Publications by authors named "Chia-Jui Yen"

127 Publications

Investigating the association between serum human papillomavirus type 16 E7 antibodies and risk of head and neck cancer.

Cancer Med 2021 May 4. Epub 2021 May 4.

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

Human papillomavirus (HPV) is recognized as a major cause of oropharyngeal cancer (OPC) in Western countries. Less is known regarding its contribution to the OPC occurring in Asia. The current study aimed to investigate the association between antibody responses to HPV16 E7 and head and neck cancer (HNC) risk in a hospital-based case-control study conducted in Taiwan with 693 HNC cases and 1,035 controls. A positive association was observed between seropositivity to HPV16 E7 and OPC risk, whereas no significant association was found in the non-OPC cases. The increased OPC risk associated with seropositivity to HPV16 E7 was more significant among nonbetel quid or noncigarette users. Seropositivity to HPV16 E7 showed moderate agreement with P16 expression in OPC. OPC patients that were seropositive to HPV16 E7 or p16 positive were more highly educated and less likely to use alcohol, betel quids, and cigarettes compared to HPV16 E7 seronegative or p16 negative OPC patients. Furthermore, patients with p16 positive OPC were more likely to be women compared to patients with p16 negative OPC, likely owing to the low prevalence of alcohol, betel quid, and cigarette users among women. Overall, this study suggested that similar to Western countries, HPV may also be an important risk factor of OPC in Taiwan. With the declining consumption of betel quids and cigarettes in Taiwan, a higher percentage of OPC cases in Taiwan will be attributed to HPV in the future. Public health measures, including HPV vaccination, need to be implemented to prevent the occurrence of HPV-positive OPC.
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http://dx.doi.org/10.1002/cam4.3944DOI Listing
May 2021

Clinical and Immunologic Responses to a B-Cell Epitope Vaccine in Patients with HER2/neu-Overexpressing Advanced Gastric Cancer-Results from Phase Ib Trial IMU.ACS.001.

Clin Cancer Res 2021 Apr 20. Epub 2021 Apr 20.

Imugene Limited, Sydney, Australia.

Purpose: HER2/neu is overexpressed in up to 30% of gastroesophageal adenocarcinomas (GEA) and linked to poor prognosis. Recombinant mAbs to treat HER2/neu-overexpressing cancers are effective with limitations, including resistance and toxicity. Therefore, we developed a therapeutic B-cell epitope vaccine (IMU-131/HER-Vaxx) consisting of three fused B-cell epitopes from the HER2/neu extracellular domain coupled to CRM197 and adjuvanted with Montanide. This phase Ib study aimed to evaluate the optimal/safe dose leading to immunogenicity and clinical responses (https//clinicaltrials.gov/ct2/show/NCT02795988).

Patients And Methods: A total of 14 patients with HER2/neu-overexpressing GEA were enrolled, and dose escalation (10, 30, 50 μg) was performed in three cohorts (C). Immunogenicity was evaluated by HER2-specific Abs and cellular responses, clinical responses by CT scans according to RECIST version 1.1.

Results: IMU-131 was safe without vaccine-related significant local/systemic reactions or serious adverse events. A total of 11 of 14 patients were evaluable for changes in tumor size and vaccine-specific immune responses. One patient showed complete, 5 partial responses, and 4 stable diseases as their best response. HER2-specific IgG levels were dose dependent. In contrast to patients in C1 and C2, all patients in C3 mounted substantial HER2-specific Ab levels. In addition, cellular vaccine responses, such as Th1-biased cytokine ratios and reduced regulatory T cell numbers, were generated. Progression-free survival was prolonged in C3, correlating with the vaccine-specific humoral and cellular responses.

Conclusions: IMU-131 was well tolerated and safe. The induced HER2-specific Abs and cellular responses were dose dependent and correlated with clinical responses. The highest dose (50 μg) was recommended for further evaluation in a phase II trial, with chemotherapy + IMU-131 or chemotherapy alone, which is currently ongoing.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3742DOI Listing
April 2021

Comparing the Clinicopathological Characteristics of Combined Hepatocellular-Cholangiocarcinoma with Other Primary Liver Cancers Using the Updated WHO Classification.

Histopathology 2021 Apr 10. Epub 2021 Apr 10.

Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is an uncommon hepatic malignancy with a poor outcome. The 2019 WHO classification modified the definition and discarded the subtypes harboring stem cell features. However, the differences among cHCC-CCA, hepatocellular carcinoma (HCC), HCC with stem cell features (HCCscf) and intrahepatic cholangiocarcinoma (iCCA) remain undetermined. The aim of the study is to investigate the characteristics of cHCC-CCA in comparisons with other primary liver cancers utilizing the updated WHO classification.

Methods And Results: We retrospectively analyzed 64 cHCC-CCA and 55 HCCscf patients from Dec2007 to May2018. A propensity score matching was conducted to compare with HCC and iCCA patients. Clinicopathological characteristics, event-free (EFS) and overall survival (OS) were evaluated with multivariate Cox proportional hazard regression. In a median follow-up of 55.9 months, patients with cHCC-CCA had a significantly poor survival as compared with HCCscf and an intermediate survival outcome between HCC and iCCA. HBV infection and high tumor infiltrating lymphocytes (TILs) were associated with a favorable survival in cHCC-CCA. In the multivariate analysis, poor hepatic reserve, absence of HBV infection, stage IV disease and low TILs were significant negative prognostic factors in cHCC-CCA. After pooling with other primary liver cancers, tumor type of cHCC-CCA and iCCA predicted the worse survival results.

Conclusion: cHCC-CCA have an intermediate survival between HCC and iCCA and HBV infection and high TILs predict the favorable survival. Our study provides clinical correlations for the new 2019 WHO classification.
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http://dx.doi.org/10.1111/his.14384DOI Listing
April 2021

Assessment of Pembrolizumab Therapy for the Treatment of Microsatellite Instability-High Gastric or Gastroesophageal Junction Cancer Among Patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 Clinical Trials.

JAMA Oncol 2021 Apr 1. Epub 2021 Apr 1.

David Geffen School of Medicine, University of California, Los Angeles.

Importance: Immunotherapy has been associated with improved outcomes among patients who have received previous treatment for microsatellite instability-high (MSI-H) tumors.

Objective: To evaluate the antitumor activity of pembrolizumab therapy vs chemotherapy among patients with MSI-H advanced gastric or gastroesophageal junction (G/GEJ) cancer regardless of the line of therapy in which it was received.

Design, Setting, And Participants: This post hoc analysis of the phase 2 KEYNOTE-059 (third-line treatment or higher) single-arm trial and the phase 3 KEYNOTE-061 (second-line treatment) and KEYNOTE-062 (first-line treatment) randomized trials included patients with advanced G/GEJ cancer from 52 sites in 16 countries enrolled in KEYNOTE-059, 148 sites in 30 countries enrolled in KEYNOTE-061, and 200 sites in 29 countries enrolled in KEYNOTE-062. Patients were enrolled from March 2, 2015, to March 26, 2016, in KEYNOTE-059; from June 4, 2015, to July 26, 2016, in KEYNOTE-061; and from September 18, 2015, to May 26, 2017, in KEYNOTE-062, with data cutoff dates of August 8, 2018; October 26, 2017; and March 26, 2019; respectively.

Interventions: Pembrolizumab monotherapy in KEYNOTE-059, pembrolizumab monotherapy or chemotherapy (paclitaxel) in KEYNOTE-061, and pembrolizumab monotherapy, pembrolizumab plus chemotherapy (cisplatin and 5-fluorouracil or capecitabine), or chemotherapy alone in KEYNOTE-062.

Main Outcomes And Measures: Response was assessed centrally using Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1; MSI-H status was determined centrally by polymerase chain reaction testing.

Results: At data cutoff, 7 of 174 patients (4.0%) in KEYNOTE-059, 27 of 514 patients (5.3%) in KEYNOTE-061, and 50 of 682 patients (7.3%) in KEYNOTE-062 had MSI-H tumors. Among those with MSI-H tumors, the median overall survival was not reached (NR) for pembrolizumab in KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 or for pembrolizumab plus chemotherapy in KEYNOTE-062. The median progression-free survival (PFS) for pembrolizumab was NR (95% CI, 1.1 months to NR) in KEYNOTE-059 and 17.8 months (95% CI, 2.7 months to NR) in KEYNOTE-061 (vs 3.5 months [95% CI, 2.0-9.8 months] for chemotherapy). In KEYNOTE-062, the median PFS was 11.2 months (95% CI, 1.5 months to NR) for pembrolizumab, NR (95% CI, 3.6 months to NR) for pembrolizumab plus chemotherapy, and 6.6 months (95% CI, 4.4-8.3 months) for chemotherapy. The objective response rate (ORR) for pembrolizumab was 57.1% in KEYNOTE-059 and 46.7% (vs 16.7% for chemotherapy) in KEYNOTE-061. In KEYNOTE-062, the ORR was 57.1% for pembrolizumab , 64.7% for pembrolizumab plus chemotherapy, and 36.8% for chemotherapy.

Conclusions And Relevance: Findings from this study indicate that MSI-H status may be a biomarker for pembrolizumab therapy among patients with advanced G/GEJ cancer regardless of the line of therapy in which it was received.

Trial Registration: ClinicalTrials.gov Identifiers: NCT02335411, NCT02370498, and NCT02494583.
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http://dx.doi.org/10.1001/jamaoncol.2021.0275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017478PMC
April 2021

Metformin Resensitizes Sorafenib-Resistant HCC Cells Through AMPK-Dependent Autophagy Activation.

Front Cell Dev Biol 2020 21;8:596655. Epub 2021 Jan 21.

Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.

Despite the activation of autophagy may enable residual cancer cells to survive and allow tumor relapse, excessive activation of autophagy may eventually lead to cell death. However, the details of the association of autophagy with primary resistance in hepatocellular carcinoma (HCC) remain less clear. In this study, cohort analysis revealed that HCC patients receiving sorafenib with HBV had higher mortality risk. We found that high epidermal growth factor receptor (EGFR) expression and activity may be linked to HBV-induced sorafenib resistance. We further found that the resistance of EGFR-overexpressed liver cancer cells to sorafenib is associated with low activity of AMP-activated protein kinase (AMPK) and CCAAT/enhancer binding protein delta (CEBPD) as well as insufficient autophagic activation. In response to metformin, the AMPK/cAMP-response element binding protein (CREB) pathway contributes to CEBPD activation, which promotes autophagic cell death. Moreover, treatment with metformin can increase sorafenib sensitivity through AMPK activation in EGFR-overexpressed liver cancer cells. This study suggests that AMPK/CEBPD-activated autophagy could be a potent strategy for improving the efficacy of sorafenib in HCC patients.
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http://dx.doi.org/10.3389/fcell.2020.596655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931828PMC
January 2021

Palbociclib and cetuximab compared with placebo and cetuximab in platinum-resistant, cetuximab-naïve, human papillomavirus-unrelated recurrent or metastatic head and neck squamous cell carcinoma: A double-blind, randomized, phase 2 trial.

Oral Oncol 2021 04 8;115:105192. Epub 2021 Feb 8.

Head and Neck Oncology Division, Japanese National Cancer Center, Chiba, Japan.

Objectives: This study examined whether palbociclib and cetuximab prolonged overall survival (OS) versus placebo and cetuximab.

Materials And Methods: In this double-blind, randomized, phase 2 trial (PALATINUS), patients with platinum-resistant, cetuximab-naïve, human papillomavirus-unrelated recurrent/metastatic head and neck squamous-cell carcinoma received cetuximab and either palbociclib (arm A) or placebo (arm B). The primary endpoint was OS; 120 patients were required to have ≥80% power to detect a hazard ratio (HR) of 0.6 (median OS of 10 months in arm A and 6 months in arm B) using a one-sided, log-rank test (P = 0.10).

Results: 125 patients were randomized (arm A: 65, arm B: 60). Median follow-up was 15.9 months (IQR, 11.3-22.7). Median OS was 9.7 months in arm A and 7.8 months in arm B (HR, 0.82; 95% CI, 0.54-1.25; P = 0.18). Median progression-free survival was 3.9 months in arm A and 4.6 months in arm B (HR, 1.00; 95% CI, 0.67-1.5; P = 0.50). The most common treatment-related adverse events in arm A were rash (39 patients, 60.9%) and neutropenia (26, 40.6%; three febrile) and in arm B was rash (32, 53.3%).

Conclusion: There was no significant difference in median OS with palbociclib and cetuximab versus placebo and cetuximab.

Funding: Pfizer Inc (NCT02499120).
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http://dx.doi.org/10.1016/j.oraloncology.2021.105192DOI Listing
April 2021

Effects of Exercise in Patients Undergoing Chemotherapy for Head and Neck Cancer: A Pilot Randomized Controlled Trial.

Int J Environ Res Public Health 2021 02 1;18(3). Epub 2021 Feb 1.

Department of Physical Therapy, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.

Background: Cisplatin administration may induce muscle atrophy, thereby reducing the fitness level of patients with head and neck cancer (HNC). To date, only animal studies have been conducted to test the effectiveness of exercise interventions in diminishing side effects of cisplatin.

Aim: To determine whether exercise training improves physical fitness and health-related quality of life (HRQoL) in patients receiving chemotherapy for Head & Neck (H&N).

Material And Methods: This pilot-randomized controlled trial was conducted on 57 participants receiving chemotherapy for HNC. The participants were randomized into an exercise group and a control group. The exercise group received moderate-intensity combined aerobic, resistance and flexibility exercises three times a week for eight weeks during chemotherapy. The control group received no specific information regarding exercise. The outcome measures including body composition, muscle strength, balance, flexibility, cardiovascular fitness and health-related quality of life (HRQoL) were assessed at baseline and eight weeks following baseline.

Results: The body composition (body fat percentage, = 0.002; skeletal muscle percentage, = 0.008), dynamic balance ( = 0.01), muscle strength (upper extremity, = 0.037; lower extremity, = 0.025) and HRQoL ( = 0.001) showed a significant difference between the exercise group and the control group eight weeks following baseline. Significant deteriorations were noted in flexibility, muscle strength, cardiovascular fitness and several domains of HRQoL scale in the control group at eight weeks following baseline.

Conclusions: This study found that a combined aerobic, resistance and flexibility exercise program during chemotherapy may improve physical fitness (i.e., muscle strength, balance, flexibility and body composition) and HRQoL and alleviate the deterioration of cardiovascular fitness in patients with HNC. Further research studies with large sample sizes are warranted to investigate the long-term effects of exercise in this population.
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http://dx.doi.org/10.3390/ijerph18031291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908197PMC
February 2021

Serum alpha-fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with ramucirumab.

Br J Cancer 2021 Apr 3;124(8):1388-1397. Epub 2021 Feb 3.

Kindai University, Osaka, Japan.

Background: Post hoc analyses assessed the prognostic and predictive value of baseline alpha-fetoprotein (AFP), as well as clinical outcomes by AFP response or progression, during treatment in two placebo-controlled trials (REACH, REACH-2).

Methods: Serum AFP was measured at baseline and every three cycles. The prognostic and predictive value of baseline AFP was assessed by Cox regression models and Subpopulation Treatment Effect Pattern Plot method. Associations between AFP (≥ 20% increase) and radiographic progression and efficacy were assessed.

Results: Baseline AFP was confirmed as a continuous (REACH, REACH-2; p < 0.0001) and dichotomous (≥400 vs. <400 ng/ml; REACH, p < 0.01) prognostic factor, and was predictive for ramucirumab survival benefit in REACH (p = 0.0042 continuous; p < 0.0001 dichotomous). Time to AFP (hazard ratio [HR] 0.513; p < 0.0001) and radiographic (HR 0.549; p < 0.0001) progression favoured ramucirumab. Association between AFP and radiographic progression was shown for up to 6 (odds ratio [OR] 5.1; p < 0.0001) and 6-12 weeks (OR 1.8; p = 0.0065). AFP response was higher with ramucirumab vs. placebo (p < 0.0001). Survival was longer in patients with an AFP response than patients without (13.6 vs. 5.6 months, HR 0.451; 95% confidence interval, 0.354-0.574; p < 0.0001).

Conclusions: AFP is an important prognostic factor and a predictive biomarker for ramucirumab survival benefit. AFP ≥ 400 ng/ml is an appropriate selection criterion for ramucirumab.

Clinical Trial Registration: ClinicalTrials.gov, REACH (NCT01140347) and REACH-2 (NCT02435433).
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http://dx.doi.org/10.1038/s41416-021-01260-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039038PMC
April 2021

Recent Advances in Photodynamic Therapy for Deep-Seated Tumors with the Aid of Nanomedicine.

Biomedicines 2021 Jan 12;9(1). Epub 2021 Jan 12.

Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.

Photodynamic therapy (PDT) works through photoactivation of a specific photosensitizer (PS) in a tumor in the presence of oxygen. PDT is widely applied in oncology to treat various cancers as it has a minimally invasive procedure and high selectivity, does not interfere with other treatments, and can be repeated as needed. A large amount of reactive oxygen species (ROS) and singlet oxygen is generated in a cancer cell during PDT, which destroys the tumor effectively. However, the efficacy of PDT in treating a deep-seated tumor is limited due to three main reasons: Limited light penetration depth, low oxygen concentration in the hypoxic core, and poor PS accumulation inside a tumor. Thus, PDT treatments are only approved for superficial and thin tumors. With the advancement of nanotechnology, PDT to treat deep-seated or thick tumors is becoming a reachable goal. In this review, we provide an update on the strategies for improving PDT with nanomedicine using different sophisticated-design nanoparticles, including two-photon excitation, X-ray activation, targeting tumor cells with surface modification, alteration of tumor cell metabolism pathways, release of therapeutic gases, improvement of tumor hypoxia, and stimulation of host immunity. We focus on the difficult-to-treat pancreatic cancer as a model to demonstrate the influence of advanced nanomedicine in PDT. A bright future of PDT application in the treatment of deep-seated tumors is expected.
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http://dx.doi.org/10.3390/biomedicines9010069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828119PMC
January 2021

Effect of ramucirumab on ALBI grade in patients with advanced HCC: Results from REACH and REACH-2.

JHEP Rep 2021 Apr 13;3(2):100215. Epub 2020 Nov 13.

Massachusetts General Hospital Cancer Center, Harvard Medical Center, Boston, MA, USA.

Background & Aims: The albumin-bilirubin (ALBI) grade/score is derived from a validated nomogram to objectively assess prognosis and liver function in patients with hepatocellular carcinoma (HCC). In this analysis, we assessed prognosis in terms of survival by baseline ALBI grade and monitored liver function during treatment with ramucirumab or placebo using the ALBI score in patients with advanced HCC.

Methods: Patients with advanced HCC, Child-Pugh class A with prior sorafenib treatment were randomised in REACH trials to receive ramucirumab 8 mg/kg or placebo every 2 weeks. Data were analysed by trial and as a meta-analysis of individual patient-level data (pooled population) from REACH (alpha-fetoprotein ≥400 ng/ml) and REACH-2. Patients from REACH with Child-Pugh class B were analysed as a separate cohort. The ALBI grades and scores were calculated at baseline and before each treatment cycle.

Results: Baseline characteristics by ALBI grade were balanced between treatment arms among patients in the pooled population (ALBI-1, n = 231; ALBI-2, n = 296; ALBI-3, n = 7). Baseline ALBI grade was prognostic for overall survival (OS; ALBI grade 2 1; hazard ratio [HR]: 1.38 [1.13-1.69]), after adjusting for other significant prognostic factors. Mean ALBI scores remained stable in both treatment arms compared with baseline and were unaffected by baseline ALBI grade, macrovascular invasion, tumour response, geographical region, or prior locoregional therapy. Baseline ALBI grades 2 and 3 were associated with increased incidence of liver-specific adverse events and discontinuation rates in both treatments. Ramucirumab improved OS in patients with baseline ALBI grade 1 (HR 0.605 [0.445-0.824]) and ALBI grade 2 (HR 0.814 [0.630-1.051]).

Conclusions: Compared with placebo, ramucirumab did not negatively impact liver function and improved survival irrespective of baseline ALBI grade.

Lay Summary: Hepatocellular carcinoma is the third leading cause of cancer-related death worldwide. Prognosis is affected by many clinical factors including liver function both before and during anticancer treatment. Here we have used a validated approach to assess liver function using 2 laboratory parameters, serum albumin and bilirubin (ALBI), both before and during treatment with ramucirumab in 2 phase III placebo-controlled studies. We confirm the practicality of using this more simplistic approach in assessing liver function prior to and during anticancer therapy, and demonstrate ramucirumab did not impair liver function when compared with placebo.
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http://dx.doi.org/10.1016/j.jhepr.2020.100215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772786PMC
April 2021

Phase I Dose-Escalation Study of SCB01A, a Microtubule Inhibitor with Vascular Disrupting Activity, in Patients with Advanced Solid Tumors.

Oncologist 2021 04 18;26(4):e567-e579. Epub 2020 Dec 18.

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

Lessons Learned: SCB01A is a novel microtubule inhibitor with vascular disrupting activity. This first-in-human study demonstrated SCB01A safety, pharmacokinetics, and preliminary antitumor activity. SCB01A is safe and well tolerated in patients with advanced solid malignancies with manageable neurotoxicity.

Background: SCB01A, a novel microtubule inhibitor, has vascular disrupting activity.

Methods: In this phase I dose-escalation and extension study, patients with advanced solid tumors were administered intravenous SCB01A infusions for 3 hours once every 21 days. Rapid titration and a 3 + 3 design escalated the dose from 2 mg/m to the maximum tolerated dose (MTD) based on dose-limiting toxicity (DLT). SCB01A-induced cellular neurotoxicity was evaluated in dorsal root ganglion cells. The primary endpoint was MTD. Safety, pharmacokinetics (PK), and tumor response were secondary endpoints.

Results: Treatment-related adverse events included anemia, nausea, vomiting, fatigue, fever, and peripheral sensorimotor neuropathy. DLTs included grade 4 elevated creatine phosphokinase (CPK) in the 4 mg/m cohort; grade 3 gastric hemorrhage in the 6.5 mg/m cohort; grade 2 thromboembolic event in the 24 mg/m cohort; and grade 3 peripheral sensorimotor neuropathy, grade 3 elevated aspartate aminotransferase, and grade 3 hypertension in the 32 mg/m cohort. The MTD was 24 mg/m , and average half-life was ~2.5 hours. The area under the curve-dose response relationship was linear. Nineteen subjects were stable after two cycles. The longest treatment lasted 24 cycles. SCB01A-induced neurotoxicity was reversible in vitro.

Conclusion: The MTD of SCB01A was 24 mg/m every 21 days; it is safe and tolerable in patients with solid tumors.
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http://dx.doi.org/10.1002/onco.13612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018321PMC
April 2021

Author Correction: The Impact of Liposomal Irinotecan on the Treatment of Advanced Pancreatic Adenocarcinoma: Real-World Experience in a Taiwanese Cohort.

Sci Rep 2020 Nov 13;10(1):20199. Epub 2020 Nov 13.

National Institute of Cancer Research, National Health Research Institutes, Tainan, 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/s41598-020-77250-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666201PMC
November 2020

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
December 2020

Effect of Exercise Training on Exercise Tolerance and Level of Oxidative Stress for Head and Neck Cancer Patients Following Chemotherapy.

Front Oncol 2020 18;10:1536. Epub 2020 Aug 18.

Department of Physical Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Background: Chemotherapy decreases fitness performance via repression of cardiopulmonary function and oxidative stress. This study was designed to investigate whether exercise intervention could improve exercises capacity and reduce systemic oxidative stress in patients with head and neck (H&N) cancer receiving chemotherapy.

Methods: This is a single-center study. Forty-two H&N cancer patients who were undergoing chemotherapy were recruited in this study. An 8-week exercise intervention was performed by conducting the combination of aerobic and resistance exercise 3 days a week. The exercise training was conducted by a physiotherapist. The exercise capacity and exercise responses were measured from blood pressure (BP) and heart rate (HR). Oxidative stress markers from human plasma, such as total antioxidant capacity, 8-hydroxy-2'-deoxyguanosine, malondialdehyde, and carbonyl content, were tested by activity kits.

Results: We provide compelling evidence that exercise training ameliorated exercise responses and increased exercise capacity by repressing resting BP and increasing 1- and 3-min BP recovery. We also found the resting HR was reduced, and the 1- and 3-min HR recovery was increased after exercise training. In addition, the rating of perceived exertion after the peak exercise was reduced after exercise intervention. We also found that exercise training repressed oxidative stress markers by elevation of total antioxidant capacity and suppression of 8-OHd and carbonyl content in plasma.

Discussion: We clearly demonstrate that exercise can promote exercise capacity and reduce oxidative stress in H&N cancer patients receiving chemotherapy, which might guide new therapeutic approaches for cancer patients, especially those undergoing chemotherapy.
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http://dx.doi.org/10.3389/fonc.2020.01536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461975PMC
August 2020

Efficacy and Safety of Ramucirumab in Asian and Non-Asian Patients with Advanced Hepatocellular Carcinoma and Elevated Alpha-Fetoprotein: Pooled Individual Data Analysis of Two Randomized Studies.

Liver Cancer 2020 Aug 5;9(4):440-454. Epub 2020 May 5.

Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Objective: REACH-2 and REACH were randomized, placebo-controlled, double-blind, multicenter phase 3 trials which showed survival benefits of ramucirumab treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP). We evaluated the efficacy and safety of ramucirumab in Asian and non-Asian patients with AFP ≥400 ng/mL from REACH-2 and REACH.

Methods: We pooled Asian and non-Asian patients from the REACH-2 and REACH trials and performed an individual patient data meta-analysis. Overall survival (OS) and progression-free survival were evaluated using the Kaplan-Meier method. Hazard ratios (HRs) were estimated with a stratified Cox regression model.

Results: In the pooled REACH-2 and REACH patient population, 291 Asian patients were randomly assigned to receive ramucirumab ( = 168) or placebo ( = 123), and 251 non-Asian patients received ramucirumab ( = 148) or placebo ( = 103). The median OS was significantly longer in the ramucirumab arm in comparison to the placebo arm for Asian patients (8.08 vs. 4.76 months, stratified HR 0.73 [95% CI 0.56-0.95], = 0.0189) and non-Asian patients (7.98 vs. 5.22 months, stratified HR 0.65 [95% CI 0.49-0.86], = 0.0028). The overall response rate (ORR) and disease control rate (DCR) were significantly higher in the ramucirumab arm compared to the placebo arm for Asian patients (ORR: 4.2 vs. 0.8%; DCR: 53.6 vs. 33.3%) and non-Asian patients (ORR: 6.8 vs. 1.0%; DCR: 59.5 vs. 41.7%). The most common grade ≥3 treatment-emergent adverse events reported in the ramucirumab arm were hypertension (7.7%), decreased appetite (1.2%), and ascites (1.2%) for Asian patients and hypertension (16.9%), ascites (8.8%), asthenia (4.7%), and fatigue (5.4%) for non-Asian patients.

Discussion And Conclusion: This pooled analysis of the REACH-2/REACH trials demonstrates significant benefits, with a manageable safety profile, of ramucirumab treatment in Asian and non-Asian patients with advanced HCC and baseline AFP ≥400 ng/mL.
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http://dx.doi.org/10.1159/000506946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506228PMC
August 2020

Insulin and Metformin Control Cell Proliferation by Regulating TDG-Mediated DNA Demethylation in Liver and Breast Cancer Cells.

Mol Ther Oncolytics 2020 Sep 24;18:282-294. Epub 2020 Jun 24.

Department of Life Sciences, National Cheng Kung University, Tainan City 701, Taiwan.

Type 2 diabetes mellitus (T2DM) is a frequent comorbidity of cancer. Hyperinsulinemia secondary to T2DM promotes cancer progression, whereas antidiabetic agents, such as metformin, have anticancer effects. However, the detailed mechanism for insulin and metformin-regulated cancer cell proliferation remains unclear. This study identified a mechanism by which insulin upregulated the expression of c-Myc, sterol regulatory element-binding protein 1 (SREBP1), and acetyl-coenzyme A (CoA) carboxylase 1 (ACC1), which are important regulators of lipogenesis and cell proliferation. Thymine DNA glycosylase (TDG), a DNA demethylase, was transactivated by c-Myc upon insulin treatment, thereby decreasing 5-carboxylcytosine (5caC) abundance in the SREBP1 promoter. On the other hand, metformin-activated AMP-activated protein kinase (AMPK) increased DNA methyltransferase 3A (DNMT3A) activity to increase 5-methylcytosine (5mC) abundance in the TDG promoter. This resulted in decreased TDG expression and enhanced 5caC abundance in the SREBP1 promoter. These findings demonstrate that c-Myc activates, whereas AMPK inhibits, TDG-mediated DNA demethylation of the SREBP1 promoter in insulin-promoted and metformin-suppressed cancer progression, respectively. This study indicates that TDG is an epigenetic-based therapeutic target for cancers associated with T2DM.
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http://dx.doi.org/10.1016/j.omto.2020.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378318PMC
September 2020

Two-year follow-up of a randomized phase III clinical trial of nivolumab vs. the investigator's choice of therapy in the Asian population for recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141).

Head Neck 2020 10 24;42(10):2852-2862. Epub 2020 Jun 24.

Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Background: The present study evaluated the 2-year survival of the Asian population in the CheckMate 141 trial.

Methods: The CheckMate 141 trial included patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). In the present study, 34 Asian patients (nivolumab group: 23 patients; investigator's choice of therapy [IC] group: 11 patients) were analyzed.

Results: The median overall survival (OS) was 12.1 and 6.2 months for the nivolumab and IC groups, respectively. The estimated 2-year OS rates were 22.7% and 0% for the nivolumab and IC groups, respectively. In the nivolumab group, the patients with any treatment-related adverse events (TRAEs), including skin-related disorders, showed better OS than the patients without any TRAEs.

Conclusions: Nivolumab demonstrated prolonged OS benefits in the Asian population with platinum-refractory R/M SCCHN and a favorable safety profile. TRAEs, including skin-related disorders, may be favorable prognostic factors for nivolumab efficacy.

Clinical Trial Registration: NCT02105636.
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http://dx.doi.org/10.1002/hed.26331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540331PMC
October 2020

Phase IA/IB study of single-agent tislelizumab, an investigational anti-PD-1 antibody, in solid tumors.

J Immunother Cancer 2020 06;8(1)

Linear Clinical Research, Nedlands, Western Australia, Australia.

Background: The programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) axis plays a central role in suppressing antitumor immunity; axis dysregulation can be used by cancer cells to evade the immune system. Tislelizumab, an investigational monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding to FcγR on macrophages to limit antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. The aim of this phase IA/IB study was to investigate the safety/tolerability, antitumor effects and optimal dose and schedule of tislelizumab in patients with advanced solid tumors.

Methods: Patients (aged ≥18 years) enrolled in phase IA received intravenous tislelizumab 0.5, 2, 5 or 10 mg/kg every 2 weeks; 2 or 5 mg/kg administered every 2 weeks or every 3 weeks; or 200 mg every 3 weeks; patients in phase IB received 5 mg/kg every 3 weeks. Primary objectives were to assess tislelizumab's safety/tolerability profile by adverse event (AE) monitoring and antitumor activity using RECIST V.1.1. PD-L1 expression was assessed retrospectively with the VENTANA PD-L1 (SP263) Assay.

Results: Between May 2015 and October 2017, 451 patients (n=116, IA; n=335, IB) were enrolled. Fatigue (28%), nausea (25%) and decreased appetite (20%) were the most commonly reported AEs. Most AEs were grade 1-2 severity; anemia (4.9%) was the most common grade 3-4 AE. Treatment-related AEs led to discontinuation in 5.3% of patients. Grade 5 AEs were reported in 14 patients; 2 were considered related to tislelizumab. Pneumonitis (2%) and colitis (1%) were the most common serious tislelizumab-related AEs. As of May 2019, 18% of patients achieved a confirmed objective response in phase IA and 12% in phase IB; median follow-up duration was 13.6 and 7.6 months, respectively. Pharmacokinetics, safety and antitumor activity obtained from both phase IA and IB determined the tislelizumab recommended dose; ultimately, tislelizumab 200 mg intravenous every 3 weeks was the dose and schedule recommended to be taken into subsequent clinical trials.

Conclusions: Tislelizumab monotherapy demonstrated an acceptable safety/tolerability profile. Durable responses were observed in heavily pretreated patients with advanced solid tumors, supporting the evaluation of tislelizumab 200 mg every 3 weeks, as monotherapy and in combination therapy, for the treatment of solid tumors and hematological malignancies.

Trial Registration Number: NCT02407990.
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http://dx.doi.org/10.1136/jitc-2019-000453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295442PMC
June 2020

Investigating the health disparities in the association between lifestyle behaviors and the risk of head and neck cancer.

Cancer Sci 2020 Aug 23;111(8):2974-2986. Epub 2020 Jul 23.

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

Many studies have reported a positive association between lower socioeconomic status (SES) and higher head and neck cancer (HNC) risk. Fewer studies have examined the impact of SES on the association between alcohol or cigarette use and HNC risk. The current case-control study (1104 HNC cases and 1363 controls) investigated the influence of education, a SES indicator, on the association between HNC and the use of alcohol, cigarettes, or betel quids in Taiwan, a country with universal health care. Our results showed a larger increase in HNC risk associated with alcohol among those with lower educational level (odds ratio [OR] = 2.07; 95% confidence interval [CI], 1.53-2.80) than those with higher educational level (OR = 1.38; 95% CI, 1.04-1.85) (heterogeneity-P = .03). Educational level had an influence on the association between alcohol use and HNC risk among those with genetic susceptibility (ALDH2-deficient) to the carcinogenic effect of alcohol. The association between cigarette or betel quid use and HNC risk was similar between the high and low educational groups. National policies and social interventions have led to the decline in the prevalence of cigarette and betel quid users in Taiwan. In contrast, due to the lack of adequate alcohol control policies, alcohol consumption in Taiwan has continued to rise. A higher impact of alcohol on HNC risk among lower SES individuals even with universal health care could be the result of insufficient alcohol control policies in Taiwan.
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http://dx.doi.org/10.1111/cas.14530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419018PMC
August 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

Validation of genome-wide association study-identified single nucleotide polymorphisms in a case-control study of pancreatic cancer from Taiwan.

J Biomed Sci 2020 May 26;27(1):69. Epub 2020 May 26.

National Institute of Cancer Research, National Health Research Institutes, 1F No 367, Sheng-Li Road, Tainan, 70456, Taiwan.

Background: Due to differences in genetic background, it is unclear whether the genetic loci identified by the previous genome-wide association studies (GWAS) of pancreatic cancer also play significant roles in the development of pancreatic cancer among the Taiwanese population.

Methods: This study aimed to validate the 25 pancreatic cancer GWAS-identified single nucleotide polymorphisms (SNPs) in a case-control study (278 cases and 658 controls) of pancreatic cancer conducted in Taiwan. Statistical analyses were conducted to determine the associations between the GWAS-identified SNPs and pancreatic cancer risk. Gene-environment interaction analysis was conducted to evaluate the interactions between SNPs and environmental factors on pancreatic cancer risk.

Results: Among the 25 GWAS-identified SNPs, 7 (rs2816938 (~ 11 kb upstream of NR5A2), rs10094872 (~ 28 kb upstream of MYC), rs9581943 (200 bp upstream of PDX1) and 4 chromosome 13q22.1 SNPs: rs4885093, rs9573163, rs9543325, rs9573166) showed a statistically significant association with pancreatic cancer risk in the current study. Additional analyses showed two significant gene-environment interactions (between poor oral hygiene and NR5A2 rs2816938 and between obesity and PDX1 rs9581943) on the risk of pancreatic cancer.

Conclusions: The current study confirmed the associations between 7 of the 25 GWAS-identified SNPs and pancreatic risk among the Taiwanese population. Furthermore, pancreatic cancer was jointly influenced by lifestyle and medical factors, genetic polymorphisms, and gene-environment interaction. Additional GWAS is needed to determine the genetic polymorphisms that are more relevant to the pancreatic cancer cases occurring in Taiwan.
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http://dx.doi.org/10.1186/s12929-020-00664-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251895PMC
May 2020

The Impact of Liposomal Irinotecan on the Treatment of Advanced Pancreatic Adenocarcinoma: Real-World Experience in a Taiwanese Cohort.

Sci Rep 2020 05 4;10(1):7420. Epub 2020 May 4.

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

Liposomal irinotecan plus 5-fluorouracil/leucovorin (nal-IRI + 5-FU/LV) has shown to provide survival benefits for patients with gemcitabine-refractory metastatic pancreatic ductal adenocarcinoma (PDAC) in NAPOLI-1 trial, in which Asian patients experienced more hematological toxicity and subsequent dose modification. A retrospective chart review to investigate the administration pattern, therapeutic efficacy and safety profile of nal-IRI + 5-FU/LV in 44 consecutive patients with gemcitabine-refractory advanced PDAC treated between December 2016 and December 2018 in National Cheng Kung University Hospital, Taiwan. Most of them had metastatic diseases (88.6%), one-line of prior treatment (72.7%), ECOG PS 0-1 (72.7%) and starting dose of nal-IRI at 60 mg/m (≈52 mg/m irinotecan free-base) in 65.9%. The overall response rate was 9.1%. The median OS was 6.6 months for the entire cohort, and 7.8 and 2.7 months for patients of ECOG PS 0-1 and>2, respectively. The median OS of ECOG PS 0-1 patients with nal-IRI starting doses at 80 mg/m (≈70 mg/m irinotecan free-base, n = 13) and 60 mg/m (n = 19) were 7.5 and 8.4 months, respectively. Thirty-four percent of patients experienced manageable grade 3-4 hematological toxicity. Our results confirm the clinical benefit of nal-IRI + 5-FU/LV for patients of gemcitabine-refractory advanced PDAC with good performance status in a real-world setting.
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http://dx.doi.org/10.1038/s41598-020-64421-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198559PMC
May 2020

Programmed Cell Death-1: Programmed Cell Death-Ligand 1 Interaction Protects Human Cardiomyocytes Against T-Cell Mediated Inflammation and Apoptosis Response In Vitro.

Int J Mol Sci 2020 Mar 31;21(7). Epub 2020 Mar 31.

Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, 1 University Road, Tainan City 70403, Taiwan.

Aim: Immunological checkpoint therapy is considered a powerful method for cancer therapy and acts by re-activating autologous T cells to kill the cancer cell. Myocarditis cases have been reported in cancer patients after immunological therapy; for example, nivolumab treatment is a monoclonal antibody that blocks programmed cell death-1/programmed cell death ligand-1 ligand interaction. This project provided insight into the inflammatory response as a benchmark to investigate the potential cardiotoxic effect of T cell response to the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis in regulating cardiomyocyte injury in vitro.

Methods And Results: We investigated cardiomyopathy resulted from the PD-1/PD-L1 axis blockade using the anti-PD-1 antibody in Rockefeller University embryonic stem cells-derived cardiomyocytes (RUES2-CMs) and a melanoma tumor-bearing murine model. We found that nivolumab alone did not induce inflammatory-related proteins, including PD-L1 expression, and did not induce apoptosis, which was contrary to doxorubicin, a cardiotoxic chemotherapy drug. However, nivolumab was able to exacerbate the immune response by increasing cytokine and inflammatory gene expression in RUES2-CMs when co-cultured with CD4 T lymphocytes and induced apoptosis. This effect was not observed when RUES2-CMs were co-cultured with CD8 T lymphocytes. The in vivo model showed that the heart function of tumor-bearing mice was decreased after treatment with anti-PD-1 antibody and demonstrated a dilated left ventricle histological examination. The dilated left ventricle was associated with an infiltration of CD4 and CD8 T lymphocytes into the myocardium. PD-L1 and inflammatory-associated gene expression were significantly increased in anti-PD-1-treated tumor-bearing mice. Cleaved caspase-3 and mouse plasma cardiac troponin I expressions were increased significantly.

Conclusion: PD-L1 expression on cardiomyocytes suppressed T-cell function. Blockade of PD-1 by nivolumab enhanced cardiomyocyte inflammation and apoptosis through the enhancement of T-cell response towards cardiomyocytes.
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http://dx.doi.org/10.3390/ijms21072399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177768PMC
March 2020

Two first-in-human studies of xentuzumab, a humanised insulin-like growth factor (IGF)-neutralising antibody, in patients with advanced solid tumours.

Br J Cancer 2020 04 12;122(9):1324-1332. Epub 2020 Mar 12.

Department of Oncology, National Taiwan University Hospital, 7 Chung Shan S. Rd., Taipei, Taiwan.

Background: Xentuzumab, an insulin-like growth factor (IGF)-1/IGF-2-neutralising antibody, binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling. Two first-in-human trials assessed the maximum-tolerated/relevant biological dose (MTD/RBD), safety, pharmacokinetics, pharmacodynamics, and activity of xentuzumab in advanced/metastatic solid cancers.

Methods: These phase 1, open-label trials comprised dose-finding (part I; 3 + 3 design) and expansion cohorts (part II; selected tumours; RBD [weekly dosing]). Primary endpoints were MTD/RBD.

Results: Study 1280.1 involved 61 patients (part I: xentuzumab 10-1800 mg weekly, n = 48; part II: 1000 mg weekly, n = 13); study 1280.2, 64 patients (part I: 10-3600 mg three-weekly, n = 33; part II: 1000 mg weekly, n = 31). One dose-limiting toxicity occurred; the MTD was not reached for either schedule. Adverse events were generally grade 1/2, mostly gastrointestinal. Xentuzumab showed dose-proportional pharmacokinetics. Total plasma IGF-1 increased dose dependently, plateauing at ~1000 mg/week; at ≥450 mg/week, IGF bioactivity was almost undetectable. Two partial responses occurred (poorly differentiated nasopharyngeal carcinoma and peripheral primitive neuroectodermal tumour). Integration of biomarker and response data by Bayesian Logistic Regression Modeling (BLRM) confirmed the RBD.

Conclusions: Xentuzumab was well tolerated; MTD was not reached. RBD was 1000 mg weekly, confirmed by BLRM. Xentuzumab showed preliminary anti-tumour activity.

Clinical Trial Registration: NCT01403974; NCT01317420.
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http://dx.doi.org/10.1038/s41416-020-0774-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188670PMC
April 2020

Dishevelled 1-Regulated Superpotent Cancer Stem Cells Mediate Wnt Heterogeneity and Tumor Progression in Hepatocellular Carcinoma.

Stem Cell Reports 2020 03;14(3):462-477

Graduate Institute of Clinical Medicine, Wan Fang Hospital, Taipei Medical University, 250 Wuxing St., Xinyi, Taipei 11031, Taiwan; Laboratory of Advanced Molecular Therapeutics, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan; Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan; Integrative Therapy Center for Gastroenterologic Cancers, Taipei Medical University, Taipei 11031, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan; National Institute of Cancer Research, National Health Research Institutes (NHRIs), Zhunan 35053, Taiwan. Electronic address:

Various populations of cancer stem cells (CSCs) have been identified in hepatocellular carcinoma (HCC). Wnt signaling is variably activated in HCC and regulates CSCs and tumorigenesis. We explored cell-to-cell Wnt and stemness heterogeneity in HCC by labeling freshly isolated cancer cells with a Wnt-specific reporter, thereby identifying a small subset (0.4%-8.9%) of Wnt-activity cells. Further cellular subset analysis identified a refined subset of Wnt-activityALDH1EpCAM triple-positive (TP) cells as the most stem-like, phenotypically plastic, and tumorigenic among all putative CSC populations. These TP "superpotent CSCs" (spCSCs) specifically upregulate the expression of dishevelled 1 (DVL1) through the antagonism between abnormal spindle-like microcephaly-associated (ASPM) and the ubiquitin ligase complex Cullin-3/KLHL-12. Subsequent functional and molecular studies revealed the role of DVL1 in controlling spCSCs and their tumorigenic potential. These findings provide the mechanistic basis of the Wnt and stemness heterogeneity in HCC and highlight the important role of DVL1 spCSCs in tumor progression.
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http://dx.doi.org/10.1016/j.stemcr.2020.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066362PMC
March 2020

Phase I Dose-Escalation and -Expansion Study of Telisotuzumab (ABT-700), an Anti-c-Met Antibody, in Patients with Advanced Solid Tumors.

Mol Cancer Ther 2020 05 3;19(5):1210-1217. Epub 2020 Mar 3.

Virginia G. Piper Cancer Center, Scottsdale Healthcare, Scottsdale, Arizona.

This first-in-human phase I study evaluated the pharmacokinetics, safety, and preliminary efficacy of telisotuzumab, formerly called ABT-700, an antagonistic antibody directed against c-Met. For dose escalation (3+3 design), 3 to 6 patients with advanced solid tumors were enrolled into four dose cohorts (5-25 mg/kg). In the dose-expansion phase, a subset of patients was prospectively selected for amplification (FISH screening). Patients received telisotuzumab intravenously on day 1 every 21 days. For dose expansion, 15 mg/kg was chosen as the dose on the basis of safety, pharmacokinetics, and other data from the escalation cohorts. Forty-five patients were enrolled and received at least one dose of telisotuzumab (dose escalation, = 15; dose expansion, = 30). Telisotuzumab showed a linear pharmacokinetics profile; peak plasma concentration was proportional to dose level. There were no acute infusion reactions and no dose-limiting toxicities were observed. The most common treatment-related adverse events included hypoalbuminemia ( = 9, 20.0%) and fatigue ( = 5, 11.1%). By Response Evaluation Criteria In Solid Tumors (RECIST), 4 of 10 (40.0%) patients with -amplified tumors had confirmed partial response in target lesions (one ovarian, two gastric, and one esophageal), two (20.0%) had stable disease, three (30.0%) had progressive disease; one patient was unable to be evaluated. Among patients with nonamplified tumors ( = 35), no objective responses were observed; however, 11 patients had stable disease per RECIST criteria. In conclusion, telisotuzumab has an acceptable safety profile with clinical activity observed in patients with -amplified advanced solid tumors.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0529DOI Listing
May 2020

A selective Aurora-A 5'-UTR siRNA inhibits tumor growth and metastasis.

Cancer Lett 2020 03 23;472:97-107. Epub 2019 Dec 23.

Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan. Electronic address:

Many Aurora-A inhibitors have been developed for cancer therapy; however, the specificity and safety of Aurora-A inhibitors remain uncertain. The Aurora-A mRNA yields nine different 5'-UTR isoforms, which result from mRNA alternative splicing. Interestingly, we found that the exon 2-containing Aurora-A mRNA isoforms are predominantly expressed in cancer cell lines as well as human colorectal cancer tissues, making the Aurora-A mRNA exon 2 a promising treatment target in Aurora-A-overexpressing cancers. In this study, a selective siRNA, siRNA-2, which targets Aurora-A mRNA exon 2, was designed to translationally inhibit the expression of Aurora-A in cancer cells but not normal cells; locked nucleic acid (LNA)-modified siRNA-2 showed improved efficacy in inhibiting Aurora-A mRNA translation and tumor growth. Xenograft animal models combined with noninvasion in vivo imaging system (IVIS) analysis further confirmed the anticancer effect of LNA-siRNA-2 with improved efficiency and safety and reduced side effects. Mice orthotopically injected with colorectal cancer cells, LNA-siRNA-2 treatment not only inhibited the tumor growth but also blocked liver and lung metastasis. The results of our study suggest that LNA-siRNA-2 has the potential to be a novel therapeutic agent for cancer treatment.
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http://dx.doi.org/10.1016/j.canlet.2019.12.031DOI Listing
March 2020

A phase II study of the efficacy and safety of the MET inhibitor capmatinib (INC280) in patients with advanced hepatocellular carcinoma.

Ther Adv Med Oncol 2019 11;11:1758835919889001. Epub 2019 Dec 11.

Division of Gastroenterology, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Background: The objectives of this phase II study were to determine the clinical activity of the MET tyrosine kinase inhibitor capmatinib (INC280) in patients with MET-dysregulated advanced hepatocellular carcinoma (HCC) and to assess the safety, pharmacokinetics, and correlation of biomarkers with the response.

Methods: This phase II, open-label, single-arm study evaluated twice daily (BID) oral capmatinib in a dose-determining stage, utilizing a Bayesian Logistic Regression Model (BLRM) subject to Escalation with Overdose Control criteria, safety, pharmacokinetics, and pharmacodynamic information to determine a recommended dose for expansion (RDE) evaluating efficacy in patients with MET-dysregulated HCC.

Results: A total of 38 patients received treatment. In the dose-determining stage, patients received capmatinib 300 mg BID capsules ( = 8), and in the expansion, patients received 600 mg BID capsules ( = 28) or 400 mg BID tablets ( = 2) based on the BLRM and other relevant clinical data. No predefined qualifying adverse events (AEs) were observed during the first 28 days of treatment, and the RDE was 600 mg BID capsules (equivalent pharmacokinetics to 400 mg BID tablets). The most common any causality AEs were nausea (42%), vomiting (37%), and diarrhea (34%). In the expansion stage, in a subgroup of 10 patients with MET-high HCC, the overall response rate was 30%, including 1 durable complete response (>600 days) and 2 partial responses [1 durable (>600 days)].

Conclusions: Single agent capmatinib at the RDE is tolerable with a manageable safety profile. Antitumor activity was seen in a subset of patients with MET-dysregulated (MET-high) HCC.

Trial Registration: ClinicalTrials.gov: NCT01737827. https://clinicaltrials.gov/ct2/show/NCT01737827.
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http://dx.doi.org/10.1177/1758835919889001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906348PMC
December 2019

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

Percutaneous Computed Tomography-Guided Coaxial Core Biopsy for the Diagnosis of Pancreatic Tumors.

J Clin Med 2019 Oct 5;8(10). Epub 2019 Oct 5.

Department of Diagnostic Radiology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.

Endoscopic, ultrasound-guided tissue acquisition (EUS-TA) with rapid on-site evaluation is recommended as a first choice in the diagnosis of pancreatic lesions. Since EUS facilities and rapid on-site evaluation are not widely available, even in medical centers, an alternative for precise diagnoses of pancreatic tumor is warranted. The percutaneous computed tomography-guided, core needle biopsy (CT-CNB) is a commonly applicable method for biopsies. Our institute has developed a fat-transversing approach for pancreatic biopsies which is able to approach most tumors in the pancreas without penetrating organs or vessels. Herein, we report a 15-year experiment of pancreatic tumor coaxial CT-CNB in 420 patients. The success rate of tissue yielding by the technique was 99.3%. The overall sensitivity, specificity, and accuracy were 93.2%, 100%, and 93.4%, respectively. The diagnostic accuracy could be increased to 96.4% in 2016-2018 (after the learning curve period). The overall complication rate was 8.6%. Neither life-threatening major complications, nor seeding through the biopsy tract, were observed. Our study supported the hypothesis that CT-CNB could be a complementary option for diagnostic tissue acquisition in patients with unresectable or metastatic pancreatic tumors when EUS-TA is either unsuitable or unavailable.
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http://dx.doi.org/10.3390/jcm8101633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832146PMC
October 2019