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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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Coronary Artery Calcium Score and Polygenic Risk Score for the Prediction of Coronary Heart Disease Events.
Khan, SS, Post, WS, Guo, X, Tan, J, Zhu, F, Bos, D, Sedaghati-Khayat, B, van Rooij, J, Aday, A, Allen, NB, et al
JAMA. 2023;(20):1768-1777
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Abstract
IMPORTANCE Coronary artery calcium score and polygenic risk score have each separately been proposed as novel markers to identify risk of coronary heart disease (CHD), but no prior studies have directly compared these markers in the same cohorts. OBJECTIVE To evaluate change in CHD risk prediction when a coronary artery calcium score, a polygenic risk score, or both are added to a traditional risk factor-based model. DESIGN, SETTING, AND PARTICIPANTS Two observational population-based studies involving individuals aged 45 years through 79 years of European ancestry and free of clinical CHD at baseline: the Multi-Ethnic Study of Atherosclerosis (MESA) study involved 1991 participants at 6 US centers and the Rotterdam Study (RS) involved 1217 in Rotterdam, the Netherlands. EXPOSURE Traditional risk factors were used to calculate CHD risk (eg, pooled cohort equations [PCEs]), computed tomography for the coronary artery calcium score, and genotyped samples for a validated polygenic risk score. MAIN OUTCOMES AND MEASURES Model discrimination, calibration, and net reclassification improvement (at the recommended risk threshold of 7.5%) for prediction of incident CHD events were assessed. RESULTS The median age was 61 years in MESA and 67 years in RS. Both log (coronary artery calcium+1) and polygenic risk score were significantly associated with 10-year risk of incident CHD (hazards ratio per SD, 2.60; 95% CI, 2.08-3.26 and 1.43; 95% CI, 1.20-1.71, respectively), in MESA. The C statistic for the coronary artery calcium score was 0.76 (95% CI, 0.71-0.79) and for the polygenic risk score, 0.69 (95% CI, 0.63-0.71). The change in the C statistic when each was added to the PCEs was 0.09 (95% CI, 0.06-0.13) for the coronary artery calcium score, 0.02 (95% CI, 0.00-0.04) for the polygenic risk score, and 0.10 (95% CI, 0.07-0.14) for both. Overall categorical net reclassification improvement was significant when the coronary artery calcium score (0.19; 95% CI, 0.06-0.28) but was not significant when the polygenic risk score (0.04; 95% CI, -0.05 to 0.10) was added to the PCEs. Calibration of the PCEs and models with coronary artery calcium and/or polygenic risk scores was adequate (all χ2<20). Subgroup analysis stratified by the median age demonstrated similar findings. Similar findings were observed for 10-year risk in RS and in longer-term follow-up in MESA (median, 16.0 years). CONCLUSIONS AND RELEVANCE In 2 cohorts of middle-aged to older adults from the US and the Netherlands, the coronary artery calcium score had better discrimination than the polygenic risk score for risk prediction of CHD. In addition, the coronary artery calcium score but not the polygenic risk score significantly improved risk discrimination and risk reclassification for CHD when added to traditional risk factors.
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Intravenous versus super-selected intra-arterial chemotherapy in children with advanced unilateral retinoblastoma: an open-label, multicentre, randomised trial.
Wen, X, Fan, J, Jin, M, Jiang, H, Li, J, Han, M, Zhang, C, He, X, Luo, Y, Yang, J, et al
The Lancet. Child & adolescent health. 2023;(9):613-620
Abstract
BACKGROUND Super-selected intra-arterial chemotherapy has increasingly been used as conservative management for retinoblastoma during the past decade. However, the absence of evidence from randomised controlled trials engendered controversy in the administration route of chemotherapy. We aimed to assess the efficacy and safety of intra-arterial chemotherapy compared with intravenous chemotherapy. METHODS This open-label, multicentre, randomised trial was done at six hospitals in China. Patients with new-onset unilateral group D or E retinoblastoma (poorly defined, large, or very large tumours, according to the International Intraocular Retinoblastoma Classification) without high-risk clinical factors were included. Patients were randomly assigned (1:1) to receive intra-arterial chemotherapy (injections of 0·5 mg/kg [or depending on age] melphalan with 20 mg carboplatin [first and third cycles] or with 1 mg topotecan [second and fourth cycles]) or intravenous chemotherapy (0·05 mg/kg [or 1·5 mg/m2] vincristine, 5 mg/kg [or 150 mg/m2] etoposide, and 18·6 mg/kg [or 560 mg/m2] carboplatin for six cycles). After intra-arterial chemotherapy, patients received a subcutaneous injection of 0·1 mL nadroparin calcium twice at a 12 h interval. Both intra-arterial and intravenous chemotherapy cycles were completed every 4 weeks. No masking was done, except of independent statisticians, who were masked to the allocation information. The primary outcome was 2-year progression-free globe salvage rate, defined as the time from randomisation to tumour progression or enucleation, whichever occurred first, and was analysed by intention to treat. We also recorded predefined safety outcomes (myelosuppression and ophthalmic arterial stenosis or occlusion) and severe adverse events likely to be related to study treatment. The study is registered with the Chinese Clinical Trial Registry, ChiCTR-IPR-15006469, and is complete. FINDINGS Between June 1, 2015, and June 1, 2018, 234 patients with newly diagnosed retinoblastoma were screened and 143 eligible patients (median age 23·6 months [IQR 14·0-31·9]) were enrolled and randomly assigned to the intra-arterial chemotherapy group (n=72) or the intravenous chemotherapy group (n=71). At a median follow-up of 35·8 months (IQR 28·4-43·0), the 2-year progression-free globe salvage rate was 53% (38 of 72 patients) in the intra-arterial chemotherapy group and 27% (19 of 71 patients) in the intravenous chemotherapy group (risk ratio 1·97, 95% CI 1·27-3·07, p=0·0020). Myelosuppression was less common in the intra-arterial chemotherapy group than in the intravenous chemotherapy group (37 [51%] of 72 patients vs 50 [70%] of 71 patients; 0·73, 95% CI 0·56-0·96, p=0·021) and less severe (ptrend=0·0070). In the intra-arterial chemotherapy group, two (3%) of 72 patients had ophthalmic artery occlusion and 13 (18%) patients had ophthalmic artery stenosis. INTERPRETATION Our findings show that intra-arterial chemotherapy could significantly improve the globe salvage rate in children with advanced unilateral retinoblastoma compared with intravenous chemotherapy, with mild systemic complications and no difference in overall survival rate. Intra-arterial chemotherapy could be an acceptable first-line treatment in children with advanced unilateral retinoblastoma. FUNDING Scientific Research Program of the National Health and Family Planning Commission of China, the Clinical Research Plan of Shanghai Hospital Development Center, the National Natural Science Foundation of China, and the Science and Technology Commission of Shanghai Municipality.
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Shenlingcao oral liquid for patients with non-small cell lung cancer receiving adjuvant chemotherapy after radical resection: A multicenter randomized controlled trial.
Liu, Y, Luo, X, Liu, J, Ma, Y, Tan, J, Wang, W, Hu, J, Fu, X, Xu, L, Yu, F, et al
Phytomedicine : international journal of phytotherapy and phytopharmacology. 2023;:154723
Abstract
BACKGROUND Low quality of life (QoL) in patients with non-small cell lung cancer (NSCLC) receiving adjuvant chemotherapy after radical resection is a major global health issue. High-quality evidence for the effectiveness of Shenlingcao oral liquid (SOL) as a complementary treatment in this patients is lacking at present. PURPOSE To determine whether complementary SOL treatment in NSCLC patients receiving adjuvant chemotherapy would yield greater improvements in QoL than chemotherapy alone. STUDY DESIGN We conducted a multicenter, randomized controlled trial of stages IIA-IIIA NSCLC patients undergoing adjuvant chemotherapy in seven hospitals. METHODS Using stratified blocks, participants were randomized in a 1:1 ratio to receive SOL combined with conventional chemotherapy or conventional chemotherapy alone. The primary outcome was the change in global QoL from baseline to the fourth chemotherapy cycle, and intention-to-treat analysis was applied with a mixed-effect model. Secondary outcomes were functional QoL, symptoms, and performance status scores at the 6-month follow-up. Missing data were handled with multiple imputation and a pattern-mixture model. RESULTS Among 516 randomized patients, 446 (86.43%) completed the study. After the fourth chemotherapy cycle, in comparison with the control group, patients receiving SOL showed a lower reduction in mean global QoL (-2.76 vs. -14.11; mean difference [MD], 11.34; 95% confidence interval [CI], 8.28 to 14.41), greater improvement in physical function (MD, 11.61; 95% CI, 8.57 to 14.65), role function (MD, 10.15; 95% CI, 5.75 to 14.54), and emotional function (MD, 4.71; 95% CI, 1.85 to 7.57), and greater improvements in lung cancer-related symptoms (e.g., fatigue, nausea/vomiting, and appetite loss) and performance status during the 6-month follow-up period (treatment main effect, p < 0.05). CONCLUSION SOL treatment for NSCLC patients receiving adjuvant chemotherapy can significantly improve QoL and performance status within 6 months after radical resection. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT03712969.
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Vitamin K2 as a potential therapeutic candidate for the prevention of muscle cramps in hemodialysis patients: A prospective multicenter, randomized, controlled, crossover pilot trial.
Xu, D, Yang, A, Ren, R, Shan, Z, Li, YM, Tan, J
Nutrition (Burbank, Los Angeles County, Calif.). 2022;:111608
Abstract
OBJECTIVES Muscle cramps occur in 33% to 78% of patients with dialysis. The etiology of muscle cramps is poorly understood, and no clear evidence-based prevention or treatment strategies exist. Improved interventions are urgently needed. The aim of this study was to investigate the effect of vitamin K2 in reducing the frequency and severity of muscle cramps in hemodialysis (HD) patients. METHODS This multicenter, randomized, placebo-controlled, crossover clinical trial was conducted from June 2019 to May 2020. Each participant received vitamin K2 (360 µg/d) or placebo for two 4-wk phases, and then crossed to the alternative arm for two 4-wk phases after a 2-wk washout. The primary endpoint was the frequency of muscle cramps during HD. The secondary endpoints were severity and duration of muscle cramps during HD. RESULTS A total of 523 patients with maintenance HD were screened for muscle cramps, including 41 patients with muscle cramps refractory to conventional interventions, were enrolled. Nineteen patients in the vitamin K2-initial group and 20 in the placebo-initial group completed the protocol, and were included in the final analysis. Vitamin K2 reduced the frequency, duration, and severity of muscle cramps in HD patients (all P < 0.05). The frequency, duration, and severity of muscle cramps in HD patients increased again after crossing over to the placebo. There were no serious adverse events. One patient experienced gastrointestinal discomfort when taking vitamin K2. CONCLUSIONS This pilot trial demonstrated that vitamin K2 supplementation could decrease the frequency, duration, and severity of muscle cramps in HD patients.
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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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The wearable activity technology and action-planning trial in cancer survivors: Physical activity maintenance post-intervention.
Hardcastle, SJ, Maxwell-Smith, C, Hince, D, Bulsara, MK, Boyle, T, Tan, P, Levitt, M, Salama, P, Mohan, GRKA, Salfinger, S, et al
Journal of science and medicine in sport. 2021;(9):902-907
Abstract
OBJECTIVES The study objective was to assess whether moderate-to-vigorous intensity physical activity (MVPA) change in cancer survivors (n = 68, mean age = 64 years) was maintained 12-weeks following the Wearable Activity Technology and Action Planning (WATAAP) intervention. Secondary aims were to assess the effects of the intervention on blood pressure (BP) and body mass index (BMI), and to explore group differences between baseline and 24-weeks. DESIGN Randomized controlled trial. METHODS MVPA and sedentary behaviour were assessed using an accelerometer at baseline, the end of the intervention (12-weeks), and at 24-weeks. Generalised linear mixed models with random effects were used to examine between-group and within-group changes in MVPA, sedentary behaviour, BP and BMI. RESULTS MVPA was significantly higher in the intervention group compared with the control group at 24-weeks following adjustment for known confounders (141.4 min/wk. (95% CI = 9.1 to 273.8), p = 0.036). At 24-weeks participants in the intervention group had maintained their increased levels of MVPA (change from 12-weeks = 8.8 min/wk.; 95% CI = -43 to 61; p = 0.74). The reduction in MVPA in the control group over the first 12-weeks was also maintained at 24-weeks (5.4 min/wk.; 95% CI = -3.6 to 4.6; p = 0.80). Secondary outcomes did not differ between groups at 24-weeks. CONCLUSIONS Our results suggest distance-based interventions using wearable technology produce increases in MVPA that endure at least 12-weeks after the intervention is completed.
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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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The safety and efficacy of four different fixed combination regimens of adapalene 0.1%/benzoyl peroxide 2.5% gel for the treatment of acne vulgaris: results from a randomised controlled study.
Tan, J, Bissonnette, R, Gratton, D, Kerrouche, N, Canosa, JM
European journal of dermatology : EJD. 2018;(4):502-508
Abstract
BACKGROUND Combined use of a retinoid and antimicrobial is recommended for acne, however, local tolerability issues may compromise patient adherence and treatment outcome. OBJECTIVES This multicentre, single-blinded controlled study was designed to determine whether modified adapalene/benzoyl peroxide (A/BPO, Epiduo®, Galderma, France) regimens improve local tolerability during the first four weeks of treatment without impairing efficacy at Week 12. MATERIALS & METHODS In total, 120 subjects with mild-to-moderate acne received, during the first four weeks, A/BPO daily overnight (A/BPO-EN), A/BPO daily for three hours (A/BPO-3h), A/BPO daily overnight and a provided moisturizer lotion (A/BPO-moisturizer), or A/BPO every other night (A/BPO-EoN). Local tolerance assessments included signs and symptoms, global worst score (GWS), and total sum score (TSS). Efficacy was assessed based on lesion counts, investigator global assessment (IGA), and total lesion count reduction. Adherence, subject satisfaction, and overall safety were also assessed. RESULTS The mean TSS was significantly reduced at Week 1 with A/BPO-EoN vs. A/BPO-EN (p<0.05), and A/BPO-EoN led to the lowest GWS and a decrease in severity of stinging/burning and erythema (p<0.05). The A/BPO-moisturizer regimen prevented dryness and scaling compared with the A/BPO-EN regimen. The median decrease in lesions from baseline was similar in all groups: up to 67% for total, 72% for inflammatory, and 70% for non-inflammatory lesion counts. Adherence, IGA, patient satisfaction, and overall safety were excellent. CONCLUSIONS Modulating treatment regimens during the first four weeks improved local tolerability without impacting overall efficacy outcome after 12 weeks and may improve treatment adherence during the first weeks of therapy.