BRAFV600E mutation does not predict lymph node metastases and recurrence in Chinese papillary thyroid microcarcinoma patients.

OBJECT: Previous studies suggest BRAFV600E mutation is a marker for poor prognosis in papillary thyroid cancer, however, its ability to further risk stratify papillary thyroid microcarcinoma (PTMC) remains controversial. We aimed to explore the association between BRAFV600E mutation and the clinicopathological features and recurrence in Chinese PTMC patients. METHODS: We retrospectively reviewed 2094 PTMC patients who underwent surgery and had a valid BRAFV600E mutation test result. Among them, 1292 patients had complete follow-up data. The mutation incidence was determined. Moreover, the clinicopathological characteristics, disease-free survival (DFS), and response to therapy distribution were compared between the mutation and non-mutation groups. RESULTS: BRAFV600E mutation was observed in 90.6 % of all patients and 89.2 % of patients with complete follow-up data. No significant difference was observed in lymph node metastases (LNM) number categories between the mutation and non-mutation groups among all patients (P = 0.329) and 1292 patients (P = 0.408). Neither the 3-year DFS (97.9 % vs. 98.0 %, P = 0.832) nor the response to therapy distribution (P > 0.05) indicated a significant difference between the mutation and non-mutation groups. The 3-year DFS differs among patients having different LNM number categories (99.8 % vs. 98.5 % vs. 77.3 %, P < 0.001). Multivariate analysis revealed that high-volume (over 5) LNM (Total thyroidectomy (TT): OR = 4.000, 95 % CI 2.390-6.694, P < 0.001; Unilateral thyroidectomy (UT): OR = 4.183, 95 % CI 1.565-11.190, P = 0.004), rather than BRAFV600E mutation (P > 0.05), was an independent risk factor of response to therapy. CONCLUSIONS: Our results suggested that BRAFV600E mutation could not accurately predict LNM or the recurrence of Chinese PTMC patients. Moreover, high-volume LNM is significantly associated with PTMC prognosis.

Pharmacokinetics, safety, and tolerability of inhaled remdesivir in healthy participants.

Intravenous remdesivir (RDV) is US Food and Drug Administration-approved for hospitalized and nonhospitalized individuals with coronavirus disease 2019. RDV undergoes intracellular metabolic activation to form the active triphosphate, GS-443902, and other metabolites. Alternative administration routes, including localized pulmonary delivery, can lower systemic exposure and maximize exposure at the site of action. This study evaluated the pharmacokinetics (PK) and safety of inhaled RDV in healthy adults. This phase Ia, randomized, placebo-controlled study evaluated inhaled RDV in healthy participants randomized 4:1 to receive RDV or placebo as single doses (4 cohorts) or multiple once-daily doses (3 cohorts). Doses in cohorts 1-6 were administered as an aerosolized solution for inhalation through a sealed facemask; doses in cohort 7 were administered as an aerosolized solution for inhalation through a mouthpiece. Safety was assessed throughout the study. Seventy-two participants were enrolled (inhaled RDV, n = 58 and placebo, n = 14). Following single RDV doses, RDV, GS-704277, and GS-441524 plasma PK parameters indicated dose-proportional increases in area under the concentration-time curve (AUC) extrapolated to infinite time, AUC from time zero to last quantifiable concentration, and maximum observed concentration. Analyte plasma concentrations after multiple RDV doses were consistent with those for single-dose RDV. Analyte plasma exposures were lower when RDV was administered with a mouthpiece versus a sealed facemask. The most common adverse events included nausea, dizziness, and cough. Single- and multiple-dose inhaled RDV exhibited linear and dose-proportional plasma PK. Administration of RDV via inhalation was generally safe and well-tolerated.

Combined early dynamic 18F-FDG PET/CT and conventional whole-body 18F-FDG PET/CT in hepatocellular carcinoma.

OBJECTIVE: To investigate the diagnostic value of early dynamic 18F-FDG PET/CT(ED 18F-FDG PET/CT) combined with conventional whole-body 18F-FDG PET/CT(WB 18F-FDG PET/CT) in hepatocellular carcinoma (HCC), as well as the difference of early dynamic blood flow parameters and maximum standardized uptake value (SUVmax) in HCC patients with/without liver cirrhosis or microvascular invasion (MVI). METHODS: Twenty-two consecutive patients (mean age 57.8 years) with 28 established HCC lesions (mean size 4.5 cm) underwent a blood flow study with an 18F-FDG dynamic scan divided into 24 sequences of 5 s each and a standard PET/CT scan. On the ED PET/CT study, an experienced PET/CT physician obtained volumes of interest (VOIs) where three blood flow estimates (time to peak [TTP], blood flow [BF], and hepatic perfusion index [HPI]) were calculated. On the WB PET/CT study, a VOI was placed on the fused scan for each HCC and maximum standardized uptake value (SUVmax) was obtained. Comparison of blood flow estimates, SUVmax, and tumor/background ratio (TNR) was performed among HCCs with and without angioinvasion, as well as HCCs in cirrhotic and non-cirrhotic liver. RESULTS: Compared with WB 18F-FDG PET/CT alone, ED combined with WB 18F-FDG PET/CT can significantly increase the detection rate of moderately differentiated and poorly differentiated HCCs (both P < 0.05). HPI was higher in HCCs in patients with liver cirrhosis than those without liver cirrhosis (P = 0.044). There was no significant difference in TTP, BF, SUVmax, or TNR between HCCs in patients with liver cirrhosis and those without liver cirrhosis. There was no significant difference in blood flow estimates or SUVmax in background liver parenchyma between patients with and those without cirrhosis. TTP was shorter in HCCs with MVI than without MVI (P = 0.046). There was no significant difference in BF, HPI, SUVmax, or TNR between HCCs with MVI and without MVI. There was no significant difference in blood flow estimates or SUVmax in background liver parenchyma between patients with and those without MVI. CONCLUSION: ED combined with WB 18F-FDG PET/CT can significantly increase the detection rate of moderately differentiated and poorly differentiated HCCs. HPI was significantly higher in HCCs in patients with liver cirrhosis than those without liver cirrhosis. TTP was significantly shorter in HCCs with MVI than without MVI.

Comparison of 18F-FDG PET/MR and PET/CT for pretreatment TNM staging of hilar cholangiocarcinoma.

PURPOSE: 18F-FDG PET/MR has been applied to the diagnosis and preoperative staging in various tumor types; however, reports using PET/MR in hilar cholangiocarcinoma (HCCA) are rare. We investigated the value of PET/MR for preoperative staging and compared it with PET/CT in HCCA. METHODS: Fifty-eight patients with HCCA confirmed by pathology were retrospectively analyzed. 18F-FDG PET/CT imaging was performed first, followed with whole-body PET/MR imaging. SUVmax of tumor and normal liver tissue were measured. Paired T test was used to compare SUVmax of tumor and normal liver tissue of PET/CT and PET/MR. In addition, McNemar test was used to compare the accuracy of TNM staging and Bismuth-Corlette typing between PET/CT and PET/MR. RESULTS: There was no significant difference in SUVmax between PET/CT and PET/MR in primary tumor lesions (6.6 ± 5.5 vs. 6.8 ± 6.2, P = 0.439). SUVmax of PET/CT and PET/MR in normal liver parenchyma was significantly different (3.0 ± 0.5 vs. 2.1 ± 0.5, P < 0.001). The accuracy of PET/MR in diagnosing T staging and N staging was significantly higher than those of PET/CT (72.4% vs. 58.6%, P = 0.022 and 84.5% vs. 67.2%, P = 0.002). There was no significant difference between PET/CT and PET/MR in M staging (94.8% vs. 98.3%, P = 0.5). The classification accuracy of PET/MR in Bismuth-Corlette was significantly higher than that of PET/CT (89.7% vs. 79.3%), P = 0.031. CONCLUSIONS: The diagnostic accuracy of 18F-FDG PET/MR was superior to that of PET/CT in preoperative T staging, N staging, and Bismuth-Corlette classification of HCCA. In M staging, the diagnostic accuracy of PET/MR was similar to that of PET/CT.

Surface Lattice Modulation through Chemical Delithiation toward a Stable Nickel-Rich Layered Oxide Cathode.

Nickel-rich layered oxides (NLOs) are considered as one of the most promising cathode materials for next-generation high-energy lithium-ion batteries (LIBs), yet their practical applications are currently challenged by the unsatisfactory cyclability and reliability owing to their inherent interfacial and structural instability. Herein, we demonstrate an approach to reverse the unstable nature of NLOs through surface solid reaction, by which the reconstructed surface lattice turns stable and robust against both side reactions and chemophysical breakdown, resulting in improved cycling performance. Specifically, conformal La(OH)3 nanoshells are built with their thicknesses controlled at nanometer accuracy, which act as a Li+ capturer and induce controlled reaction with the NLO surface lattices, thereby transforming the particle crust into an epitaxial layer with localized Ni/Li disordering, where lithium deficiency and nickel stabilization are both achieved by transforming oxidative Ni3+ into stable Ni2+. An optimized balance between surface stabilization and charge transfer is demonstrated by a representative NLO material, namely, LiNi0.83Co0.07Mn0.1O2, whose surface engineering leads to a highly improved capacity retention and excellent rate capability with a strong capability to inhibit the crack of NLO particles. Our study highlights the importance of surface chemistry in determining chemical and structural behaviors and paves a research avenue in controlling the surface lattice for the stabilization of NLOs toward reliable high-energy LIBs.

Psoralea corylifolia L.: a comprehensive review of its botany, traditional uses, phytochemistry, pharmacology, toxicology, quality control and pharmacokinetics.

Psoralea corylifolia L. (PCL), referred to as "Bu-gu-zhi" in Chinese, has great medicinal values since ancient times. PCL is the dried ripe fruit of Psoralea corylifolia L., which has been widely used in traditional Chinese medicine (TCM) for the treatment of kidney-yang deficiency, enuresis and urinary frequency, chills and pain of the waist and knees, dawn diarrhea and vitiligo. In this paper, a systematic of the botany, traditional uses, phytochemistry, pharmacology, toxicology, quality control and pharmacokinetics of PCL was presented, along with future research directions. According to the results, PCL contains approximately 163 chemical components, including coumarins, flavonoids, monoterpene phenols, benzofurans, glycosides, lipids, fatty acids, and volatile oils. PCL and its active ingredients have a variety of pharmacological activities, such as anti-inflammatory, antibacterial, antiviral, antioxidant, antitumor, antiosteoporosis, cardioprotective, neuroprotective, and immunomodulatory. Further study of quality control standards and potential mechanisms of PCL is also needed. In addition, more toxicological studies will also contribute to the progress of clinical trials.

Newly identified lncRNA-45 promotes breast cancer metastasis through activating the mTOR signaling pathway.

BACKGROUND: Metastasis, a complex multi-stage process, is the primary cause of breast cancer-related death. Unfortunately, the molecular mechanisms underlying tumor metastasis have not been fully elucidated thus far. Long noncoding RNAs (lncRNAs) dictate the behaviours of tumor cells via multiple signaling pathways, resulting in tumor cell migration and invasion, as well as all stages of cancer progression. LncRNAs function as regulators in shaping cellular activities directly through influencing key genes involved in biological processes of the tumor, and representing promising novel targets in cancer diagnosis and therapy. We therefore sought to define the correlations between lncRNA expression and breast cancer metastasis, especially to investigate the functional pathway underlying lncRNA-mediated tumor invasion and metastasis process. RESULTS: In this study, we compared the lncRNA transcriptome profiles between primary breast cancer 4T1 cells and high metastatic 4T1-LG12 cells. We found that many differently expressed lncRNAs greatly correlated to the metastatic propensity of 4T1-LG12 cells, particularly lncRNA-45, a new lncRNA without functional annotations, which was found to be the most upregulated lncRNA transcribed by an internal region within the regulatory associated with protein of mechanistic target of rapamycin kinase (mTOR) complex 1 (Rptor) gene. LncRNA-45 was uncovered to be involved in the epithelial-to-mesenchymal transition process of breast cancer cells, as evidenced by the observation that lncRNA-45 knockdown significantly suppressed the invasive capability of parental 4T1-LG12 cells. Molecular mechanistic investigation showed that reduced activity of mTORC1-associated pathway led to a decrease of total ribosomal protein S6 kinase, polypeptide 1 (S6K1) content and enhancement of autophagy, consequently compromising the metastatic propensity in lncRNA-45 knockdown cells. CONCLUSIONS: Overall, our experiments uncovered that the newly identified lncRNA-45 played a regulatory role in breast cancer cell metastasis.

Respiratory-gated PET imaging with reduced acquisition time for suspect malignancies: the first experience in application of total-body PET/CT.

OBJECTIVES: This study aimed to investigate the performance of respiratory-gating imaging with reduced acquisition time using the total-body positron emission tomography/computed tomography (PET/CT) scanner. METHODS: Imaging data of 71 patients with suspect malignancies who underwent total-body 2-[18F]-fluoro-2-deoxy-D-glucose PET/CT for 15 min with respiration recorded were analyzed. For each examination, four reconstructions were performed: Ungated-15, using all coincidences; Ungated-5, using data of the first 5 min; Gated-15 using all coincidences but with respiratory gating; and Gated-6 using data of the first 6 min with respiratory gating. Lesions were quantified and image quality was evaluated; both were compared between the four image sets. RESULTS: A total of 390 lesions were found in the thorax and upper abdomen. Lesion detectability was significantly higher in gated-15 (97.2%) than in ungated-15 (93.6%, p = 0.001) and ungated-5 (92.3%, p = 0.001), but comparable to Gated-6 (95.9%, p = 0.993). A total of 131 lesions were selected for quantitative analyses. Lesions in Gated-15 presented significantly larger standardized uptake values, tumor-to-liver ratio, and tumor-to-blood ratio, but smaller metabolic tumor volume, compared to those in Ungated-15 and Ungated-5 (all p < 0.001). These differences were more obvious in small lesions and in lesions from sites other than mediastinum/retroperitoneum. However, these indices were not significantly different between Gated-15 and Gated-6. Higher, but acceptable, image noise was identified in gated images than in ungated images. CONCLUSIONS: Respiratory-gating imaging with reduced scanning time using the total-body PET/CT scanner is superior to ungated imaging and can be used in the clinic. KEY POINTS: • In PET imaging, respiratory gating can improve lesion presentation and detectability but requires longer imaging time. • This single-center study showed that the total-body PET scanner allows respiratory-gated imaging with reduced and clinically acceptable scanning time.

Optimizing acquisition times for total-body positron emission tomography/computed tomography with half-dose 18F-fluorodeoxyglucose in oncology patients.

BACKGROUND: The present study aimed to explore the boundary of acquisition time and propose an optimized acquisition time range for total-body positron emission tomography (PET)/computed tomography (CT) oncological imaging using half-dose (1.85 MBq/kg) 18F-fluorodeoxyglucose activity based on diagnostic needs. METHODS: In this retrospective study based on a total-body PET system (uEXPLORER), an exploration cohort (October 2019-December 2019) of 46 oncology patients was first studied. The acquisition time for all patients was 15 min, and the acquired images were reconstructed and further split into 15-, 8-, 5-, 3-, 2-, and 1-min duration groups (abbreviated as G15, G8, G5, G3, G2, and G1). The image quality and lesion detectability of reconstructed PET images with different acquisition times were evaluated subjectively (5-point scale, lesion detection rate) and objectively (standardized uptake values, tumor-to-background ratio). In the same way, the initial optimized acquisition times were further validated in a cohort of 147 oncology patients (December 2019-June 2021) by using the Gs images (the images obtained using the 15- and 10-min acquisition times) as controls. RESULTS: In the exploration cohort, the subjective scores for G1, G2, G3, G5, and G8 images were 2.0 ± 0.2, 2.9 ± 0.3, 3.0 ± 0.0, 3.9 ± 0.2, and 4.2 ± 0.4, respectively. Two cases in G1 were rated as 1 point. No significant difference in scores was observed between G5 and G8 (p > 0.99). In general, groups with a longer acquisition time showed lower background uptake and lesion conspicuity. Compared with G15, lesion detection rate significantly reduced to 85.3% in G1 (p < 0.05). In the validation cohort, the subjective score was 3.0 ± 0.2 for G2, 3.0 ± 0.1 for G3, 3.6 ± 0.5 for G5, 4.0 ± 0.3 for G8, and 4.4 ± 0.5 for Gs. Only the scores between G2 and G3 were not significantly different (p > 0.99). The detection rates (204 lesions) significantly reduced to 94.1-90.2% in G3 and G2 (all p < 0.05). CONCLUSION: A 2-min acquisition time provided acceptable performance in certain groups and specific medical situations. And protocols with acquisition times ≥ 5 min could provide comparable lesion detectability as regular protocols, showing better compatibility and feasibility with clinical practice.

Exploration of the total-body PET/CT reconstruction protocol with ultra-low 18F-FDG activity over a wide range of patient body mass indices.

PURPOSE: The purpose of this study was to investigate the image quality and diagnostic performance of different reconstructions over a wide range of patient body mass indices (BMIs) obtained by total-body PET/CT with ultra-low 18F-FDG activity (0.37 MBq/kg). METHODS: A total of 63 patients who underwent total-body PET/CT with ultra-low activity (0.37 MBq/kg) 18F-FDG were enrolled. Patients were grouped by their BMIs. Images were reconstructed with the following two algorithms: the ordered subset expectation maximization (OSEM) algorithm (2, 3 iterations), both with time of flight (TOF) and point spread function (PSF) corrections (hereinafter referred as OSEM2, OSEM3) and HYPER Iterative algorithm (ß-values of 0.3, 0.4, 0.5, 0.6) embedded TOF and PSF technologies (hereinafter referred as HYPER0.3, HYPER0.4, HYPER0.5 and HYPER0.6, respectively). Subjective image quality was assessed by two experienced nuclear medicine physicians according to the Likert quintile, including overall image quality, image noise and lesion conspicuity. The standard deviation (SD) and signal-to-noise ratio (SNR) of the liver, and maximum standard uptake value (SUVmax), peak standard uptake value (SUVpeak), tumour background ratio (T/N) and the largest diameter of lesions were quantitatively analysed by a third reader who did not participate in the subjective image assessment. RESULTS: Increased noise was associated with increased BMI in all reconstruction groups. Significant differences occurred in the liver SNR among BMI categories of OSEM reconstructions (P < 0.001) but no difference was seen in the HYPER Iterative reconstructions between any of the BMI categories (P > 0.05). With the increase in BMI, overall image quality and image noise scores decreased significantly in all reconstructions, but there was no statistically significant difference of lesion conspicuity. The overall image quality score of the obese group was not qualified (score = 2.7) in OSEM3, while the others were qualified. The lesion conspicuity scores were significantly higher in HYPER Iterative reconstructions and lower in OSEM2 than in OSEM3 (all P < 0.05). The values of SUVmax, SUVpeak and T/N in HYPER0.3, HYPER0.4 and HYPER0.5 were higher than those in OSEM3. In different reconstructions, there was a correlation between lesion size (median, 1.55 cm; range, 0.7-11.0 cm) and SUVpeak variation rate compared to OSEM3 (r = 0.388, - 0.515, - 0.495, - 0.464, and - 0.423, respectively, and all P < 0.001). CONCLUSION: Considering the image quality and lesion analysis in 18F-FDG total-body PET/CT with ultra-low activity injection, OSEM reconstructions with 3 iterations meet the clinical requirements in patients with BMI < 30. In patients with BMI ≥ 30, it is recommended that the HYPER Iterative algorithm (ß-value of 0.3-0.5) be used to ensure consistent visual image quality and quantitative assessment.

Double-edge sword roles of iron in driving energy production versus instigating ferroptosis.

Iron is vital for many physiological functions, including energy production, and dysregulated iron homeostasis underlies a number of pathologies. Ferroptosis is a recently recognized form of regulated cell death that is characterized by iron dependency and lipid peroxidation, and this process has been reported to be involved in multiple diseases. The mechanisms underlying ferroptosis are complex, and involve both well-described pathways (including the iron-induced Fenton reaction, impaired antioxidant capacity, and mitochondrial dysfunction) and novel interactions linked to cellular energy production. In this review, we examine the contribution of iron to diverse metabolic activities and their relationship to ferroptosis. There is an emphasis on the role of iron in driving energy production and its link to ferroptosis under both physiological and pathological conditions. In conclusion, excess reactive oxygen species production driven by disordered iron metabolism, which induces Fenton reaction and/or impairs mitochondrial function and energy metabolism, is a key inducer of ferroptosis.

Reduction of radiation accumulation in salivary glands through oral vitamin C during 68Ga-PSMA-11 total-body dynamic PET/CT imaging.

OBJECTIVE: This study explored the utility of oral vitamin C in reducing radiation accumulation in the salivary glands during total-body dynamic PET/computed tomography (CT) imaging with 68Ga labeled Prostate-specific membrane antigen (68Ga-PSMA-11). METHODS: We enrolled 31 patients who underwent total-body dynamic PET/CT imaging with 68Ga-PSMA-11, of which 11 were given oral vitamin C 30 min after starting the dynamic PET acquisition, whereas the others did not. The volume of interest was automatically segmented on the parotid and submandibular salivary glands once the PET acquisition was completed. The standard uptake value (SUV)mean and its slope during 30-60 min of the acquisition were compared between the trial and control groups. RESULTS: The SUVmean of the left and right parotid and submandibular glands in the trial group were 15.37 ± 3.07, 15.03 ± 2.64, 14.92 ± 4.38 and 15.38 ± 4.18, respectively. The respective values of the control group were 19.37 ± 3.82, 20.08 ± 3.55, 22.61 ± 5.62 and 22.73 ± 5.90. The SUVmean slope during 30-60 min of acquisition for the left and right parotid and submandibular glands in the trial group were 0.63 ± 0.13, 0.64 ± 0.14, 0.56 ± 0.25 and 0.62 ± 0.26, respectively. The respective values of the control group were 0.84 ± 0.21, 0.84 ± 0.17, 1.01 ± 0.34 and 1.02 ± 0.37. CONCLUSION: Oral vitamin C could reduce the accumulation of radiation in the salivary glands during 68Ga-PSMA-11 total-body dynamic PET/CT imaging.

Investigating ultra-low-dose total-body [18F]-FDG PET/CT in colorectal cancer: initial experience.

PURPOSE: This study was to evaluate the effects of an ultra-low dose of [18F]-FDG on the image quality of total-body PET/CT and its lesion detectability in colorectal cancer (CRC). METHODS: Sixty-two CRC patients who underwent total-body PET/CT (uEXPLORER, United Imaging Healthcare, Shanghai, China) with an ultra-low dose (0.37 MBq/kg) of [18F]-FDG were enrolled in this retrospective study. The PET images were reconstructed with the entire 15-min dataset first and then split into 13-, 8-, 5-, 4-, 3-, 2-, and 1-min duration groups to simulate fast scanning images. For simplicity, the images reconstructed with the data from 15 to 1 min were referred to as G15, G13, and so on until G1. Subjective image quality was assessed with 5-point Likert scales. The objective image quality parameters included the SUVmax, SUVmean, and signal-to-noise ratio (SNR) of the liver and blood pool and the SUVmax and tumor-to-background ratio (TBR) of the lesions. G15 served as the control to evaluate lesion detectability. RESULTS: A total of 62 patients (43 men, 19 women; age 41-88, mean ± SD 64.0 ± 10.9 years) with 64 CRC primary tumor lesions and 10 low-grade intraepithelial neoplasia (LGIN) lesions were enrolled in this study. The subjective scores were highest for G15 (4.5 ± 0.5) and then decreased from G13 (4.3 ± 0.4) to G8 (3.7 ± 0.5). The liver SNR increased with the extension of acquisition time from G8 (17.2 ± 2.8) to G13 (20.6 ± 3.4) and G15 (21.9 ± 3.4). The liver SNR of G8 was not significantly different from that of G13 (p = 0.15) and was significantly different from that of G15 (p = 0.001). All 64 CRC lesions could be identified in all image groups, even on G1. One of ten LGINs was missed on G1, G2, and G3, and one LGIN was missed on G1, G2, G3, and G4. G15 served as the control, and 100% (48/48) lymph nodes could be found on G13 and G8 compared to 93.8% (45/48) lymph nodes on G5 and G4, 85.4% (41/48) lymph nodes on G3, 81.3% (39/48) lymph nodes on G2, and 77.1% (37/48) lymph nodes on G1. For liver metastases, there were no missed liver lesions on G13 and G8 and 3, 4, 6, 7, and 9 missed liver lesions on G5, G4, G3, G2, and G1, respectively. For other areas of metastasis, including the lung, peritoneum, and ovaries, there were no missed lesions in any group. CONCLUSIONS: Total-body PET/CT with an ultra-low dose of [18F]-FDG can maintain satisfactory image quality and lesion detectability in CRC.

Feasibility of Acquisitions Using Total-Body PET/CT with an Ultra-Low 18F-FDG Activity.

The present study aimed to evaluate the feasibility of ultra-low 18F-FDG activity in total-body PET/CT oncologic studies. Methods: Thirty patients with cancer were enrolled prospectively and underwent a total-body PET/CT scan 60 min after injection of an ultra-low 18F-FDG activity (0.37 MBq/kg). Of the 30 enrolled patients, 11 were diagnosed with colorectal cancer (CRC). PET raw data were acquired within 15 min and reconstructed using data from the first 1, 2, 4, 8, and 10 min and the entire 15 min (G1, G2, G4, G8, G10, and G15, respectively). Image quality was qualitatively assessed twice by 2 readers using a 5-point Likert scale. The Cohen κ-test was used to investigate the intra- and interreader agreement. The SUVmax of lesions; the SUVmax, SUVmean, and SD of the livers; the tumor-to-background ratio; and the signal-to-noise ratio were measured and compared. The acquisition time for a clinically acceptable image quality using an ultra-low-activity injection was determined. In a matched-pair study, 11 patients with CRC who received a full 18F-FDG activity (3.7 MBq/kg) with an acquisition time of 2 min were selected retrospectively by matching sex, height, weight, body mass index, glucose level, uptake time, and pathologic types with the 11 CRC subjects in the prospective study. Qualitative and quantitative analyses were performed and compared between the 11 patients with CRC in the ultra-low-activity group and their matched full-activity controls. Results: Qualitative analysis of image quality showed good intra- and interreader agreements (all κ > 0.7). All the images acquired for 8 min or longer scored over 3 (indicating clinical acceptability). There was no significant difference in tumor-to-background ratio and liver signal-to-noise ratio among all the images acquired for 8 min or longer. In the matched study, no significant difference was found in the image quality score and quantitative parameters between the ultra-low-activity group with an 8-min acquisition and the full-activity group with a 2-min acquisition. Conclusion: An ultra-low 18F-FDG activity with an 8-min acquisition in a total-body PET/CT study can achieve acceptable image quality equivalent to that in the full-activity group after a 2-min acquisition.

Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients.

BACKGROUND: Remdesivir improves clinical outcomes in patients hospitalized with moderate-to-severe coronavirus disease 2019 (Covid-19). Whether the use of remdesivir in symptomatic, nonhospitalized patients with Covid-19 who are at high risk for disease progression prevents hospitalization is uncertain. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving nonhospitalized patients with Covid-19 who had symptom onset within the previous 7 days and who had at least one risk factor for disease progression (age ≥60 years, obesity, or certain coexisting medical conditions). Patients were randomly assigned to receive intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. The primary efficacy end point was a composite of Covid-19-related hospitalization or death from any cause by day 28. The primary safety end point was any adverse event. A secondary end point was a composite of a Covid-19-related medically attended visit or death from any cause by day 28. RESULTS: A total of 562 patients who underwent randomization and received at least one dose of remdesivir or placebo were included in the analyses: 279 patients in the remdesivir group and 283 in the placebo group. The mean age was 50 years, 47.9% of the patients were women, and 41.8% were Hispanic or Latinx. The most common coexisting conditions were diabetes mellitus (61.6%), obesity (55.2%), and hypertension (47.7%). Covid-19-related hospitalization or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.03 to 0.59; P = 0.008). A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a Covid-19-related medically attended visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07 to 0.56). No patients had died by day 28. Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group. CONCLUSIONS: Among nonhospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than placebo. (Funded by Gilead Sciences; PINETREE ClinicalTrials.gov number, NCT04501952; EudraCT number, 2020-003510-12.).

Corrigendum: Machine Learning-Based Analysis of Magnetic Resonance Radiomics for the Classification of Gliosarcoma and Glioblastoma.

[This corrects the article DOI: 10.3389/fonc.2021.699789.].

Increased Frequency of Circulating Classical Monocytes in Patients with Rosacea.

PURPOSE: Monocyte subsets, including classical, intermediate and non-classical monocytes, are involved in the pathogenesis of inflammatory or autoimmune diseases. The pathogenic role of monocytes in the peripheral blood mononuclear cells (PBMCs) of patients with rosacea remains unclear. This study aimed to assess frequencies of monocyte subsets in PBMCs from rosacea patients before and after clinical treatment. PATIENTS AND METHODS: We applied flow cytometry to examine frequencies of monocyte subsets in 116 patients with rosacea, while patients with 26 systemic lupus erythematosus (SLE), 28 acne and 42 normal healthy subjects without skin problems (HC) were recruited as controls. Expression of C-C chemokine receptor 2 (CCR2) on monocytes and plasma levels of CC-chemokine ligand 2 (CCL2), high mobility group box-1 (HMGB-1), interleukin-1 beta (IL-1ß) and tumor necrosis factor alpha (TNF-α) were measured in HC and rosacea patients before and after treatment. RESULTS: The frequency of classical monocytes, but not intermediate or non-classical monocytes, was higher in rosacea as compared with HC, which decreased after treatment. Frequencies of monocyte subsets showed no gender difference, while increased with age in patients but not in HC. Frequencies of classical monocytes in patients with erythematotelangiectatic rosacea (ETR) and ETR-papulopustular rosacea (PPR) overlap were significantly higher than HC or patients with only PPR or phymatous rosacea (PhR). There was a significant higher expression of CCR2 in classical monocytes, with higher plasma levels of CCL2, HMGB-1, IL-1ß and TNF-α in patients than in HC, which all significantly decreased after treatment. CONCLUSION: Our data indicated a possible association between abnormal classical monocytes frequencies and rosacea.

Machine Learning-Based Analysis of Magnetic Resonance Radiomics for the Classification of Gliosarcoma and Glioblastoma.

OBJECTIVE: To identify optimal machine-learning methods for the radiomics-based differentiation of gliosarcoma (GSM) from glioblastoma (GBM). MATERIALS AND METHODS: This retrospective study analyzed cerebral magnetic resonance imaging (MRI) data of 83 patients with pathologically diagnosed GSM (58 men, 25 women; mean age, 50.5 ± 12.9 years; range, 16-77 years) and 100 patients with GBM (58 men, 42 women; mean age, 53.4 ± 14.1 years; range, 12-77 years) and divided them into a training and validation set randomly. Radiomics features were extracted from the tumor mass and peritumoral edema. Three feature selection and classification methods were evaluated in terms of their performance in distinguishing GSM and GBM: the least absolute shrinkage and selection operator (LASSO), Relief, and Random Forest (RF); and adaboost classifier (Ada), support vector machine (SVM), and RF; respectively. The area under the receiver operating characteristic curve (AUC) and accuracy (ACC) of each method were analyzed. RESULTS: Based on tumor mass features, the selection method LASSO + classifier SVM was found to feature the highest AUC (0.85) and ACC (0.77) in the validation set, followed by Relief + RF (AUC = 0.84, ACC = 0.72) and LASSO + RF (AUC = 0.82, ACC = 0.75). Based on peritumoral edema features, Relief + SVM was found to have the highest AUC (0.78) and ACC (0.73) in the validation set. Regardless of the method, tumor mass features significantly outperformed peritumoral edema features in the differentiation of GSM from GBM (P < 0.05). Furthermore, the sensitivity, specificity, and accuracy of the best radiomics model were superior to those obtained by the neuroradiologists. CONCLUSION: Our radiomics study identified the selection method LASSO combined with the classifier SVM as the optimal method for differentiating GSM from GBM based on tumor mass features.

Differentiation Between Glioblastoma Multiforme and Metastasis From the Lungs and Other Sites Using Combined Clinical/Routine MRI Radiomics.

BACKGROUND: Differentiation between cerebral glioblastoma multiforme (GBM) and solitary brain metastasis (MET) is important. The existing radiomic differentiation method ignores the clinical and routine magnetic resonance imaging (MRI) features. PURPOSE: To differentiate between GBM and MET and between METs from the lungs (MET-lung) and other sites (MET-other) through clinical and routine MRI, and radiomics analyses. METHODS AND MATERIALS: A total of 350 patients were collected from two institutions, including 182 patients with GBM and 168 patients with MET, which were all proven by pathology. The ROI of the tumor was obtained on axial postcontrast MRI which was performed before operation. Seven radiomic feature selection methods and four classification algorithms constituted 28 classifiers in two classification strategies, with the best classifier serving as the final radiomics model. The clinical and combination models were constructed using the nomograms developed. The performance of the nomograms was evaluated in terms of calibration, discrimination, and clinical usefulness. Student's t-test or the chi-square test was used to assess the differences in the clinical and radiological characteristics between the training and internal validation cohorts. Receiver operating characteristic curve analysis was performed to assess the performance of developed models with the area under the curve (AUC). RESULTS: The classifier fisher_decision tree (fisher_DT) showed the best performance (AUC: 0.696, 95% CI:0.608-0.783) for distinguishing between GBM and MET in internal validation cohorts; the classifier reliefF_random forest (reliefF_RF) showed the best performance (AUC: 0.759, 95% CI: 0.613-0.904) for distinguishing between MET-lung and MET-other in internal validation cohorts. The combination models incorporating the radiomics signature and clinical-radiological characteristics were superior to the clinical-radiological models in the two classification strategies (AUC: 0.764 for differentiation between GBM in internal validation cohorts and MET and 0.759 or differentiation between MET-lung and MET-other in internal validation cohorts). The nomograms showed satisfactory performance and calibration and were considered clinically useful, as revealed in the decision curve analysis. DATA CONCLUSION: The combination of radiomic and non-radiomic features is helpful for the differentiation among GBM, MET-lung, and MET-other.

Total-body 18F-FDG PET/CT scan in oncology patients: how fast could it be?

PURPOSE: The aim of the study was to determine a faster PET acquisition protocol for a total-body PET/CT scanner by assessing the image quality that is equivalent to a conventional digital PET/CT scanner from both a phantom and a clinical perspective. METHODS: A phantom study using a NEMA/IEC NU-2 body phantom was first performed in both a total-body PET/CT (uEXPLORER) and a routine digital PET/CT (uMI 780), with a hot sphere to background activity concentration ratio of 4:1. The contrast recovery coefficient (CRC), background variability (BV), and recovery coefficient (RC: RCmax and RCmean) were assessed in the uEXPLORER with different scanning durations and reconstruction protocols, which were compared to those acquired from the uMI 780 with clinical acquisition settings. The coefficient of variation (COV) of the uMI 780 with clinical settings was calculated and used as a threshold reference to determine the optimized scanning duration and reconstruction protocol for the uEXPLORER. The obtained protocol from the phantom study was subsequently tested and validated in 30 oncology patients. Images acquired from the uMI 780 with 2-3 min per bed position were referred as G780 and served as the reference for comparison. All PET raw data from the uEXPLORER were reconstructed using the data-cutting technique to simulate a 30-s, 45-s, or 60-s acquisition duration, respectively. The iterations were 2 and 3 for the uEXPLORER, referred as G30s_3i, G45s_2i, G45s_3i, G60s_2i, and G60s_3i, respectively. A 5-point Likert scale was used in the qualitative analysis to assess the image quality. The image quality was also evaluated by the liver COV, the lesion target-to-background ratio (TBR), and the lesion signal-to-noise ratio (SNR). RESULTS: In the phantom study, CRC, BV, RCmax, and RCmean in the uEXPLORER with different scanning durations and reconstruction iterations were compared with those in the uMI 780 with clinical settings. A minor fluctuation was found among different scanning durations. COV of the uMI 780 with clinical settings was 11.6%, and a protocol with a 30-45-s scanning duration and 2 or 3 iterations for the uEXPLORER was found to provide an equivalent image quality as the uMI 780. An almost perfect agreement was shown with a kappa value of 0.875. The qualitative score of the G30s_3i in the uEXPLORER was inferior to the G780 reference (p = 0.001); however, the scores of other groups in the uEXPLORER with a 45-s and above acquisition time were higher than the G780 in the uMI 780. In quantitative analysis, the delay time between the two scans in the two orders was not significantly different. There was no significant difference of the liver COV between the G780 and G30s_3i (p = 0.162). A total of 33 lesions were analyzed in the clinical patient study. There was no significant difference in lesion TBR between the reference G780 and the G45s_2i obtained from the uEXPLORER (p = 0.072), while the latter showed a higher lesion SNR value compared to that in uMI 780 with clinical settings (p < 0.001). CONCLUSIONS: This study showed that a fast PET protocol with a 30-45-s acquisition time in the total-body uEXPLORER PET/CT can provide an equivalent image quality as the conventional digital uMI 780 PET/CT with longer clinical acquisition settings.