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Fibroblast Activation Protein-Targeted Radioligand Therapy with 177Lu-EB-FAPI for Metastatic Radioiodine-Refractory Thyroid Cancer: First-in-Human, Dose-Escalation Study.
Fu, H, Huang, J, Zhao, T, Wang, H, Chen, Y, Xu, W, Pang, Y, Guo, W, Sun, L, Wu, H, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023;(23):4740-4750
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Abstract
PURPOSE Fibroblast activation protein (FAP) is a promising target for tumor treatment. In this study, we aimed to investigate the safety and efficacy of the albumin binder-conjugated FAP-targeted radiopharmaceutical, 177Lu-EB-FAPI (177Lu-LNC1004), in patients with metastatic radioiodine-refractory thyroid cancer (mRAIR-TC). PATIENTS AND METHODS This open-label, non-randomized, first-in-human, dose-escalation, investigator-initiated trial had a 3+3 design and involved a 6-week 177Lu-LNC1004 treatment cycle in patients with mRAIR-TC at 2.22 GBq initially, with subsequent cohorts receiving an incremental 50% dose increase until dose-limiting toxicity (DLT) was observed. RESULTS 177Lu-LNC1004 administration was well tolerated, with no life-threatening adverse events observed. No patients experienced DLT in Group A (2.22 GBq/cycle). One patient experienced grade 4 thrombocytopenia in Group B (3.33 GBq/cycle); hence, another three patients were enrolled, none of whom experienced DLT. Two patients experienced grade 3 and 4 hematotoxicity in Group C (4.99 GBq/cycle). The mean whole-body effective dose was 0.17 ± 0.04 mSv/MBq. Intense 177Lu-LNC1004 uptake and prolonged tumor retention resulted in high mean absorbed tumor doses (8.50 ± 12.36 Gy/GBq). The mean effective half-lives for the whole-body and tumor lesions were 90.20 ± 7.68 and 92.46 ± 9.66 hours, respectively. According to RECIST, partial response, stable disease, and progressive disease were observed in 3 (25%), 7 (58%), and 2 (17%) patients, respectively. The objective response and disease control rates were 25% and 83%, respectively. CONCLUSIONS FAP-targeted radioligand therapy with 177Lu-LNC1004 at 3.33 GBq/cycle was well tolerated in patients with advanced mRAIR-TC, with high radiation dose delivery to the tumor lesions, encouraging therapeutic efficacy, and acceptable side effects.
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A phase 2 study of sorafenib combined with conventional therapies in refractory central nervous system leukemia.
Chen, X, Huang, J, Xu, N, Fan, Z, Nie, D, Huang, F, Sun, Q, Zhang, X, Liang, X, Shi, P, et al
Cancer. 2022;(11):2138-2147
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Abstract
BACKGROUND Patients with refractory central nervous system leukemia (CNSL) have a dismal prognosis and lack effective therapy. Case reports have shown that sorafenib is effective against brain metastases, including leukemia. METHODS To explore the efficacy of sorafenib combined with conventional therapies for refractory CNSL, a phase 2 study was conducted. The primary end point was the complete remission rate (CRR) within 8 weeks of treatment. Secondary end points included the overall response rate (ORR), event-free survival (EFS), overall survival (OS), and adverse events (AEs). RESULTS Twenty-six patients with refractory CNSL were enrolled; they included 17 with isolated CNSL, 7 with hematological relapse, and 2 with another extramedullary relapse. After 8 weeks of treatment, 21 patients achieved complete remission, 2 achieved partial remission, and 3 achieved no remission for a CRR of 80.8% (95% CI, 62.1%-91.5%) and an ORR of 88.5% (95% CI, 71.0%-96.0%). Twenty patients survived, and 6 died. The 2-year EFS and OS rates were 75.0% (95% CI, 54.5%-88.3%) and 76.9% (95% CI, 54.2%-90.4%), respectively. Six patients experienced grade 3 or 4 treatment-related AEs, including moderate chronic graft-vs-host disease (n = 3), grade 3 or 4 acute graft-vs-host disease (n = 2), and grade 3 skin rash (n = 1). No treatment-related deaths occurred during the therapy of refractory CNSL. CONCLUSIONS Sorafenib combined with conventional therapies is effective and safe for refractory CNSL. LAY SUMMARY Sorafenib combined with conventional therapies is effective and safe for refractory central nervous system leukemia.
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Effect of Standardized Grape Powder Consumption on the Gut Microbiome of Healthy Subjects: A Pilot Study.
Yang, J, Kurnia, P, Henning, SM, Lee, R, Huang, J, Garcia, MC, Surampudi, V, Heber, D, Li, Z
Nutrients. 2021;(11)
Abstract
Grapes provide a rich source of polyphenols and fibers. This study aimed to evaluate the effect of the daily consumption of 46 g of whole grape powder, providing the equivalent of two servings of California table grapes, on the gut microbiome and cholesterol/bile acid metabolism in healthy adults. This study included a 4-week standardization to a low-polyphenol diet, followed by 4 weeks of 46 g of grape powder consumption while continuing the low-polyphenol diet. Compared to the baseline, 4 weeks of grape powder consumption significantly increased the alpha diversity index of the gut microbiome. There was a trend of increasing Verrucomicrobia (p = 0.052) at the phylum level, and a significant increase in Akkermansia was noted. In addition, there was an increase in Flavonifractor and Lachnospiraceae_UCG-010, but a decrease in Bifidobacterium and Dialister at the genus level. Grape powder consumption significantly decreased the total cholesterol by 6.1% and HDL cholesterol by 7.6%. There was also a trend of decreasing LDL cholesterol by 5.9%, and decreasing total bile acid by 40.9%. Blood triglyceride levels and body composition were not changed by grape powder consumption. In conclusion, grape powder consumption significantly modified the gut microbiome and cholesterol/bile acid metabolism.
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A phase I trial of the CDK 4/6 inhibitor palbociclib in pediatric patients with progressive brain tumors: A Pediatric Brain Tumor Consortium study (PBTC-042).
Van Mater, D, Gururangan, S, Becher, O, Campagne, O, Leary, S, Phillips, JJ, Huang, J, Lin, T, Poussaint, TY, Goldman, S, et al
Pediatric blood & cancer. 2021;(4):e28879
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Abstract
BACKGROUND Disruption of cell-cycle regulators is a potential therapeutic target for brain tumors in children and adolescents. The aim of this study was to determine the maximum tolerated dose (MTD) and describe toxicities related to palbociclib, a selective cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in pediatric patients with progressive/refractory brain tumors with intact retinoblastoma protein. METHODS Palbociclib was administered orally starting at 50 mg/m2 daily for the first 21 days of a 28-day course. Dose escalation was according to the Rolling-6 statistical design in less heavily (stratum I) and heavily pretreated (stratum II) patients, and MTD was determined separately for each group. Pharmacokinetic studies were performed during the first course, and pharmacodynamic studies were conducted to evaluate relationships between drug levels and toxicities. RESULTS A total of 21 patients were enrolled on stratum I and 14 patients on stratum II. The MTD for both strata was 75 mg/m2 . Palbociclib absorption (mean Tmax between 4.9 and 6.6 h) and elimination (mean half-life between 11.3 and 19.5 h) were assessed. The most common toxicity was myelosuppression. Higher palbociclib exposure was associated with grade 3/4 neutropenia and leukopenia. Dose limiting toxicities included grade 4 neutropenia and grade 3 thrombocytopenia and dehydration. No patients had an objective response to palbociclib therapy. CONCLUSIONS Palbociclib was safely administered to children and adolescents at a dosage of 75 mg/m2 for 21 consecutive days followed by seven days of rest in both strata. Future studies will establish its optimal utilization in pediatric patients with brain tumors.
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Elevated Serum Small Dense Low-Density Lipoprotein Cholesterol May Increase the Risk and Severity of Coronary Heart Disease and Predict Cardiovascular Events in Patients with Type 2 Diabetes Mellitus.
Huang, J, Gu, JX, Bao, HZ, Li, SS, Yao, XQ, Yang, M, Li, Y, Zhang, AM, Yin, Y, Zhang, N, et al
Disease markers. 2021;:5597028
Abstract
BACKGROUND Coronary heart disease (CHD) is a common and severe complication in type 2 diabetes mellitus (T2DM) patients. Increased amount of circulatory small dense low-density lipoprotein cholesterol (sdLDL-C) particles is known to be a sign of dyslipidemia and can result in atherosclerosis. However, the association between serum sdLDL-C levels and CHD in T2DM patients remains unclear. METHODS A total of 3684 T2DM patients who received selective coronary angiography (CAG) were selected. For analyzing the association between sdLDL-C and CHD severity in T2DM, the patients with CHD were further divided into four subgroups according to the quartiles of sdLDL-C. A multivariate logistic regression was used for analyzing the risks and severity of CHD. A total of 3427 patients with continuous stable CHD were recruited and followed up for 5 years. RESULTS Serum sdLDL-C levels in the CHD group were significantly increased compared with those in the non-CHD group [0.80 (0.49) mmol/L vs. 0.70 (0.30) mmol/L, p < 0.001]. The results from CHD subgroup analysis indicated that the sdLDL-C levels in patients with multiple-vessel disease and high Gensini score (GS) were significantly increased. By adjusting the confounding factors and analyzing with multiple logistic regression, we found that sdLDL-C independently correlated with the presence and severity of CHD (CHD: OR = 2.257; multiple-vessel disease: OR = 3.288; high GS: OR = 2.554). A total of 484 major cardiovascular events (MACEs) were documented. After Kaplan-Meier analysis and chi-squared analysis, the incidence of MACEs in the high sdLDL-C group was higher than that in the low sdLDL-C group (16.04% vs. 12.25%, p = 0.002). CONCLUSION In T2DM patients, elevated serum sdLDL-C may increase the severity of CHD and predict cardiovascular events in the future. Therefore, serum sdLDL-C may be a potential biomarker for the surveillance of CHD in T2DM patients.
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Nicotinamide phosphoribosyltransferase as a biomarker for the diagnosis of infectious pleural effusions.
Huang, J, Guo, L, Kang, HW, Lv, D, Lin, W, Li, CF, Huang, XQ, Ding, QL
Scientific reports. 2021;(1):21121
Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) has been reported to be involved in infectious diseases, but it is unknown whether it plays a role in infectious pleural effusions (IPEs). We observed the levels of NAMPT in pleural effusions of different etiologies and investigated the clinical value of NAMPT in the differential diagnosis of infectious pleural effusions. A total of 111 patients with pleural effusion were enrolled in the study, including 25 parapneumonic effusions (PPEs) (17 uncomplicated PPEs, 3 complicated PPEs, and 5 empyemas), 30 tuberculous pleural effusions (TPEs), 36 malignant pleural effusions (MPEs), and 20 transudative effusions. Pleural fluid NAMPT levels were highest in the patients with empyemas [575.4 (457.7, 649.3) ng/ml], followed by those with complicated PPEs [113.5 (103.5, 155.29) ng/ml], uncomplicated PPEs [24.9 (20.2, 46.7) ng/ml] and TPEs [88 (19.4, 182.6) ng/ml], and lower in patients with MPEs [11.5 (6.5, 18.4) ng/ml] and transudative effusions [4.3 (2.6, 5.1) ng/ml]. Pleural fluid NAMPT levels were significantly higher in PPEs (P < 0.001) or TPEs (P < 0.001) than in MPEs. Moreover, Pleural fluid NAMPT levels were positively correlated with the neutrophil percentage and lactate dehydrogenase (LDH) levels and inversely correlated with glucose levels in both PPEs and TPEs, indicating that NAMPT was implicated in the neutrophil-associated inflammatory response in infectious pleural effusion. Further, multivariate logistic regression analysis showed pleural fluid NAMPT was a significant predictor distinguishing PPEs from MPEs [odds ratio (OR) 1.180, 95% confidence interval (CI) 1.052-1.324, P = 0.005]. Receiver-operating characteristic (ROC) analysis demonstrated that NAMPT was a promising diagnostic factor for the diagnosis of infectious effusions, with the areas under the curve for pleural fluid NAMPT distinguishing PPEs from MPEs, TPEs from MPEs, and IPEs (PPEs and TPEs) from NIPEs were 0.92, 0.85, and 0.88, respectively. In conclusion, pleural fluid NAMPT could be used as a biomarker for the diagnosis of infectious pleural effusions.
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Cost-Effectiveness Analysis of First-Line FOLFIRI Combined With Cetuximab or Bevacizumab in Patients With RAS Wild-Type Left-Sided Metastatic Colorectal Cancer.
Han, J, Xiao, D, Tan, C, Zeng, X, Hu, H, Zeng, S, Jiang, Q, She, L, Yao, L, Li, L, et al
Cancer control : journal of the Moffitt Cancer Center. 2020;(1):1073274820902271
Abstract
BACKGROUND The FIRE-3 phase III clinical trial demonstrated the marked advantage of prolonging the median overall survival of patients with final RAS wild-type (WT) left-sided metastatic colorectal cancer (mCRC) by 38.3 months after treatment with irinotecan, fluorouracil, and leucovorin (FOLFIRI) plus cetuximab and by 28.0 months after treatment with FOLFIRI plus bevacizumab. However, the substantial cost increase and economic impact of using cetuximab imposes a considerable burden on patients and society. METHODS A Markov model based on the data collected in the FIRE-3 trial was developed to investigate the cost-effectiveness of treating patients with FOLFIRI plus either cetuximab or bevacizumab from the perspective of the Chinese health-care system. Costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated over a lifetime horizon. One-way and probabilistic sensitivity analyses were performed by varying potentially modifiable parameters. RESULTS In our analysis, the total treatment costs in the bevacizumab and cetuximab groups were $92 549.31 and $94 987.31, respectively, and the QALYs gained were 1.58 and 2.05. In the base-case analysis, compared with bevacizumab, left-sided RAS WT patients receiving cetuximab gained 0.47 more QALYs at an ICER of $5187.23/QALY ($3166.23/LY). The 1-way sensitivity analysis showed that the most influential parameter was the cost of cetuximab. Probabilistic sensitivity analysis indicated that the cost-effective probability of cetuximab group was 92.8% under the willingness-to-pay threshold of $24 081. CONCLUSIONS Treatment with FOLFIRI plus cetuximab in Chinese patients with left-sided RAS WT mCRC may improve health outcomes and use financial resources more efficiently than FOLFIRI plus bevacizumab.
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Microfluidic Chip Method for Multi-SNPs Genotyping in Individual Risk Assessment of Micronutrient Deficiency.
Zhang, CH, Huo, JS, Chen, S, Xu, YC, Sun, J, Huang, J
Biomedical and environmental sciences : BES. 2019;(6):471-475
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Value of folate receptor-positive circulating tumour cells in the clinical management of indeterminate lung nodules: A non-invasive biomarker for predicting malignancy and tumour invasiveness.
Zhou, Q, Geng, Q, Wang, L, Huang, J, Liao, M, Li, Y, Ding, Z, Yang, S, Zhao, H, Shen, Q, et al
EBioMedicine. 2019;:236-243
Abstract
BACKGROUND Non-invasive lung adenocarcinoma could benefit from limited resection, nonetheless, there is a lack of method to determine preoperative tumour invasiveness. We aimed to investigate whether folate receptor-positive circulating tumour cells (FR+-CTCs) in combination with maximum tumour diameter (MTD) determines, before surgery, the invasiveness of small-sized, indeterminate solitary pulmonary nodules (SPNs). METHODS A total of 382 patients with suspicious lung adenocarcinoma on computed tomography who were expected to undergo lung resection were enrolled in this study at three participating institutes and randomly assigned into training and validation cohorts. Before surgery, 3 mL peripheral blood was collected from all participants. FR+-CTCs were analyzed using immunomagnetic leukocyte depletion and quantitated by ligand-targeted PCR method. After surgery, the resected tissues were diagnosed by pathologists according to IASLC/ATS/ERS classification. FINDINGS FR+-CTC levels in the peripheral blood can differentiate benign from malignant nodules with a sensitivity of 78·6%-82·7% and a specificity of 68·8%-78·4%. Both FR+-CTC and MTD are independent predictive indices of invasive tumours for lung adenocarcinoma ≤2 cm based on multivariate analyses. Further, FR+-CTC count in combination with MTD can differentiate non-invasive cancers from invasive cancers with a sensitivity of 63·6%-81·8% and a specificity of 71·4%-89·7%. INTERPRETATION Detection of FR+-CTC is a reliable method to differentiate malignancy of indeterminate SPNs. Combining of FR+-CTC count and MTD could possibly enhance preoperative determination of the invasiveness of lung nodules and guide surgeons to select limited lung resection and avoid overtreatment for patients with non-invasive lesions. FUND None.
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Resequencing Epithelial Sodium Channel Genes Identifies Rare Variants Associated With Blood Pressure Salt-Sensitivity: The GenSalt Study.
Gu, X, Gu, D, He, J, Rao, DC, Hixson, JE, Chen, J, Li, J, Huang, J, Wu, X, Rice, TK, et al
American journal of hypertension. 2018;(2):205-211
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Abstract
BACKGROUND A resequencing study of renal epithelial sodium channel (ENaC) genes was conducted to identify rare variants associated with blood pressure (BP) salt-sensitivity. METHODS The Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study was conducted among 1,906 participants who underwent a 7-day low-sodium followed by a 7-day high-sodium feeding-study. The 300 most salt-sensitive and 300 most salt-resistant GenSalt participants were selected for the resequencing study. Three ENaC genes (SCNN1A, SCNN1B, and SCNN1G) were resequenced using capillary-based sequencing methods. Traditional burden tests were utilized to examine association between rare variants and BP salt-sensitivity. Associations of low-frequency and common variants were tested using single-marker analyses. RESULTS Carriers of SCNN1A rare variants had a 0.52 [95% confidence interval (CI): 0.32-0.85] decreased odds of BP salt-sensitivity compared with noncarriers. Neither SCNN1B nor SCNN1G associated with salt-sensitivity of BP in rare variant analyses (P = 0.65 and 0.48, respectively). In single-marker analyses, 3 independent common variants in SCNN1A, rs11614164, rs4764586, and rs3741914, associated with salt-sensitivity after Bonferroni correction (P = 4.4 × 10-4, 1.1 × 10-8, and 1.3 × 10-3). Each copy of the minor allele of rs4764586 was associated with a 1.36-fold (95% CI: 1.23-1.52) increased odds of salt-sensitivity, whereas each copy of the minor allele of rs11614164 and rs3741914 was associated with 0.68-fold (95% CI: 0.55-0.84) and 0.69-fold (95% CI: 0.54-0.86) decreased odds of salt-sensitivity, respectively. CONCLUSIONS This study demonstrated for the first time a relationship between rare variants in the ENaC pathway and BP salt-sensitivity. Future replication and functional studies are needed to confirm the findings in this study. CLINICAL TRIAL REGISTRY Trial Number NCT00721721.