Construction and Preliminary Evaluation of Two 18F-Labeled Radiopharmaceuticals for Myocardial Perfusion Imaging.

AIMS: PET myocardial perfusion imaging (MPI) is the gold standard for the noninvasive diagnosis of ischemic myocardial. Construction of 18F-labeled PET MPI probe showed benefits to reduce the imaging cost, and enhance the image quality and patient-friendliness. METHODS: Two 18F-labeled MPI probes (18F-BoMPI) were developed. Detailed in vitro/vivo evaluation including photophysical properties, in vitro stability, myocardial cell uptake kinetics and mechanisms, cytotoxicity and IC50, biodistribution and plasma clearance curve were investigated. Resting and stressing myocardial perfusion PET imaging were performed in healthy and myocardial ischemic mice. RESULTS: 18F-BoMPI could be quickly labeled and easily postprocessed, and demonstrated excellent in vitro stability. Cell assays indicated that 18F-BoMPI exhibited mitochondria-targeting but potential-independent myocardial uptake. In vivo evaluation revealed the effective myocardial uptake and rapid background clearance. PET MPI confirmed effective probe accumulation in the healthy heart, but rapidly clearance in the background, making heart clearly delineated in the images. Ischemic myocardial could be clearly distinguished as the region of radioactivity sparsity in PET MPI. CONCLUSION: The 18F-labeled probes showed great potentials to reduce the practicability threshold of PET MPI.

Development of a Supermolecular Radionuclide-Drug Conjugate System for Integrated Radiotheranostics for Non-small Cell Lung Cancer.

Radionuclide-drug conjugates (RDCs) designed from small molecule or nanoplatform shows complementary characteristics. We constructed a new RDC system with integrated merits of small molecule and nanoplatform-based RDCs. Erlotinib was labeled with 131I to construct the bulk of RDC (131I-ER). Floxuridine was mixed with 131I-ER to develop a hydrogen bond-driving supermolecular RDC system (131I-ER-Fu NPs). The carrier-free 131I-ER-Fu NPs supermolecule not only demonstrated integrated merits of small molecule and nanoplatform-based RDC, including clear structure definition, stable quality control, prolonged circulation lifetime, enhanced tumor specificity and retention, and rapidly nontarget clearance, but also exhibited low biological toxicity and stronger antitumor effects. In vivo imaging also revealed its application for tumor localization of nonsmall cell lung cancer (NSCLC) and screening of patients suitable for epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. We considered that 131I-ER-Fu NPs showed potentials as an integrated platform for the radiotheranostics of NSCLC.

3DFRINet: A Framework for the Detection and Diagnosis of Fracture Related Infection in Low Extremities Based on 18F-FDG PET/CT 3D Images.

Fracture related infection (FRI) is one of the most devastating complications after fracture surgery in the lower extremities, which can lead to extremely high morbidity and medical costs. Therefore, early comprehensive evaluation and accurate diagnosis of patients are critical for appropriate treatment, prevention of complications, and good prognosis. 18Fluoro-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is one of the most commonly used medical imaging modalities for diagnosing FRI. With the development of deep learning, more neural networks have been proposed and become powerful computer-aided diagnosis tools in medical imaging. Therefore, a fully automated two-stage framework for FRI detection and diagnosis, 3DFRINet (Three Dimension FRI Network), is proposed for 18F-FDG PET/CT 3D imaging. The first stage can effectively extract and fuse the features of both modalities to accurately locate the lesion by the dual-branch design and attention module. The second stage reduces the dimensionality of the image by using the maximum intensity projection, which retains the effective features while reducing the computational effort and achieving excellent diagnostic performance. The diagnostic performance of lesions reached 91.55% accuracy, 0.9331 AUC, and 0.9250 F1 score. 3DFRINet has an advantage over six nuclear medicine experts in each classification metric. The statistical analysis shows that 3DFRINet is equivalent or superior to the primary nuclear medicine physicians and comparable to the senior nuclear medicine physicians. In conclusion, this study first proposed a method based on 18F-FDG PET/CT three-dimensional imaging for FRI location and diagnosis. This method shows superior lesion detection rate and diagnostic efficiency and therefore has good prospects for clinical application.

Repurposing homoharringtonine for thyroid cancer treatment through TIMP1/FAK/PI3K/AKT signaling pathway.

Homoharringtonine (HHT), an alkaloid isolated from Cephalotaxus, is an effective anti-leukemia agent and exhibits inhibitory effects in various solid tumors. However, the impacts of HHT treatment on thyroid cancer (TC) remain unclear. Our findings demonstrated that HHT exhibited remarkable anti-TC activity that involved inhibiting cell proliferation, invasion, and migration, as well as inducing apoptosis. Proteomics analysis revealed that the expression of the tissue inhibitor of metalloproteinase 1 (TIMP1) was downregulated in TC cells after HHT treatment. TIMP1 overexpression promoted TC progression and partially reversed the anti-TC effects of HHT, while TIMP1 downregulation inhibited TC progression and enhanced the anti-TC effects of HHT. Furthermore, TIMP1 re-expression attenuated the enhancement of anti-TC effects of HHT induced by TIMP1 knockdown. Mechanistically, HHT exerted anti-TC effects by downregulating TIMP1 expression and then inactivating the FAK/PI3K/AKT signaling pathway. Taken together, our study demonstrated that HHT could inhibit TC progression by inhibiting the TIMP1/FAK/PI3K/AKT signaling pathway.

Development of a NIR fluorescent probe for fluorescence-assisted EGFR-TKI applicable patients screening and drug resistance monitoring.

EGFR tyrosine kinase inhibitor exerts significant benefits to non-small cell lung cancer patient, but was also limited by the applicable patient screening and drug resistance. Here we presented with an EGFR-targeted and reactive oxygen species-responsive NIR probe (LX) to achieve both patient screening and drug resistance monitoring for EGFR-tyrosine kinase inhibitor. LX inherited EGFR selectivity and preference from EGFR-tyrosine kinase inhibitor, which only showed specificity to tumor with EGFR mutation. Meanwhile, the near-infrared fluorescence of LX was initially inhibited and could be turned on by intratumoral reactive oxygen species. When LX could bind to tumor EGFR, reactive oxygen species-responsive specific fluorescence was generated to indicate the applicability of tumors to EGFR-tyrosine kinase inhibitor. However, no specific LX fluorescence could be observed in inapplicable tumors due to the lack of specificity between tumor EGFR and LX. Meanwhile, when drug resistance was developed during treatments, obvious intratumoral reactive species oxygen decrease happened, which was also deemed as a significant signal of the drug resistance. By visualizing intratumoral reactive oxygen species fluctuation by responsive fluorescence, drug resistance could be monitored and reported.

A novel wavelet-transform-based convolution classification network for cervical lymph node metastasis of papillary thyroid carcinoma in ultrasound images.

Preoperative assessment of cervical lymph nodes metastasis (CLNM) for accurate qualitative and locating diagnosis is important for choosing the best treatment option for patients with papillary thyroid cancer. Non-destructive, non-invasive ultrasound is currently the imaging method of choice for lymph node metastatic assessment. For lymph node characteristics and ultrasound images, this paper proposes a multitasking network framework for diagnosing metastatic lymph nodes in ultrasound images, in which localization module not only provides information on the location of lymph nodes to focus on the peripheral and self regions of lymph nodes, but also provides structural features of lymph nodes for subsequent classification module. In the classification module, we design a novel wavelet-transform-based convolution network. Wavelet transform is introduced into the deep learning convolution module to analyze ultrasound images in both spatial and frequency domains, which effectively enriches the feature information and improves the classification performance of the model without increasing the model parameters. We collected 510 patient data (N = 1376) from Shanghai Sixth People's Hospital regarding ultrasound lymph nodes in the neck, as well as used three publicly available ultrasound datasets, including SCUI2020 (N = 2914), DDTI (N = 480), and BUSI (N = 780). Compared to the optimal two-stage model, our model has improved its accuracy and AUC indexes by 5.83% and 4%, which outperforms the two-stage architectures and also surpasses the latest classification networks.

Transiently impaired endothelial function during thyroid hormone withdrawal in differentiated thyroid cancer patients.

Purpose: Endothelial dysfunction, which was associated with chronic hypothyroidism, was an early event in atherosclerosis. Whether short-term hypothyroidism following thyroxine withdrawal during radioiodine (RAI) therapy was associated with endothelial dysfunction in patients with differentiated thyroid cancer (DTC) was unclear. Aim of the study was to assess whether short-term hypothyroidism could impair endothelial function and the accompanied metabolic changes in the whole process of RAI therapy. Methods: We recruited fifty-one patients who underwent total thyroidectomy surgery and would accept RAI therapy for DTC. We analyzed thyroid function, endothelial function and serum lipids levels of the patients at three time points: the day before thyroxine withdrawal(P1), the day before 131I administration(P2) and 4-6 weeks after RAI therapy(P3). A high-resolution ultrasound named flow-mediated dilation (FMD) was used to measure endothelial function of the patients. Results: We analyzed the changes of FMD, thyroid function and lipids at three time points. FMD(P2) decreased significantly compared to FMD(P1) (P1vsP2, 8.05 ± 1.55vs 7.26 ± 1.50, p<0.001). There was no significant difference between FMD(P3) and FMD(P1) after restoring TSH (thyroid stimulating hormone) suppression therapy (P1 vs P3, 8.05 ± 1.55 vs 7.79 ± 1.38, p=0.146). Among all parameters, the change of low-density lipoprotein (ΔLDL) was the only factor correlated negatively with the change of FMD (ΔFMD) throughout the RAI therapy process (P1-2, r=-0.326, p=0.020; P2-3, r=-0.306, p=0.029). Conclusion: Endothelial function was transiently impaired in DTC patients at short-term hypothyroidism state during the RAI therapy, and immediately returned to the initial state after restoring TSH suppression therapy.

Interleukin-6 promotes the dedifferentiation of papillary thyroid cancer cells.

Radioiodine treatment is a fundamental therapy for patients with papillary thyroid cancer (PTC). Sodium/iodide symporter (NIS)-mediated iodine uptake is a prerequisite for the efficacy of radioiodine therapy. Interleukin-6 (IL-6) is a pro-tumor cytokine, but its regulation of NIS expression in PTC has not been elucidated. In this study, we found that IL-6 enhanced the proliferation ability of PTC cells. Moreover, the negative association between IL-6 and NIS expression in thyroid cancer tissues was demonstrated. IL-6 downregulated thyroid-specific genes such as NIS, thyroid peroxidase, and thyroid-stimulating hormone receptor and thyroid-specific transcription factors including thyroid transcription factor-1 (TTF-1) and paired box protein-8 (PAX-8). The inhibitory effects of IL-6 on NIS expression were alleviated by mitogen-activated protein kinase and Janus kinase inhibitors. Depletion of c-Jun or STAT3 also rescued IL-6-induced NIS downregulation, with STAT3 depletion exerting a stronger effect. TTF-1 protein expression was also restored by depleting c-Jun or STAT3. STAT3 depletion, but not c-Jun depletion, alleviated the inhibitory effect of IL-6 on PAX-8 expression. Moreover, the downregulation of NIS by IL-6 was rescued by overexpressing TTF-1 and PAX-8. Tocilizumab, an IL-6 receptor blocker, did not have any cytostatic activity in PTC cells, and it also failed to induce redifferentiation in vitro. However, we found that the drug blocked the inhibitory effect of IL-6 on NIS expression. In summary, IL-6 inhibits NIS transcription in PTC cells by activating mitogen-activated protein kinase and Janus kinase signaling.

Predicting 18F-FDG SUVs of metastatic pulmonary nodes from CT images in patients with differentiated thyroid cancer by using a convolutional neural network.

Purpose: The aim of this study was to predict standard uptake values (SUVs) from computed tomography (CT) images of patients with lung metastases from differentiated thyroid cancer (DTC-LM). Methods: We proposed a novel SUVs prediction model using 18-layer Residual Network for generating SUVmax, SUVmean, SUVmin of metastatic pulmonary nodes from CT images of patients with DTC-LM. Nuclear medicine specialists outlined the metastatic pulmonary as primary set. The best model parameters were obtained after five-fold cross-validation on the training and validation set, further evaluated in independent test set. Mean absolute error (MAE), mean squared error (MSE), and mean relative error (MRE) were used to assess the performance of regression task. Specificity, sensitivity, F1 score, positive predictive value, negative predictive value and accuracy were used for classification task. The correlation between predicted and actual SUVs was analyzed. Results: A total of 3407 nodes from 74 patients with DTC-LM were collected in this study. On the independent test set, the average MAE, MSE and MRE was 0.3843, 1.0133, 0.3491 respectively, and the accuracy was 88.26%. Our proposed model achieved high metric scores (MAE=0.3843, MSE=1.0113, MRE=34.91%) compared with other backbones. The predicted SUVmax (R2 = 0.8987), SUVmean (R2 = 0.8346), SUVmin (R2 = 0.7373) were all significantly correlated with actual SUVs. Conclusion: The novel approach proposed in this study provides new ideas for the application of predicting SUVs for metastatic pulmonary nodes in DTC patients.

Clinical characteristics and long-term outcomes for parapharyngeal metastases of well-differentiated thyroid cancer during 131 I therapy and follow-up.

OBJECTIVE: Parapharyngeal metastases (PPM) are rarely observed in patients with well-differentiated thyroid cancer (WDTC). Radioiodine (131 I) therapy has been the main treatment for metastatic and recurrent DTC after thyroidectomy. This study was performed to evaluate the clinicopathological features and long-term outcomes associated with survival of patients with PPM at the end of follow-up. DESIGN: In total, 14,984 consecutive patients with DTC who underwent 131 I therapy after total or near-total thyroidectomy from 2004 to 2021 were retrospectively reviewed. Therapeutic efficacy was evaluated using the Response Evaluation Criteria in Solid Tumours v1.1 and logistic regression analysis. The disease status was determined using dynamic risk stratification. Disease-specific survival (DSS) was assessed using the Kaplan-Meier method and a Cox proportional hazards model. PATIENTS: Seventy-five patients with PPM from WDTC were enroled in this study. Their median age at the initial diagnosis of PPM was 40.2 ± 14.1 years, and the patients comprised 32 men and 43 women (male:female ratio, 1.00:1.34). Of the 75 patients, 43 (57.33%) presented with combined distant metastases. Fifty-seven (76.00%) patients had 131 I avidity and 18 had non-131 I avidity. At the end of follow-up, 22 (29.33%) patients showed progressive disease. Sixteen of the 75 patients died; of the remaining 59 patients, 6 (8.00%) had an excellent response, 6 (8.00%) had an indeterminate response, 10 (13.33%) had an biochemical incomplete response, and 37 (49.33%) had a structural incomplete response. Multivariate analysis confirmed that age at initial PPM diagnosis, the maximal size of PPM, and 131 I avidity had significant effects on progressive disease of PPM lesions (p = .03, p= .02, and p < .01, respectively). The 5- and 10-year DSS rates were 98.49% and 62.10%, respectively. Age of ≥55 years at initial diagnosis of PPM and the presence of concomitant distant metastasis were independently associated with a poor prognosis (p = .03 and p = .04, respectively). CONCLUSION: The therapeutic effect for PPM was closely associated with 131 I avidity, age at initial PPM diagnosis, and maximal size of PPM at the end of follow-up. Age of ≥55 years at initial diagnosis of PPM and the presence of concomitant distant metastasis were independently associated with poor survival.

TSH ≥30 mU/L may not be necessary for successful 131I remnant ablation in patients with differentiated thyroid cancer.

Purpose: To determine whether thyroid-stimulating hormone level ≥ 30 mU/L is necessary for radioiodine (131I) remnant ablation (RRA) in patients with differentiated thyroid cancer (DTC), as well as its influencing factors and predictors. Methods: A total of 487 DTC patients were retrospectively enrolled in this study. They were divided into two groups (TSH < 30 and ≥ 30 mU/L) and further divided into eight subgroups (0-<30, 30-<40, 40-<50, 50-<60, 60-<70, 70-<80, 80-<90, and 90-<100 mU/L). The simultaneous serum lipid level, successful rate of RRA and its influencing factors in different groups were analyzed. The receiver operating characteristic curves derived from pre-ablative thyroglobulin (pre-Tg) and pre-Tg/TSH ratio were compared for RRA success prediction performance. Results: There was no statistical difference in success rates of RRA between the two groups (P = 0.247) and eight subgroups (P = 0.685). Levels of total cholesterol (P < 0.001), triglyceride (P = 0.006), high-density lipoprotein cholesterol (P = 0.024), low-density lipoprotein cholesterol (P = 0.001), apolipoprotein B (P < 0.001), and apolipoprotein E (P = 0.002) were significantly higher while apoA/apoB ratio (P = 0.024) was significantly lower at TSH ≥ 30 mU/L group. Pre-Tg level, gender, and N stage were influencing factors for RRA. The area under the curve of pre-Tg level and pre-Tg/TSH ratio was 0.7611 (P < 0.0001) and 0.7340 (P < 0.0001) for all enrolled patients and 0.7310 (P = 0.0145) and 0.6524 (P = 0.1068) for TSH < 30 mU/L, respectively. Conclusion: TSH ≥ 30 mU/L may not be necessary for the success of RRA. Patients with higher serum TSH levels prior to RRA will suffer from severer hyperlipidemia. Pre-Tg level could be used as a predictor for the success of RRA, especially when TSH < 30 mU/L.

HIF-1α/YAP Signaling Rewrites Glucose/Iodine Metabolism Program to Promote Papillary Thyroid Cancer Progression.

Background: The management of aggressive and progressive metastatic papillary thyroid cancer (PTC) is very difficult. An inverse relationship between radioiodine and F-18 fluorodeoxyglucose (FDG) uptake (''flip-flop'' phenomenon) is described for invasive PTC during dedifferentiation. However, no satisfactory biologic explanation for this phenomenon. Hypoxia is an important microenvironmental factor that promotes cancer progression and glycolysis. The Hippo-YAP is a highly conserved tumor suppressor pathway and contributes to cancer metabolic reprogramming. Thus, we investigated the underlying molecular mechanisms of glucose/iodine metabolic reprogramming in PTC, focusing on the tumor hypoxia microenvironment and Hippo-YAP signaling. Methods: Immunohistochemistry staining was conducted to evaluate the expressions of hypoxia-inducible factor 1α (HIF-1α), yes-associated protein (YAP), glucose transporters 1 (GLUT1) and sodium iodine symporter (NIS) in matched PTC and the adjacent noncancerous tissues. PTC cell lines were cultured under normoxic (20% O2) and hypoxic (1% O2) conditions and the glycolysis level and NIS expression were measured. Further, we characterized the molecular mechanism of glucose/iodine metabolic reprogramming in PTC cell. Finally, we validated the results in vivo by establishing subcutaneous xenografts in nude mice. Results: The expression levels of HIF1-α, YAP and GLUT1 were upregulated in PTC tissues and YAP expression was positively associated with HIF-1α, GLUT1 and TNM stages. Meanwhile, the expression of NIS was negatively correlated with YAP. Further, in vitro studies indicated that hypoxia-induced YAP activation was critical for accelerating glycolysis and reducing NIS expression in PTC cells. Inhibition of YAP had the opposite effects in vitro and tumorigenicity in vivo. Hypoxia inhibited the Hippo signaling pathway resulting in the inactivation of YAP phosphorylation, further promoting the nuclear localization of YAP in PTC cells. The mechanism is that hypoxic stress promoted YAP binding to HIF-1α in the nucleus and maintained HIF-1α protein stability. The YAP/HIF-1α complex bound and directly activated the GLUT1 transcription to accelerate glycolysis. Meanwhile, HIF-1α/YAP signaling might indirectly reduce the expression of NIS by promoting the output of MAPK signaling. In vivo studies confirmed the YAP-mediated reprogramming of glucose/iodine metabolism promoted PTC progression. Conclusions: Collectively, our data revealed a novel regulatory mechanism of the glucose/iodine metabolic program rewritten by HIF-1α/YAP signaling in PTC. Inhibition of HIF-1α/YAP signaling alone or in combination with other potential markers may effectively combat aggressive PTC.

A Novel Model of Thyroid Nodule Segmentation for Ultrasound Images.

Ultrasonography is regarded as an effective technique for the detection, diagnosis and monitoring of thyroid nodules. Segmentation of thyroid nodules on ultrasound images is important in clinical practice. However, because in ultrasound images there is an unclear boundary between thyroid nodules and surrounding tissues, the accuracy of segmentation remains a challenge. Although the deep learning model provides an accurate and convenient method for thyroid nodule segmentation, it is unsatisfactory of the existing model in segmenting the margin of thyroid nodules. In this study, we developed boundary attention transformer net (BTNet), a novel segmentation network with a boundary attention mechanism combining the advantages of a convolutional neural network and transformer, which could fuse the features of both long and short ranges. Boundary attention is improved to focus on learning the boundary information, and this module enhances the segmentation ability of the network boundary. For features of different scales, we also incorporate a deep supervision mechanism to blend the outputs of different levels to enhance the segmentation effect. As the BTNet model incorporates the long range-short range connectivity effect and the boundary-regional cooperation capability, our model has excellent segmentation performance in thyroid nodule segmentation. The development of BTNet was based on the data set from Shanghai Jiao Tong University School of Medicine Affiliated Sixth People's Hospital and the public data set. BTNet achieved good performance in the segmentation of thyroid nodules with an intersection-over-union of 0.810 and Dice coefficient of 0.892 Moreover, our work revealed great improvement in the boundary metrics; for example, the boundary distance was 7.308, the boundary overlap 0.201 and the boundary Dice 0.194, all with p values <0.05.

Automated classification of cervical lymph-node-level from ultrasound using Depthwise Separable Convolutional Swin Transformer.

There are few studies on cervical ultrasound lymph-node-level classification which is very important for qualitative diagnosis and surgical treatment of diseases. Currently, ultrasound examination relies on the subjective experience of physicians to judge the level of the cervical lymph nodes, which is easily misclassified. Unlike other automated diagnostic tasks, lymph-node-level classification needs to focus on global structural information. Besides, there is a large range of sternocleidomastoid muscles in levels II, III and IV, which leads to small inter-class differences in these levels, so it also needs to focus on key local areas to extract strong distinguishable features. In this paper, we propose the Depthwise Separable Convolutional Swin Transformer, introducing the deepwise separable convolution branch into the self-attention mechanism to capture discriminative local features. Meanwhile, to address the problem of data imbalance, a new loss function is proposed to improve the performance of the classification network. In addition, for the ultrasound data collected by different devices, low contrast and blurring problems of ultrasound imaging, a unified pre-processing algorithm is designed. The model was validated on 1146 cases of cervical ultrasound lymph node collected from the Sixth People's Hospital of Shanghai. The average accuracy precision, sensitivity, specificity, and F1 value of the model for the valid dataset after five-fold cross-validation were 80.65%, 80.68%, 78.73%, 95.99% and 79.42%, respectively. It has been verified by visualization methods that the Region of Interest (ROI) of the model is similar or consistent with the observed region of the experts.

Change in Antithyroglobulin Antibody Levels is a Good Predictor of Responses to Therapy in Antithyroglobulin Antibody-Positive Pediatric Papillary Thyroid Carcinoma Patients.

Objective: Antithyroglobulin antibodies (TgAbs) could be used as a surrogate tumor marker of TgAb-positive-differentiated thyroid carcinoma. This study aims to determine whether the change in TgAb levels over time could be used as a predictor of responses to therapy in pediatric papillary thyroid carcinoma (PTC) patients. Methods: We retrospectively analyzed the records of 48 pediatric PTC patients with TgAb levels ≥50 IU/ml 6 months after initial 131I treatment. Suppressed thyroglobulin (Tg) levels 6 months after initial 131I treatment were used to divide the patients into positive Tg (P-Tg, Tg ≥ 0.2 ng/ml) and negative Tg (N-Tg, Tg < 0.2 ng/ml) groups. Responses to therapy were classified as the acceptable response (AR) group and the not acceptable response (NAR) group. Results: Of 48 enrolled patients with 58 months (range, 24-143 months) of follow-up, 28 patients had NAR and 20 patients had AR. TgAb levels were decreasing ≥50% in 28 patients, decreasing <50% in 8 patients, and increasing in 12 patients. Multivariate analysis showed that high initial risk stratification and TgAb levels decreasing <50% or increasing were significantly associated with NAR (p < 0.05). Changes in Tg levels were also associated with NAR in the P-Tg group (p < 0.05). Conclusion: Changes in TgAb levels over time could be used as a predictor of responses to therapy in TgAb-positive pediatric PTC patients. Changes in Tg levels over time are also associated with NAR to therapy in both TgAb-positive and Tg-positive pediatric PTC patients.

AUE-Net: Automated Generation of Ultrasound Elastography Using Generative Adversarial Network.

PROBLEM: Ultrasonography is recommended as the first choice for evaluation of thyroid nodules, however, conventional ultrasound features may not be able to adequately predict malignancy. Ultrasound elastography, adjunct to conventional B-mode ultrasound, can effectively improve the diagnostic accuracy of thyroid nodules. However, this technology requires professional elastography equipment and experienced physicians. AIM: in the field of computational medicine, Generative Adversarial Networks (GANs) were proven to be a powerful tool for generating high-quality images. This work therefore utilizes GANs to generate ultrasound elastography images. METHODS: this paper proposes a new automated generation method of ultrasound elastography (AUE-net) to generate elastography images from conventional ultrasound images. The AUE-net was based on the U-Net architecture and optimized by attention modules and feature residual blocks, which could improve the adaptability of feature extraction for nodules of different sizes. The additional color loss function was used to balance color distribution. In this network, we first attempted to extract the tissue features of the ultrasound image in the latent space, then converted the attributes by modeling the strain, and finally reconstructed them into the corresponding elastography image. RESULTS: a total of 726 thyroid ultrasound elastography images with corresponding conventional images from 397 patients were obtained between 2019 and 2021 as the dataset (646 in training set and 80 in testing set). The mean rating accuracy of the AUE-net generated elastography images by ultrasound specialists was 84.38%. Compared with that of the existing models in the visual aspect, the presented model generated relatively higher quality elastography images. CONCLUSION: the AUE-net generated ultrasound elastography images showed natural appearance and retained tissue information. Accordingly, it seems that B-mode ultrasound harbors information that can link to tissue elasticity. This study may pave the way to generate ultrasound elastography images readily without the need for professional equipment.

Unexpected Retrosternal Goiter Interpreted as Hyperfunctioning Metastasis on the Posttherapeutic 131I SPECT/CT.

ABSTRACT: We present a 38-year-old man who underwent total thyroidectomy with radical right neck dissection due to papillary thyroid cancer was referred for 131I treatment. The patient was in subclinical hypothyroidism with remarkable stimulated Tg level after 4 weeks of l-thyroxine withdrawal before 131I treatment, which indicated hyperfunctioning metastasis. Posttherapeutic 131I whole-body scan combined with 131I SPECT/CT performed on day 3 after 131I administration revealed an elevated 131I uptake mass in cervicothoracic region. To our surprise, the mass was histologically confirmed to be a retrosternal goiter.

Pregnancy Does not Affect the Prognoses of Differentiated Thyroid Cancer Patients With Lung Metastases.

CONTEXT: Pregnancy-related hormones may stimulate thyroid cancer growth, but whether pregnancy affects the prognoses of patients with lung metastases from differentiated thyroid cancer (DTC-LM) after surgery and radioiodine therapy is unclear. OBJECTIVE: To assess the impact of pregnancy on DTC-LM through the comparison of prognoses between female patients with DTC-LM who did and did not become pregnant after surgery and radioiodine therapy. METHODS: We retrospectively analyzed the records of 124 female patients aged 16 to 35 years who underwent surgery and radioiodine therapy for DTC-LM. These patients were divided into pregnancy group (n = 37) and nonpregnancy group (n = 87) according to whether they became pregnant after surgery and radioiodine therapy, regardless of whether they had a pregnant history before treatment. RESULTS: The 5- and 10-year progression-free survival rates were 94.52% and 63.22% in pregnancy group versus 89.82% and 58.13% in nonpregnancy group. The 5- and 10-year cumulative overall survival rates of pregnancy group were 97.30% and 85.77% versus 93.50% and 81.95% in nonpregnancy group (all P > 0.05). The median time of follow-up in the pregnancy and nonpregnancy groups was 82 months (25-136 months) and 68 months (13-133 months), respectively. Non-radioiodine-avid LM and primary tumors needing repeated resection were independent predictors of poor progression-free survival for patients in pregnancy group. CONCLUSION: Pregnancy does not affect the prognoses of patients with DTC-LM after surgery and radioiodine therapy. Non-radioiodine-avid LM and repeated primary tumor surgeries are independent risk factors for poor prognoses of pregnant patients.

HIF-1α-Mediated Telomerase Reverse Transcriptase Activation Inducing Autophagy Through Mammalian Target of Rapamycin Promotes Papillary Thyroid Carcinoma Progression During Hypoxia Stress.

Background: It is important to properly understand the molecular mechanisms of aggressive tumors among papillary thyroid carcinomas (PTCs) that are often the most indolent. Hypoxia inducible factor-1α (HIF-1α), induced by hypoxia, plays pivotal roles in the development and metastasis of the many tumors, including PTCs. Upregulation of telomerase reverse transcriptase (TERT) activity is found in highly invasive PTCs. Further, previous studies have reported that autophagy serves as a protective mechanism to facilitate PTC cell survival. We, therefore, hypothesized that there was a link between HIF-1α, TERT, and autophagy in promoting PTC progression. Methods: Immunohistochemistry staining was conducted to evaluate the expressions of HIF-1α, TERT, and autophagy marker, LC3-II, in matched PTC tumors and corresponding nontumor tissues. Two PTC cell lines (TPC-1 and BCPAP) were used in subsequent cytological function studies. Cell viability, proliferation, apoptosis, migration, and invasion were assessed during hypoxia, genetic enhancement and inhibition of TERT, and chemical and genetic inhibition of autophagy. The protein expression levels of the corresponding biomarkers were determined by Western blotting, and autophagy flow was detected. We characterized the molecular mechanism of PTC cell progression. Results: The protein expression levels of HIF-1α, TERT, and LC3-II were upregulated in PTCs and were significantly correlated with high tumor-node-metastasis stage. Further, an in vitro study indicated that HIF-1α induced by hypoxia functioned as a transcriptional activator by binding with sequences potentially located in the TERT promoter and was positively correlated with the malignant behavior of PTC cell lines. Overexpression of TERT inhibited the kinase activity of mammalian target of rapamycin (mTOR), resulting in the activation of autophagy. Functionally, TERT-induced autophagy provided a survival advantage to PTC cells during hypoxia stress. Conclusions: We identified a novel molecular mechanism involving the HIF-1α/TERT axis, which promoted PTC progression by inducing autophagy through mTOR during hypoxia stress. These findings may provide a basis for the new treatment of aggressive PTCs.

Interleukin 6 regulates the expression of programmed cell death ligand 1 in thyroid cancer.

Programmed cell death ligand 1 (PD-L1), inducing T cell exhaustion to facilitate immune escape of tumor cells, is upregulated by interleukin 6 (IL-6) in T cell lymphoma and ovarian cancer. The purpose of this study is to investigate the expression of IL-6 and PD-L1 in thyroid cancer, and whether IL-6 regulates PD-L1 expression. As a result, IL-6 and PD-L1 were highly expressed in thyroid cancer tissues. Multivariate logistic analysis showed that tumor size, distant metastasis, and risk stratification were significantly associated with IL-6 expression (P < .05), and multifocality, lymph node metastasis, distant metastasis, risk stratification, and IL-6 expression were identified as the independent predictors of PD-L1 expression (P < .05). The invasiveness of thyroid cancer was significantly enhanced after IL-6 treatment or PD-L1 overexpression. PD-L1 positive rate correlated with IL-6 expression in cancer tissues (P < .001), and after IL-6 treatment, the PD-L1 expression in TPC-1 and BCPAP significantly increased. The mitogen-activated protein kinase pathway (MAPK) and the Janus-activated kinase (JAK)-signal transducers and activators of transcription 3 (STAT3) signaling pathways were activated by IL-6, and the IL-6-induced PD-L1 expression decreased after treatment with these two signaling pathway inhibitors. Knockdown of transcription factors c-Jun and stat3 suppressed the expression of PD-L1 induced by IL-6, and these two factors could bind to PD-L1 gene promoter directly and promote its transcription. It is concluded that IL-6 and PD-L1 are overexpressed in thyroid cancer and are related to tumor invasiveness. IL-6 upregulates PD-L1 expression through the MAPK and JAK-STAT3 signaling pathways, which function via transcription factors c-Jun and stat3.