Investigating the Underlying Molecular Mechanisms of Yunke on Bone Metastases from Prostate Cancer.

Objective: To explore analgesic effect and bone repair mechanism of non-radioactive technetium-99 conjugated with methylene diphosphonate (99Tc-MDP, brand name, Yunke) on bone metastases (BM). Procedures: In vivo experiment, mouse BM models of prostate cancer RM-1 cell were constructed and divided into Control, Yunke, 99Tc+SnCl2 and MDP groups based on medicine composition. Tumor specimens were inspected for size, X-ray, microCT and histopathology. In vitro experiment, with Cell Counting Kit-8 (CCK8), scratch, clone, apoptosis, Polymerase Chain Reaction (PCR) and Western Blot experiments, effects of Yunke on RM-1 cells and osteoclast-related cells were observed. Results: In vivo experiment, there was no difference in tumor size between Yunke and control group. Contrasted with control group, in Yunke group, trabecular spacing (Tb.Sp) of tumor bone was lower, bone volume/total volume (BV/TV) on marrow cavity and bone cortex were higher. Tunnel staining showed that positive rate of apoptosis in Yunke group was higher than that in control group. Ki67 staining showed that Yunke could not inhibit proliferation of tumor cells. In vitro experiment, CCK8 and scratch experiments showed that Yunke neither can inhibit proliferation nor can inhibit migration of RM-1 cells. High concentration of Yunke promoted late apoptosis of RM-1 cells. Yunke could inhibit BMM cell proliferation, differentiation of osteoclasts, and osteoclast-related transcription factors. Yunke displayed different degrees of inhibitory effects on MAPKs signaling pathway during osteoclast differentiation. It had obvious inhibitory effects on osteoclast-related transcription factors, such as cFOS, NFATC1, ACP-5, CTSK, D2 and MMP-9, the strongest inhibitory effects were observed with ACP-5, CTSK and D2. Yunke also displayed different degrees of inhibitory effects on protein activities of JNK, pERK, ERK and pP38. Conclusion: Yunke cannot inhibit the proliferation and migration of RM-1 cells, so we think it is not recommended for the treatment of primary tumors and prevention of occurrence of tumors metastatic to bones. The mechanism of therapeutic effect of Yunke on BM by inhibiting proliferation of BMM, inhibiting MAPKs signal transduction and activation of transcription factors during differentiation process of BMM-derived osteoclasts, inhibiting number and size of osteoclasts, inhibiting bone resorption and protecting bone destruction through enhancing bone hardness and bone mass. Thereby, we believe that Yunke is more suitable for promoting the repair induced by BMs, delaying its progression and reducing the occurrence of SREs.

Do radioiodine-avid lymph nodes from differentiated thyroid cancer on the initial posttherapy scan need repeated 131I therapy?

Background: Residual/recurrent lymph node metastase (LNM) is often found after differentiated thyroid cancer (DTC) surgery. This study aimed to investigate whether patients complicated with radioiodine-avid (131I+) lymph nodes from DTC on the initial posttherapy scan (PTS) need repeated 131I therapy. Methods: From June 2013 to August 2022, DTC patients with 131I+ lymph nodes on the initial PTS who received at least two cycles of 131I therapy were retrospectively enrolled. They were divided into a complete response (CR) group and an incomplete response (IR) group according to their response to the initial 131I therapy based on the 2015 American Thyroid Association (ATA) guidelines. Results: A total of 170 DTC patients with 131I+ lymph nodes on the initial PTS were included; 42/170 (24.7%) patients were classified into the CR group and 128/170 (75.9%) were classified into the IR group according to their response to the initial 131I therapy. None of the 42 CR patients had disease progression at the subsequent follow-up, and 37/170 (21.8%) IR patients improved after repeated therapy. Univariate analysis showed that N stage (P=0.002), stimulated thyroglobulin (sTg) level before initial 131I therapy (P<0.001), LNM size (P<0.001), number of total residual/recurrent LNM (P=0.021), radioiodine-nonavid (131I-) LNM (P=0.002) and ultrasound features (P<0.001) were related to the initial treatment response. On multivariate analysis, sTg level (OR=1.186, P<0.001) and LNM size (OR=1.533, P=0.004) were independent risk factors for IR after initial 131I therapy. The optimal sTg level and LNM size cutoff value for predicting the treatment response after initial 131I therapy were 18.2 µg/l and 5mm. Conclusion: This study suggested that approximately one-quarter of patients with 131I+ lymph nodes on initial PTS, especially those with N0 or N1a stage, lower sTg level, smaller LNM size, ≤2 residual/recurrent LNMs, negative ultrasound features and no 131I- LNM, remain stable after one cycle of 131I therapy and do not need repeated therapy.

Comparison of 2D-QCA, 3D-QCA and coronary angiography derived FFR in predicting myocardial ischemia assessed by CZT-SPECT MPI.

BACKGROUND: Angiography derived fractional flow reserve (angio-FFR) has been proposed. This study aimed to assess its diagnostic performance with cadmium-zinc-telluride single emission computed tomography (CZT-SPECT) as reference. METHODS AND RESULTS: Patients underwent CZT-SPECT within 3 months of coronary angiography were included. Angio-FFR computation was performed using computational fluid dynamics. Percent diameter (%DS) and area stenosis (%AS) were measured by quantitative coronary angiography. Myocardial ischemia was defined as a summed difference score ≥ 2 in a vascular territory. Angio-FFR ≤ 0.80 was considered abnormal. 282 coronary arteries in 131 patients were analyzed. Overall accuracy of angio-FFR to detect ischemia on CZT-SPECT was 90.43%, with a sensitivity of 62.50% and a specificity of 98.62%. The diagnostic performance (= area under ROC = AUC) of angio-FFR [AUC = 0.91, 95% confidence intervals (CI) 0.86-0.95] was similar as those of %DS (AUC = 0.88, 95% CI 0.84-0.93, p = 0.326) and %AS (AUC = 0.88, 95% CI 0.84-0.93 p = 0.241) by 3D-QCA, but significantly higher than those of %DS (AUC = 0.59, 95% CI 0.51-0.67, p < 0.001) and %AS (AUC = 0.59, 95% CI 0.51-0.67, p < 0.001) by 2D-QCA. However, in vessels with 50-70% stenoses, AUC of angio-FFR was significantly higher than those of %DS (0.80 vs. 0.47, p < 0.001) and %AS (0.80 vs. 0.46, p < 0.001) by 3D-QCA and %DS (0.80 vs. 0.66, p = 0.036) and %AS (0.80 vs. 0.66, p = 0.034) by 2D-QCA. CONCLUSION: Angio-FFR had a high accuracy in predicting myocardial ischemia assessed by CZT-SPECT, which is similar as 3D-QCA but significantly higher than 2D-QCA. While in intermediate lesions, angio-FFR is better than 3D-QCA and 2D-QCA in assessing myocardial ischemia.

Relationship between standardized uptake value on 18F-FDG PET and PD-L1 expression in clear cell renal cell carcinoma.

Purpose: Partial clear cell renal cell carcinoma (CCRCC) may be sensitive to immune checkpoint inhibitor treatment targeting the programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) pathway. Assessing the levels of PD-L1 using non-invasive imaging is useful to select immunotherapy-sensitive patients. Currently, whether PD-L1 levels in CCRCC correlate with 18F fluorodeoxyglucose (18F-FDG) uptake is unknown. This study aimed to assess whether 18F-FDG-positron emission tomography (PET) imaging could be used to infer PD-L1 levels in CCRCC. Methods: Immunohistochemistry (IHC) was used to assess PD-L1 levels in samples of tumors obtained retrospectively from a cohort of 58 patients with CCRCC who also received 18F-FDG PET/CT imaging. The IHC scores for PD-L1 were compared with the 18F-FDG maximum standardized uptake value (SUVmax), and the mean standardized uptake value (SUVmean) value, with the clinical characteristics of CCRCC, and with the IHC scores of enzymes related to glucose metabolism (glucose transporter type 1 (GLUT1), hexokinase 2 (HK2), lactate dehydrogenase A (LDHA)), and Von Hippel-Lindau tumor suppressor (VHL). Results: Increased renal venous invasion, lymph node metastasis, tumor size, SUVmean, and SUVmax correlated significantly with higher PD-L1 levels (P < 0.05). The IHC scores of VHL and LDHA correlated positively with those of PD-L1 (P = 0.035, P = 0.011, respectively). Significant correlations between PD-L1 levels and SUVmean and lymph node metastasis were observed upon multivariate analysis. SUVmean combined with lymph node metastasis predicted that 20.59% of the low probability group would express PD-L1, 29.41% of the medium probability group would express PD-L1, and 71.43% of the high probability group would express PD-L1. Conclusion: The status of lymph node metastasis, SUVmax, and SUVmean of the primary lesion correlated with PD-L1 levels in CCRCC. A combination of lymph node metastasis status and SUVmean could be utilized to predict PD-L1 levels, thus allowing monitoring of a tumor's immunotherapy response.

Recombinant human thyrotropin (rhTSH)-aided radioiodine treatment for non-toxic multinodular goitre.

BACKGROUND: Multinodular goitre is common in women. Treatments for non-toxic multinodular goitre include surgery, levothyroxine suppressive therapy, and radioiodine. Radioiodine therapy is the only non-surgical alternative for non-toxic multinodular goitre. However, a high amount of radioiodine is needed to enable the thyroid nodules to adequately take up the radioiodine, because the multinodular goitre takes up a low amount of iodine. Recombinant human thyrotropin (rhTSH) has been used to increase radioiodine uptake and reduce thyroid volume of the multinodular goitre. Whether the improved reduction of the goitre resulting from rhTSH-stimulated radioiodine therapy is beneficial to the person remains controversial. OBJECTIVES: To assess the effects of recombinant human thyrotropin-aided radioiodine treatment for non-toxic multinodular goitre. SEARCH METHODS: We searched the CENTRAL, MEDLINE, Scopus as well as ICTRP Search Portal and ClinicalTrials.gov. The date of the last search of all databases was 18 December 2020. SELECTION CRITERIA: We included randomised controlled clinical trials (RCTs) comparing the effects of rhTSH-aided radioiodine treatment compared with radioiodine alone for non-toxic multinodular goitre, with at least 12 months of follow-up. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts for relevance. Screening for inclusion, data extraction, and risk of bias assessment were carried out by one review author and checked by a second. Our main outcomes were health-related quality of life (QoL), hypothyroidism, adverse events, thyroid volume, all-cause mortality, and costs. We used a random-effects model to perform meta-analyses, and calculated risk ratios (RRs) for dichotomous outcomes, and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We evaluated the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included six RCTs. A total of 197 participants were allocated to rhTSh-aided radioiodine therapy, and 124 participants were allocated to radioiodine. A single dose of radioiodine was administered 24 hours after the intramuscular injection of a single dose of rhTSH. The duration of follow-up ranged between 12 and 36 months. Low-certainty evidence from one study, with 85 participants, showed uncertain effects for QoL for either intervention. RhTSH-aided radioiodine increased hypothyroidism compared with radioiodine alone (64/197 participants (32.5%) in the rhTSH-aided radioiodine group versus 15/124 participants (12.1%) in the radioiodine alone group; RR 2.53, 95% CI 1.52 to 4.20; 6 studies, 321 participants; moderate-certainty evidence in favour of radioiodine alone). A total of 118/197 participants (59.9%) in the rhTSH-aided radioiodine group compared with 60/124 participants (48.4%) in the radioiodine alone group experienced adverse events (random-effects RR 1.24, 95% CI 0.94 to 1.63; 6 studies, 321 participants; fixed-effect RR 1.23, 95% CI 1.02 to 1.49 in favour of radioiodine only; low-certainty evidence). RhTSH-aided radioiodine reduced thyroid volume with a MD of 11.9% (95% CI 4.4 to 19.4; 6 studies, 268 participants; moderate-certainty evidence). One study with 28 participants reported one death in the radioiodine alone group (very-low certainty evidence). No study reported on costs. AUTHORS' CONCLUSIONS: RhTSH-aided radioiodine treatment for non-toxic multinodular goitre, compared to radioiodine alone, probably increased the risk of hypothyroidism but probably led to a greater reduction in thyroid volume. Data on QoL and costs were sparse or missing.

FDG PET Predicts the Effects of 131I and Prognosis for Patients with Bone Metastases from Differentiated Thyroid Carcinoma.

BACKGROUND: 18F-FDG PET and 131I scans are important in the detection of metastases from differentiated thyroid carcinoma (DTC). The relationship of FDG and radioiodine (RAI) metabolism in bone metastases (BMs) from DTC and its prognostic value on RAI treatment is not clear. METHODS: The retrospective study included DTC patients with BMs from two medical centers, who underwent 18F-FDG PET/CT scans and RAI therapy. Therapeutic response was evaluated by serum thyroglobulin (Tg) levels and anatomical imaging changes. RESULTS: The analyses were performed on 30 patients with 72 BMs. Forty-two (42/72, 58%) lesions displayed simultaneous 131I and 18F-FDG uptake. BMs with positive 18F-FDG uptake had a less favorable response to RAI therapy in comparison to those with negative 18F-FDG uptake (p = 0.018), even in 131I-avid lesions (p = 0.033). Sixteen (53%) patients had disease progression with a median PFI of 26 months (range: 3 to 89 months). Compared to those with 131I-avid but non-FDG-avid BMs, patients presenting with 18F-FDG-avid BMs had shorter PFI, whether with 131I uptake (p = 0.002) or without (p = 0.002). CONCLUSION: More than half of BMs (58%) from DTC show simultaneous 18F-FDG and 131I uptakes which are contrary to the flip-flop phenomenon (131I negative and 18F-FDG positive). Regardless of 131I uptake, 18F-FDG uptake of BMs portends a less favorable therapeutic response and poorer prognosis for patients with DTC.

Whole-body MRI versus 18F-FDG PET/CT for pretherapeutic assessment and staging of lymphoma: a meta-analysis.

PURPOSE: 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) is the reference standard in staging of 18F-FDG-avid lymphomas; however, there is no recommended functional imaging modality for indolent lymphomas. Therefore, we aimed to compare the performance of whole-body magnetic resonance imaging (WB-MRI) with that of 18F-FDG PET/CT for lesion detection and initial staging in patients with aggressive or indolent lymphoma. MATERIALS AND METHODS: We searched the MEDLINE, EMBASE, and CENTRAL databases for studies that compared WB-MRI with 18F-FDG PET/CT for lymphoma staging or lesion detection. The methodological quality of the studies was assessed using version 2 of the "Quality Assessment of Diagnostic Accuracy Studies" tool. The pooled staging accuracy (µ) of WB-MRI and 18F-FDG PET/CT for initial staging and for assessing possible heterogeneity (χ2) across studies were calculated using commercially available software. RESULTS: Eight studies comprising 338 patients were included. In terms of staging, the meta-analytic staging accuracies of WB-MRI and 18F-FDG PET/CT for Hodgkin lymphoma and aggressive non-Hodgkin lymphoma (NHL) were 98% (95% CI, 94%-100%) and 98% (95% CI, 94%-100%), respectively. The pooled staging accuracy of 18F-FDG PET/CT dropped to 87% (95% CI, 72%-97%) for staging in patients with indolent lymphoma, whereas that of WB-MRI remained 96% (95% CI, 91%-100%). Subgroup analysis indicated an even lower staging accuracy of 18F-FDG PET/CT for staging of less FDG-avid indolent NHLs (60%; 95% CI, 23%-92%), in contrast to the superior performance of WB-MRI (98%; 95% CI, 88%-100%). CONCLUSION: WB-MRI is a promising radiation-free imaging technique that may serve as a viable alternative to 18F-FDG PET/CT for staging of 18FDG-avid lymphomas, where 18F-FDG PET/CT remains the standard of care. Additionally, WB-MRI seems a less histology-dependent functional imaging test than 18F-FDG PET/CT and may be the imaging test of choice for staging of indolent NHLs with low 18F-FDG avidity.

Effect of hypoparathyroid on bone mineral density of lumber spine in postmenopausal women with differentiated thyroid cancinoma.

OBJECTIVE: To investigate the effect of hypoparathyroid on bone mineral density in postmenopausal women with differentiated thyroid carcinoma (DTC). SUBJECT AND METHODS: Postmenopausal women with postoperative DTC, and undergoing thyroid residual ablation or for metastases treatment were collected and followed for two years. They were divided into hypoparathyroid group (PTH<15pg/mL) and a normal cognitive group (PTH>15pg/mL). Bone mineral density (BMD) at the lumbar spine was analyzed using dual-energy X-ray absorptiometry (DXA) at baseline, 6, 12 and 24 months. All patients had calcium and active vitamin D supplementation. RESULTS: The thyroid cancers included 211 papillary carcinomas, 14 follicular carcinomas. The majority of them were retired from previous work (157/225, 70%). There were 45 DTC patients in hypoparathyroid group and 180 patients in PTH normal group (postmenopausal controls). They are comparable in age, TSH suppression, BMD at baseline. There is no significant difference in BMD of lumbar spine between hypoparathyroid group and postmenopausal controls at baseline 6, 12 and 24 months follow-up which were1.03±0.14 and 1.04±0.18 (t=0.4, P=0.69), 1.04±0.13 and 1.01±0.19 (t=1.25, P=0.21), 1.06±0.15 and 1.02±0.16 (t=1.16, P=0.26), 1.06±0.21 and 1.01±0.17 (t=0.93, P=0.29), respectively. Areal BMD was increased by 2.9% in hypoparathyroid group in the lumbar spine at 12 and 24 months follow-up, while decrease of 2.9% in postmenopausal controls. No increase in BMD at lumbar spine was found in postmenopausal controls. CONCLUSION: Transient hypoparathyroid increased BMD at lumbar spine by DXA in postmenopausal DTC patients compared to postmenopausal controls.

A comparative study of 18F-FDG PET/CT and ultrasonography in the diagnosis of breast cancer and axillary lymph node metastasis.

BACKGROUND: The aim of this study was to compare the diagnostic value of 18F-FDG-PET/CT (PET/CT) with ultrasonography (US) in detection of primary breast cancer and axillary lymph nodes (ALN) metastasis of breast cancer. METHODS: One hundred and sixty four patients with breast carcinoma were recruited and analyzed retrospectively. All patients underwent PET-CT and US. The PET/CT scan results for the diagnosis of primary breast cancer were compared with US. The diagnostic accuracy of PET/CT in detecting ALN metastasis was compared with histopathology. RESULTS: In 164 patients with cytologically established breast carcinoma, the sensitivity of PET/CT and US in the diagnosis of breast cancer were 86% (141/164), 91% (149/164), respectively. The sensitivity, specificity of PET/CT and US in ALN staging were 46% and 54%, 91% and 91%, respectively. The diagnostic accuracy of PET/CT correlated with the ALN size, the SUVmax of primary breast cancer (P=0.02 and 0.04). CONCLUSIONS: PET/CT is very expensive, and not superior to US in detection of primary breast cancer and in ALN staging, but superior in detecting distant metastases. PET/CT cannot be recommended as a primary diagnostic procedure in early breast cancer. US should still remain the first line for the diagnosis of stage I breast cancer. In relation to the detection of axillary node metastases, both PET/CT and ultrasonography have poor sensitivity, and cannot replace staging by using the sentinel node procedure.

(18)F-FDG Uptake Characteristics in Differentiating Benign from Malignant Nasopharyngeal Lesions in Children.

The characteristics of FDG uptake in the physiologic and malignant nasopharynx were investigated in the paper which was correlated with either pathologic findings or clinical follow-up. Three patients had pathologically established nasopharyngeal malignancy. In the 3 nasopharyngeal malignancies, 2 had diffusely and expansively increased FDG uptake, and one had asymmetric uptake. Our results indicated that the difference between adenoid hypertrophy and malignancy is asymmetric or diffusely expansive (18)F-FDG uptake with or without correlating morphologic lesion on diagnostic CT in children under 10 years of age. The typical characteristics of physiologic and inflammatory (18)F-FDG uptake in nasopharynx are symmetrically trapezoid. Diffusely increased nasopharyngeal FDG uptake can be considered physiologic if SUVmax is less than 7.6 but should be carefully assessed by pharyngorhinoscopy if SUVmax is greater than 11 and there is no correlating morphologic lesion on diagnostic CT. The diffusely, expansively increased uptake, and asymmetric uptake in particular, should be considered as malignancy. Further biopsy is especially indicated in patients with retropharyngeal space and bilateral cervical lymph node abnormality but no history of malignancy.