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Multicenter Randomized Double-Blind Phase III Trial of Donafenib in Progressive Radioactive Iodine-Refractory Differentiated Thyroid Cancer.
Lin, Y, Qin, S, Yang, H, Shi, F, Yang, A, Han, X, Liu, B, Li, Z, Ji, Q, Tang, L, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023;(15):2791-2799
Abstract
PURPOSE The phase II/III study of donafenib was initiated when there was no available treatment indicated for Chinese patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC). Donafenib, an oral tyrosine kinase inhibitor (TKI), showed good efficacy and tolerability in the phase II study. We aimed to further evaluate the antitumor activity and safety of donafenib in Chinese patients with RAIR-DTC. PATIENTS AND METHODS This multicenter, double-blind, placebo-controlled, phase III study enrolled 191 patients with progressive RAIR-DTC and randomized in a ratio of 2:1 to donafenib (300 mg twice daily, n = 128) or matched placebo (n = 63). An open-label donafenib treatment period was allowed upon disease progression. The primary endpoint was progression-free survival (PFS) assessed by the independent review committee. The second endpoints include objective response rate (ORR), disease control rate (DCR), safety, etc. RESULTS Donafenib demonstrated prolonged median PFS over placebo [12.9 vs. 6.4 months; hazard ratio (HR), 0.39; 95% confidence interval (CI), 0.25-0.61; P < 0.0001] in Chinese patients with RAIR-DTC. Improved ORR (23.3% vs. 1.7%; P = 0.0002) and DCR (93.3% vs. 79.3%; P = 0.0044) were observed in the donafenib group over placebo. For donafenib, the most common grade ≥ 3 treatment-related adverse events (AE) included hypertension (13.3%) and hand-foot syndrome (12.5%), 42.2% underwent dose reduction or interruption, and 6.3% experienced discontinuation. CONCLUSIONS Donafenib was well-tolerated and demonstrated clinical benefit in terms of improved PFS, ORR, and DCR in patients with RAIR-DTC. The results suggest that donafenib could be a new treatment option for patients with RAIR-DTC.
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A Randomized, Phase III Study of Lenvatinib in Chinese Patients with Radioiodine-Refractory Differentiated Thyroid Cancer.
Zheng, X, Xu, Z, Ji, Q, Ge, M, Shi, F, Qin, J, Wang, F, Chen, G, Zhang, Y, Huang, R, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021;(20):5502-5509
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Abstract
PURPOSE Lenvatinib has shown efficacy in treating radioiodine-refractory differentiated thyroid cancer (RR-DTC) in the multinational phase III SELECT study; however, it has not been tested in Chinese patients with RR-DTC. PATIENTS AND METHODS Chinese patients with confirmed RR-DTC (n = 151) were randomly assigned 2:1 to receive lenvatinib 24 mg/day or placebo in 28-day cycles. The primary endpoint was progression-free survival, and key secondary endpoints included objective response rate and safety. Analyses for progression-free survival and objective response rate were conducted using Response Evaluation Criteria in Solid Tumors v1.1 and confirmed by independent imaging review. All adverse events were assessed and monitored. RESULTS Progression-free survival was significantly longer with lenvatinib treatment [n = 103; median 23.9 months; 95% confidence interval (CI), 12.9-not estimable] versus placebo (n = 48; median 3.7 months; 95% CI, 1.9-5.6; hazard ratio = 0.16; 95% CI, 0.10-0.26; P < 0.0001). The objective response rate was 69.9% (95% CI, 61.0-78.8) in the lenvatinib arm and 0% (95% CI, 0-0) in the placebo arm. At data cutoff, 60.2% of patients receiving lenvatinib remained on treatment; treatment-emergent adverse events led to lenvatinib discontinuation in 8.7% of patients. Overall, treatment-emergent adverse events of grade ≥3 occurred in 87.4% of patients in the lenvatinib arm, the most common being hypertension (62.1%) and proteinuria (23.3%). CONCLUSIONS Lenvatinib at a starting dose of 24 mg/day significantly improved progression-free survival and objective response rate in Chinese patients with RR-DTC versus placebo. There were no new or unexpected toxicities. Results are consistent with those from SELECT involving patients with RR-DTC.
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Donafenib in Progressive Locally Advanced or Metastatic Radioactive Iodine-Refractory Differentiated Thyroid Cancer: Results of a Randomized, Multicenter Phase II Trial.
Lin, YS, Yang, H, Ding, Y, Cheng, YZ, Shi, F, Tan, J, Deng, ZY, Chen, ZD, Wang, RF, Ji, QH, et al
Thyroid : official journal of the American Thyroid Association. 2021;(4):607-615
Abstract
Background: An unmet need for more effective and affordable kinase inhibitors remains in patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) in China, where only sorafenib is approved for this indication. This study evaluated the 24-week objective response rate (ORR) to donafenib-a new, domestic multikinase inhibitor-in the treatment of locally advanced or metastatic RAIR-DTC in patients with measurable lesions. Two dose regimens (300 mg twice daily vs. 200 mg twice daily) were used to determine its optimal dosage and safety for further phase III studies. Methods: This study was a randomized, open-label, multicenter phase II trial. Thirty-five adult RAIR-DTC patients with at least one measurable targeted lesion according to RECIST 1.1 were enrolled from 12 centers in China and randomized to receive either 200 mg (17 patients) or 300 mg (18 patients) of donafenib orally twice daily for 24 weeks. The primary endpoint was ORR, and the secondary endpoints included progression-free survival (PFS) among others. Additionally, biochemical (serum thyroglobulin) and structural (total tumor diameter [TTD]) responses were assessed, change (ΔTTD) rates were calculated, and safety was evaluated. Results: The ORRs for the 200- and 300-mg arms were 12.5% and 13.33% (p = 1.000), respectively. The 300-mg arm had a nonsignificant, longer median PFS than the 200-mg arm (14.98 months vs. 9.44 months) (p = 0.351). There was a trend toward more tumor shrinkage in the 300-mg arm compared with the 200-mg arm (average ΔTTD rate -0.52 ± 0.71 vs. -0.04 ± 1.55 mm/month, p = 0.103). Most treatment-related adverse events (AEs) in both arms were grades 1-2. The most common grade 3 treatment-related AEs in both arms were palmar-plantar erythrodysesthesia and hypertension; the sum occurrence rates of these two AEs in the 200-mg and 300-mg arms were 11.43% and 22.86%, respectively. Conclusions: Donafenib was generally well tolerated. Both donafenib regimens demonstrated similar efficacy in terms of the ORR in locally advanced or metastatic RAIR-DTC. The results warrant further studies on donafenib as a new, feasible treatment option for RAIR-DTC patients. Clinical Trials.gov IDs: NCT02870569; CTR20160220.
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Stereotactic ablative body radiotherapy (SABR) for bone only oligometastatic breast cancer: A prospective clinical trial.
David, S, Tan, J, Savas, P, Bressel, M, Kelly, D, Foroudi, F, Loi, S, Siva, S
Breast (Edinburgh, Scotland). 2020;:55-62
Abstract
BACKGROUND Stereotactic ablative body radiotherapy (SABR) is an emerging noninvasive approach for the treatment of oligometastases. Limited prospective evidence is available in breast cancer. OBJECTIVES To determine the safety and feasibility of single fraction SABR for patients with bone only oligometastatic breast cancer. Secondary endpoints were local and distant progression-free survival (LPFS and DPFS), toxicity and response assessment. METHODS AND MATERIALS In this single institution prospective trial we screened patients with computed tomography, bone scan, and sodium fluoride positron emission tomography. Eligible patients had one to three bone only oligometastases. All patients were treated at a dose of 20Gy in 1 fraction to each metastasis. Kaplan-Meier methods were used to determine local and distant progression free survival (LPFS and DPFS). Toxicity was graded using Common Terminology Criteria for Adverse Event version 4.0. RESULTS 15 eligible patients were recruited to the study. Median follow-up time was 24 months. The treatment was feasible in 12 (80%) of patients with 3 (20%) of patients having treatment delayed by more than 3 days. 10 (67%) of patients experienced grade 1 treatment related toxicity, 4 (27%) experienced grade 2 toxicity and no patients experienced grade 3 or 4 treatment related toxicity. The two-year LPFS was 100%, DPFS was 67%. CONCLUSION We observed that SABR is feasible, well tolerated and effective in this cohort with two thirds of patients disease-free at two years. In selected patients with bone-only oligometastatic disease, SABR could be considered a treatment option. Randomised trials are required to assess the impact of SABR on overall survival when compared to the standard of care.
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Randomized phase 3 evaluation of trifarotene 50 μg/g cream treatment of moderate facial and truncal acne.
Tan, J, Thiboutot, D, Popp, G, Gooderham, M, Lynde, C, Del Rosso, J, Weiss, J, Blume-Peytavi, U, Weglovska, J, Johnson, S, et al
Journal of the American Academy of Dermatology. 2019;(6):1691-1699
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Abstract
BACKGROUND Acne vulgaris often affects the face, shoulders, chest, and back, but treatment of nonfacial acne has not been rigorously studied. OBJECTIVES Assess the safety and efficacy of trifarotene 50 μg/g cream, a novel topical retinoid, in moderate facial and truncal acne. METHODS Two phase III double-blind, randomized, vehicle-controlled, 12-week studies of once-daily trifarotene cream versus vehicle in subjects aged 9 years or older. The primary end points were rate of success on the face, as determined by the Investigator's Global Assessment (clear or almost clear and ≥2-grade improvement), and absolute change from baseline in inflammatory and noninflammatory counts from baseline to week 12. The secondary end points were rate of success on the trunk (clear or almost clear and ≥2-grade improvement) and absolute change in truncal inflammatory and noninflammatory counts from baseline to week 12. Safety was assessed through adverse events, local tolerability, vital signs, and routine laboratory testing results. RESULTS In both studies, at week 12 the facial success rates according to the Investigator's Global Assessment and truncal Physician's Global Assessment and change in inflammatory and noninflammatory lesion counts (both absolute and percentage) were all highly significant (P < .001) in favor of trifarotene when compared with the vehicle. LIMITATIONS Adjunctive topical or systemic treatments were not studied. CONCLUSION These studies demonstrate that trifarotene appears to be safe, effective, and well tolerated in treatment of both facial and truncal acne.
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A De Novo heterozygous frameshift mutation identified in BCL11B causes neurodevelopmental disorder by whole exome sequencing.
Qiao, F, Wang, C, Luo, C, Wang, Y, Shao, B, Tan, J, Hu, P, Xu, Z
Molecular genetics & genomic medicine. 2019;(9):e897
Abstract
BACKGROUND Next-generation sequencing has been invaluable to delineate the genetic etiology of neurodevelopmental disorders (NDDs) in recent years. BCL11B, encoding Cys2 His2 zinc finger transcription factor, is essential for the development of immune and neural systems. METHODS Herein, we describe a Chinese girl presenting craniofacial abnormalities, developmental delay and intellectual disability with speech impairment. Exomes of genes were enriched with the Agilent SureSelect QXT ALL Human Exon V6 kit and sequenced on Illumina Hiseq 2500 platform. RESULTS After variants filtering and annotation, we identified a de novo heterozygous 11bp frameshift mutation NM_138576.4: c.2190_2200delGGACGCACGAC (p.Thr730Thrfs*151) in exon 4 of BCL11B, which is expected to escape nonsense-mediated mRNA decay and probably result in a truncated protein with lack of the C-terminal DNA-binding zinc-finger domains. CONCLUSION This is the first report of NDD caused by a BCL11B variant in a Chinese population. The mutation identified in this report broadens the knowledge of mutation spectrum of BCL11B and might help in genetic counseling and reducing reproductive risk.
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Standardized Uptake Value Using Thyroid Quantitative SPECT/CT for the Diagnosis and Evaluation of Graves' Disease: A Prospective Multicenter Study.
Dong, F, Li, L, Bian, Y, Li, G, Han, X, Li, M, Liu, J, Xue, Y, Li, Y, Hu, Y, et al
BioMed research international. 2019;:7589853
Abstract
The clinical applications of the quantitative single photon emission computed tomography (SPECT)/computed tomography (CT) are being expanded to a variety of fields of nuclear medicine. However, clinical application of quantitative SPECT/CT for the evaluation of Graves' disease (GD) still needs further investigation. Our aim was to investigate the feasibility of standard uptake value (SUV) of the thyroid for the clinical diagnosis and evaluation of GD. In this prospective multicenter study, 116 patients diagnosed with GD (Graves group) and 74 healthy volunteers (control group) were enrolled from 8 different hospitals. All patients underwent technetium pertechnetate (99mTcO4 -) SPECT/CT imaging with Q.Metrix quantitative software and 24-hour thyroid radioactive iodine uptake (24h-RAIU) test. The SUVmax and SUVmean in Graves group were significantly higher than those of control group (P<0.01). Cut-off values of SUVmax and SUVmean to predict GD were 231.425 and 116.66 by ROC curves, respectively. The SUVmax and SUVmean in Graves patients were significantly related to serum thyroxine level with correlation coefficient of 0.493 and 0.512 for FT3 and 0.449 and 0.464 for FT4, respectively (all P<0.01). Additionally, the SUVmax and SUVmean in GD positively correlated with 24h-RAIU with a coefficient of 0.832 and 0.830, respectively (P<0.01). The volumes determined by Q.Metrix (35.65 ± 20.56ml) of 72 subjects also positively correlated with that from ultrasound (36.67 ± 21.00ml) with a coefficient of 0.927 (P<0.01). SUV measurements derived from thyroid SPECT/CT may be useful for the clinical diagnosis and evaluation of GD.
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Effectiveness and safety of Devil's Claw tablets in patients with general rheumatic disorders.
Warnock, M, McBean, D, Suter, A, Tan, J, Whittaker, P
Phytotherapy research : PTR. 2007;(12):1228-33
Abstract
Arthritis and other rheumatic conditions (AORC) are the leading cause of disability, are associated with poor quality of life and incur considerable direct and indirect costs. It is considered that the instance of AORC will continue to increase. To assess the effectiveness, safety and tolerability of Harpagophytum (Bioforce) in the treatment of AORC, a single group open study of 8 weeks duration (259 patients) was performed in the United Kingdom. Effectiveness was assessed by numeric rating scales, the Western Ontario and McMasters Universities Osteoarthritis (WOMAC) Index and the Algofunctional Hand Osteoarthritis Index. Tolerance was measured by a numeric rating scale and safety by self-reporting, blood analysis and liver function tests. Quality of life was measured by SF-12 questionnaire. There were statistically significant (p < 0.0001) improvements in patient assessment of global pain, stiffness and function. There were also statistically significant reductions in mean pain scores for hand, wrist, elbow, shoulder, hip, knee and back pain. Quality of life measurements (SF-12) were significantly increased from baseline and 60% patients either reduced or stopped concomitant pain medication. Harpagophytum is an effective and well-tolerated serious treatment option for mild to moderate degenerative rheumatic disorders providing improved quality of life measure.
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An open study to assess the safety and efficacy of Aesculus hippocastanum tablets (Aesculaforce 50mg) in the treatment of chronic venous insufficiency.
Dickson, S, Gallagher, J, McIntyre, L, Suter, A, Tan, J
Journal of herbal pharmacotherapy. 2004;(2):19-32
Abstract
An open study was carried out to assess, primarily, the safety and tolerability of Aesculus hippocastanum in the treatment of CVI. Patients underwent 8 consecutive weeks of treatment and were asked to take one 50 mg Aesculus hippocastanum tablet, twice daily. In total, 91 adverse events were reported, of which only 4 were rated as probably related to the study drug. Patients judged the tolerability of the study medication in the majority of the cases at visits 2 and 3 (90 and 95%, respectively) to be "good" or "fairly good." Only 2 patients rated tolerability as poor at visit 3. For each of the symptoms investigated the difference in the median value between baseline and visit 3 was found to be statistically significant and both the ankle and lower leg circumference decreased. The PPG measurements were rejected after analysis since validation measurements carried out after the trial showed that the PPG technique had an internal error of around 30%. Nevertheless, the majority of patients rated efficacy to be "very good" or "good," with only 10 patients reporting no effect by the end of the study. The results of this study indicate that Aesculaforce 50 mg tablets are a safe, well-tolerated and efficacious treatment for Widmer stage I and II CVI.
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Phase 1 study of HPV16-specific immunotherapy with E6E7 fusion protein and ISCOMATRIX adjuvant in women with cervical intraepithelial neoplasia.
Frazer, IH, Quinn, M, Nicklin, JL, Tan, J, Perrin, LC, Ng, P, O'Connor, VM, White, O, Wendt, N, Martin, J, et al
Vaccine. 2004;(2):172-81
Abstract
PURPOSE Persistent infection of cervical epithelium with "high risk" human papillomavirus (HPV) results in cervical intraepithelial neoplasia (CIN) from which squamous cancer of the cervix can arise. A study was undertaken to evaluate the safety and immunogenicity of an HPV16 immunotherapeutic consisting of a mixture of HPV16 E6E7 fusion protein and ISCOMATRIX adjuvant (HPV16 Immunotherapeutic) for patients with CIN. EXPERIMENTAL DESIGN Patients with CIN (n = 31) were recruited to a randomised blinded placebo controlled dose ranging study of immunotherapy. RESULTS Immunotherapy was well tolerated. Immunised subjects developed HPV16 E6E7 specific immunity. Antibody, delayed type hypersensitivity, in vitro cytokine release, and CD8 T cell responses to E6 and E7 proteins were each significantly greater in the immunised subjects than in placebo recipients. Loss of HPV16 DNA from the cervix was observed in some vaccine and placebo recipients. CONCLUSIONS The HPV16 Immunotherapeutic comprising HPV16E6E7 fusion protein and ISCOMATRIX adjuvant is safe and induces vaccine antigen specific cell mediated immunity.