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.

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.

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.

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.

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.

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.

Interleukins in Thyroid Cancer: From Basic Researches to Applications in Clinical Practice.

Inflammation is crucial to tumorigenesis and progression of many cancers. Inflammatory molecules in tumor microenvironment exert pro- or anti-tumor effects. Among them, interleukin, mainly produced by CD3+ and CD4+ T lymphocytes, is a class of small molecule proteins which play an important role in intercellular communication. Numerous studies have confirmed that interleukins are closely related to thyroid cancer. Interleukins regulate the proliferation and migration of thyroid cancer cells and they have prospects in discriminating benign and malignant thyroid diseases, predicting the risk of tumorigenesis, evaluating the prognosis and monitoring the recurrence of thyroid cancer. Besides, the effective application of interleukins in treatment of thyroid cancer has been confirmed by some cell and animal researches. The present review will introduce the potential mechanisms of interleukins in thyroid cancer and focus on the applications of interleukins in clinical practice of thyroid cancer, which will help update understanding of the progress of interleukins researches in thyroid cancer.

High Expression of Interleukin-12A and Its Association with the Clinicopathology and Prognosis of Differentiated Thyroid Cancer.

BACKGROUND: The inflammatory microenvironment is closely related to the occurrence and development of cancer. Members of the interleukin-12 (IL-12) cytokine family play synergistic or antagonistic roles in the tumor microenvironment, in the form of classic heterodimers or newly discovered monomers or homodimers. OBJECTIVE: The purpose of this study was to investigate the association between IL-12A and the clinicopathology and prognosis of differentiated thyroid cancer (DTC). METHODS: A total of 101 pathologically confirmed DTC patients were included in this study. Immunohistochemistry was performed to assess IL-12A expression in DTC and corresponding paracancerous tissues. The associations of IL-12A with clinicopathology and prognosis were evaluated. RESULTS: IL-12A was expressed in both normal thyroid tissues and DTC, but its expression level was significantly higher in DTC than in normal thyroid tissues (p < 0.001). IL-12A was positively correlated with tumor size (p = 0.027), risk stratification (p = 0.020), and TNM (Tumor-Node-Metastasis) stage (p = 0.024), but not with age, sex, pathological type, multifocality, extrathyroid extension, lymph node metastasis, and distant metastasis (all p > 0.05). Lymphocytic thyroiditis was found in 26/101 patients (25.7%), which was negatively associated with IL-12A expression (p = 0.018). Multivariate logistic regression analysis showed that risk stratification was the significant independent predictor of IL-12A expression. The rate of disease persistence or recurrence (P&R) was 13/101 (12.9%), and a positive relationship was found between IL-12A expression and P&R (p = 0.020). Disease-free survival was affected by factors such as tumor size, extrathyroid extension, tumor stage (T stage), and IL-12A expression, with p values of 0.006, 0.048, 0.002, and 0.012, respectively. Multivariate Cox proportional-hazards analysis showed that tumor size ≥2 cm (hazard ratio [HR] = 4.041 [95% CI: 1.144-14.274], p = 0.031) and high IL-12A expression (HR = 4.027 [95% CI 1.014-15.994], p = 0.049) were independent predictors of prognosis of DTC patients. CONCLUSIONS: IL-12A is highly expressed in DTC and is associated with disease aggressiveness. In addition, IL-12A is an independent predictor of the outcome of DTC.

ImmunoPET: Concept, Design, and Applications.

Immuno-positron emission tomography (immunoPET) is a paradigm-shifting molecular imaging modality combining the superior targeting specificity of monoclonal antibody (mAb) and the inherent sensitivity of PET technique. A variety of radionuclides and mAbs have been exploited to develop immunoPET probes, which has been driven by the development and optimization of radiochemistry and conjugation strategies. In addition, tumor-targeting vectors with a short circulation time (e.g., Nanobody) or with an enhanced binding affinity (e.g., bispecific antibody) are being used to design novel immunoPET probes. Accordingly, several immunoPET probes, such as 89Zr-Df-pertuzumab and 89Zr-atezolizumab, have been successfully translated for clinical use. By noninvasively and dynamically revealing the expression of heterogeneous tumor antigens, immunoPET imaging is gradually changing the theranostic landscape of several types of malignancies. ImmunoPET is the method of choice for imaging specific tumor markers, immune cells, immune checkpoints, and inflammatory processes. Furthermore, the integration of immunoPET imaging in antibody drug development is of substantial significance because it provides pivotal information regarding antibody targeting abilities and distribution profiles. Herein, we present the latest immunoPET imaging strategies and their preclinical and clinical applications. We also emphasize current conjugation strategies that can be leveraged to develop next-generation immunoPET probes. Lastly, we discuss practical considerations to tune the development and translation of immunoPET imaging strategies.

Distant metastases from pathologically proven benign follicular nodules of the thyroid: clinicopathological features and predictors of long-term survival.

OBJECTIVE: Distant metastases are rarely observed in patients with initial pathologically proven benign follicular nodules of the thyroid. This study aimed to evaluate the clinicopathological features and independent variables associated with survival in such patients with distant metastases. METHODS: In total, 10,992 consecutive differentiated thyroid cancer (DTC) patients treated with 131I after total or near-total thyroidectomy from 2000 to 2018 were retrospectively reviewed. RESULTS: Thirty-nine patients with initial pathologically proven benign follicular nodules of the thyroid were enrolled. Among them, 26 were pathologically diagnosed as thyroid adenoma, 8 as benign nodular goiter, 4 as thyroid adenoma combined with benign nodular goiter, and 1 as normal thyroid tissue. Of 26 patients with the initial pathological slides obtained, eight cases were rediagnosed as minimally invasive thyroid carcinoma (MI-FTC), 10 as follicular tumor of uncertain malignant potential (FT-UMP), and five as well-differentiated tumor of UMP (WDT-UMP). Monitoring of thyroglobulin (Tg) changes after initial thyroidectomy and preablation-stimulated Tg (psTg) level were significantly associated with 5-year OS rate (P = 0.007 and P = 0.005, respectively). The presence of radioactive-refractory DTC (RR-DTC), monitoring of Tg changes after initial thyroidectomy, and psTg level had significant effects on 10-year OS rate (P = 0.002, P < 0.001, and P = 0.005, respectively). Lack of monitoring of Tg changes after initial thyroidectomy and RR-DTC were independent factors associated with poor prognosis (P = 0.003 and P = 0.008, respectively). CONCLUSIONS: MI-FTC, FT-UMP, and WDT-UMP tended to be ignored and/or misdiagnosed as benign follicular lesions. Lack of monitoring of Tg changes after initial thyroidectomy and the presence of RR-DTC were identified as independent factors associated with poor survival.

Long-Term Outcomes and Prognoses of Elderly Patients (≥65-Years-Old) With Distant Metastases From Well-Differentiated Thyroid Cancer During Radioiodine Therapy and Follow-Up.

Objective: The objective of this study was to investigate the clinicopathological characteristics, long-term outcomes, and prognostic factors of elderly patients with distant metastases at initial diagnosis from well-differentiated thyroid cancer (WDTC) during radioactive iodine (131I) treatment and follow-up. Methods: A retrospective review of medical records identified 183 elderly patients with DTC who underwent 131I treatment at our institution between 2006 and 2019. Results: In total, 57 elderly WDTC patients with distant metastases were enrolled in this study. After 131I treatment, 32 (56.14%) patients had 131I avidity and 25 (43.86%) had non-131I avidity; 35 (61.40%) cases were classified as radioiodine refractory (RR)-WDTC and 22 (38.60%) as non-RR-WDTC. At the end of follow-up, 25 (43.86%) patients had died and 32 (56.14%) were alive. The 5- and 10-year overall survival (OS) rates were 71.50% and 30.49%, respectively, while the 5- and 10-year disease-specific survival (DSS) rates were 76.89% and 48.71%, respectively. Multivariate analyses showed that gross extrathyroidal extension and RR-DTC were independent prognostic factors for poor OS (P=0.04 and P=0.03, respectively), while gross extrathyroidal extension, extrapulmonary distant metastases, and RR-WDTC were independent prognostic factors for poor DSS at the end of follow-up (P=0.02, P=0.03, and P=0.02, respectively). Conclusions: WDTC with distant metastases at initial diagnosis accounted for 31.15% of all elderly patients with DTC. Gross extrathyroidal extension and RR-DTC were the major factors associated with poor OS; gross extrathyroidal extension, extrapulmonary distant metastases, and RR-DTC were independent prognostic factors for poor DSS in elderly DTC patients with distant metastases.

Molecular imaging of ß-cells: diabetes and beyond.

Since diabetes is becoming a global epidemic, there is a great need to develop early ß-cell specific diagnostic techniques for this disorder. There are two types of diabetes (i.e., type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM)). In T1DM, the destruction of pancreatic ß-cells leads to reduced insulin production or even absolute insulin deficiency, which consequently results in hyperglycemia. Actually, a central issue in the pathophysiology of all types of diabetes is the relative reduction of ß-cell mass (BCM) and/or impairment of the function of individual ß-cells. In the past two decades, scientists have been trying to develop imaging techniques for noninvasive measurement of the viability and mass of pancreatic ß-cells. Despite intense scientific efforts, only two tracers for positron emission tomography (PET) and one contrast agent for magnetic resonance (MR) imaging are currently under clinical evaluation. ß-cell specific imaging probes may also allow us to precisely and specifically visualize transplanted ß-cells and to improve transplantation outcomes, as transplantation of pancreatic islets has shown promise in treating T1DM. In addition, some of these probes can be applied to the preoperative detection of hidden insulinomas as well. In the present review, we primarily summarize potential tracers under development for imaging ß-cells with a focus on tracers for PET, SPECT, MRI, and optical imaging. We will discuss the advantages and limitations of the various imaging probes and extend an outlook on future developments in the field.

Clinical outcomes and prognostic factors in patients with no less than three distant organ system metastases from differentiated thyroid carcinoma.

OBJECTIVES: For patients with differentiated thyroid carcinoma (DTC), distant metastases are commonly identified in the lungs and bones. However, they are relatively rare in other distant organs, such as the liver, kidneys, or brain. The aim of the current study was to describe the clinical outcomes and evaluate the prognostic factors of patients with no less than three different distant organ system metastases from DTC. METHODS: This study retrospectively identified 717 patients diagnosed with DTC with distant metastases between January 2005 and December 2017. Patient response to radioactive iodine (RAI) therapy was monitored by changes in serum thyroglobulin levels and imaging changes. Five-year and 10-year overall survival (OS) rates were calculated by the Kaplan-Meier methods and Cox proportional hazards. RESULTS: Among the 717 participants, 37 (5.16%) patients had no less than three different distant organ system metastases from DTC. Five-year and 10-year OS were 45.9% and 37.8% in patients with three or more distant organ system metastases while 74.5% and 64.9% in individuals with one or two distant organ system metastases, respectively. RAI avidity and RAIR-DTC were main independent prognostic factors influencing the clinical outcomes for both groups of patients. The presence of 3 or more different distant organ system metastases was the only independent prognostic factors for 10-year OS by multivariate analysis. CONCLUSIONS: Patients with no less than three distant organ system metastases from DTC had poor prognosis. RAI avidity and RAIR-DTC were main factors influencing overall survival for patients with distant metastases from DTC in both groups.

Exploiting Nanomaterial-mediated Autophagy for Cancer Therapy.

Autophagy is a conserved process that is critical for sequestering and degrading proteins, damaged or aged organelles, and for maintaining cellular homeostasis under stress conditions. Despite its dichotomous role in health and diseases, autophagy usually promotes growth and progression of advanced cancers. In this context, clinical trials using chloroquine and hydroxychloroquine as autophagy inhibitors have suggested that autophagy inhibition is a promising approach for treating advanced malignancies and/or overcoming drug resistance of small molecule therapeutics (i.e., chemotherapy and molecularly targeted therapy). Efficient delivery of autophagy inhibitors may further enhance the therapeutic effect, reduce systemic toxicity, and prevent drug resistance. As such, nanocarriers-based drug delivery systems have several distinct advantages over free autophagy inhibitors that include increased circulation of the drugs, reduced off-target systemic toxicity, increased drug delivery efficiency, and increased solubility and stability of the encapsulated drugs. With their versatile drug encapsulation and surface-functionalization capabilities, nanocarriers can be engineered to deliver autophagy inhibitors to tumor sites in a context-specific and/or tissue-specific manner. This review focuses on the role of nanomaterials utilizing autophagy inhibitors for cancer therapy, with a focus on their applications in different cancer types.

CD146-Targeted Multimodal Image-Guided Photoimmunotherapy of Melanoma.

For melanoma resistant to molecularly targeted therapy and immunotherapy, new treatment strategies are urgently needed. A molecularly targeted theranostic pair may thus be of importance, where the diagnostic probe facilitates patient stratification and the therapeutic companion treats the selected cases. For this purpose, flow cytometry is used to assess the CD146 level in melanoma cells. Based on YY146, a CD146-specific monoclonal antibody, an imaging probe 89Zr-Df-YY146 is synthesized and its diagnostic performance is evaluated by positron emission tomography (PET) imaging. Furthermore, a photoimmunotherapy (PIT) agent IR700-YY146 is developed and the therapeutic effect of IR700-YY146 PIT is assessed comprehensively. CD146 is highly expressed in A375 and SK-MEL-5 cells. 89Zr-Df-YY146 PET readily detects CD146-positive A375 melanomas. Tumor accumulation of 89Zr-Df-YY146 peaks at 72 h with an uptake value of 26.48 ± 3.28%ID g-1, whereas the highest uptake of the nonspecific 89Zr-Df-IgG is 4.80 ± 1.75%ID g-1. More importantly, IR700-YY146 PIT effectively inhibits the growth of A375 tumors, owing to production of reactive oxygen species, decreased glucose metabolism, and reduced expression of CD146. To conclude, 89Zr-Df-YY146 and IR700-YY146 are a promising theranostic pair with the former revealing CD146 expression in melanoma as a PET probe and the latter specifically treating CD146-positive melanoma as an effective PIT agent.

Can pretreatment 18F-FDG PET tumor texture features predict the outcomes of osteosarcoma treated by neoadjuvant chemotherapy?

PURPOSE: To investigate whether tumor texture features derived from pretreatment with 18F-fluorodeoxyglucose positron emission tomography (FDG PET) can predict histological response or event-free survival (EFS) in patients with localized osteosarcoma of the extremities treated by neoadjuvant chemotherapy (NAC). METHODS: We retrospectively reviewed 35 patients with American Joint Committee on Cancer stage II extremity osteosarcoma treated with NAC and surgery. Primary tumor traditional parameters and texture features were measured for all 18F-FDG PET images prior to treatment. After surgery, histological responses to NAC were evaluated on the postsurgical specimens. A receiver operating characteristic curve (ROC) was constructed to evaluate the optimal predictive performance among the various indices. EFS was calculated using the Kaplan-Meier method and prognostic significance was assessed by Cox proportional hazards analysis. RESULTS: Pathologic examination revealed 16 (45.71%) good responders and 19 (54.29%) poor responders. Although both the texture features (least axis, dependence nonuniformity, run length nonuniformity, and size zone nonuniformity) and metabolic tumor volume (MTV) can predict tumor response of osteosarcoma to NAC, the traditional indicator MTV has the best performance according to ROC curve analysis (area under the curve = 0.918, p < 0.0001). In multivariate analysis, MTV (p < 0.0001), histological response (p = 0.0003), and texture feature of coarsenessNGTDM (neighboring gray tone difference matrix) (p = 0.005) were independently associated with EFS. CONCLUSIONS: Intratumoral heterogeneity of baseline 18F-FDG uptake measured by PET texture analysis can predict tumor response and EFS of patients with extremity osteosarcoma treated by NAC, but the conventional parameter MTV provides better predictive power and is a strong independent prognostic factor. KEY POINTS: • The baseline 18 F-FDG PET tumor texture features can predict tumor NAC response for patients with osteosarcoma. • Coarseness NGTDM is a new and independent prognostic factor for osteosarcoma. • MTV provides the best predictive power and is a strong independent prognostic factor for patients with osteosarcoma.

Targeted next-generation sequencing in papillary thyroid carcinoma patients looking for germline variants predisposing to the disease.

PURPOSESS: The purpose of this study was using next-generation sequencing technique to explore the potential association between germline variants of 14 targeted genes and papillary thyroid carcinoma (PTC) predisposition as well as disease progression. METHODS: In all, 516 subjects were enrolled in this study including 416 PTC patients and 100 healthy controls. PTC patients were divided into distant metastasis group and non-distant metastasis group. Patients in distant metastasis group were further divided into radioiodine-refractory PTC (RR-PTC) and non-RR-PTC depending on their response to radioiodine therapy. Genomic DNA was extracted from peripheral blood sample and MiSeq Benchtop Sequencer was used for sequencing. RESULTS: We found rs11246050 in NLRP6 (dominant model, OR/95% CI: 2.028/1.091-3.769, p = 0.025), rs2286742 and rs3740530 in HABP2 (recessive model, OR/95% CI: 9.644/1.307-71.16, p = 0.026 and 3.989/1.413-11.26, p = 0.009), rs2736098 in TERT (recessive model, OR/95% CI: 2.322/1.028-5.242. p = 0.042) and rs62054619 in GAS8-AS1 (recessive model, OR/95% CI: 2.219/1.067-4.617, p = 0.033) were associated with the risk of PTC. rs1137282 in KRAS (dominant model, OR/95% CI: 0.5430/0.3192-0.9236, p = 0.024), rs1347591 and rs4461062 in NUP93 (dominant model, OR/95% CI: 0.6121/0.4128-0.9076, p = 0.015 and 0.6156/0.4157-0.9117, p = 0.015) were associated with low risk of distant metastatic disease in PTC patients. rs33954691 in TERT was associated with the risk of RR-PTC under dominant model (OR/95% CI: 3.161/1.596-6.262). CONCLUSIONS: Germline variants of related genes could be associated with the susceptibility of PTC as well as disease progression (distant metastasis and radioiodine-refractory status). However, these results must be further verified and the potential biological functions of these germline variants in the pathogenesis of PTC remain to be determined in future studies.

A Preliminary Study of Ankle Single Photon Emission Computed Tomography/Computed Tomography in Patients With Bony Impingement Syndrome: Association With the Visual Analogue Scale Pain Score.

Both osteoarthritis and impingement syndrome are the disorders commonly observed in sports medicine. However, failure in pain alleviation by surgical intervention introduces challenges in the diagnosis and decision-making for orthopedists. Hybrid single photon emission computed tomography/computed tomography (SPECT/CT) provides both functional and structural information of ankle pathology. The purpose of this retrospective study was to evaluate whether bone tracer uptake by ankle SPECT/CT is related to the lesion type and visual analog scale (VAS) pain score for patients with osteoarthritis and bony impingement. Fifty individuals with chronic ankle pain who underwent pretreatment ankle SPECT/CT were included in the current study. The median follow-up period was 2.5 (range 1.8 to 3.2) years. The lesion types were categorized by the positions of anatomical changes and bone tracer uptake. The VAS pain score was recorded 2 weeks before and 1.5 year after surgical intervention. Twenty-nine (58%) of 50 patients had osseous impingement. Among them, 16 (55.2%), 4 (13.8%), and 9 (31%) patients had anterior, posterior, and both types of ankle impingement, respectively. The uptake grade of bone tracer was significantly related to the lesion type of ankle impingement (p < .001). The VAS pain score was significantly correlated with bone tracer uptake before treatment (p < .001). Bone tracer uptake was related to the lesion type of impingement detected by SPECT/CT and was confirmed by surgical findings. The VAS pain score was significantly correlated with the bone tracer uptake. Preoperative ankle SPECT/CT may be helpful to clinically correlate the VAS pain score in the pre- and postsurgical periods for patients with osteoarthritis and bony impingement syndrome.