Novel and Advanced Ultrasound Techniques for Thyroid Thermal Ablation.

Thyroid radiofrequency ablation and microwave ablation are widely adopted minimally invasive treatments for diverse thyroid conditions worldwide. Fundamental skills such as the trans-isthmic approach and the moving shot technique are crucial for performing thyroid ablation, and advanced techniques, including hydrodissection and vascular ablation, improve safety and efficacy and reduce complications. Given the learning curve associated with ultrasound-guided therapeutic procedures, operators need training and experience. While training models exist, limited attention has been given to ultrasound maneuvers in ablation needle manipulation. This article introduces two essential maneuvers, the zigzag moving technique and the alienate maneuver, while also reviewing the latest ultrasound techniques in thyroid ablation, contributing valuable insights into this evolving field.

Therapeutic inhibition of ATR in differentiated thyroid cancer.

Ataxia telangiectasia and Rad3-related protein (ATR) is a critical component of the DNA damage response and a potential target in the treatment of cancers. An ATR inhibitor, BAY 1895344, was evaluated for its use in differentiated thyroid cancer (DTC) therapy. BAY 1895344 inhibited cell viability in four DTC cell lines (TPC1, K1, FTC-133, and FTC-238) in a dose-dependent manner. BAY 1895344 treatment arrested DTC cells in the G2/M phase, increased caspase-3 activity, and caused apoptosis. BAY 1895344 in combination with either sorafenib or lenvatinib showed mainly synergistic effects in four DTC cell lines. The combination of BAY 1895344 with dabrafenib plus trametinib revealed synergistic effects in K1 cells that harbor BRAFV600E. BAY 1895344 monotherapy retarded the growth of K1 and FTC-133 tumors in xenograft models. The combinations of BAY 1895344 plus lenvatinib and BAY 1895344 with dabrafenib plus trametinib were more effective than any single therapy in a K1 xenograft model. No appreciable toxicity appeared in animals treated with either a single therapy or a combination treatment. Our findings provide the rationale for the development of clinical trials of BAY 1895344 in the treatment of DTC.

Outcomes of Patients With Metastatic Differentiated Thyroid Cancer After Excellent Response to Treatment.

Background: To evaluate the outcomes in differentiated thyroid cancer (DTC) patients who achieved excellent response to initial treatment and developed distant metastasis during follow-up. Methods: Thyroid cancer patients registered in Chang Gung Memorial Hospital thyroid cancer database between January 1979 and December 2019 were assessed. Results: Among 1053 DTC patients with excellent response to initial therapy, 14 (1.3%) patients developed metastatic disease during follow-up, including 6 males and 8 females with median age of 50.2 years [interquartile range (IQR), 39.9-53.7]. Nine (64.3%) patients had papillary cancer, four (28.6%) had follicular cancer, and one (7.1%) had Hürthle cell cancer. Most patients (92.9%) had stage I disease at diagnosis. The sites of metastasis were lung (71.4%), bone (7.1%), mediastinum (7.1%) and multiple sites (14.3%). With a median follow-up of 18.3 years (IQR, 14.8-23.8), 2 patients had disease-specific mortality. The 5- and 10-year disease-specific survival after the diagnosis of distant metastasis was 92% and 74%, respectively. Multiple sites of metastasis was associated with increased risk of mortality (P = 0.022). Conclusions: A small proportion of DTC patients with an excellence response to initial therapy developed distant metastasis during follow-up. Multiple organ distant metastases conferred a worse disease-specific survival.

Risk Factors and Prognosis for Metastatic Follicular Thyroid Cancer.

Background: Follicular thyroid cancer (FTC) is the second most common malignancy of thyroid. About 7%-23% of patients with FTC have distant metastasis. The aim of this study was to investigate the risk factors associated with distant metastasis and the impact of distant metastasis on survival in FTC patients. Methods: Patients with FTC were analyzed using a prospectively maintained dataset of thyroid cancer registered at a tertiary hospital in Taiwan between December 1976 and May 2020. Results: A total of 190 patients with a mean follow-up of 7.7 years were included in this study, including 29 with distant metastasis at diagnosis, 14 who developed metastasis during follow-up, and 147 without metastasis. Multivariate analysis adjusted for age, gender, tumor stage, and extrathyroidal invasion revealed old age (≥ 55 years) (adjusted odds ratio, 27.6; 95% confidence interval [CI], 8.75-86.8; P < 0.001) and extrathyroidal invasion (odds ratio, 24.1; 95% CI, 3.50-166.5; P = 0.001) were significantly associated with an increased risk of distant metastasis. Metastasis was correlated with higher cancer-specific mortality (adjusted hazard ratio, 35.5; 95% CI, 6.1-206.1; P < 0.001). In addition, patients with metastatic FTC diagnosed on initial presentation had the lowest 10-year cancer-specific survival rate (26.0%), followed by those who developed metastatic disease after initial treatment (76.6%), while patients without metastasis were all alive (100%) (P ≤ 0.002 for all comparisons). Conclusions: Age and extrathyroidal invasion are significant risk factors for distant metastasis of FTC. Patients with metastatic FTC, especially when diagnosed on initial presentation, have dismal survival outcomes.

Survival and Death Causes in Thyroid Cancer in Taiwan: A Nationwide Case-Control Cohort Study.

The incidence of thyroid cancer has increased substantially worldwide. However, the overall mortality risk and actual causes of death in thyroid cancer patients have not been extensively evaluated. In this study, patients with thyroid cancer diagnosed between 2001 and 2017 were analyzed from Taiwan's National Health Insurance Research Database. We compared these patients with control subjects matched for age, gender, history of cardiovascular disease (CVD), hyperlipidemia, diabetes mellitus, hypertension, and occupation to assess the risk of overall mortality and cause-specific mortality. Finally, our cohort comprised 30,778 patients with thyroid cancer. Three hundred and ninety-eight deaths (1.29%) occurred during a median follow-up of 60.0 months (range: 30.3 to 117.6 months). The primary cause of death was thyroid cancer mortality (31.2%), followed by other malignancy-related mortality (29.9%) and CVD mortality (12.3%). The overall mortality risk was similar between the thyroid cancer and control groups (unadjusted hazard ratio (HR): 0.98; 95% confidence interval (CI): 0.88-1.10); the adjusted HR was 1.07 (95% CI: 0.95-1.20) after multivariate adjustment for age, gender, history of CVD, hyperlipidemia, diabetes mellitus, hypertension, and occupation. The risk of other malignancy-related mortality was comparable between two groups. CVD mortality risk was lower in the thyroid cancer group, with an unadjusted HR of 0.51 (95% CI: 0.38-0.69) and adjusted HR of 0.56 (95% CI: 0.42-0.76). In conclusion, patients with thyroid cancer had excellent overall survival. Thyroid cancer-specific mortality was the leading cause of death, highlighting the importance of thyroid cancer management. Thyroid cancer patients had lower CVD mortality risk than the general population.

Efficacy and Biomarker Analysis of Adavosertib in Differentiated Thyroid Cancer.

Differentiated thyroid cancer (DTC) patients are usually known for their excellent prognoses. However, some patients with DTC develop refractory disease and require novel therapies with different therapeutic mechanisms. Targeting Wee1 with adavosertib has emerged as a novel strategy for cancer therapy. We determined the effects of adavosertib in four DTC cell lines. Adavosertib induces cell growth inhibition in a dose-dependent fashion. Cell cycle analyses revealed that cells were accumulated in the G2/M phase and apoptosis was induced by adavosertib in the four DTC tumor cell lines. The sensitivity of adavosertib correlated with baseline Wee1 expression. In vivo studies showed that adavosertib significantly inhibited the xenograft growth of papillary and follicular thyroid cancer tumor models. Adavosertib therapy, combined with dabrafenib and trametinib, had strong synergism in vitro, and revealed robust tumor growth suppression in vivo in a xenograft model of papillary thyroid cancer harboring mutant BRAFV600E, without appreciable toxicity. Furthermore, combination of adavosertib with lenvatinib was more effective than either agent alone in a xenograft model of follicular thyroid cancer. These results show that adavosertib has the potential in treating DTC.

Efficacy of adavosertib therapy against anaplastic thyroid cancer.

Wee1 is a kinase that regulates the G2/M progression by the inhibition of CDK1, which is critical for ensuring DNA damage repair before initiation of mitotic entry. Targeting Wee1 may be a potential strategy in the treatment of anaplastic thyroid cancer, a rare but lethal disease. The therapeutic effects of adavosertib, a Wee1 inhibitor for anaplastic thyroid cancer was evaluated in this study. Adavosertib inhibited cell growth in three anaplastic thyroid cancer cell lines in a dose-dependent manner. Cell cycle analysis revealed cells were accumulated in the G2/M phase. Adavosertib induced caspase-3 activity and led to apoptosis. Adavosertib monotherapy showed significant retardation of the growth of two anaplastic thyroid cancer tumor models. The combination of adavosertib with dabrafenib and trametinib revealed strong synergism in vitro and demonstrated robust suppression of tumor growth in vivo in anaplastic thyroid cancer xenograft models with BRAFV600E mutation. The combination of adavosertib with either sorafenib or lenvatinib also demonstrated synergism in vitro and had strong inhibition of tumor growth in vivo in an anaplastic thyroid cancer xenograft model. No appreciable toxicity appeared in mice treated with either a single agent or combination treatment. Our findings suggest adavosertib holds the promise for the treatment of patients with anaplastic thyroid cancer.

Primary lung cancer with radioiodine avidity: A thyroid cancer cohort study.

BACKGROUND: A proportion of lung cancers show sodium/iodide symporter (NIS) expression. Lung cancers with NIS expression may uptake radioiodine (RAI) and show RAI-avid lesions on RAI scan for differentiated thyroid cancer (DTC) surveillance. AIM: To investigate the possibility of RAI uptake by lung cancer in a cohort with thyroid cancer. METHODS: RAI-avid lung cancers were analyzed using a prospectively maintained database of patients with thyroid cancer who were registered at a medical center between December 1, 1976 and May 28, 2018. NIS expression in lung cancer was assessed using immunohistochemical staining. RESULTS: Of the 5000 patients with thyroid cancer from the studied dataset, 4602 had DTC. During follow-up, 33 patients developed primary lung cancer. Of these patients, nine received an iodine-131 (131I) scan within 1 year before the diagnosis of lung cancer. One of these nine lung cancers was RAI-avid. NIS expression was evaluated, and three of the eight available lung cancers revealed NIS expression. The proportions of lung cancer cells with NIS expression were 60%, 15%, and 10%. The RAI-avid lung cancer had the highest level of expression (60%). The RAI-avid lung cancer had a spiculated border upon single-photon emission computed tomography/computed tomography, which led to an accurate diagnosis. CONCLUSION: A proportion of lung cancer demonstrates NIS expression and is RAI-avid. Clinicians should be aware of this possibility in the interpretation of RAI scintigraphy.

Establishment of an ectopically expressed and functional PRMT1 for proteomic analysis of arginine-methylated proteins.

Protein arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), plays crucial roles in a variety of cellular processes. Mammalian PRMT1 exists in a large protein complex in cells, which has been implied in modulating the regulatory and catalytic properties of this enzyme. Establishment of a mammalian comparative approach will help to identify putative substrates of PRMT1 in an authentic condition. Here, we showed that ectopically expressed PRMT1 in mammalian HEK293 cells not only exhibited catalytic properties comparable to the endogenous enzyme but also existed in a functional complex together with endogenous PRMT1 and thus functioned as an endogenous counterpart. In addition, the measured methylation level of cellular proteins using a tritium-labeled methyl donor was accordingly enhanced upon ectopic expression of PRMT1. Subsequent proteomic analysis with such PRMT1-expressing cells allowed us to identify several known and putative methylated proteins. In vitro methylation of selected proteins, eukaryotic translation initiation factor 4A-I and vimentin, by cellular PRMT1 was shown. Together, we have demonstrated the functional equivalence of ectopically expressed PRMT1 in HEK293 cells and its application to systematically identify the substrate proteins in a mammalian cell context.

[Magnetic resonance myocardial perfusion imaging for evaluating myocardial viability after myocardial infarction].

OBJECTIVE: To assess the value of magnetic resonance (MR) myocardial perfusion imaging (MRMPI) in evaluating the myocardial viability in patients with myocardial infarction. METHODS: MRMPI was performed in 51 patients with myocardial infarction using a 1.5 T MR scanner. All the patients were examined using IR-turbo FLASH sequence during the first-pass and delayed phase 5-30 min after injection of 0.1 mmol/kg Gd-DTPA at the rate of 4 ml/s. The short axis images were acquired during the first-pass, and both the short axis and long axis images were obtained during the delayed phase. The left ventricular wall on the short-axis slice was divided into 8 segments. A correlative study of the results of the rest and stress (99m)Tc single photon emission computed tomography (SPECT) was carried out in 21 patients. RESULTS: In the 51 patients with myocardial infarction, 42(82.3%) showed hypoperfusion during the first-pass imaging and 50(98%) had delayed hyperenhancement. In the 21 patients receiving SPECT, 48 nonviable segments was detected among the 168 segments scanned by (99m)TcSPECT, and MRMPI showed delayed hyperenhancement in all the infracted areas. Of the 120 viable segments detected by rest and stress (99m)Tc SPECT, 97 segments (80.8%) were found to be free of delayed hyperenhancement by MRMPI. With the rest and stress (99m)Tc SPECT as the reference, the sensitivity and the specificity of MRMPI were 100.0% and 80.8%, respectively. CONCLUSION: MRMPI allows effective identification of the myocardial viability and nonviability as well as the severity and extent of the myocardial infraction.

Mitochondrial anchoring of PKCalpha by PICK1 confers resistance to etoposide-induced apoptosis.

Various pathways, including regulation of functions of the Bcl-2 family, are implicated in the survival promotion by PKCalpha, however the molecular mechanisms are still obscure. We have previously demonstrated that PKCalpha is selectively anchored to mitochondria by PICK1 in fibroblasts NIH 3T3. In this study, we show that over-expression of PICK1 in leukemia REH confers resistance to etoposide-induced apoptosis, which requires an interaction with PKCalpha as the non-interacting mutant PICK1 loses the pro-survival activity. The PKCalpha selective inhibitor Gö6976 also abolishes the anti-apoptotic effect indicating a requirement for PKC activity. Disruption of PICK1/PKCalpha interactions by inhibitory peptides significantly increases cellular susceptibility to etoposide. Similar effects are also observed in HL60 cells, which exhibit an intrinsic resistance to etoposide. Molecular analysis shows that the wild type PICK1, but not the non-interacting mutant, prevents the loss of mitochondrial membrane potential with a coincident increase in phosphorylation of the anti-apoptotic Bcl-2(Ser70) and a decrease in dimerization of the pro-apoptotic Bax. PICK1 may provide the spatial proximity for phosphorylation of Bcl-2(Ser70) by PKCalpha which then leads to a higher survival. Taken together, our results suggest that PICK1 may mediate the pro-survival activity of PKCalpha by serving as a molecular link between PKCalpha and mitochondria.