Synthesis of 64Cu-, 55Co-, and 68Ga-Labeled Radiopharmaceuticals Targeting Neurotensin Receptor-1 for Theranostics: Adjusting In Vivo Distribution Using Multiamine Macrocycles.

The development of theranostic radiotracers relies on their binding to specific molecular markers of a particular disease and the use of corresponding radiopharmaceutical pairs thereafter. This study reports the use of multiamine macrocyclic moieties (MAs), as linkers or chelators, in tracers targeting the neurotensin receptor-1 (NTSR-1). The goal is to achieve elevated tumor uptake, minimal background interference, and prolonged tumor retention in NTSR-1-positive tumors. Methods: We synthesized a series of neurotensin antagonists bearing MA linkers and metal chelators. The MA unit is hypothesized to establish a strong interaction with the cell membrane, and the addition of a second chelator may enhance water solubility, consequently reducing liver uptake. Small-animal PET/CT imaging of [64Cu]Cu-DOTA-SR-3MA, [64Cu]Cu-NT-CB-NOTA, [68Ga]Ga-NT-CB-NOTA, [64Cu]Cu-NT-CB-DOTA, and [64Cu]Cu-NT-Sarcage was acquired at 1, 4, 24, and 48 h after injection using H1299 tumor models. [55Co]Co-NT-CB-NOTA was also tested in HT29 (high NTSR-1 expression) and Caco2 (low NTSR-1 expression) colorectal adenocarcinoma tumor models. Saturation binding assay and internalization of [55Co]Co-NT-CB-NOTA were used to test tracer specificity and internalization in HT29 cells. Results: In vivo PET imaging with [64Cu]Cu-NT-CB-NOTA, [68Ga]Ga-NT-CB-NOTA, and [55Co]Co-NT-CB-NOTA revealed high tumor uptake, high tumor-to-background contrast, and sustained tumor retention (≤48 h after injection) in NTSR-1-positive tumors. Tumor uptake of [64Cu]Cu-NT-CB-NOTA remained at 76.9% at 48 h after injection compared with uptake 1 h after injection in H1299 tumor models, and [55Co]Co-NT-CB-NOTA was retained at 60.2% at 24 h compared with uptake 1 h after injection in HT29 tumor models. [64Cu]Cu-NT-Sarcage also showed high tumor uptake with low background and high tumor retention 48 h after injection Conclusion: Tumor uptake and pharmacokinetic properties of NTSR-1-targeting radiopharmaceuticals were greatly improved when attached with different nitrogen-containing macrocyclic moieties. The study results suggest that NT-CB-NOTA labeled with either 64Cu/67Cu, 55Co/58mCo, or 68Ga (effect of 177Lu in tumor to be determined in future studies) and NT-Sarcage labeled with 64Cu/67Cu or 55Co/58mCo may be excellent diagnostic and therapeutic radiopharmaceuticals targeting NTSR-1-positive cancers. Also, the introduction of MA units to other ligands is warranted in future studies to test the generality of this approach.

The efficacy and safety in radioactive iodine refractory thyroid cancer patients treated with sorafenib.

Background: Sorafenib included in Chinese medical insurance is the earliest targeted drug for radioactive iodine refractory differentiated thyroid cancer (RR-DTC). This study is to further demonstrate the clinical efficacy and safety of sorafenib used in Zhujiang Hospital of Southern Medical University. Methods: RR-DTC patients treated at our Department of Nuclear Medicine in Zhujiang Hospital of Southern Medical University (October 2017-May 2020) were retrospectively analyzed. Treatment effects, progression-free survival (PFS), and adverse effects (AEs) during medication were evaluated. Results: Of the 31 patients included, 26 patients were evaluated for efficacy with a median follow-up time of 17.5 months (4.0-51.0 months). The disease control rate (DCR) was 57.7% (n = 15) and the objective response rate (ORR) was 26.9% (n = 7). Most patients with disease control had thyroglobulin decreases of more than 60% (p = 0.004), ORRs were favorable in patients with lung metastasis and lung-only metastasis (p = 0.010 and 0.001, respectively). The PFS of the 26 patients analyzed was 16.5 months (95%CI: 14.41 -23.90 months). In the subgroup analysis, female, patients with lung-only metastasis, hand-foot skin syndrome (HFS), and thyroglobulin response ≥ 60% observed longer PFS (p = 0.038, 0.045, 0.035, and 0.000, respectively), while patients with bone metastasis had lower PFS (p = 0.035). The most common toxicity profile was HFS (93.5%), followed by diarrhea (83.9%), alopecia (74.2%). All the side effects were mainly grade 1-2. Grade 3-4 adverse reactions were more common in diarrhea and HFS. Conclusions: Sorafenib has promising efficacy in RR-DTC, especially in patients with lung metastasis and lung-only metastasis. The AEs of sorafenib were generally mild, and the main AE was HFS.

Corrigendum: Incorporation size of lymph node metastasis focus and pre-ablation stimulated Tg could more effectively predict clinical outcomes in differentiated thyroid cancer patients without distant metastases.

[This corrects the article DOI: 10.3389/fendo.2023.1094339.].

Incorporation size of lymph node metastasis focus and pre-ablation stimulated Tg could more effectively predict clinical outcomes in differentiated thyroid cancer patients without distant metastases.

Background: The size of lymph node metastasis (LNM) and pre-ablation stimulated Tg (ps-Tg) were key predictors of clinical prognosis in differentiated thyroid cancer (DTC) patients, however, very few studies combine the above two as predictors of clinical prognosis of DTC patients. Methods: Persistent/recurrent disease and clinicopathologic factors were analyzed in 543 DTC patients without distant metastases who underwent LN dissection, near-total/total thyroidectomy, and radioiodine ablation. Results: In the multivariate analysis, size of LNM, ps-Tg, and the activity of 131I significantly correlated with long-term remission. The optimal cutoff size of LNM 0.4 cm-1.4 cm (intermediate-risk patients) and >1.4cm (high-risk patients) increased the recurrence risk (hazard ratio [95% CI], 4.674 [2.881-7.583] and 13.653 [8.135-22.913], respectively). Integration of ps-Tg into the reclassification risk stratification showed that ps-Tg ≤ 10.0 ng/mL was relevant to a greatly heightened possibility of long-term remission (92.2%-95.4% in low-risk patients, 67.3%-87.0% in intermediate-risk patients, and 32.3%-57.7% in high-risk patients). Conclusion: The cutoff of 0.4 cm and 1.4 cm for a definition of size of LNM in DTC patients without distant metastases can reclassify risk assessment, and incorporating ps-Tg could more effectively predict clinical outcomes and modify the postoperative management plan.

Outcome of patients with differentiated thyroid cancer treated with empirical radioiodine therapy on the basis of Thyroglobulin Elevation Negative Iodine Scintigraphy (TENIS) syndrome without structural disease: a retrospective cohort study.

BACKGROUND: For differentiated thyroid cancer (DTC) patients with thyroglobulin (Tg) elevation and negative iodine scintigraphy (commonly termed "TENIS" syndrome) after thyroidectomy, radioactive iodine (RAI) therapy, and thyroid-stimulating hormone (TSH) suppression therapy, empirical RAI therapy may be considered. However, the outcome data of TENIS syndrome without structural disease after empirical RAI therapy have not shown clear evidence of improvement in survival. We assessed the efficacy of such empirical RAI therapy in TENIS syndrome without structural disease and evaluated the progression-free survival (PFS). METHODS: A total of 80 papillary thyroid cancer (PTC) patients with TENIS syndrome without structural disease were included in this retrospective study. 52 patients were treated with empirical RAI therapy while another 28 patients were untreated. The progression-free survival (PFS) of both groups was defined as the main outcome. The secondary outcome was the comparison of serum Tg levels 12 months after being diagnosed as TENIS syndrome. RESULTS: The PFS of the empirical RAI therapy group was better than the untreated group (p < 0.001). Moreover, there was significant difference in Tg normalization between patients treated with empirical therapy and without treatment (p = 0.001). Empirical RAI therapy (p = 0.001) predicts better PFS. Male gender (p = 0.041) and empirical RAI therapy (p = 0.002) predict better remission in serum Tg level. CONCLUSION: Patients with TENIS syndrome without structural disease can benefit from empirical RAI therapy in both PFS and Tg normalization.

Locoregional progression-free survival of bone metastases from differentiated thyroid cancer.

To evaluate the locoregional progression-free survival (LPFS) of bone metastatic lesions from differentiated thyroid cancer (DTC) after radioiodine therapy (RAIT) and to define its influencing factors, we performed a retrospective cohort analysis of 89 patients with bone metastases from DTC who received RAIT in our department over a 17-year period. The median follow-up time was calculated using the reverse Kaplan-Meier method. The log-rank test and a multivariate Cox proportional hazards regression model were performed in the analysis of prognostic indicators for LPFS. In this research, the median follow-up time for all patients was 47 (95% CI, 35.752-58.248) months, and that for patients with no progression was 42 months. The longest follow-up time was 109 months. The median LPFS time was 58 (95% CI, 32.602-83.398) months, and the 3- and 5-year LPFS probabilities were 57.8 and 45.1%, respectively. Multivariate analysis revealed bone structural changes as an independent risk factor for LPFS (P= 0.004; hazard ratio, 49.216; 95% CI, 3.558-680.704). Furthermore, the non-total-lesion uptake subgroup presented a worse LPFS than the total-lesion uptake subgroup in patients with structural bone lesions (P = 0.027). RAIT can improve the LPFS of radioiodine-avid bone metastases from DTC, especially those without bone structural changes.

Progressive changes in the major salivary gland after radioiodine therapy for differentiated thyroid cancer: a single-center retrospective ultrasound cohort study.

This study aimed to determine the prevalence of radioiodine-induced salivary gland damage by evaluating progressive changes in salivary glands using ultrasound. Four hundred forty-six patients with differentiated thyroid carcinoma who underwent total or near-total thyroidectomy and postoperative radioiodine therapy were retrospectively reviewed. From the first to the fifth follow-up visits, the positive rate of major salivary gland changes on ultrasound gradually increased from 2.0% to 33.0% (P<0.001) and possibly stabilized at the fifth visit (approximately 36 months). The first positive result was detected at an average of 20.78±8.72 months. Only 21 of the 161 positive cases eventually achieved negative ultrasound results (Fisher's test, P<0.001), and the 21 cases simply showed a coarse echotexure. In conclusion, ultrasound changes appeared late, and most of these changes were not reversed.

Integrated Physiological and Transcriptomic Analyses Reveal a Regulatory Network of Anthocyanin Metabolism Contributing to the Ornamental Value in a Novel Hybrid Cultivar of Camellia Japonica.

Camellia japonica is a plant species with great ornamental and gardening values. A novel hybrid cultivar Chunjiang Hongxia (Camellia japonica cv. Chunjiang Hongxia, CH) possesses vivid red leaves from an early growth stage to a prolonged period and is, therefore, commercially valuable. The molecular mechanism underlying this red-leaf phenotype in C. japonica cv. CH is largely unknown. Here, we investigated the leaf coloration process, photosynthetic pigments contents, and different types of anthocyanin compounds in three growth stages of the hybrid cultivar CH and its parental cultivars. The gene co-expression network and differential expression analysis from the transcriptome data indicated that the changes of leaf color were strongly correlated to the anthocyanin metabolic processes in different leaf growth stages. Genes with expression patterns associated with leaf color changes were also discussed. Together, physiological and transcriptomic analyses uncovered the regulatory network of metabolism processes involved in the modulation of the ornamentally valuable red-leaf phenotype and provided the potential candidate genes for future molecular breeding of ornamental plants such as Camellia japonica.

BRAF V600E and lymph node metastases in papillary thyroid cancer.

OBJECTIVE: To evaluate the relationship between the BRAF V600E mutation in lymph node metastasis (LNM) and its invasive characteristics in papillary thyroid cancer (PTC). MATERIAL AND METHODS: A total of 373 PTC patients were enrolled in this study conducted at Zhujiang Hospital of Southern Medical University between January 2017 and December 2018. PTCs with cervical lymph node metastases were verified pathohistologically, and primary tumors and LNM were examined for the BRAF V600E mutation. Patients were excluded from the study if the BRAF V600E mutation was examined only in primary tumors or only in LNM. RESULTS: Of the 373 patients examined, BRAF V600E mutation frequency in primary tumors was slightly higher than in LNM (81.5% vs 78.0%, P = 0.000), the intra-class correlation coefficient (ICC) was 0.865 (95% CI 0.835-0.890). The BRAF V600E mutation in both primary tumor and LNM negatively correlated with the size of the largest metastatic focus of LNM (Odds ratio, OR = 0.297, 95% CI 0.143-0.616, P = 0.001; OR = 0.242, 95% CI 0.119-0.492, P = 0.000, respectively). There was no relationship between BRAF V600E mutation in LNM and the number, extranodal extension or stage of LNM (P > 0.05). CONCLUSION: The BRAF V600E mutation in LNM may not be related to the invasive characteristics of LNM in PTC.

Mothers' prenatal tobacco smoke exposure is positively associated with the occurrence of developmental coordination disorder among children aged 3-6 years: A cross-sectional study in a rural area of Shanghai, China.

INTRODUCTION: Prenatal tobacco smoke exposure is a potential risk factor for developmental coordination disorder (DCD) in children, but evidence on the relationship between DCD in children and tobacco smoke exposure in women is limited in China. We conducted a cross-sectional study to understand the prevalence of prenatal tobacco smoke exposure among mothers and the prevalence of DCD among children and to explore if mothers' prenatal tobacco smoke exposure is positively associated with the occurrence of DCD among children. METHODS: During 2018, we sampled 8586 children aged 3-6 years and their mothers in Songjiang district, Shanghai. DCD in children was identified by MABC-2 screening combined with pediatrician confirmation. Prenatal tobacco smoke exposure among mothers was classified into firsthand smoke (FHS) and secondhand smoke (SHS) exposure. SAS 9.2 software was applied to calculate the prevalence of DCD in children, the prevalence of prenatal FHS and SHS exposure in mothers and to analyze the differences by chi-squared test and logistic regression. RESULTS: Among the 8586 women, the prevalence of prenatal FHS and SHS exposure was 0.94% and 20.79%, respectively. The prevalence of DCD in children was 6.65%, which was significantly higher in boys (7.64%) than in girls (5.51%), and children aged 3 years (9.77%) had a higher prevalence of DCD than children aged 4, 5 or 6 years (7.44%, 5.27% and 4.28%, respectively). In comparison with children whose mother was not exposed to prenatal FHS or SHS, the odds of having DCD was higher in children whose mother was exposed to prenatal FHS (OR=4.42; 95% CI: 2.62-7.44) and SHS (OR=1.77; 95% CI: 1.47-2.14), even after adjustment for potential confounders. CONCLUSIONS: The occurrence of DCD among children is positively associated with prenatal tobacco smoke exposure among the mothers. It is crucial to implement tobacco control measures to decrease the prevalence of smoking among pregnant women and SHS exposure at home as well as in the work environment. ABBREVIATIONS: DCD: developmental coordination disorder, ADHD: attention deficit hyperactivity disorder, FHS: firsthand smoke, SHS: secondhand smoke, MABC-2: movement assessment battery for children-2nd edition, GATS: global adult tobacco survey, SD: standard deviation, OR: odds ratio, CI: confidence interval, DAGs: directed acyclic graphs.

Postoperative thyroid remnants for differentiated thyroid cancer may not affect the outcome of high-dose radioiodine therapy.

OBJECTIVES: This study aims to provide a way to estimate the volume of the thyroid remnant and determine its relationship with the outcome of radioiodine (RAI) therapy in depth. MATERIALS AND METHODS: A retrospective analysis was performed on patients who underwent initial RAI therapy between January 2010 and January 2016. The patients were divided into five groups based on the thyroid remnant estimated by post-therapy whole-body scan(post-Rx WBS), thyroid scintigraphy and ultrasonography. The relationship between the volume of thyroid remnant and the outcome of RAI therapy were evaluated by univariate analysis and multivariate analysis. RESULTS: Of 703 patients, the majority could be found different size of thyroid remnants using the three imaging methods, and only few patients(2.1%) could reach no thyroid remnant. There was no association between the volume of thyroid remnant and the outcome of RAI therapy in univariate analysis (χ2 = 1.633, P = 0.652) and multivariate analysis (P > 0.05). In the subgroup of patients with high-risk factors, there was still no significant difference (intermediate risk subgroup: P = 0.338 vs high risk subgroup: P = 0.263). CONCLUSION: Different sizes of thyroid remnants were left after surgery. However, in high radioiodine activity, the volume of thyroid remnants may not affect the outcome of RAI therapy even in patients with some high-risk factors, so the high radioiodine activities may resolve the the problem caused by thyroid remnants in some cases.

SIZE OF THE LARGEST METASTATIC FOCUS TO THE LYMPH NODE IS ASSOCIATED WITH INCOMPLETE RESPONSE OF PN1 PAPILLARY THYROID CARCINOMA.

Objective: To evaluate the influence of the size of the metastatic focus in lymph nodes (LNs) on therapeutic response among papillary thyroid cancer (PTC) and cervical pathologically proven LN metastases (pN1). Methods: Patients with pN1 PTC who underwent total or near-total thyroidectomy, LN dissection, and postoperative radioactive iodine therapy in a university hospital between 2014 and 2016 were retrospectively reviewed. Furthermore, 554 patients were assigned to three groups according to the size of the metastatic focus in the LNs (≤0.2 cm, 0.2 to 1.0 cm, ≥1.0 cm). Structural incomplete response (SIR) was defined as structural or functional evidence of disease with any thyroglobulin level and/or anti-thyroglobulin antibodies. Results: Among the 554 patients, the proportion of patients with SIR was 2.5% (4/161) in group 1, 13.9% (37/267) in group 2, and 46.8% (59/126) in group 3 (χ2 = 100.073; P<.001). The optimal cutoff value of the size of the largest metastatic focus to the LNs was 0.536 cm to predict SIR with a corresponding sensitivity of 0.82, a specificity of 0.716, and an area under the curve of 0.821 (95% confidence interval [CI], 0.777 to 0.864; P<.001). Size of the largest metastatic focus to the LNs was confirmed to be an independent predictive factor for SIR (odds ratio, 9.650; 95% CI, 4.925 to 18.909; P<.001). Conclusion: In patients with pN1 PTC, there is an association between the size of the largest metastatic focus to the LNs and incomplete response. Abbreviations: AJCC = American Joint Committee on Cancer; ATA = American Thyroid Association; BIR = biochemical incomplete response; CI = confidence interval; ER = excellent response; ETE = extranodal extension; 18F-FDG = 18F-fluorodeoxyglucose; IDR = indeterminate response; LN = lymph node; OR = odds ratio; PET/CT = positron emission tomography/computed tomography; pN1 = pathologically proven LN metastases; PTC = papillary thyroid carcinoma; RAI = radioactive iodine; ROC = receiver operating characteristic; SIR = structural incomplete response; sTg = stimulated thyroglobulin; TgAb = anti-thyroglobulin antibody; TSH = thyroid-stimulating hormone.

Clinical significance of the BRAFV600E mutation in PTC and its effect on radioiodine therapy.

The goal of this study was to explore the relationship of the BRAFV600E mutation with clinicopathologic factors and evaluate the effect of radioactive iodine (RAI) therapy in a large group of intermediate- and high-risk papillary thyroid cancer (PTC) patients with the BRAFV600E mutation and without distant metastases. We collected data for PTC patients who underwent total or near-total thyroidectomy and RAI treatment in our hospital from January 2014-December 2017. There were 1220 PTC patients who met the criteria, and the BRAFV600E mutation was observed in 979 of them (80.2%). Multivariate analysis identified that the BRAFV600E mutation remained independently associated with age at diagnosis, and bilaterality (OR = 1.023, 95% CI = 1.012-1.039, P < 0.001; OR = 1.685, 95% CI = 1.213-2.341, P = 0.002, respectively). In addition, the patients with bilateral PTCs had a higher prevalence of extrathyroid invasion, capsular invasion and fusion of metastatic lymph nodes than the unilateral PTC patients. The response to RAI therapy was evaluated in both the entire series and the patients with a high recurrence risk; no significant difference was discerned between the BRAFV600E mutation and the wild-type groups (P = 0.237 and P = 0.498, respectively). To summarize, our results confirmed that PTC patients with the BRAFV600E mutation exhibit more aggressive characteristics. In addition, the patients with bilateral PTC have a higher incidence of extrathyroid invasion. Moreover, BRAFV600E mutation PTC patients did not show a poorer clinical response after postsurgical RAI therapy, suggesting that RAI therapy may improve the general clinical outcome of these patients.

A comparison of two different fluid resuscitation management protocols for pediatric burn patients: A retrospective study.

OBJECTIVE: Pediatric burn patients are more susceptible to burn shock than adults, and an effective fluid management protocol is critical to successful resuscitation. Our research aim was to investigate the safety and efficacy of two protocols for pediatric burn patients for use within the first 24h. METHODS: A total of 113 pediatric burn patients were enrolled from January 2007 to October 2012. Of those patients, 57 received fluid titration regimens of alternating crystalloids and colloids once within 2h in the first 24h after burn (Group A), whereas the remaining patients received regimens of alternating crystalloids and colloids once within 1h in the first 24h after burn (Group B). The safety, fluid volume infused and urine output were recorded and compared. RESULTS: All the patients survived in the first 24h after burn. There were no significant differences between Group A and Group B in lactic acid (LA) level and base excess (BE). The water infused in Group A were greater than that of Group B in the first 24h (P=0.024). No significant differences were found in total volume intake and hourly urine output between the 2 groups in the first 24h. CONCLUSION: The implementation of fluid resuscitation using either protocol A or protocol B is safe and effective for pediatric burn patients in the first 24h. The total fluid infused were similar between two protocols. But using protocol A may be more convenient and labor-saving for nurses.