Publications by authors named "Wu-Chou Su"

200 Publications

Safety and antitumor activity of α-PD-L1 antibody as monotherapy or in combination with α-TIM-3 antibody in patients with microsatellite instability-high/mismatch repair-deficient tumors.

Clin Cancer Res 2021 Aug 31. Epub 2021 Aug 31.

Department of Internal Medicine, Seoul National University College of Medicine.

Purpose: Immune checkpoint inhibitors show high response rates and durable clinical benefit in microsatellite instability-high/mismatch repair-deficient (MSI‑H/dMMR) tumors. However, 50 to 60% do not respond to single-agent anti-PD‑1/PD-L1 antibodies, and approximately 50% of responders relapse within 6 to12 months. This phase 1b trial evaluated safety and antitumor activity of anti-PD-L1 antibody LY3300054 monotherapy or in combination with anti-TIM-3 antibody LY3321367 in patients with MSI‑H/dMMR advanced solid tumors.

Experimental Design: Eligible patients {greater than or equal to}18 years without prior anti-PD‑1/PD‑L1 therapy received LY3300054 monotherapy (=40) or combination (=20); patients with PD-1/PD-L1 inhibitor-resistant/refractory tumors received the combination (=22). LY3300054 (700 mg) and anti-TIM-3 antibody (Cycles 1-2: 1200mg, Cycle 3 onwards: 600mg) were administered intravenously every 2 weeks. Primary endpoints were safety and tolerability.

Results: Eighty-two patients were enrolled. Most had colorectal (=39, 47.6%) or endometrial (=14, 17.1%) tumors. >70% of patients in the PD‑1/PD-L1 inhibitor-resistant/refractory combination cohort had received {greater than or equal to}3 treatment lines. Treatment-related adverse events (TRAEs) occurred in 22 patients (55.0%) receiving monotherapy, 13 (65.0%) in the PD‑1/PD-L1 inhibitor-naïve combination cohort, and 6 (27.3%) in the PD‑1/PD-L1 inhibitor-resistant/refractory combination cohort. 2 patients (5.0%) receiving monotherapy and 3 (7.1%) receiving the combination experienced grade {greater than or equal to}3 TRAEs. Objective responses occurred in 13 patients (32.5%) with monotherapy, 9 (45.0%) in the PD‑1/PD-L1 inhibitor-naive combination cohort, and 1 patient (4.5%) in the PD-1/PD-L1 inhibitor-resistant/refractory combination cohort.

Conclusions: LY3300054 monotherapy and combined LY3300054/anti-TIM-3 had manageable safety profiles. Both regimens showed promising clinical activity against PD-1/PD-L1 inhibitor-naïve MSI-H/dMMR tumors. The combination had limited clinical benefit in patients with PD-1/PD-L1 inhibitor-resistant/refractory MSI‑H/dMMR tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-21-0261DOI Listing
August 2021

Resistance profiles of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced non-small-cell lung cancer: a multicenter study using targeted next-generation sequencing.

Eur J Cancer 2021 Aug 12;156:1-11. Epub 2021 Aug 12.

Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address:

Introduction: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for advanced non-small-cell lung cancer (NSCLC) with ALK rearrangement. However, the mechanisms of resistance remain largely unclear.

Methods: This prospective multicenter study analyzed cell-free DNA (cfDNA) and/or cancer tissues of patients with NSCLC after progression on ALK TKI(s), using targeted next-generation sequencing. Patients' clinicopathologic characteristics and treatment outcomes were analyzed.

Results: Overall, 88 patients were enrolled; 31 cancer tissues and 90 cfDNA samples were analyzed. Five (16%) ALK mutations (L1196M ×2, I1171T, D1203N, G1269A/F1174L) and 3 possible bypass mutations (NRAS G12V, EGFR R108K, PIK3CA E545K) were found in 32 crizotinib-resistant cancers. Four (22%) ALK mutations (G1128A, G1202R, G1269A, I1171T/E1210K) and 3 possible bypass mutations (KIT D820E, MET E1012∗, EGFR P265_C291del) were found in 18 ceritinib-resistant cancers. Four (17%) ALK mutations (G1202R ×2, W1295C, G1202R/L1196M) and 1 possible bypass mutation (EGFR P753S) were found in 24 alectinib-resistant cancers. Two (11%) ALK mutations (G1202R/G1269A ×2) and 2 possible bypass mutations (BRAF V600E, MET D1246N) were found in 18 lorlatinib-resistant cancers. In patients with simultaneous paired tissue and cfDNA samples (n = 20), mutations were identified in 9 (45%) and 6 (30%) cases, respectively; the concordance rate was 45%.

Conclusions: The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2021.06.043DOI Listing
August 2021

Survival benefit of osimertinib combination therapy in patients with T790M-positive non-small-cell lung cancer refractory to osimertinib treatment.

Lung Cancer 2021 08 19;158:137-145. Epub 2021 Jun 19.

Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Medical Imaging, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan. Electronic address:

Objectives: Osimertinib is the main treatment choice for pretreated patients with advanced non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) T790M mutations. However, the choice of subsequent therapy when progressive disease has developed after osimertinib treatment remains a major therapeutic challenge. This study evaluated the efficacy of osimertinib-based combination therapies in patients who developed progressive disease after treatment with osimertinib.

Material And Methods: We enrolled NSCLC patients harbouring T790M mutations pretreated with first- or second-generation EGFR tyrosine-kinase inhibitors and were receiving osimertinib at two tertiary referral centres between August 2015 and July 2019, and the subsequent treatment efficacy was assessed.

Results: Osimertinib-based combination therapy yielded better overall survival (OS) than chemotherapy alone (not achieved vs. 7.8 months; hazard ratio, 0.39; 95 % confidence interval 0.17-0.89; P = 0.025) according to the Cox proportional hazards model adjusted for possible confounders. Synergism (combination index <1) between AZD9291 and chemotherapy and a higher proportion of apoptosis cells in combination treatment were also demonstrated in the T790M-positive PC9 cell line with acquired resistance to AZD9291.

Conclusion: Our data supported the hypothesis that osimertinib-based combination therapy is associated with improved OS among patients with clinical progression following the use of osimertinib. These findings warrant further validation in a randomised controlled study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2021.06.014DOI Listing
August 2021

Converged Rab37/IL-6 trafficking and STAT3/PD-1 transcription axes elicit an immunosuppressive lung tumor microenvironment.

Theranostics 2021 12;11(14):7029-7044. Epub 2021 May 12.

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

Increased IL-6 level, M2 macrophages and PD-1CD8 T cells in tumor microenvironments (TME) have been identified to correlate with resistance to checkpoint blockade immunotherapy, yet the mechanism remains poorly understood. Rab small GTPase-mediated trafficking of cytokines is critical in immuno-modulation. We have previously reported dysregulation of Rab37 in lung cancer cells, whereas the roles of Rab37 in tumor-infiltrating immune cells and cancer immunotherapy are unclear. The tumor growth of the syngeneic mouse allograft in wild type or knockout mice was analyzed. Imaging analyses and vesicle isolation were conducted to determine Rab37-mediated IL-6 secretion. STAT3 binding sites at promoter in T cells were identified by chromatin immunoprecipitation assay. Multiplex fluorescence immunohistochemistry was performed to detect the protein level of Rab37, IL-6 and PD-1 and localization of the tumor-infiltrating immune cells in allografts from mice or tumor specimens from lung cancer patients. We revealed that Rab37 regulates the secretion of IL-6 in a GTPase-dependent manner in macrophages to trigger M2 polarization. Macrophage-derived IL-6 promotes STAT3-dependent mRNA expression in CD8 T cells. Clinically, tumors with high stromal Rab37 and IL-6 expression coincide with tumor infiltrating M2-macrophages and PD1CD8 T cells that predicts poor prognosis in lung cancer patients. In addition, lung cancer patients with an increase in plasma IL-6 level are found to be associated with immunotherapeutic resistance. Importantly, combined blockade of IL-6 and CTLA-4 improves survival of tumor-bearing mice by reducing infiltration of PD1CD8 T cells and M2 macrophages in TME. Rab37/IL-6 trafficking pathway links with IL-6/STAT3/PD-1 transcription regulation to foster an immunosuppressive TME and combined IL-6/CTLA-4 blockade therapy exerts potent anti-tumor efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.60040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171097PMC
August 2021

The relative importance of predictive factors for single first-generation EGFR-TKI use for more than 5 years in patients with advanced non-small cell lung cancer: Taiwan multicenter TIPS-5 study.

Ther Adv Med Oncol 2021 22;13:17588359211018022. Epub 2021 May 22.

Division of Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, No.110, Sec. 1, Jianguo N. Road, Taichung, 402.

Background: The relative importance of predictive factors for advanced non-small cell lung cancer (NSCLC) patients on epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment remains unclear.

Materials And Methods: We retrospectively enrolled advanced NSCLC patients with single first-generation EGFR-TKI treatment for ⩾5 years (Y) in Taiwan. Clinical data was collected and compared with those of another cohort with single first-line EGFR-TKI treatment for <5 Y. Plasma cell-free DNA (cfDNA) samples were collected from patient subsets, pre- and post-TKI, in the >5 Y group.

Results: Overall, 128 and 278 patients were enrolled in the ⩾5 Y and <5 Y groups, respectively. Significant factors in the multivariate analysis of patients' characteristics including Eastern Cooperative Oncology Group performance status 0-1, postoperative recurrence, without brain metastasis, oligometastasis (each score of 2), female sex, erlotinib use, and without bone metastasis (each score of 1), were incorporated into a risk scoring system. The area under the receiver operating characteristic curve was 0.82 [95% confidence interval (CI): 0.78-0.86]. Of the plasma cfDNA samples from 33 patients in the ⩾5 Y group, only 1 had a T790M in 25 patients without progressive disease. In 27 patients with single agent use for ⩾96 months, 22 (81.5%) received local treatment (surgery or radiotherapy) for the primary lung tumor before and during TKI treatment.

Conclusion: For NSCLC patients with single first-generation EGFR-TKI use for ⩾5 Y, factors with different relative importance exist and the risk-scoring model is feasible with modest accuracy. The role of local treatment for primary tumors in patients with long-term TKI use requires further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/17588359211018022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142001PMC
May 2021

Five Year Survival Update From KEYNOTE-010: Pembrolizumab Versus Docetaxel for Previously Treated, Programmed Death-Ligand 1-Positive Advanced NSCLC.

J Thorac Oncol 2021 May 26. Epub 2021 May 26.

The Netherlands Cancer Institute, Amsterdam, the Netherlands.

Introduction: In the KEYNOTE-010 study, pembrolizumab improved overall survival (OS) versus docetaxel in patients with previously treated, advanced NSCLC with programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50% and ≥1%. We report 5-year efficacy and safety follow-up for the KEYNOTE-010 study.

Methods: Patients were randomized to pembrolizumab 2 mg/kg or 10 mg/kg once every 3 weeks or docetaxel 75 mg/m once every 3 weeks for up to 35 cycles (2 y). Patients who completed pembrolizumab treatment and subsequently had recurrence could receive second-course pembrolizumab for up to 17 cycles (1 y). Pembrolizumab doses were pooled in this analysis.

Results: A total of 1034 patients were randomized (pembrolizumab, n = 691; docetaxel, n = 343). Median study follow-up was 67.4 months (range: 60.0‒77.9). The hazard ratio (95% confidence interval) for OS was 0.55 (0.44‒0.69) for patients with PD-L1 TPS ≥50% and 0.70 (0.61‒0.80) with PD-L1 TPS ≥1%. The 5-year OS rates for pembrolizumab versus docetaxel were 25.0% versus 8.2% in patients with PD-L1 TPS ≥50% and 15.6% versus 6.5% with PD-L1 TPS ≥1%. Among 79 patients who completed 35 cycles/2 years of pembrolizumab, the OS rate 3 years after completion (∼5 y from randomization) was 83.0%. A total of 21 patients received second-course pembrolizumab; 11 (52.4%) had an objective response after starting the second course and 15 (71.4%) were alive at data cutoff. Exploratory biomarker analysis revealed that higher tissue tumor mutational burden (≥175 mutations per exome) was associated with improved outcomes with pembrolizumab.

Conclusions: Pembrolizumab continued to provide long-term benefit than docetaxel in patients with previously treated advanced NSCLC with PD-L1 TPS ≥50% and ≥1%. Our findings confirm pembrolizumab as a standard-of-care treatment in the second-line or later setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2021.05.001DOI Listing
May 2021

Biocompatible hole scavenger-assisted graphene oxide dots for photodynamic cancer therapy.

Nanoscale 2021 May;13(18):8431-8441

Department of Chemical Engineering, National Cheng Kung University, Tainan 70101, Taiwan. and Center of Applied Nanomedicine, National Cheng Kung University, Tainan 70101, Taiwan. and Hierarchical Green-Energy Materials (Hi-GEM) Research Center, National Cheng Kung University, Tainan 70101, Taiwan.

Photodynamic therapy (PDT) receives scholarly attention for its low invasiveness and mild adverse effects. Among the reactive oxygen species for PDT, H2O2 is advantageous for achieving long life and low cytotoxicity. Nitrogen-doped graphene oxide dots (NGODs), which are small (∼4.4 nm) and highly biocompatible, can serve as a photosensitizer for PDT. The charge transfer in NGODs is efficient because the NGOD structure is highly crystalline and its carbon-π orbitals are extensively conjugated with nitrogen-nonbonding orbitals. In the presence of ascorbic acid (AA), to scavenge photogenerated holes, NGODs effectively produce H2O2 under white-light irradiation and their H2O2 rate is proportional to the AA concentration. This AA-supplemented PDT effectively kills lung, head and neck, colon, and oral cancer cells and it is highly safe for normal cells. During PDT, the NGODs are uptaken into the cell body and they produce concentrated H2O2 and subsequently induce both the apoptosis and necrosis pathways for cell death. The unique structure of NGODs confines the transfer of the photogenerated electrons for H2O2 production. This study demonstrates the high potential for efficacious and accurate deployment of the proposed NGOD-AA combination in PDT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d1nr01476eDOI Listing
May 2021

EGFR-TKI plus bevacizumab versus EGFR-TKI monotherapy for patients with EGFR mutation-positive advanced non-small cell lung cancer-A propensity score matching analysis.

J Formos Med Assoc 2021 Sep 14;120(9):1729-1739. Epub 2021 Apr 14.

Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan.

Background: Recent study showed that the combination of erlotinib and bevacizumab had better disease control than erlotinib monotherapy in patients with advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). However, there is lack of real-world evidence for this therapeutic regimen. We aimed to compare outcomes between patients with EGFR mutant NSCLC treated with EGFR-tyrosine kinase inhibitors (TKI) and bevacizumab and those treated with EGFR-TKI alone in a real-world setting.

Methods: Patients with advanced EGFR-mutant NSCLC who received first-line EGFR-TKI in a tertiary referral center from October 1, 2013 to December 31, 2019 were retrospectively analyzed. We performed 1:2 propensity score-matching: one EGFR-TKI and bevacizumab recipient with two patients who received EGFR-TKI alone. Progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan-Meier method. The prognostic factors were analyzed using Cox proportional hazards regression analysis.

Results: Total 313 patients were enrolled. After propensity score matching, 45 patients who received first-line EGFR-TKI and bevacizumab and 89 patients who received EGFR-TKI alone were analyzed. The combination group showed improved PFS (17.0 vs. 11.0 months; hazard ratio [HR] = 0.48; p = 0.002) compared to the monotherapy group. In subgroup analysis of patients with an L858R mutation, the combination group showed longer PFS (23.1 vs. 10.7 months; HR = 0.40; p = 0.011) and OS (not reached vs. 40.6 months; HR = 0.27; p = 0.040) than the EGFR-TKI monotherapy group.

Conclusion: Our data suggest that the combination of EGFR-TKI and bevacizumab could improve PFS in patients with EGFR-mutant NSCLC. In patients harboring L858R mutation, the combination therapy provides better OS than TKI alone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jfma.2021.03.023DOI Listing
September 2021

Overcoming Radiation Resistance by Iron-Platinum Metal Alloy Nanoparticles in Human Copper Transport 1-Overexpressing Cancer Cells via Mitochondrial Disturbance.

Int J Nanomedicine 2021 9;16:2071-2085. Epub 2021 Mar 9.

Center of Applied Nanomedicine, National Cheng Kung University, Tainan, 701, Taiwan.

Background: Radiation therapy remains an important treatment modality in cancer therapy, however, resistance is a major problem for treatment failure. Elevated expression of glutathione is known to associate with radiation resistance. We used glutathione overexpressing small cell lung cancer cell lines, SR3A-13 and SR3A-14, established by transfection with γ-glutamylcysteine synthetase (γ-GCS) cDNA, as a model for investigating strategies of overcoming radiation resistance. These radiation-resistant cells exhibit upregulated human copper transporter 1 (hCtr1), which also transports cisplatin. This study was initiated to investigate the effect and the underlying mechanism of iron-platinum nanoparticles (FePt NPs) on radiation sensitization in cancer cells.

Materials And Methods: Uptakes of FePt NPs in these cells were studied by plasma optical emission spectrometry and transmission electron microscopy. Effects of the combination of FePt NPs and ionizing radiation were investigated by colony formation assay and animal experiment. Intracellular reactive oxygen species (ROS) were assessed by using fluorescent probes and imaged by a fluorescence-activated-cell-sorting caliber flow cytometer. Oxygen consumption rate (OCR) in mitochondria after FePt NP and IR treatment was investigated by a Seahorse XF24 cell energy metabolism analyzer.

Results: These hCtr1-overexpressing cells exhibited elevated resistance to IR and the resistance could be overcome by FePt NPs via enhanced uptake of FePt NPs. Overexpression of hCtr1 was responsible for the increased uptake/transport of FePt NPs as demonstrated by using -transfected parental SR3A (SR3A-hCtr1-WT) cells. Increased ROS and drastic mitochondrial damages with substantial reduction of oxygen consumption rate were observed in FePt NPs and IR-treated cells, indicating that structural and functional insults of mitochondria are the lethal mechanism of FePt NPs. Furthermore, FePt NPs also increased the efficacy of radiotherapy in mice bearing SR3A-hCtr1-WT-xenograft tumors.

Conclusion: These results suggest that FePt NPs can potentially be a novel strategy to improve radiotherapeutic efficacy in hCtr1-overexpressing cancer cells via enhanced uptake and mitochondria targeting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/IJN.S283147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955785PMC
April 2021

Extracellular Vesicle miR-200c Enhances Gefitinib Sensitivity in Heterogeneous EGFR-Mutant NSCLC.

Biomedicines 2021 Feb 28;9(3). Epub 2021 Feb 28.

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

Intratumoral heterogeneity in epidermal growth factor receptor (EGFR)-mutant mutant non-small-cell lung cancer (NSCLC) explains the mixed responses to EGFR-tyrosine kinase inhibitors (TKIs). However, some studies showed tumors with low abundances of EGFR mutation still respond to EGFR-TKI, and the mechanism remained undetermined. Extracellular vesicles (EVs) can transmit antiapoptotic signals between drug-resistant and drug-sensitive cells. Herein, we profiled EVs from EGFR-mutant cells to identify a novel mechanism explaining why heterogenous EGFR-mutant NSCLC patients still respond to EGFR-TKIs. We first demonstrated that the EVs from EGFR-mutant changes the wild-type cells' sensitivity to gefitinib by adding EV directly or coculturing EGFR wild-type (CL1-5) cells and EGFR-mutant (PC9) cells. In animal studies, only the combined treatment of PC9 EV and gefitinib delayed the tumor growth of CL1-5 cells. MicroRNA analysis comparing EV miRNAs from PC9 cells to those from CL1-5 cells showed that mir200 family members are most abundant in PC9 EVs. Furthermore, mir200a and mir200c were found upregulated in plasma EVs from good responders to EGFR-TKIs. Finally, the transfection of CL1-5 cells with miR200c inactivates downstream signaling pathways of EGFR, the EMT pathway, and enhances gefitinib sensitivity. Overall, our results suggest that in heterogeneous EGFR-mutant NSCLC, tumor cells transmit EV miRNAs that may affect sensitivity to EGFR-TKIs and provide potential prognostic biomarkers for EGFR-mutant NSCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biomedicines9030243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997352PMC
February 2021

Development of the CK-MB-1 trastuzumab-resistant HER2-positive breast cancer cell line and xenograft animal models.

Cancer Med 2021 04 5;10(7):2370-2379. Epub 2021 Mar 5.

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

Background: Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer who fail to respond to anti-HER2 treatments have poor prognoses. Most trastuzumab-resistant breast cancer cell lines available from biobanks feature either phosphoinositide-3-kinase, catalytic, alpha (PIK3CA) mutation or the loss of phosphatase and tensin homolog (PTEN). However, PIK3CA mutations and/or PTEN loss do not account for most trastuzumab-resistant tumors in humans.

Methods: Breast cancer cells were collected from one patient's malignant ascites. These cells were cultured and maintained to develop a stable cell line, which we named CK-MB-1. We used western blotting to evaluate protein expression. The PIK3CA status of CK-MB-1 cells was analyzed using Sanger sequencing and validated using next-generation sequencing. In vivo, CK-MB-1 xenograft tumor models were developed in zebrafish and immunodeficient mice.

Results: CK-MB-1 cells maintained the major characteristics of the parental tumor including HER2 positivity and estrogen receptor negativity. The HER2 gene amplification of CK-MB-1 cells was detected by fluorescence in situ hybridization. The integrity of PTEN was confirmed by its positive protein expression and the absence of gene mutations. No common PIK3CA mutation was detected. Compared with the findings in two other HER2-positive trastuzumab-resistant cell lines, CK-MB-1 cells exhibited greater resistance to trastuzumab, chemotherapeutics, and small-molecule drugs. Trastuzumab resistance in CK-MB-1 cells was confirmed in vivo using the NOD SCID mouse model.

Conclusions: CK-MB-1 cells represent a stable HER2-positive trastuzumab-resistant breast cancer cell line. The resistance of CK-MB-1 cells does not originate from the PTEN or phosphoinositide 3-kinase signaling pathway, which can provide an alternative approach for potential drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.3824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982635PMC
April 2021

Phase I dose escalation study of sorafenib plus S-1 for advanced solid tumors.

Sci Rep 2021 Mar 1;11(1):4834. Epub 2021 Mar 1.

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

S-1, an oral pyrimidine fluoride-derived agent, is effective against various cancers. Sorafenib, an oral multikinase inhibitor, was found to prolong the survival of various cancers and enhance the cytotoxicity of chemotherapeutic agents. We conducted a phase I dose escalation study to determine dose-limiting toxicity (DLT) and maximal tolerated dose (MTD) of S-1 when combined with sorafenib for refractory solid tumors. Eligible patients received escalating doses (30, 35, and 40 mg/m bid) of S-1 Day 1 (D1)-D14 and continuous sorafenib 400 mg bid from cycle 1 D8 every 21 days in a standard 3 + 3 study design. Primary endpoint was MTD. Thirteen patients were enrolled between May 2010 and Feb 2012. DLT developed in two (one grade 3 erythema and one prolonged grade 2 hand-foot-skin reaction) of the 6 patients at 35 mg/m dose level. One pancreatic neuroendocrine tumor (pNET) patient achieved a durable partial response (27.9 months). Four colon cancer patients had stable disease and 3 of them had progression-free survival greater than 6 months. This study determined the recommended (MTD) S-1 dose of 30 mg/m bid for this regimen. This result warrants further phase II studies for advanced pNET and colon cancer to evaluate the efficacy of this combination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-84279-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921110PMC
March 2021

Nanomedicine-Based Strategies Assisting Photodynamic Therapy for Hypoxic Tumors: State-of-the-Art Approaches and Emerging Trends.

Biomedicines 2021 Feb 1;9(2). Epub 2021 Feb 1.

Center of Applied Nanomedicine, National Cheng Kung University, Tainan 70101, Taiwan.

Since the first clinical cancer treatment in 1978, photodynamic therapy (PDT) technologies have been largely improved and approved for clinical usage in various cancers. Due to the oxygen-dependent nature, the application of PDT is still limited by hypoxia in tumor tissues. Thus, the development of effective strategies for manipulating hypoxia and improving the effectiveness of PDT is one of the most important area in PDT field. Recently, emerging nanotechnology has benefitted progress in many areas, including PDT. In this review, after briefly introducing the mechanisms of PDT and hypoxia, as well as basic knowledge about nanomedicines, we will discuss the state of the art of nanomedicine-based approaches for assisting PDT for treating hypoxic tumors, mainly based on oxygen replenishing strategies and the oxygen dependency diminishing strategies. Among these strategies, we will emphasize emerging trends about the use of nanoscale metal-organic framework (nMOF) materials and the combination of PDT with immunotherapy. We further discuss future perspectives and challenges associated with these trends in both the aspects of mechanism and clinical translation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biomedicines9020137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912771PMC
February 2021

Sub-multiplicative interaction between polygenic risk score and household coal use in relation to lung adenocarcinoma among never-smoking women in Asia.

Environ Int 2021 02 29;147:105975. Epub 2020 Dec 29.

Department of Internal Medicine, Kaohsiung Medical University Hospital, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, especially in Xuanwei, China. We investigated the potential interaction between genetic susceptibility and coal use in FLCCA. We analyzed GWAS-data from Taiwan, Shanghai, and Shenyang (1472 cases; 1497 controls), as well as a separate study conducted in Xuanwei (152 cases; 522 controls) for additional analyses. We summarized genetic susceptibility using a polygenic risk score (PRS), which was the weighted sum of the risk-alleles from the 10 previously identified loci. We estimated associations between a PRS, coal use (ever/never), and lung adenocarcinoma with multivariable logistic regression models, and evaluated potential gene-environment interactions using likelihood ratio tests. There was a strong association between continuous PRS and lung adenocarcinoma among never coal users (Odds Ratio (OR) = 1.69 (95% Confidence Interval (CI) = 1.53, 1.87), p=1 × 10). This effect was attenuated among ever coal users (OR = 1.24 (95% CI: 1.03, 1.50), p = 0.02, p-interaction = 6 × 10). We observed similar attenuation among coal users from Xuanwei. Our study provides evidence that genetic susceptibility to lung adenocarcinoma among never-smoking Asian women is weaker among coal users. These results suggest that lung cancer pathogenesis may differ, at least partially, depending on exposure to coal combustion products. Notably, these novel findings are among the few instances of sub-multiplicative gene-environment interactions in the cancer literature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envint.2020.105975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378844PMC
February 2021

First-line treatment with irreversible tyrosine kinase inhibitors associated with longer OS in EGFR mutation-positive non-small cell lung cancer.

Thorac Cancer 2021 02 18;12(3):287-296. Epub 2020 Dec 18.

Department of Internal Medicine and Institute of Clinical Medicine, College of Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.

Background: Few studies have compared the efficacy of the irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), afatinib, with that of reversible EGFR-TKIs. Therefore, this study assessed the effectiveness of afatinib, erlotinib, and gefitinib in terms of OS (overall survival) and progression-free survival (PFS) in EGFR mutation-positive advanced non-small cell lung cancer (NSCLC) patients.

Methods: Patients with EGFR mutation-positive advanced NSCLC who sought treatment from December 2013 to June 2018, at a tertiary referral center were retrospectively analyzed. These patients were treated with afatinib or a reversible EGFR-TKI (erlotinib or gefitinib) until disease progression, intolerable adverse events, or death. The Kaplan-Meier and log-rank tests were then used to compare the OS and PFS of the patients. We further analyzed the survival differences among the subgroup of patients without brain metastases.

Results: Of the 363 patients enrolled, 134 and 229 received first-line afatinib and first-line reversible EGFR-TKI, respectively. Those given afatinib had better OS (39.3 vs. 26.0 months; HR 0.65, P = 0.033) and PFS (14.1 vs.11.2 months; HR 0.58, P < 0.001). Of the 246 patients without brain metastases, 93 and 153 received first-line afatinib and a first-line reversible EGFR-TKI, respectively. Those given afatinib had a better OS (52.6 vs. 24.9 months; HR 0.62, P = 0.0030) and PFS (17.7 vs. 11.1 months; HR 0.51, P < 0.001). The survival benefit was more significant in the subgroup of patients with L858R substitutions.

Conclusions: The results indicated that afatnib resulted in significantly better OS and PFS than gefitnib and erlotinib for EGFR mutation-positive advanced NSCLC patients without brain metastases.

Key Points: Significant findings of the study Afatnib resulted in significantly better overall survival and progression-free survival than gefitnib and erlotinib for EGFR mutation-positive advanced non-small cell lung cancer patients without brain metastases. What this study adds This study helps fill the gap in our limited understanding of the differences in the efficacy of the irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), afatinib, with that of reversible EGFR-TKIs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1759-7714.13462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862787PMC
February 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/onco.13612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018321PMC
April 2021

Safety and Clinical Activity of a New Anti-PD-L1 Antibody as Monotherapy or Combined with Targeted Therapy in Advanced Solid Tumors: The PACT Phase Ia/Ib Trial.

Clin Cancer Res 2021 Mar 23;27(5):1267-1277. Epub 2020 Nov 23.

Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee.

Purpose: This phase Ia/Ib PACT study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of a new programmed cell death ligand 1 (PD-L1) inhibitor, LY3300054, as monotherapy or in combination with ramucirumab, abemaciclib, or merestinib (a type II MET kinase inhibitor) in patients with advanced, refractory solid tumors (NCT02791334).

Patients And Methods: Patients were enrolled into cohorts of escalating LY3300054 dose (phase Ia) as monotherapy ( = 15) or combined with ramucirumab ( = 10), abemaciclib ( = 24), or merestinib ( = 12). The phase Ib dose expansion enrolled 8 patients with melanoma in the monotherapy arm and 12 patients with pancreatic cancer in the merestinib combination arm. Combination treatments were administered concurrently from day 1 of each cycle. A 14-day lead-in abemaciclib arm was also explored. Primary endpoints were dose-limiting toxicity (DLT) and safety.

Results: Treatment-related adverse events included fatigue and nausea in the monotherapy arm (13% for each), hypothyroidism (30%) in the ramucirumab arm, diarrhea (54%) in the abemaciclib arm, and nausea (25%) in the merestinib arm. DLTs associated with hepatoxicity were observed in 3 of 4 patients in the abemaciclib lead-in cohorts. No DLTs or grade 3 or 4 hepatoxicity were reported in the concurrent abemaciclib arm. Pharmacokinetic characteristics were comparable with other PD-L1 inhibitors. One patient in each arm experienced a partial response per RECIST v1.1 lasting ≥7 months.

Conclusions: LY3300054 was well tolerated without unexpected safety concerns when administered alone or concurrently with ramucirumab, abemaciclib, or merestinib. Lead-in abemaciclib before combining with LY3300054 was not feasible due to hepatotoxicity. Durable clinical benefits were seen in all regimens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-2821DOI Listing
March 2021

Safety, Efficacy, and Pharmacokinetics of Almonertinib (HS-10296) in Pretreated Patients With EGFR-Mutated Advanced NSCLC: A Multicenter, Open-label, Phase 1 Trial.

J Thorac Oncol 2020 12 9;15(12):1907-1918. Epub 2020 Sep 9.

Department of Oncology, Shanghai Chest Hospital, Shanghai, People's Republic of China.

Introduction: Almonertinib (HS-10296) is a novel, third-generation EGFR tyrosine kinase inhibitor (EGFR TKI) that targets both EGFR-sensitizing and T790M resistance mutations. This first-in-human trial aimed to evaluate the safety, efficacy, and pharmacokinetics of almonertinib in patients with locally advanced or metastatic EGFR mutation-positive NSCLC that had progressed after pevious EGFR TKI therapy.

Methods: This phase 1, open-label, multicenter clinical trial (NCT0298110) included dose-escalation (55, 110, 220, and 260 mg) and dose-expansion cohorts (55, 110, and 220 mg) with once daily oral administration of almonertinib. In each expansion cohort, tumor biopsies were obtained for the determination of EGFR T790M status. The safety, tolerability, antitumor activity, and pharmacokinetics of almonertinib were evaluated.

Results: A total of 120 patients (26 patients in the dose-escalation cohort and 94 patients in the dose-expansion cohort) were enrolled. The maximum tolerated dose was not defined in the dose-escalation phase; the 260 mg regimen was not further evaluated in the dose-expansion phase owing to safety concerns and saturation of exposure. The most common treatment-related grade greater than or equal to 3 adverse events were increased blood creatine phosphokinase (10%) and increased alanine aminotransferase (3%). Among 94 patients with the EGFR T790M mutation in the dose-expansion cohort, the investigator-assessed objective response rate and disease control rate were 52% (95% confidence interval [CI]: 42-63) and 92% (95% CI: 84-96), respectively. Median progression-free survival was 11.0 months (95% CI: 9.5-not reached) months.

Conclusions: Almonertinib is safe, tolerable and effective for patients with locally advanced or metastatic NSCLC harboring the EGFR T790M mutation who were pretreated with EGFR TKIs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2020.09.001DOI Listing
December 2020

Immune Checkpoint Inhibitor-Induced Myasthenia Gravis.

Front Neurol 2020 16;11:634. Epub 2020 Jul 16.

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

The development of immune checkpoint inhibitors (ICIs) has been a major breakthrough in cancer immunotherapy. The increasing use of ICIs has led to the discovery of a broad spectrum of immune-related adverse events (irAEs). Immune-related myasthenia gravis (irMG) is a rare but life-threatening irAE. In this review, the clinical presentations of irMG are described and the risk of irMG-related mortality is examined using information from relevant studies. In 47 reported cases of irMG with clear causes of mortality, irMG appeared to be a distinct category of neuromuscular disorders and differed from classical MG in terms of its demographic patient characteristics, pathogenesis, serology profile, response to treatment, associated complications, and prognosis. Because of the high mortality of irMG, measures to increase the vigilance of medical teams are necessary to ensure the timely identification of the signs of irMG and early treatment, particularly in the early course of ICI therapy. The diagnostic plans should be comprehensive and include the evaluation of other organ systems, such as the dermatological, gastrointestinal, respiratory, neuromuscular, and cardiovascular systems, in addition to the traditional diagnostic tests for MG. Treatment plans should be individualized on the basis of the extent of organ involvement and clinical severity. Additional therapeutic studies on irMG in the future are required to minimize irAE-related mortality and increase the safety of patients with cancer in the ICI era.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2020.00634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378376PMC
July 2020

Ultra-Short Circulating Tumor DNA (usctDNA) in Plasma and Saliva of Non-Small Cell Lung Cancer (NSCLC) Patients.

Cancers (Basel) 2020 Jul 24;12(8). Epub 2020 Jul 24.

School of Dentistry, University of California Los Angeles, Los Angeles, CA 90095, USA.

Mutations identified in the epidermal growth factor receptor (EGFR) predict sensitivity to EGFR-targeted therapy for non-small cell lung carcinoma (NSCLC). We previously reported that Electric Field-Induced Release and Measurement (EFIRM)-based liquid biopsy could detect EGFR ctDNA with >94% concordance with tissue-based genotyping. A side-by-side comparison of concordance of EFIRM and droplet digital PCR (ddPCR) for the detection of the two front-line actionable EFGR mutations was performed with paired plasma and saliva samples from 13 NSCLC patients. Deep sequencing analysis based on single-strand DNA library preparation was employed to determine the size distributions of EGFR L858R ctDNA in plasma and saliva samples. EFIRM detected both EGFR mutations with 100% sensitivity in both plasma and saliva samples, whereas ddPCR detected EGFR mutations with sensitivities of 84.6% and 15.4%, respectively. In saliva samples, the majority of EGFR L858R ctDNA fragments detected were <80 bp. Deep sequencing analysis of ctDNA enriched for the EGFR L858R mutation revealed the significant presence of EGFR L858R ctDNA as ultra-short circulating tumor DNA (usctDNA) with the size of 40-60 bp in patient plasma and saliva. Most of usctDNAs are not amplifiable with the current ddPCR assay. Further examination using cell lines and patient biofluids revealed that the majority of usctDNAs were predominately localized in the exosomal fraction. Our study revealed the abundant existence of EGFR ctDNA in the plasma and saliva of NSCLC patients is usctDNA. usctDNA is a novel type of targets for liquid biopsy that can be efficiently detected by EFIRM technology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12082041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464208PMC
July 2020

Clinical Frailty Scale in Predicting Postoperative Outcomes in Older Patients Undergoing Curative Surgery for Urologic Malignancies: A Prospective Observational Cohort Study.

Urology 2020 Oct 23;144:38-45. Epub 2020 Jul 23.

Division of Geriatrics and Gerontology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Gerontology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address:

Objective: To examine the utility of the Clinical Frailty Scale (CFS) in predicting outcomes in older adults with urologic malignancies undergoing curative surgeries.

Methods: This prospective observational cohort study was conducted in a university-based tertiary medical center. Patients aged 75 years or older who were scheduled to undergo curative surgery for a urologic malignancy from January 2017 to December 2017 were recruited. Patients were grouped according to the CFS scores. The primary postoperative outcome measures were a major complication within 30 days and a decline in the activities of daily living (ADL) within 30 days and 90 days. Multivariable analyses and the area under the receiver operating characteristic curve were performed to investigate the association between the CFS and postoperative outcomes.

Results: A total of 82 patients, 50% women, were enrolled with mean age 81.6 years. The CFS was significantly associated with postoperative outcomes in a dose-response relationship. When compared with those with a CFS <5, patients with CFS scores ≥5 had a 10.3-times higher risk for a major complication, 8.5-times and 21.4-times higher risk for a decline in ADL within 30 days and 90 days. The area under the receiver operating characteristic curves for the CFS to predict a major complication, the 30-day decline in ADL and the 90-day decline in ADL were 0.60, 0.73, and 0.79.

Conclusion: A higher CFS score predicted a higher risk of poor outcomes in this population. It is recommended that patients with higher CFS scores, especially above 5, are needed to receive further multidisciplinary perioperative care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.urology.2020.06.069DOI Listing
October 2020

Electric Field-Induced Release and Measurement (EFIRM): Characterization and Technical Validation of a Novel Liquid Biopsy Platform in Plasma and Saliva.

J Mol Diagn 2020 08 1;22(8):1050-1062. Epub 2020 Jun 1.

UCLA School of Dentistry, University of California, Los Angeles, Los Angeles, California; Liquid Diagnostics LLC, San Clemente, California. Electronic address:

Electric field-induced release and measurement (EFIRM) is a novel, plate-based, liquid biopsy platform capable of detecting circulating tumor DNA containing EGFR mutations directly from saliva and plasma in both early- and late-stage patients with non-small-cell lung cancer. We investigated the properties of the target molecule for EFIRM and determined that the platform preferentially detects single-stranded DNA molecules. We then investigated the properties of the EFIRM assay and determined the linearity, linear range, precision, and limit of detection for six different EGFR variants (the four most common g.Exon19del variants), p.T790M, and p.L858R). The limit of detection was in single-digit copy number for the latter two mutations, and the limit of detection for Exon19del was 5000 copies. Following these investigations, technical validations were performed for four separate EFIRM liquid biopsy assays, qualitative and quantitative assays for both saliva and plasma. We conclude that EFIRM liquid biopsy is an assay platform that interrogates a biomarker not targeted by any other extant platform (namely, circulating single-stranded DNA molecules). The assay has acceptable performance characteristics in both quantitative and qualitative assays on both saliva and plasma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmoldx.2020.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416077PMC
August 2020

Impact of cooking oil fume exposure and fume extractor use on lung cancer risk in non-smoking Han Chinese women.

Sci Rep 2020 04 21;10(1):6774. Epub 2020 Apr 21.

Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.

Smoking tobacco is the major risk factor for developing lung cancer. However, most Han Chinese women with lung cancer are nonsmokers. Chinese cooking methods usually generate various carcinogens in fumes that may inevitably be inhaled by those who cook the food, most of whom are female. We investigated the associations of cooking habits and exposure to cooking fumes with lung cancer among non-smoking Han Chinese women. This study was conducted on 1,302 lung cancer cases and 1,302 matched healthy controls in Taiwan during 2002-2010. Two indices, "cooking time-years" and "fume extractor use ratio," were developed. The former was used to explore the relationship between cumulative exposure to cooking oil fumes and lung cancer; the latter was used to assess the impact of fume extractor use for different ratio-of-use groups. Using logistic models, we found a dose-response association between cooking fume exposure and lung cancer (odds ratios of 1, 1.63, 1.67, 2.14, and 3.17 across increasing levels of cooking time-years). However, long-term use of a fume extractor in cooking can reduce the risk of lung cancer by about 50%. Furthermore, we provide evidence that cooking habits, involving cooking methods and oil use, are associated with risk of lung cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-63656-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174336PMC
April 2020

Comparative effectiveness and cost-effectiveness of three first-line EGFR-tyrosine kinase inhibitors: Analysis of real-world data in a tertiary hospital in Taiwan.

PLoS One 2020 8;15(4):e0231413. Epub 2020 Apr 8.

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

Introduction: Comparison of the effectiveness and cost-effectiveness of three first-line EGFR-tyrosine kinase inhibitors (TKIs) would improve patients' clinical benefits and save costs. Using real-world data, this study attempted to directly compare the effectiveness and cost-effectiveness of first-line afatinib, erlotinib, and gefitinib.

Methods: During May 2011-December 2017, all patients with non-small cell lung cancer (NSCLC) visiting a tertiary center were invited to fill out the EuroQol five-dimension (EQ-5D) questionnaires and World Health Organization Quality of Life, brief version (WHOQOL-BREF), and received follow-ups for survival and direct medical costs. A total of 379 patients with EGFR mutation-positive advanced NSCLC under first-line TKIs were enrolled for analysis. After propensity score matching for the patients receiving afatinib (n = 48), erlotinib (n = 48), and gefitinib (n = 96), we conducted the study from the payers' perspective with a lifelong time horizon.

Results: Patients receiving afatinib had the worst lifetime psychometric scores, whereas the differences in quality-adjusted life expectancy (QALE) were modest. Considering 3 treatments together, afatinib was dominated by erlotinib. Erlotinib had an incremental cost-effectiveness of US$17,960/life year and US$12,782/QALY compared with gefitinib. Acceptability curves showed that erlotinib had 58.6% and 78.9% probabilities of being cost-effective given a threshold of 1 Taiwanese per capita GDP per life year and QALY, respectively.

Conclusion: Erlotinib appeared to be cost-effective. Lifetime psychometric scores may provide additional information for effectiveness evaluation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231413PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141611PMC
July 2020

Silver-coated zero-valent iron nanoparticles enhance cancer therapy in mice through lysosome-dependent dual programed cell death pathways: triggering simultaneous apoptosis and autophagy only in cancerous cells.

J Mater Chem B 2020 05 8;8(18):4122-4131. Epub 2020 Apr 8.

Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, 70101, Taiwan.

In this study, we demonstrated that zero-valent iron (ZVI), which is widely used to remediate environmental contamination through the production of high-energy reactive oxygen species (ROS), exhibited differential cytotoxicity in cancerous cells and nonmalignant cells. Nanoparticles (NPs) with different shells exhibited distinct potencies against cancerous cells, which depended on their iron-to-oxygen ratios. Silver-coated ZVI NPs ([email protected]) had the highest potency among synthesized ZVI NPs, and they simultaneously exhibited adequate biocompatibility with nonmalignant keratinocytes. The assessment of the intracellular dynamics of iron species revealed that the uptake of [email protected] was similar between cancerous cells and nonmalignant cells during the first 2 h; however, only cancerous cells rapidly converted NPs into iron ions and generated large amounts of intracellular ROS, which was followed by apoptosis and autophagy induction. The aforementioned processes were prevented in the presence of iron ion chelators or by preoxidizing NPs before administration. Neutralization of lysosomal pH effectively reduced [email protected] NP-induced programmed cell death. In the xenograft mouse model, cancer growth was significantly inhibited by a single dose of systematically administered NPs without significant weight loss in animals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c9tb01477bDOI Listing
May 2020

Nivolumab safety and efficacy in advanced, platinum-resistant, non-small cell lung cancer, radical radiotherapy-ineligible patients: A phase II study in Taiwan.

J Formos Med Assoc 2020 Dec 22;119(12):1817-1826. Epub 2020 Feb 22.

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

Background/purpose: There is a lack of data on nivolumab treatment outcomes in Taiwanese patients with advanced or recurrent non-small cell lung cancer (NSCLC) ineligible for radical radiotherapy and resistant to platinum-based chemotherapy. We investigated the safety and efficacy of nivolumab in this population.

Methods: In this ongoing, multicenter, open-label, single-arm, phase II study, patients aged ≥20 years with a performance status of 0-1 and stage IIIB/IV or recurrent NSCLC received nivolumab 3 mg/kg every 2 weeks in 6-week cycles. Interim data obtained between 27 January 2016 and 21 May 2017 were analyzed. Safety, based on adverse event (AE) reporting, was the primary endpoint. Efficacy assessment parameters included overall response rate (ORR), overall survival (OS), and progression-free survival (PFS).

Results: Among 53 treated patients with advanced NSCLC (median age 61.0 years; 62.3% male), mean treatment duration was 99.7 days. AEs (any grade) and serious AEs were reported by 92.5% and 47.2% of patients, respectively. Adverse drug reactions (ADRs; any) occurred in 58.5% of patients; grade ≥3 ADRs occurred in 13.2% of patients. Five deaths occurred; two cases (neoplasm progression and septic shock) were considered treatment-emergent. Common ADRs were fatigue (17.0%) and rash (13.2%). Common immune-related treatment-emergent AEs were rash (17.0%) and pruritus (13.2%). The centrally assessed ORR was 9.4% (5/53). The median OS and median PFS were 11.5 months and 1.4 months, respectively.

Conclusion: Nivolumab appeared to be safe and effective in Taiwanese patients. These interim results suggest that nivolumab is a suitable treatment option for this population.

Clinical Trial Registration: NCT02582125.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jfma.2020.01.004DOI Listing
December 2020

Long-Term Outcomes and Retreatment Among Patients With Previously Treated, Programmed Death-Ligand 1‒Positive, Advanced Non‒Small-Cell Lung Cancer in the KEYNOTE-010 Study.

J Clin Oncol 2020 05 20;38(14):1580-1590. Epub 2020 Feb 20.

The Netherlands Cancer Institute, Amsterdam, the Netherlands.

Purpose: In the KEYNOTE-010 study, pembrolizumab improved overall survival (OS) versus docetaxel in previously treated, programmed death-ligand 1 (PD-L1)‒expressing advanced non‒small-cell lung cancer (NSCLC) in patients with a tumor proportion score (TPS) ≥ 50% and ≥ 1%. We report KEYNOTE-010 long-term outcomes, including after 35 cycles/2 years or second-course pembrolizumab.

Methods: Of 1,033 patients randomly assigned (intention to treat), 690 received up to 35 cycles/2 years of pembrolizumab 2 mg/kg (n = 344) or 10 mg/kg (n = 346) every 3 weeks, and 343 received docetaxel 75 mg/m every 3 weeks. Eligible patients with disease progression after 35 cycles/2 years of pembrolizumab could receive second-course treatment (up to 17 cycles). Pembrolizumab doses were pooled because no between-dose difference was observed at primary analysis.

Results: Pembrolizumab continued to improve OS over docetaxel in the PD-L1 TPS ≥ 50% and ≥ 1% groups (hazard ratio [HR], 0.53; 95% CI, 0.42 to 0.66; < .00001; and HR, 0.69; 95% CI, 0.60 to 0.80; .00001, respectively) after a 42.6-month (range, 35.2-53.2 months) median follow-up. Estimated 36-month OS rates were 34.5% versus 12.7% and 22.9% versus 11.0%, respectively. Grade 3-5 treatment-related adverse events occurred in 16% versus 37% of patients, respectively. Seventy-nine of 690 patients completed 35 cycles/2 years of pembrolizumab; 12-month OS and progression-free survival rates after completing treatment were 98.7% (95% CI, 91.1% to 99.8%) and 72.5% (95% CI, 59.9% to 81.8%), respectively. Seventy-five patients (95%) had objective response (RECIST v1.1, blinded independent central review) and 48 (64%) had ongoing response. Grade 3-5 treatment-related adverse events occurred in 17.7% of patients. Fourteen patients received second-course pembrolizumab: 5 completed 17 cycles, 6 (43%) had partial response, and 5 (36%) had stable disease.

Conclusion: Pembrolizumab provided long-term OS benefit over docetaxel, with manageable safety, durable responses among patients receiving 2 years of treatment, and disease control with second-course treatment, further supporting pembrolizumab for previously treated, PD-L1‒expressing advanced NSCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.02446DOI Listing
May 2020

Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study.

Lancet Oncol 2020 03 3;21(3):373-386. Epub 2020 Feb 3.

Department of Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address:

Background: Preclinical data suggest that EGFR tyrosine kinase inhibitors (TKIs) plus MET TKIs are a possible treatment for EGFR mutation-positive lung cancers with MET-driven acquired resistance. Phase 1 safety data of savolitinib (also known as AZD6094, HMPL-504, volitinib), a potent, selective MET TKI, plus osimertinib, a third-generation EGFR TKI, have provided recommended doses for study. Here, we report the assessment of osimertinib plus savolitinib in two global expansion cohorts of the TATTON study.

Methods: In this multi-arm, multicentre, open-label, phase 1b study, we enrolled adult patients (aged ≥18 years) with locally advanced or metastatic, MET-amplified, EGFR mutation-positive non-small-cell lung cancer, who had progressed on EGFR TKIs. We considered two expansion cohorts: parts B and D. Part B consisted of three cohorts of patients: those who had been previously treated with a third-generation EGFR TKI (B1) and those who had not been previously treated with a third-generation EGFR TKI who were either Thr790Met negative (B2) or Thr790Met positive (B3). In part B, patients received oral osimertinib 80 mg and savolitinib 600 mg daily; after a protocol amendment (March 12, 2018), patients who weighed no more than 55 kg received a 300 mg dose of savolitinib. Part D enrolled patients who had not previously received a third-generation EGFR TKI and were Thr790Met negative; these patients received osimertinib 80 mg plus savolitinib 300 mg. Primary endpoints were safety and tolerability, which were assessed in all dosed patients. Secondary endpoints included the proportion of patients who had an objective response per RECIST 1.1 and was assessed in all dosed patients and all patients with centrally confirmed MET amplification. Here, we present an interim analysis with data cutoff on March 29, 2019. This study is registered with ClinicalTrials.gov, NCT02143466.

Findings: Between May 26, 2015, and Feb 14, 2019, we enrolled 144 patients into part B and 42 patients into part D. In part B, 138 patients received osimertinib plus savolitinib 600 mg (n=130) or 300 mg (n=8). In part D, 42 patients received osimertinib plus savolitinib 300 mg. 79 (57%) of 138 patients in part B and 16 (38%) of 42 patients in part D had adverse events of grade 3 or worse. 115 (83%) patients in part B and 25 (60%) patients in part D had adverse events possibly related to savolitinib and serious adverse events were reported in 62 (45%) patients in part B and 11 (26%) patients in part D; two adverse events leading to death (acute renal failure and death, cause unknown) were possibly related to treatment in part B. Objective partial responses were observed in 66 (48%; 95% CI 39-56) patients in part B and 23 (64%; 46-79) in part D.

Interpretation: The combination of osimertinib and savolitinib has acceptable risk-benefit profile and encouraging antitumour activity in patients with MET-amplified, EGFR mutation-positive, advanced NSCLC, who had disease progression on a previous EGFR TKI. This combination might be a potential treatment option for patients with MET-driven resistance to EGFR TKIs.

Funding: AstraZeneca.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(19)30785-5DOI Listing
March 2020

Assessment of Serological Early Biomarker Candidates for Lung Adenocarcinoma by using Multiple Reaction Monitoring-Mass Spectrometry.

Proteomics Clin Appl 2020 07 16;14(4):e1900095. Epub 2020 Feb 16.

Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.

Purpose: Plasma markers that enable diagnosis in the early stage of lung cancer is not discovered. A liquid chromatography multiple reaction monitoring-mass spectrometry (LC-MRM-MS) assay for identifying potential early marker proteins for lung adenocarcinoma is developed.

Experimental Design: LC-MRM-MS assay is used for measuring the level of 35 candidate peptides in plasma from 102 lung adenocarcinoma patients (including n = 50, 16, 24, and 12 in stage I, II, III, and IV, respectively.) and 84 healthy controls. Stable isotope labeled standard peptides are synthesized to accurately measure the amount of these proteins.

Results: Seven proteins are able to distinguish stage I patients from controls. These proteins are combined in to a protein marker panel which improve the sensitivity to discriminate stage I patients from controls with cross-validated area under the curve = 0.76. Besides, it is found that low expression of eukaryotic initiation factor 4A-I and high expression of lumican show significantly poor prognosis in overall survival (p = 0.012 and 0.0074, respectively), which may be used as prognostic biomarkers for lung cancer.

Conclusions And Clinical Relevance: Proteins highlighted here may be used for early detection of lung adenocarcinoma or therapeutics development after validation in a larger cohort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/prca.201900095DOI Listing
July 2020

Predicting Lung Cancer Occurrence in Never-Smoking Females in Asia: TNSF-SQ, a Prediction Model.

Cancer Epidemiol Biomarkers Prev 2020 02 17;29(2):452-459. Epub 2019 Dec 17.

Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.

Background: High disease burden suggests the desirability to identify high-risk Asian never-smoking females (NSF) who may benefit from low-dose CT (LDCT) screening. In North America, one is eligible for LDCT screening if one satisfies the U.S. Preventive Services Task Force (USPSTF) criteria or has model-estimated 6-year risk greater than 0.0151. According to two U.S. reports, only 36.6% female patients with lung cancer met the USPSTF criteria, while 38% of the ever-smokers ages 55 to 74 years met the USPSTF criteria.

Methods: Using data on NSFs in the Taiwan Genetic Epidemiology Study of Lung Adenocarcinoma and the Taiwan Biobank before August 2016, we formed an age-matched case-control study consisting of 1,748 patients with lung cancer and 6,535 controls. Using these and an estimated age-specific lung cancer 6-year incidence rate among Taiwanese NSFs, we developed the Taiwanese NSF Lung Cancer Risk Models using genetic information and simplified questionnaire (TNSF-SQ). Performance evaluation was based on the newer independent datasets: Taiwan Lung Cancer Pharmacogenomics Study (LCPG) and Taiwan Biobank data after August 2016 (TWB2).

Results: The AUC based on the NSFs ages 55 to 70 years in LCPG and TWB2 was 0.714 [95% confidence intervals (CI), 0.660-0.768]. For women in TWB2 ages 55 to 70 years, 3.94% (95% CI, 2.95-5.13) had risk higher than 0.0151. For women in LCPG ages 55 to 74 years, 27.03% (95% CI, 19.04-36.28) had risk higher than 0.0151.

Conclusions: TNSF-SQ demonstrated good discriminative power. The ability to identify 27.03% of high-risk Asian NSFs ages 55 to 74 years deserves attention.

Impact: TNSF-SQ seems potentially useful in selecting Asian NSFs for LDCT screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-19-1221DOI Listing
February 2020
-->