patients with hepatocellular carcinoma (HCC). Clinical trials of immuno-oncology regimens in other cancer types have shed light on issues of study design, including how to choose candidate regimens based on early-phase trial results, statistical considerations in trials with multiple primary endpoints, and the importance of predictive biomarkers. In this review, the updated data from early-phase trials of combination immunotherapy for HCC are summarised. Since the most extensively tested combination regimens for advanced HCC comprise anti-PD-1/anti-PD-L1 agents plus antiangiogenic agents, the relative benefit and antitumor mechanism of antiangiogenic multikinase inhibitors versus specific VEGF/VEGFR inhibitors are discussed. Other critical issues in the development of combination immunotherapy, including optimal management of immune-related adverse events and the value of ICI therapy in combination with locoregional treatment for HCC, are also explored.
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http://dx.doi.org/10.1016/j.jhep.2019.09.025DOI Listing
February 2020

An Open-Label, Single-Arm, Two-Stage, Multicenter, Phase II Study to Evaluate the Efficacy of TLC388 and Genomic Analysis for Poorly Differentiated Neuroendocrine Carcinomas.

Oncologist 2020 05 18;25(5):e782-e788. Epub 2019 Dec 18.

Taipei Veterans General Hospital, Taipei, Taiwan.

Background: The discovery of effective therapeutic options for treating metastatic poorly differentiated neuroendocrine carcinoma (NEC) after prior platinum-based chemotherapy remains elusive. This study analyzed the efficacy of TLC388 (Lipotecan) Hydrochloride, a novel camptothecin analog, for pretreated patients with metastatic NEC.

Methods: This single-arm, two-stage, phase II clinical trial was conducted at four community and academic centers in Taiwan. Patients aged 20 years or older with confirmed metastatic NEC and who had received prior systemic therapy with etoposide plus cisplatin were enrolled between July 2015 and May 2018. Patients received 40 mg/m of TLC388 intravenously on days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxic effects. Gene mutations were analyzed by next-generation sequencing.

Results: Twenty-three patients with a median age of 61 (range, 44-73) years, 18 of whom were men (78%), were enrolled. Patients received a median of 2 (range, 0-6) treatment cycles. Among 20 evaluable patients, 3 patients exhibited stable disease and no patient experienced a complete or partial remission, resulting in a disease control rate of 15%. Median progression-free survival was 1.8 (95% confidence interval [CI], 0.4-15) months, and the median overall survival was 4.3 (95% CI, 1.7-15) months. The most common treatment-related hematologic adverse events at grade 3 or higher were leukopenia (22.7%), anemia (31.8%), and thrombocytopenia (18.2%). The most frequent mutated genes in 35 patients with NEC were ARSA, DPYD, HEXB, BRCA1, HPD, MYBPC3, BBS2, IL7R, HSD17B4, and PRODH.

Conclusion: TLC388 demonstrates limited antitumor activity in metastatic NEC. ClinicalTrials.gov identifier: NCT02457273.

Implications For Practice: Poorly differentiated neuroendocrine carcinomas (NECs) are rare and aggressive. Currently, effective therapeutic options for treating metastatic poorly differentiated NECs beyond platinum-based chemotherapy remain elusive. In this single-arm, multicenter, phase II study, 23 patients with NEC were enrolled and received TLC388 (Lipotecan) Hydrochloride, which is a novel camptothecin analog. The results demonstrated the disease control rate of 15%, the median progression-free survival of 1.8 (95% confidence interval [CI], 0.4-15) months, and the median overall survival of 4.3 (95% CI, 1.7-15) months. Most importantly, several novel genetic mutations and pathways were identified. These results offer the opportunity to develop future treatment strategies in this rare cancer.
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http://dx.doi.org/10.1634/theoncologist.2019-0490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216444PMC
May 2020

Differential Organ-Specific Tumor Response to Immune Checkpoint Inhibitors in Hepatocellular Carcinoma.

Liver Cancer 2019 Nov 6;8(6):480-490. Epub 2019 Aug 6.

Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.

Background And Aims: Immune checkpoint inhibitors (ICIs) exhibit significant clinical activity in patients with advanced hepatocellular carcinoma (HCC). This study explored whether tumor response to ICIs in HCC varies among different organs.

Methods: We reviewed the data of patients with advanced HCC who had received ICIs. Patients with measurable diseases were enrolled. Organ-specific response criteria, adapted from RECIST 1.1 and immune-related RECIST, were used to evaluate the objective response to ICIs in tumors located in the liver, lung, lymph node, and other intra-abdominal sites.

Results: Of the 75 enrolled patients with advanced HCC, 51 and 11 patients had chronic hepatitis B virus and chronic hepatitis C virus infection, respectively. Regarding ICI treatment, 58, 1, and 16 patients had undergone anti-PD-1/anti-PD-L1 monoclonal antibody (mAb) alone, anti-CTLA4 mAb alone, and anti-PD-1 mAb plus anti-CTLA4 mAb, respectively; 20 and 55 patients had received ICIs as first-line or ≥second-line therapy. The overall objective response rate (ORR) was 28.0%. In total, 58, 34, 19, and 18 patients had measurable hepatic tumors and lung, lymph node, and other intra-abdominal metastases, and the corresponding organ-specific ORRs were 22.4, 41.2, 26.3, and 38.9%, respectively. Of the 39 patients who had both hepatic and extrahepatic tumors, 12 had disease control in extrahepatic tumors while progressive disease (PD) in hepatic tumors, whereas only 4 exhibited disease control in hepatic tumors while PD in extrahepatic tumors ( = 0.046, McNemar test). Of the 16 patients with only evaluable tumors in the liver and lungs at baseline, 8 had disease control in the lungs while PD in the liver, and none experienced disease control in the liver while PD in the lungs ( = 0.005).

Conclusions: The hepatic tumors of HCC may be less responsive to ICIs than extrahepatic lesions. Lung metastases responded most favorably to ICIs. The mechanisms underlying this differential response to ICIs warrant further investigation.
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http://dx.doi.org/10.1159/000501275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883443PMC
November 2019

A multicenter, phase I/II trial of biweekly S-1, leucovorin, oxaliplatin and gemcitabine in metastatic pancreatic adenocarcinoma-TCOG T1211 study.

Eur J Cancer 2020 01 22;124:123-130. Epub 2019 Nov 22.

National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan; Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; Department of Internal Medicine, Kaohsiung Medical University Hospital and Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address:

Background: This phase I/II study evaluated the feasibility and efficacy of S-1, leucovorin, oxaliplatin and gemcitabine (SLOG), a triplet regimen, for treating patients with metastatic pancreatic ductal adenocarcinoma (PDAC).

Methods: Patients with chemo-naive, metastatic PDAC were eligible to receive fixed-rate infusion (10 mg/m/min) of gemcitabine of 800 mg/m followed by oxaliplatin of 85 mg/m on day 1 plus oral S-1 and leucovorin (20 mg/m) twice daily from days 1 to 7 in a 2-week cycle. The dose of S-1 would be escalated from 20, 30, 35 to 40 mg/m2 in a 3 + 3 designed phase I part to determine the maximum tolerated dose (MTD) for phase II study, in which the primary end-point was objective response rate (ORR). The recommended dose of S-1 was from phase I. This trial is registered at ClinicalTrials.gov: NCT01415713.

Results: Seventy-three patients were enrolled. In the phase I study (n = 19), the MTD of S-1 was 35 mg/m twice daily. Of 54 patients in phase II, the ORR was 40.7% (95% confidence interval [CI], 28%-55%). The median progression-free survival and overall survival were 7.6 (95% CI, 5.6-11.0) and 11.4 (95% CI, 8.1-16.3) months, respectively. The most common grade III/IV adverse event was neutropenia (40.7%). Twenty-four percent of patients had SLOG treatment for more than 1 year. The mean relative dose intensities of gemcitabine, oxaliplatin, and S-1 were 92%, 92% and 89%, respectively.

Conclusion: Biweekly SLOG is a feasible regimen with promising activity and safety profiles. A randomised study comparing SLOG versus modified folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) in advanced PDAC is ongoing (ClinicalTrials.gov: NCT03443492).
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http://dx.doi.org/10.1016/j.ejca.2019.10.023DOI Listing
January 2020

Early alpha-foetoprotein response associated with treatment efficacy of immune checkpoint inhibitors for advanced hepatocellular carcinoma.

Liver Int 2019 11 31;39(11):2184-2189. Epub 2019 Aug 31.

Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei City, Taiwan.

Background: Post-treatment decline in serum alpha-foetoprotein (AFP) levels has been shown to predict the treatment efficacy of antiangiogenic therapy for advanced hepatocellular carcinoma (HCC). We explored whether a decline in AFP levels was also associated with treatment outcomes of immune checkpoint inhibitors (ICIs) in patients with advanced HCC.

Methods: We reviewed all patients who received ICI therapy for advanced HCC. AFP response was evaluated in patients with the pretreatment AFP level of >20 ng/mL. We defined early AFP response as a >20% decline in serum AFP levels within the first 4 weeks of treatment initiation relative to pretreatment levels. We then studied whether early AFP response was associated with treatment outcomes.

Results: Sixty patients were enrolled in this study; 43 of them were evaluable for early AFP response. The objective response rate of early AFP responders was significantly higher than that of early AFP nonresponders (73% vs. 14%, P < .001). Early AFP responders, compared with early AFP nonresponders, exhibited significantly longer overall survival (OS) (median, 28.0 vs 11.2 months, P = .048) and progression-free survival (PFS) (median, 15.2 vs 2.7 months, P = .002). After adjusting for other clinicopathological variables and treatments, early AFP response remained an independent predictor for longer OS (hazard ratio [HR] = 0.089, 95% confidence interval [CI] = 0.018-0.441; P = .003) and PFS (HR = 0.128, 95% CI = 0.041-0.399; P < .001).

Conclusion: Early AFP response was associated with higher treatment efficacy of ICIs for advanced HCC. Additional validation studies are nonetheless warranted.
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http://dx.doi.org/10.1111/liv.14210DOI Listing
November 2019

Cost-effectiveness of preventing hepatitis B virus reactivation in patients with lymphoma and resolved HBV infection.

J Formos Med Assoc 2020 Jan 22;119(1 Pt 2):335-344. Epub 2019 Jun 22.

Department of Oncology, National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan; Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address:

Background/purpose: Hepatitis B virus (HBV) reactivation may occur in >10% of patients with lymphoma and resolved HBV infection who undergo rituximab-containing chemotherapy. Preventive strategies may have marked impact on resource allocation in HBV endemic areas. This study aims to compare the cost-effectiveness between prophylactic antiviral therapy and HBV DNA monitoring for the prevention of HBV-related complications.

Methods: Data sources are studies of HBV-related events and survival for patients with lymphoma and resolved HBV infection published since 2006. Decision tree analysis was used to compare the incremental cost-effectiveness ratio (ICER) of preventing HBV-related death or liver decompensation for patients who undergo first-line rituximab-containing chemotherapy. Sensitivity analysis was performed to examine the impact of the preventive efficacy, the duration of prophylactic antiviral therapy, and the cost of different interventions. The direct medical cost was derived from the database of the NHI Administration, Taiwan. The time frame of our analysis was set to 3 years after the completion of chemotherapy.

Results: The median ICER of prophylactic antiviral therapy, according to current practice guidelines, ranged between USD 150,000 and 250,000 if we apply the guidelines generally. When a long-course (12 months after completion of chemotherapy according to clinical guidelines) prophylactic therapy was assumed, Option A was cheaper and more effective only in the anti-HBs-negative subgroup (median ICER US$149,932 vs. US$161,526, p = 0.013).

Conclusion: Identification of anti-HBs-negative subgroups is critical to improve the cost-effectiveness of prophylactic antiviral therapy in lymphoma patients with resolved HBV infection.
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http://dx.doi.org/10.1016/j.jfma.2019.05.027DOI Listing
January 2020

Development of a PD-L1-Expressing Orthotopic Liver Cancer Model: Implications for Immunotherapy for Hepatocellular Carcinoma.

Liver Cancer 2019 May 22;8(3):155-171. Epub 2018 Jun 22.

Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.

Background: Anti-programmed cell death-1(anti-PD1) treatment has shown promising antitumor efficacy in patients with advanced hepatocellular carcinoma (HCC). This study sought to explore the functional significance of programmed death ligand-1 (PD-L1) expression in tumor cells in the tumor microenvironment.

Methods: The mouse liver cancer cell line BNL-MEA was transfected with PD-L1 plasmids and stable clones expressing PD-L1 were selected. An orthotopic HCC model was generated by implanting the cells into the subcapsular space of BALB/c mice. Cell growth features were measured by proliferation assay, colony formation, flow cytometry (in vitro), ultrasonography, and animal survival (in vivo). The changes in T-cell function were examined by cytokine assay, expression of T-cell related genes, and flow cytometry. The efficacy of anti-PD1 therapy was compared between the parental and PD-L1-expressing tumors.

Results: PD-L1 expression did not affect growth characteristics of BNL-MEA cells but downregulated the expression of genes related to T-cell activation in the tumor microenvironment. Co-culture of PD-L1-expressing BNL-MEA cells with CD8+ T cells reduced T-cell proliferation and expression of cytokines IFNγ and TNFα. Tumors with PD-L1 expression showed better response to anti-PD1 therapy and depletion of CD8+ T cells abolished the antitumor effect. The difference in treatment response between parental and PD-L1-expressing tumors disappeared when a combination of anti-PD1 and sorafenib was given.

Conclusions: PD-L1 expression in HCC cells may inhibit T-cell function in the liver tumor microenvironment. Anti-PD1 therapy appeared more effective in PD-L1-expressing than nonexpressing tumors, but the difference was diminished by the addition of sorafenib.
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http://dx.doi.org/10.1159/000489318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547269PMC
May 2019

Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian cohort analysis.

J Hepatol 2019 09 7;71(3):543-552. Epub 2019 Jun 7.

Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.

Background & Aims: Nivolumab, an immune checkpoint inhibitor, is approved in several countries to treat sorafenib-experienced patients with HCC, based on results from the CheckMate 040 study (NCT01658878). Marked differences exist in HCC clinical presentation, aetiology, treatment patterns and outcomes across regions. This analysis assessed the safety and efficacy of nivolumab in the Asian cohort of CheckMate 040.

Methods: CheckMate 040 is an international, multicentre, open-label, phase I/II study of nivolumab in adults with advanced HCC, regardless of aetiology, not amenable to curative resection or local treatment and with/without previous sorafenib treatment. This analysis included all sorafenib-experienced patients in the intent-to-treat (ITT) overall population and Asian cohort. The analysis cut-off date was March 2018.

Results: There were 182 and 85 patients in the ITT population and Asian cohort, respectively. In both populations, most patients were older than 60 years, had BCLC (Barcelona Clinic Liver Cancer) Stage C disease, and had received previous systemic therapy. A higher percentage of Asian patients had HBV infections, extrahepatic metastases and prior therapies. Median follow-up was 31.6 and 31.3 months for the ITT and Asian patients, respectively. Objective response rates were 14% and 15% in the ITT population and Asian cohort, respectively. In the Asian cohort, patients with HBV, HCV or those who were uninfected had objective response rates of 13%, 14% and 21%, respectively. The median duration of response was longer in the ITT (19.4 months) vs. Asian patients (9.7 months). Median overall survival was similar between the ITT (15.1 months) and Asian patients (14.9 months), and unaffected by aetiology in Asian patients. The nivolumab safety profile was similar and manageable across both populations.

Conclusion: Nivolumab safety and efficacy are comparable between sorafenib-experienced ITT and Asian patients.

Lay Summary: The CheckMate 040 study evaluated the safety and efficacy of nivolumab in patients with advanced hepatocellular carcinoma who were refractory to previous sorafenib treatment or chemotherapy. This subanalysis of the data showed that treatment responses and safety in patients in Asia were similar to those of the overall treatment population, providing support for nivolumab as a treatment option for these patients. Clinical trial number: NCT01658878.
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http://dx.doi.org/10.1016/j.jhep.2019.05.014DOI Listing
September 2019

Considerations of heterogeneity in clinical trials for hepatocellular carcinoma.

Expert Rev Gastroenterol Hepatol 2019 Jul 27;13(7):615-621. Epub 2019 May 27.

b Department of Oncology , National Taiwan University Hospital , Taipei , Taiwan.

: Clinical trials in hepatocellular carcinoma (HCC) exhibit a high degree of heterogeneity. These heterogeneities may lead to unexpected results among clinical trials. : In this review, we address the heterogeneity noted in early phase HCC trials, trials involving transarterial chemoembolization, and advanced HCC trials. Furthermore, we discuss possible methods to attenuate the detrimental effects of heterogeneity when conducting clinical trials. : Clinical trials in HCC exhibit an inherently high degree of heterogeneity because of various reasons: tumor heterogeneity, different cirrhotic backgrounds, various etiologies of cirrhosis, and geographical differences in practice and expertise. Such heterogeneity may cause imbalance among the enrolled patient population, premature withdrawal from the clinical trial, and variable response to the treatment. In addition, methodological heterogeneity also exists in designing trial protocol and response evaluation. All these factors may eventually lead to conflicting results among clinical trials. Accounting for these heterogeneities is important to foster the success of future trials. In recent years, significant progress with molecular targeted agents and immune checkpoint inhibitors was made in advanced HCC. These new agents are also being tested in clinical trials involving earlier stage HCC and will also face the challenge of these issues.
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http://dx.doi.org/10.1080/17474124.2019.1621165DOI Listing
July 2019

Low-dose nab-paclitaxel-based combination chemotherapy in heavily pretreated pancreatic cancer patients.

J Formos Med Assoc 2020 Jan 7;119(1 Pt 1):97-105. Epub 2019 Mar 7.

Department of Oncology, National Taiwan University Hospital, Taiwan; Graduate Institutes of Clinical Medicine, National Taiwan University College of Medicine, Taiwan; Graduate Institutes of Oncology, National Taiwan University College of Medicine, Taiwan; National Taiwan University Cancer Center, Taiwan. Electronic address:

Background: Heavily pretreated pancreatic cancer patients have a grave prognosis. In this case series study, we evaluated the safety and efficacy of nab-paclitaxel-based chemotherapy for such patients.

Methods: The data of pancreatic adenocarcinoma patients (n = 40) treated with nab-paclitaxel after the failure of gemcitabine or fluoropyrimidines at our institution in 2013-2015 were reviewed.

Results: The median number of prior chemotherapy regimens was two (range, 1-6). Eighteen patients had an Eastern Cooperative Oncology Group performance status of ≥2. The regimens comprised nab-paclitaxel combined with the following drugs: gemcitabine (n = 28), gemcitabine and fluoropyrimidine (n = 3), platinum and fluoropyrimidine (n = 4), fluoropyrimidine (n = 4), and irinotecan and fluoropyrimidine (n = 1). The median dose of nab-paclitaxel was 63 (range, 51-72) mg/m/dose, with the schedule of D1/15, D1/8, and D1/8/15 followed in 23, 14, and 3 patients, respectively. The median overall survival was 5.1 (95% CI, 4.6-5.7) months. Among 32 evaluable patients, two partial responses and six stable diseases were observed. The median progression-free survival was 2.6 (95% CI, 1.9-3.2) months. Grade 3/4 leucopenia or neutropenia was observed in three and two patients, respectively. Grade 3/4 anemia was observed in four patients. Other significant (grade 3 or more) nonhematological toxicities were not frequent, except for sepsis/infection (n = 7). However, more severe anemia or sepsis/infection was significantly associated with disease control.

Conclusion: In heavily pretreated pancreatic adenocarcinoma patients, low-dose nab-paclitaxel-based chemotherapy was fairly tolerable with modest efficacy.
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http://dx.doi.org/10.1016/j.jfma.2019.01.015DOI Listing
January 2020

Klotho-beta and fibroblast growth factor 19 expression correlates with early recurrence of resectable hepatocellular carcinoma.

Liver Int 2019 09 11;39(9):1682-1691. Epub 2019 Jul 11.

Department of Oncology, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.

Background And Aims: Fibroblast growth factor 19 (FGF19) and fibroblast growth factor receptor 4 (FGFR4) signalling play critical roles in hepatocarcinogenesis. This study explored the potential of FGF19- and FGFR4-related biomarkers in predicting early tumour recurrence (ETR) and survival in patients with resectable hepatocellular carcinoma (HCC).

Methods: We examined the mRNA expressions of FGF19, FGFR4, klotho-beta (KLB), cyclin D1 (CCND1) and FGF4 in 151 surgically resected, primary unifocal HCCs through quantitative real-time polymerase chain reaction. Generalized additive models were fitted to detect nonlinear effects of continuous covariates and define thresholds of biomarker expressions. Univariate and multivariate analyses were performed to evaluate prognostic values of these biomarkers for tumour recurrence and patient survival.

Results: Overexpression of FGF19, FGFR4, KLB, CCND1 and FGF4 mRNA was detected in 40%, 32%, 26%, 15% and 35% of 151 tumours respectively. ETR was the strongest prognostic factor predicting worse overall survival (hazard ratio [HR], 5.678; 95% confidence interval, 3.7-8.713; P < 0.001). Furthermore, we revealed that mRNA expression levels of KLB (HR, 3.857; P = 0.021) and FGF19 (HR, 3.248; P = 0.017) were significantly associated with the occurrence of ETR.

Conclusions: Frequent overexpression of FGF19/FGFR4-related biomarkers was detected in resectable HCC. Expression levels of KLB and FGF19 may determine patient survival outcomes through their effects on ETR.
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http://dx.doi.org/10.1111/liv.14055DOI Listing
September 2019

Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis.

BMJ 2018 Nov 8;363:k4226. Epub 2018 Nov 8.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, China

Objective: To provide a complete toxicity profile, toxicity spectrum, and a safety ranking of immune checkpoint inhibitor (ICI) drugs for treatment of cancer.

Design: Systematic review and network meta-analysis.

Data Sources: Electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) were systematically searched to include relevant studies published in English between January 2007 and February 2018.

Review Methods: Only head-to-head phase II and III randomised controlled trials comparing any two or three of the following treatments or different doses of the same ICI drug were included: nivolumab, pembrolizumab, ipilimumab, tremelimumab, atezolizumab, conventional therapy (chemotherapy, targeted therapy, and their combinations), two ICI drugs, or one ICI drug with conventional therapy. Eligible studies must have reported site, organ, or system level data on treatment related adverse events. High quality, single arm trials and placebo controlled trials on ICI drugs were selected to establish a validation group.

Results: 36 head-to-head phase II and III randomised trials (n=15 370) were included. The general safety of ICI drugs ranked from high to low for all adverse events was as follows: atezolizumab (probability 76%, pooled incidence 66.4%), nivolumab (56%, 71.8%), pembrolizumab (55%, 75.1%), ipilimumab (55%, 86.8%), and tremelimumab (54%, not applicable). The general safety of ICI drugs ranked from high to low for severe or life threatening adverse events was as follows: atezolizumab (49%, 15.1%), nivolumab (46%, 14.1%), pembrolizumab (72%, 19.8%), ipilimumab (51%, 28.6%), and tremelimumab (28%, not applicable). Compared with conventional therapy, treatment-related adverse events for ICI drugs occurred mainly in the skin, endocrine, hepatic, and pulmonary systems. Taking one ICI drug was generally safer than taking two ICI drugs or one ICI drug with conventional therapy. Among the five ICI drugs, atezolizumab had the highest risk of hypothyroidism, nausea, and vomiting. The predominant treatment-related adverse events for pembrolizumab were arthralgia, pneumonitis, and hepatic toxicities. The main treatment-related adverse events for ipilimumab were skin, gastrointestinal, and renal toxicities. Nivolumab had a narrow and mild toxicity spectrum, mainly causing endocrine toxicities. Integrated evidence from the pooled incidences, subgroup, and sensitivity analyses implied that nivolumab is the best option in terms of safety, especially for the treatment of lung cancer.

Conclusions: Compared with other ICI drugs used to treat cancer, atezolizumab had the best safety profile in general, and nivolumab had the best safety profile in lung cancer when taking an integrated approach. The safety ranking of treatments based on ICI drugs is modulated by specific treatment-related adverse events.

Systematic Review Registration: PROSPERO CRD42017082553.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222274PMC
http://dx.doi.org/10.1136/bmj.k4226DOI Listing
November 2018

Immunomodulatory Effects of Current Targeted Therapies on Hepatocellular Carcinoma: Implication for the Future of Immunotherapy.

Semin Liver Dis 2018 Nov 24;38(4):379-388. Epub 2018 Oct 24.

Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.

Multikinase inhibitors with antiangiogenic properties used to be standard therapy for patients with advanced hepatocellular carcinoma (HCC). Recently, several antiangiogenic agents (lenvatinib, cabozantinib, and ramucirumab) have demonstrated antitumor activity for advanced HCC in randomized controlled trials. However, the landscape of drug development for HCC may change dramatically with the advent of immune checkpoint inhibitor therapy, particularly the anti-programmed cell death-1 (anti-PD1) agents. In addition, early-phase clinical trials of combination of anti-PD-1 and antiangiogenic agents have shown very promising anti-tumor activity in patients with advanced HCC. Therefore, the critical research questions at present are whether this combination strategy will be the next generation of standard therapy and which antiangiogenic agents will be the optimal partner for the combination. All of the 4 multikinase inhibitors for HCC (sorafenib, regorafenib, lenvatinib, and cabozantinib) have been reported to have immune modulatory effects. The authors systematically reviewed the pre-clinical evidence of their immune modulatory effects to explore whether these effects were mediated by angiogenesis inhibition or by other "off-target" effects on the tumor microenvironment. Studies of sorafenib comprised the majority (58 of the 71) of the research articles reviewed. Potentially beneficial effects on anti-tumor immunity may result from increased M1 polarization of macrophages and stimulation of CD8 T cell function. On the other hand, high dosage of the kinase inhibitors in pre-clinical models and hypoxia associated with angiogenesis may contribute to immune suppression in the tumor microenvironment. Sorafenib and other multikinase inhibitors may promote anti-tumor immunity through modulation of multiple immune cell types as well as the tumor microenvironment. The optimal immune modulatory dosage should be defined to facilitate design of future combination regimens.
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http://dx.doi.org/10.1055/s-0038-1673621DOI Listing
November 2018

Quantification of HBV core antibodies may help predict HBV reactivation in patients with lymphoma and resolved HBV infection.

J Hepatol 2018 08 16;69(2):286-292. Epub 2018 Mar 16.

Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan; National Taiwan University Cancer Center, Taipei, Taiwan. Electronic address:

Background & Aims: Absence or low anti-HBV surface antibody (anti-HBs) is associated with an increased risk of HBV reactivation in patients with lymphoma and resolved HBV infection receiving rituximab-containing chemotherapy. Quantification of anti-HBV core antibody (anti-HBc) is a new marker associated with the natural history and treatment response of chronic HBV infection. This study investigated whether baseline anti-HBc and anti-HBs levels may better predict HBV reactivation.

Methods: We prospectively measured the HBV DNA levels of patients with lymphoma and resolved HBV infection receiving rituximab-cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone-based chemotherapy and started an antiviral therapy upon HBV reactivation, defined as a greater than 10-fold increase in HBV DNA compared with previous nadir levels. Anti-HBs and anti-HBc were quantified by a double-sandwich assay. Receiver-operating-characteristic-curve analysis was used to determine the optimal baseline anti-HBc/anti-HBs levels for predicting HBV reactivation.

Results: HBV reactivation occurred in 24 of the 197 patients enrolled, with an incidence of 11.6/100 person-years. For the 192 patients with enough serum samples for analysis, low anti-HBs (<56.48 mIU/ml) and high anti-HBc (≥6.41 IU/ml) at baseline were significantly associated with high risk of HBV reactivation (hazard ratio [HR] 8.48 and 4.52, respectively; p <0.01). The multivariate analysis indicated that (1) patients with both high anti-HBc and low anti-HBs at baseline (36 of 192 patients) had an HR of 17.29 for HBV reactivation (95% CI 3.92-76.30; p <0.001), and (2) HBV reactivation may be associated with inferior overall survival (HR 2.41; 95% CI 1.15-5.05; p = 0.02).

Conclusions: Baseline anti-HBc/anti-HBs levels may predict HBV reactivation in these patients with lymphoma and help optimize prophylactic antiviral therapy for high-risk patients.

Lay Summary: In this study, we identified a subgroup of patients with lymphoma and resolved hepatitis B virus infection that had a high risk of hepatitis B virus reactivation after receiving rituximab-containing chemotherapy. These findings will help optimize a preventive strategy, especially in hepatitis B virus endemic regions with limited healthcare resources. Clinical trial number: NCT 00931229.
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http://dx.doi.org/10.1016/j.jhep.2018.02.033DOI Listing
August 2018

Simultaneous visualization of the subfemtomolar expression of microRNA and microRNA target gene using HILO microscopy.

Chem Sci 2017 Sep 31;8(9):6670-6678. Epub 2017 Jul 31.

Department of Chemistry , Tunghai University , Taichung 407 , Taiwan . Email:

The family of microRNAs (miRNAs) not only plays an important role in gene regulation but is also useful for the diagnosis of diseases. A reliable method with high sensitivity may allow researchers to detect slight fluctuations in ultra-trace amounts of miRNA. In this study, we propose a sensitive imaging method for the direct probing of miR-10b (miR-10b-3p, also called miR-10b*) and its target ( mRNA) in fixed cells based on the specific recognition of molecular beacons combined with highly inclined and laminated optical sheet (HILO) fluorescence microscopy. The designed dye-quencher-labelled molecular beacons offer excellent efficiencies of fluorescence resonance energy transfer that allow us to detect miRNA and the target mRNA simultaneously in hepatocellular carcinoma cells using HILO fluorescence microscopy. Not only can the basal trace amount of miRNA be observed in each individual cell, but the obtained images also indicate that this method is useful for monitoring the fluctuations in ultra-trace amounts of miRNA when the cells are transfected with a miRNA precursor or a miRNA inhibitor (anti-miR). Furthermore, a reasonable causal relation between the miR-10b and expression levels was observed in miR-10b* precursor-transfected cells and miR-10b* inhibitor-transfected cells. The trends of the miRNA alterations obtained using HILO microscopy completely matched the RT-qPCR data and showed remarkable reproducibility (the coefficient of variation [CV] = 0.86%) and sensitivity (<1.0 fM). This proposed imaging method appears to be useful for the simultaneous visualisation of ultra-trace amounts of miRNA and target mRNA and excludes the procedures for RNA extraction and amplification. Therefore, the visualisation of miRNA and the target mRNA should facilitate the exploration of the functions of ultra-trace amounts of miRNA in fixed cells in biological studies and may serve as a powerful tool for diagnoses based on circulating cancer cells.
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http://dx.doi.org/10.1039/c7sc02701jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625256PMC
September 2017

Safety and Antitumor Activity of Pembrolizumab in Patients With Programmed Death-Ligand 1-Positive Nasopharyngeal Carcinoma: Results of the KEYNOTE-028 Study.

J Clin Oncol 2017 Dec 24;35(36):4050-4056. Epub 2017 Aug 24.

Chiun Hsu, National Taiwan University Hospital, Graduate Institute of Oncology, National Taiwan University College of Medicine, and National Taiwan University Cancer Center, Taipei, Taiwan, Republic of China; Se-Hoon Lee, Seoul National University Hospital, Seoul, South Korea; Samuel Ejadi, Virginia G. Piper Cancer Center, Scottsdale, AZ; Roger B. Cohen, University of Pennsylvania, Philadelphia, PA; Janice M. Mehnert, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ; Alain Algazi, University of California, San Francisco, San Francisco, CA; Sanatan Saraf, Pradeep Thanigaimani, and Jonathan D. Cheng, Merck & Co., Inc., Kenilworth, NJ; Caroline Even, Gustave Roussy, Villejuif; Christophe Le Tourneau, Institut Curie, Paris; Christophe Le Tourneau, INSERM U900 Research Unit, Saint-Cloud, France; Emilie M.J. van Brummelen, Netherlands Cancer Institute, Amsterdam, the Netherlands; and Aaron R. Hansen, Princess Margaret Cancer Centre, Toronto, ON, Canada.

Purpose To establish the safety profile and antitumor activity of the anti-programmed death 1 receptor monoclonal antibody, pembrolizumab, in patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) that expressed programmed death-ligand 1 (PD-L1). Patients and Methods KEYNOTE-028 (NCT02054806) is a nonrandomized, multicohort, phase Ib trial of pembrolizumab in patients with PD-L1-positive advanced solid tumors. Key eligibility criteria for the NPC cohort included unresectable or metastatic disease, failure on prior standard therapy, and PD-L1 expression in 1% or more of tumor cells or tumor-infiltrating lymphocytes. Patients received pembrolizumab 10 mg/kg every 2 weeks up to 2 years or until disease progression or unacceptable toxicity. Primary end point was objective response rate (ORR) per investigator review. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) every 8 weeks for the first 6 months and every 12 weeks thereafter. Results Twenty-seven patients received pembrolizumab. Median age was 52.0 years (range, 18 to 68 years); 92.6% received prior therapies for RM-NPC; 70.4% had received three or more therapies. Partial response and stable disease were observed in seven and 14 patients, respectively, for an ORR of 25.9% (95% CI, 11.1 to 46.3) over a median follow-up of 20 months. ORR by central review was similar (26.3%). Drug-related adverse events that occurred in 15% or more of patients included rash (25.9%), pruritus (25.9%), pain (22.2%), hypothyroidism (18.5%), and fatigue (18.5%). Grade ≥ 3 drug-related adverse events occurred in eight patients (29.6%), and there was one drug-related death (sepsis). As of the data cutoff (June 20, 2016), two patients remained on pembrolizumab treatment. Conclusion Pembrolizumab demonstrated antitumor activity and a manageable safety profile in patients with RM-NPC.
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http://dx.doi.org/10.1200/JCO.2017.73.3675DOI Listing
December 2017
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