68Ga-RM2 PET-MRI versus MRI alone for evaluation of patients with biochemical recurrence of prostate cancer: a single-centre, single-arm, phase 2/3 imaging trial.

BACKGROUND: National Comprehensive Cancer Network guidelines include prostate-specific membrane antigen (PSMA)-targeted PET for detection of biochemical recurrence of prostate cancer. However, targeting a single tumour characteristic might not be sufficient to reflect the full extent of disease. Gastrin releasing peptide receptors (GRPR) have been shown to be overexpressed in prostate cancer. In this study, we aimed to evaluate the diagnostic performance of the GRPR-targeting radiopharmaceutical 68Ga-RM2 in patients with biochemical recurrence of prostate cancer. METHODS: This single-centre, single-arm, phase 2/3 trial was done at Stanford University (USA). Adult patients (aged ≥18 years) with biochemical recurrence of prostate cancer, a Karnofsky performance status of 50 or higher, increasing prostate-specific antigen concentration 0·2 ng/mL or more after prostatectomy or 2 ng/mL or more above nadir after radiotherapy, and non-contributory conventional imaging (negative CT or MRI, and bone scan) were eligible. All participants underwent 68Ga-RM2 PET-MRI. The primary outcome was the proportion of patients with PET-positive findings on 68Ga-RM2 PET-MRI compared with MRI alone after initial therapy, at a per-patient and per-lesion level. The primary outcome would be considered met if at least 30% of patients had one or more lesions detected by 68Ga-RM2 PET-MRI and the detection by 68Ga-RM2 PET-MRI was significantly greater than for MRI. Each PET scan was interpreted by three independent masked readers using a standardised evaluation criteria. This study is registered with ClinicalTrials.gov, NCT02624518, and is complete. FINDINGS: Between Dec 12, 2015, and July 27, 2021, 209 men were screened for eligibility, of whom 100 were included in analyses. Median follow-up was 49·3 months (IQR 36·7-59·2). The primary endpoint was met; 68Ga-RM2 PET-MRI was positive in 69 (69%) patients and MRI alone was positive in 40 (40%) patients (p<0·0001). In the per-lesion analysis 68Ga-RM2 PET-MRI showed significantly higher detection rates than MRI alone (143 vs 96 lesions; p<0·0001). No grade 1 or worse events were reported. INTERPRETATION: 68Ga-RM2 PET-MRI showed better diagnostic performance than MRI alone in patients with biochemical recurrence of prostate cancer. Further prospective comparative studies with PSMA-targeted PET are needed to gain a better understanding of GRPR and PSMA expression patterns in these patients. FUNDING: The US Department of Defense.

Ascorbic Acid and Iron Supplement Treatment Improves Stem Cell-Mediated Cartilage Regeneration in a Minipig Model.

BACKGROUND: The transplantation of mesenchymal stem cells (MSCs) into cartilage defects has led to variable cartilage repair outcomes. Previous in vitro studies have shown that ascorbic acid and reduced iron independently can improve the chondrogenic differentiation of MSCs. However, the combined effect of ascorbic acid and iron supplementation on MSC differentiation has not been investigated. PURPOSE: To investigate the combined in vivo effects of ascorbic acid and a US Food and Drug Administration (FDA)-approved iron supplement on MSC-mediated cartilage repair in mature Göttingen minipigs. STUDY DESIGN: Controlled laboratory study. METHODS: We pretreated bone marrow-derived MSCs with ascorbic acid and the FDA-approved iron supplement ferumoxytol and then transplanted the MSCs into full-thickness cartilage defects in the distal femurs of Göttingen minipigs. Untreated cartilage defects served as negative controls. We evaluated the cartilage repair site with magnetic resonance imaging at 4 and 12 weeks after MSC implantation, followed by histological examination and immunofluorescence staining at 12 weeks. RESULTS: Ascorbic acid plus iron-pretreated MSCs demonstrated a significantly better MOCART (magnetic resonance observation of cartilage repair tissue) score (73.8 ± 15.5), better macroscopic cartilage regeneration score according to the International Cartilage Repair Society (8.6 ± 2.0), better Pineda score (2.9 ± 0.8), and larger amount of collagen type II (28,469 ± 21,313) compared with untreated controls (41.3 ± 2.5, 1.8 ± 2.9, 12.8 ± 1.9, and 905 ± 1326, respectively). The obtained scores were also better than scores previously reported in the same animal model for MSC implants without ascorbic acid. CONCLUSION: Pretreatment of MSCs with ascorbic acid and an FDA-approved iron supplement improved the chondrogenesis of MSCs and led to hyaline-like cartilage regeneration in the knee joints of minipigs. CLINICAL RELEVANCE: Ascorbic acid and iron supplements are immediately clinically applicable. Thus, these results, in principle, could be translated into clinical applications.

Differentiation of benign and malignant lymph nodes in pediatric patients on ferumoxytol-enhanced PET/MRI.

The composition of lymph nodes in pediatric patients is different from that in adults. Most notably, normal lymph nodes in children contain less macrophages. Therefore, previously described biodistributions of iron oxide nanoparticles in benign and malignant lymph nodes of adult patients may not apply to children. The purpose of our study was to evaluate if the iron supplement ferumoxytol improves the differentiation of benign and malignant lymph nodes in pediatric cancer patients on 18F-FDG PET/MRI. Methods: We conducted a prospective clinical trial from May 2015 to December 2018 to investigate the value of ferumoxytol nanoparticles for staging of children with cancer with 18F-FDG PET/MRI. Ferumoxytol is an FDA-approved iron supplement for the treatment of anemia and has been used "off-label" as an MRI contrast agent in this study. Forty-two children (7-18 years, 29 male, 13 female) received a 18F-FDG PET/MRI at 2 (n=20) or 24 hours (h) (n=22) after intravenous injection of ferumoxytol (dose 5 mg Fe/kg). The morphology of benign and malignant lymph nodes on ferumoxytol-enhanced T2-FSE sequences at 2 and 24 h were compared using a linear regression analysis. In addition, ADCmean-values, SUV-ratio (SUVmax lesion/SUVmean liver) and R2*-relaxation rate of benign and malignant lymph nodes were compared with a Mann-Whitney-U test. The accuracy of different criteria was assessed with a receiver operating characteristics (ROC) curve. Follow-up imaging for at least 6 months served as the standard of reference. Results: We examined a total of 613 lymph nodes, of which 464 (75.7%) were benign and 149 (24.3%) were malignant. On ferumoxytol-enhanced T2-FSE images, benign lymph nodes showed a hypointense hilum and hyperintense parenchyma, while malignant lymph nodes showed no discernible hilum. This pattern was not significantly different at 2 h and 24 h postcontrast (p=0.82). Benign and malignant lymph nodes showed significantly different ferumoxytol enhancement patterns, ADCmean values of 1578 and 852 x10-6 mm2/s, mean SUV-ratios of 0.5 and 2.8, and mean R2*-relaxation rate of 127.8 and 84.4 Hertz (Hz), respectively (all p<0.001). The accuracy of ADCmean, SUV-ratio and pattern (area under the curve (AUC): 0.99; 0.98; 0.97, respectively) was not significantly different (p=0.07). Compared to these three parameters, the accuracy of R2* was significantly lower (AUC: 0.93; p=0.001). Conclusion: Lymph nodes in children show different ferumoxytol-enhancement patterns on MRI than previously reported for adult patients. We found high accuracy (>90%) of ADCmean, SUV-ratio, pattern, and R2* measurements for the characterization of benign and malignant lymph nodes in children. Ferumoxytol nanoparticle accumulation at the hilum can be used to diagnose a benign lymph node. In the future, the delivery of clinically applicable nanoparticles to the hilum of benign lymph nodes could be harnessed to deliver theranostic drugs for immune cell priming.

Tracking Stem Cell Implants in Cartilage Defects of Minipigs by Using Ferumoxytol-enhanced MRI.

Background Cartilage repair outcomes of matrix-associated stem cell implants (MASIs) in patients have been highly variable. Conventional MRI cannot help distinguish between grafts that will and grafts that will not repair the underlying cartilage defect until many months after the repair. Purpose To determine if ferumoxytol nanoparticle labeling could be used to depict successful or failed MASIs compared with conventional MRI in a large-animal model. Materials and Methods Between January 2016 and December 2017, 10 Göttingen minipigs (n = 5 male; n = 5 female; mean age, 6 months ± 5.1; age range, 4-20 months) received implants of unlabeled (n = 12) or ferumoxytol-labeled (n = 20) viable and apoptotic MASIs in cartilage defects of the distal femur. All MASIs were serially imaged with MRI on a 3.0-T imaging unit at week 1 and weeks 2, 4, 8, 12, and 24, with calculation of T2 relaxation times. Cartilage regeneration outcomes were assessed by using the MR observation of cartilage repair tissue (MOCART) score (scale, 0-100), the Pineda score, and histopathologic quantification of collagen 2 production in the cartilage defect. Findings were compared by using the unpaired Wilcoxon rank sum test, a linear regression model, the Fisher exact test, and Pearson correlation. Results Ferumoxytol-labeled MASIs showed significant T2 shortening (22.2 msec ± 3.2 vs 27.9 msec ± 1.8; P < .001) and no difference in cartilage repair outcomes compared with unlabeled control MASIs (P > .05). At week 2 after implantation, ferumoxytol-labeled apoptotic MASIs showed a loss of iron signal and higher T2 relaxation times compared with ferumoxytol-labeled viable MASIs (26.6 msec ± 4.9 vs 20.8 msec ± 5.3; P = .001). Standard MRI showed incomplete cartilage defect repair of apoptotic MASIs at 24 weeks. Iron signal loss at 2 weeks correlated with incomplete cartilage repair, diagnosed at histopathologic examination at 12-24 weeks. Conclusion Ferumoxytol nanoparticle labeling can accelerate the diagnosis of successful and failed matrix-associated stem cell implants at MRI in a large-animal model. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Sneag and Potter in this issue.

Ursodeoxycholic acid induces apoptosis in hepatocellular carcinoma xenografts in mice.

AIM: To evaluate the efficacy of ursodeoxycholic acid (UDCA) as a chemotherapeutic agent for the treatment of hepatocellular carcinoma (HCC). METHODS: BALB/c nude mice were randomized into four groups 24 h before subcutaneous injection of hepatocarcinoma BEL7402 cells suspended in phosphate buffered saline (PBS) into the right flank. The control group (n = 10) was fed a standard diet while treatment groups (n = 10 each) were fed a standard daily diet supplemented with different concentrations of UDCA (30, 50 and 70 mg/kg per day) for 21 d. Tumor growth was measured once each week, and tumor volume (V) was calculated with the following equation: V = (L × W(2)) × 0.52, where L is the length and W is the width of the xenograft. After 21 d, mice were killed under ether anesthesia, and tumors were excised and weighed. Apoptosis was evaluated through detection of DNA fragmentation with gel electrophoresis and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. Western blot analysis was performed to determine the expression of apoptosis-related proteins BAX, BCL2, APAF1, cleaved caspase-9, and cleaved caspase-3. RESULTS: UDCA suppressed tumor growth relative to controls. The mean tumor volumes were the following: control, 1090 ± 89 mm(3); 30 mg/kg per day, 612 ± 46 mm(3); 50 mg/kg per day, 563 ± 38 mm(3); and 70 mg/kg per day, 221 ± 26 mm(3). Decreased tumor volumes reached statistical significance relative to control xenografts (30 mg/kg per day, P < 0.05; 50 mg/kg per day, P < 0.05; 70 mg/kg per day, P < 0.01). Increasing concentrations of UDCA led to increased DNA fragmentation observed on gel electrophoresis and in the TUNEL assay (control, 1.6% ± 0.3%; 30 mg/kg per day, 2.9% ± 0.5%; 50 mg/kg per day, 3.15% ± 0.7%, and 70 mg/kg per day, 4.86% ± 0.9%). Western blot analysis revealed increased expression of BAX, APAF1, cleaved-caspase-9 and cleaved-caspase-3 proteins, which induce apoptosis, but decreased expression of BCL2 protein, which is an inhibitor of apoptosis, following administration of UDCA. CONCLUSION: UDCA suppresses growth of BEL7402 hepatocellular carcinoma cells in vivo, in part through apoptosis induction, and is thus a candidate for therapeutic treatment of HCC.

[Protective effect of wenfei huayin recipe on lung of rats with chronic obstructive pulmonary diseases].

OBJECTIVE: To explore the mechanism of Wenfei Huayin Recipe (WHR) in treating chronic obstructive pulmonary diseases (COPD). METHODS: The COPD model was induced by modified fumigating method and intra-tracheal instillation of lipopolysaccharide. Then reformed COPD model of cold-phlegm retention in Fei syndrome type. All the model rats were randomly divided into two groups, the model group and the treated group, treated respectively with WHR and saline for 14 successive days. Besides, a blank group without any intervention was set up for control. The general condition, weight growth rate, pathological changes of lung tissue under light microscope, ultrastructure under electron microscope, arterial blood gas analysis and levels of interleukin 4 (IL-4), interleukin 8 (IL-8), tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) in lung homogenate by radio-immunity assay were observed. RESULTS: In the treated group, as compared with the control group, the symptoms of aversion to cold, swarming, wheezing, the degree of epithelial cell degeneration and necrosis, the inflammatory cell infiltration and the volume of cilia lodging, sloughing, and bullae of lung were lessened and weight growth rate was higher (P<0.01). Moreover, the treated group was superior to the control group in decreasing levels of PaCO2, IL-4, IL-8, TNF-alpha and increasing PaO2, IFN-gamma and IFN-gamma/IL-4 ratio (P<0.01 or P<0.05). CONCLUSION: WHR can correct the Th1/Th2 imbalance and inhibit the inflammatory reaction, displaying an important role in improving the airway function and structure in COPD rats.

[Effects of drug cupping therapy on immune function in chronic asthmatic bronchitis patients during protracted period].

UNLABELLED: To observe the clinical effect of drug cupping therapy (DCT, cupping therapy with pingchuan ointment made by the authors themselves in the cups) on chronic asthmatic bronchitis (CAB) during the protracted period, and explore its effect on immune function. METHODS: Seventy-seven patients were randomly divided into two groups:the treated group (n=40) treated by orally taken Liuwei Dihuang Pill (LDP) and DCT and the control group (n=37) with LDP and common cupping therapy without drug in cups. The changes of T-lymphocyte subset, levels of interferon-gamma (IFN-gamma), interleukin (IL), immunoglobulin (Ig), complement 3 and 4 (C3 and C4) were detected before and after treatment. RESULTS: The total effective rate was higher in the treated group than that in the control group (90.0% vs. 59.5%, P < 0.01). The levels of CD4+, CD4+ /CD8+, IL-2, IFN-gamma, C3, C4, IgA, IgG and IgM increased, while the levels of IgE, IL-4, IL-10 and CD8+ decreased after treatment in both groups (P < 0.05 or P < 0.01), the improvements were better in the treated group than that in the control group (P < 0.05). CONCLUSION: DCT shows better curative effects than that of common cupping therapy without drug, it could improve the cellular and humoral immunity in CAB patients.

[Clinical study on treatment of liver fibrosis in patients of hepatitis B by kangxian baogan decoction].

OBJECTIVE: To explore the clinical effect and therapeutic mechanism of Kangxian Baogan Decoction (KXBGD) on liver fibrosis caused by chronic hepatitis B. METHODS: Eight-one patients with chronic hepatitis B were divided into two groups randomly. The 54 patients in the treated group were treated by KXBGD and the 27 patients in the control group were treated by conventional liver protecting treatment. Serum levels of hyaluronic acid (HA), procollagen type III (PC III), collagen type IV (C-IV), laminin (LN), transforming growth factor beta 1 (TGF beta 1) and tumor necrosis factor-alpha (TNF-alpha) were measured before and after treatment, meanwhile, liver function and pathological changes of liver tissues were observed. RESULTS: The total effective rate in the treated group was significantly higher than that in the control group. Serum levels of HA, PC III, C-IV, LN, TGF beta 1 and TNF-alpha in the treated group obviously reduced after treatment, and the liver function got better with significant difference as compared with those in the control group (P < 0.05 or P < 0.01). Pathological examination of liver biopsy showed that the fibrous tissue in the liver reduced. CONCLUSION: KXBGD has a definite effect of anti-liver fibrosis.

[Effect of tongxinluo capsule on plasma endothelin and calcitonin gene related peptide in patients with unstable angina pectoris].

OBJECTIVE: To investigate the effect of Tongxinluo capsule (TXLC) on the patients with unstable angina pectoris (UAP). METHODS: Patients of UAP were divided into two groups, the treated group (n = 60) was treated with TXLC and the Danshen group (n = 30) was treated with composite Danshen tablet. The plasma endothelin (ET) and calcitonin gene related peptide (CGRP) were measured before and after treatment. Data were compared between the two groups and also compared with those measured in 20 healthy subjects for control. RESULTS: ET level was higher and CGRP level lower significantly in UAP patients than that in healthy subjects significantly (P < 0.05). After TXLC treatment, ET significantly lowered (P < 0.01) and CGRP increased (P < 0.05). But in the Danshen group after treatment, the former decreased (P < 0.05), while the latter remained unchanged (P > 0.05). The effect of TXLC was better than that of composite Danshen tablet. CONCLUSION: TXLC is an effective drug for UAP treatment, which could efficiently regulate the ET and CGRP metabolism and ameliorate the degree of myocardial ischemia damage.