Tumor and metastatic lymph nodes metabolic activity on 18F-FDG-PET/CT to predict progression-free survival in locally advanced cervical cancer.

OBJECTIVE: The present study investigated the predictive diseases progression value of preoperative fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in patients with local advanced cervical cancer (LACC). METHODS: In total, 267 patients [median age 58 (range: 27-85) years old] with LACC underwent 18F-FDG PET/CT prior to any treatment. The maximum standardized uptake values (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary lesion and metastatic lymph nodes were measured on PET/CT and correlated with clinicopathological features and progression-free survival (PFS). RESULTS: The median follow-up was 36.52 (range: 3.09-61.29) months. During the observation period, 80 (30.0%) patients exhibited disease progression. Univariate analysis showed that FIGO stage, concurrent chemoradiotherapy (CRT), serum level of carcinoembryonic antigen (CEA) and squamous cell carcinoma antigen (SCC-Ag), primary tumor MTV (pMTV) and TLG (pTLG), lymph nodes SUVmax (nSUVmax) and TLG (nTLG), and total metabolic activity (sMTV, sTLG) were associated with PFS. nSUVmax ≥ 5.29, CEA ≥ 7.11 ng/ml and deficiency of concurrent CRT were independent risk factor for PFS (p = 0.006, p = 0.008, p = 0.014). The 3-year PFS for patients with high nSUVmax were 42.2% compared to 56.3% for low nSUVmax values. CONCLUSION: Pretreatment cervical and lymph nodes metabolic parameters were associated with PFS in patients with LACC.

Subregion-specific 18F-FDG PET-CT radiomics for the pre-treatment prediction of EGFR mutation status in solid lung adenocarcinoma.

This study aimed to assess the efficacy of fluor-18 fluorodeoxyglucose (18F-FDG) PET/CT using sub-regional-based radiomics in predicting epidermal growth factor receptor (EGFR) mutation status in pretreatment patients with solid lung adenocarcinoma. A retrospective analysis included 269 patients (134 EGFR+ and 135 EGFR-) who underwent pretreatment 18F-FDG PET/CT scans and EGFR mutation testing. The most metabolically active intratumoral sub-region was identified, and radiomics features from whole tumors or sub-regional regions were used to build classification models. The dataset was split into a 7:3 ratio for training and independent testing. Feature subsets were determined by Pearson correlation and the Kruskal Wallis test and radiomics classifiers were built with support vector machines or logistic regressions. Evaluation metrics, including accuracy, area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were employed for different classifiers. Results indicated that the sub-region-based classifier outperformed the whole-tumor classifier in terms of accuracy (73.8% vs. 66.2%), AUC (0.768 vs. 0.632), specificity (65.0% vs. 50.0%), PPV (70.2% vs. 62.2%), and NPV (78.8% vs. 74.0%). The clinical classifier exhibited an accuracy of 75.0%, AUC of 0.768, sensitivity of 72.5%, specificity of 77.5%, PPV of 76.3%, and NPV of 73.8%. The combined classifier, incorporating sub-region analysis and clinical parameters, demonstrated further improvement with an accuracy of 77.5%, AUC of 0.807, sensitivity of 77.5%, specificity of 77.5%, and NPV of 77.5%. The study suggests that sub-region-based 18F-FDG PET/CT radiomics enhances EGFR mutation prediction in solid lung adenocarcinoma, providing a practical and cost-efficient alternative to invasive EGFR testing.

Unexpected 99mTc-pertechnetate avidity of lymph node metastases predicts better response to radioiodine therapy in differentiated thyroid cancer patients with lymph node metastases.

OBJECTIVE: To investigate the value of 99mTc-pertechnetate scan in postoperative differentiated thyroid cancer (DTC) patients with lymph node (LN) metastases (LNM) uptake 99mTc-pertechnetate, especially the predictive value to their response to radioiodine-131 (131I) therapy. METHODS: This retrospective study collected 752 patients with DTC and LNM treated at Zhejiang Cancer Hospital between May 2012 and December 2017. Depending on the ability of LNM uptake 99mTc-pertechnetate, the patients were grouped as the 99mTc-pertechnetate-avid (n=88) vs. 99mTc-pertechnetate-non-avid (n=664) groups. And Propensity score matching (PSM) was performed at a 1:4 ratio to reduce confounding bias. RESULTS: In the PSM analysis, the 1:4 matched cohort comprised 752 patients (88 with 99mTc-pertechnetate-avid LNM, 664 with 99mTc-pertechnetate-non-avid LNM). Patients' age, initial 131I activity and frequency of iodine therapy were included as covariates. After PSM analysis, 363 patients (99mTc-pertechnetate-avid group, n=83; 99mTc-pertechnetate-non-avid group, n=280) were successfully matched. Among the 363 PSM-matched patients, 48/83 (57.8%) in the 99mTc-pertechnetate-avid group and 158/280 (56.4%) in the 99mTc-pertechnetate-non-avid group had two or more 131I treatments. The nsTg and the percentage of changes in ssTg between the 99mTc-pertechnetate-avid and 99mTc-pertechnetate-non-avid groups were significantly different ([0.05 (0.04 to 0.90) vs. 0.40 (0.04 to 4.92), p=0.018] and [-88% (-98%, -50%) vs. -66% (-86%, -30%), p < 0.001], respectively). No significant differences were observed between the two groups in the other parameters (age, pathological type, distant metastasis, follow-up time, AJCC TNM stage, initial 131I treatment activity, and 131I treatment frequency) after PSM (all p > 0.05). CONCLUSION: In patients with DTC and LNM, LNM uptake of 99mTc-pertechnetate is a rare phenomenon. Patients with 99mTc-pertechnetate-avid LNMs were more likely to benefit from 131I therapy, even after adjustment for age, 131I treatment frequency, and initial 131I activity.

Progression of radio-labeled molecular imaging probes targeting chemokine receptors.

Chemokine receptors are significantly expressed in the surface of most inflammatory cells and tumor cells. Guided by chemokines, inflammatory cells which express the relevant chemokine receptors migrate to inflammatory lesions and participate in the evolution of inflammation diseases. Similarly, driven by chemokines, immune cells infiltrate into tumor lesions not only induces alterations in the tumor microenvironment, disrupting the efficacy of tumor therapies, but also has the potential to selectively target tumoral cells and diminish tumor progression. Chemokine receptors, which are significantly expressed on the surface of tumor cell membranes, are regulated by chemokines and initiate tumor-associated signaling pathways within tumor cells, playing a complex role in tumor progression. Based on the antagonists targeting chemokine receptors, radionuclide-labeled molecular imaging probes have been developed for the emerging application of molecular imaging in diseases such as tumors and inflammation. The value and limitations of molecular probes in disease imaging are worth reviewing.

Prediction of HER2 Expression in Gastric Adenocarcinoma Based On Preoperative Noninvasive Multimodal 18F-FDG PET/CT Imaging.

RATIONALE AND OBJECTIVES: This study aims to investigate the role of a flourine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) multimodal radiomics model in predicting the status of human epidermal growth factor receptor 2 (HER2) expression preoperatively in cases of gastric adenocarcinoma. MATERIALS AND METHODS: This retrospective study included 133 patients with gastric adenocarcinoma who were classified into training (n = 93) and validation (n = 40) cohorts in a ratio of 7:3. Features were selected using Least Absolute Shrinkage and Selection Operator and Extreme Gradient Boosting (XGBoost) methods; further, prediction models were constructed using logistic regression and XGBoost. These models were evaluated and validated using area under the curve (AUC), decision curves, and calibration curves to select the best-performing model. RESULTS: Six different models were established to predict HER2 expression. Among these, the comprehensive model, which integrates seven clinical features, one CT feature, and five PET features, demonstrated AUC values of 0.95 (95% confidence interval [CI]: 0.89-1.00) and 0.76 (95% CI: 0.52-1.00) in the training and validation cohorts, respectively. Compared with other models, this model exhibited a superior net benefit on the decision curve and demonstrated good alignment agreement with the observed values on the calibration curve. Based on these findings, we constructed a nomogram for visualizing the model, providing a noninvasive preoperative method for predicting HER2 expression. CONCLUSION: The preoperative 18F-FDG PET/CT multimodal radiomics model can effectively predict HER2 expression in patients with gastric adenocarcinoma, thereby guiding clinical decision-making and advancing the field of precision medicine.

A PET/CT radiomics model for predicting distant metastasis in early-stage non-small cell lung cancer patients treated with stereotactic body radiotherapy: a multicentric study.

OBJECTIVES: Stereotactic body radiotherapy (SBRT) is a treatment option for patients with early-stage non-small cell lung cancer (NSCLC) who are unfit for surgery. Some patients may experience distant metastasis. This study aimed to develop and validate a radiomics model for predicting distant metastasis in patients with early-stage NSCLC treated with SBRT. METHODS: Patients at five institutions were enrolled in this study. Radiomics features were extracted based on the PET/CT images. After feature selection in the training set (from Tianjin), CT-based and PET-based radiomics signatures were built. Models based on CT and PET signatures were built and validated using external datasets (from Zhejiang, Zhengzhou, Shandong, and Shanghai). An integrated model that included CT and PET radiomic signatures was developed. The performance of the proposed model was evaluated in terms of its discrimination, calibration, and clinical utility. Multivariate logistic regression was used to calculate the probability of distant metastases. The cutoff value was obtained using the receiver operator characteristic curve (ROC), and the patients were divided into high- and low-risk groups. Kaplan-Meier analysis was used to evaluate the distant metastasis-free survival (DMFS) of different risk groups. RESULTS: In total, 228 patients were enrolled. The median follow-up time was 31.4 (2.0-111.4) months. The model based on CT radiomics signatures had an area under the curve (AUC) of 0.819 in the training set (n = 139) and 0.786 in the external dataset (n = 89). The PET radiomics model had an AUC of 0.763 for the training set and 0.804 for the external dataset. The model combining CT and PET radiomics had an AUC of 0.835 for the training set and 0.819 for the external dataset. The combined model showed a moderate calibration and a positive net benefit. When the probability of distant metastasis was greater than 0.19, the patient was considered to be at high risk. The DMFS of patients with high- and low-risk was significantly stratified (P < 0.001). CONCLUSIONS: The proposed PET/CT radiomics model can be used to predict distant metastasis in patients with early-stage NSCLC treated with SBRT and provide a reference for clinical decision-making. In this study, the model was established by combining CT and PET radiomics signatures in a moderate-quantity training cohort of early-stage NSCLC patients treated with SBRT and was successfully validated in independent cohorts. Physicians could use this easy-to-use model to assess the risk of distant metastasis after SBRT. Identifying subgroups of patients with different risk factors for distant metastasis is useful for guiding personalized treatment approaches.

Complete Remission Upon Peptide Receptor Radionuclide Therapy in a G2 Pancreatic Neuroendocrine Tumor.

ABSTRACT: We report the case of a 52-year-old man affected with a metastasized neuroendocrine tumor (G2) of the pancreas. After surgical removal, follow-up imaging 36 months later revealed somatostatin receptor-positive liver lesions. Because of disease progression under cold somatostatin analogs 6 months later, peptide receptor radionuclide therapy was performed, that induced complete remission (CR), supporting the notion that "hot" somatostatin analogs can achieve CR even in patients affected with pancreatic G2 neuroendocrine tumor. Of note, such cases exhibiting CR upon peptide receptor radionuclide therapy are extremely rare and further investigations may pool those exceptional treatment responders.

Retrospective Analysis of the Predictive Value of 18F-FDG PET/CT Metabolic Parameters for PD-L1 Expression in Cervical Cancer.

BACKGROUND: Immunotherapy targeting PD-1/PD-L1 has been proven to be effective for cervical cancer treatment. To explore non-invasive examinations for assessing the PD-L1 status in cervical cancer, we performed a retrospective study to investigate the predictive value of 18F-FDG PET/CT. METHODS: The correlations between PD-L1 expression, clinicopathological characteristics and 18F-FDG PET/CT metabolic parameters were evaluated in 74 cervical cancer patients. The clinicopathological characteristics included age, histologic type, tumor differentiation, FIGO stage and tumor size. The metabolic parameters included maximum standard uptake (SUVmax), mean standard uptake (SUVmean), total lesion glycolysis (TLG) and tumor metabolic volume (MTV). RESULTS: In univariate analysis, SUVmax, SUVmean, TLG, tumor size and tumor differentiation were obviously associated with PD-L1 status. SUVmax (rs = 0.42) and SUVmean (rs = 0.40) were moderately positively correlated with the combined positive score (CPS) for PD-L1 in Spearman correlation analysis. The results of multivariable analysis showed that the higher SUVmax (odds ratio = 2.849) and the lower degree of differentiation (Odds Ratio = 0.168), the greater probability of being PD-L1 positive. The ROC curve analysis demonstrated that when the cut-off values of SUVmax, SUVmean and TLG were 10.45, 6.75 and 143.4, respectively, the highest accuracy for predicting PD-L1 expression was 77.0%, 71.6% and 62.2%, respectively. The comprehensive predictive ability of PD-L1 expression, assessed by combining SUVmax with tumor differentiation, showed that the PD-L1-negative rate was 100% in the low probability group, whereas the PD-L1-positive rate was 84.6% in the high probability group. In addition, we also found that the H-score of HIF-1α was moderately positively correlated with PD-L1 CPS (rs = 0.51). CONCLUSIONS: The SUVmax and differentiation of the primary lesion were the optimum predictors for PD-L1 expression in cervical cancer. There was a great potential for 18F-FDG PET/CT in predicting PD-L1 status and selecting cervical cancer candidates for PD1/PD-L1 immune checkpoint therapy.

Lipid-Peptide-mRNA Nanoparticles Augment Radioiodine Uptake in Anaplastic Thyroid Cancer.

Restoring sodium iodide symporter (NIS) expression and function remains a major challenge for radioiodine therapy in anaplastic thyroid cancer (ATC). For more efficient delivery of messenger RNA (mRNA) to manipulate protein expression, a lipid-peptide-mRNA (LPm) nanoparticle (NP) is developed. The LPm NP is prepared by using amphiphilic peptides to assemble a peptide core and which is then coated with cationic lipids. An amphiphilic chimeric peptide, consisting of nine arginine and hydrophobic segments (6 histidine, C18 or cholesterol), is synthesized for adsorption of mRNA encoding NIS in RNase-free conditions. In vitro studies show that LP(R9H6) m NP is most efficient at delivering mRNA and can increase NIS expression in ATC cells by more than 10-fold. After intratumoral injection of NIS mRNA formulated in optimized LPm NP, NIS expression in subcutaneous ATC tumor tissue increases significantly in nude mice, resulting in more iodine 131 (131 I) accumulation in the tumor, thereby significantly inhibiting tumor growth. Overall, this work designs three arginine-rich peptide nanoparticles, contributing to the choice of liposome cores for gene delivery. LPm NP can serve as a promising adjunctive therapy for patients with ATC by restoring iodine affinity and enhancing the therapeutic efficacy of radioactive iodine.

Influence of Dehydroxymethylepoxyquinomicin on Radiosensitivity of Thyroid Carcinoma TPC-1 Cells.

Objective: To investigate the influence of dehydroxymethylepoxyquinomicin (DHMEQ), an NF-κB inhibitor, on radiosensitivity of thyroid carcinoma (TC) TPC-1 cells. Methods: The isolation of CDl33 positive cells (CD133+ TPC-1) and negative cells (CD133- TPC-1) from TPC-1 cells used immunomagnetic bead sorting. After verification of the toxicity of DHMEQ to cells by MTT and cell cloning assays, the cells were divided into four groups, of which three groups were intervened by DHMEQ, 131I radiation, and DHMEQ +131I radiation, respectively, while the fourth group was used as a control without treatment. Alterations in cell growth, apoptosis, and cell cycle were observed. Results: DHMEQ had certain toxic effects on TPC-1 cells, with an IC50 of 38.57 µg/mL (P < 0.05). DHMEQ inhibited CD133+ and CD133- TPC-1 proliferation and their clonogenesis after irradiation. DHMEQ + radiation contributed to a growth inhibition rate and an apoptosis rate higher than either or them alone (P < 0.05), with a more significant effect on CD133- TPC-1 than CD133+ TPC-1 under the same treatment conditions (P < 0.05). Conclusion: DHEMQ can increase the radiosensitivity of TC cells to 131I, inhibit tumor cell growth, and promote apoptosis. However, its effect is less significant on CD133+ TPC-1 compared with CD133- TPC-1, which may be related to the stem cell-like properties of CD133+ cells. In the future, the application of DHMEQ in TC 131I radiotherapy will effectively improve the clinical effect of patients.

miR-221-3p and miR-222-3p regulate the SOCS3/STAT3 signaling pathway to downregulate the expression of NIS and reduce radiosensitivity in thyroid cancer.

The expression levels of microRNA (miR)-221-3p and miR-222-3p in thyroid cancer have been found to be upregulated compared with those in normal tissues. The present study aimed to determine the effects and potential underlying mechanisms of miR-221-3p and miR-222-3p on the regulation of radioactive iodine (131I) uptake and radiosensitivity of thyroid cancer cells. The potential regulatory target genes of miR-221-3p and miR-222-3p were predicted by bioinformatics analysis, and reverse transcription-quantitative polymerase chain reaction was used to verify miR-221-3p, miR-222-3p and target gene expression levels in thyroid cancer tissues and cell lines. Overexpression of miR-221-3p or miR-222-3p in cell models was performed using lentivirus infection. Knockdown of miR-221-3p and miR-222-3p in cells was achieved using oligonucleotide inhibitor transfection. Western blotting was used to analyze the expression levels of target proteins. In addition, the effects of miR-221-3p and miR-222-3p on the radiosensitivity of thyroid cancer cells were verified using a colony formation assay. The results of the present study revealed that the expression levels of miR-221-3p and miR-222-3p were significantly upregulated, while the expression levels of suppressor of cytokine signaling 3 (SOCS3) were downregulated in thyroid cancer tissues. Furthermore, miR-221-3p and miR-222-3p overexpression downregulated the expression levels of SOCS3, E-cadherin and solute carrier family 5 member 5 (NIS), and upregulated the expression levels of phosphorylated STAT3 and vimentin. Following the overexpression of miR-221-3p or miR-222-3p in the FTC133 and TPC1 cell lines, their radiosensitivity was suppressed. In conclusion, the findings of the present study suggested that miR-221-3p and miR-222-3p may downregulate the expression levels of NIS and promote radioresistance. The potential mechanism was hypothesized to be associated with the miR-221-3p and miR-222-3p targeting of the SOCS3 gene, which may subsequently activate the STAT3 signaling pathway.

Clinical significance of extra-thyroid 99mTc-pertechnetate uptake before initial radioiodine therapy for differentiated thyroid carcinoma.

OBJECTIVE: To analyse the clinical characteristics of extra-thyroid 99mTc-pertechnetate uptake in order to explore the effect of the phenomenon on radioactive iodine (RAI) therapy for differentiated thyroid carcinoma (DTC) and its clinical significance. METHODS: This study retrospectively selected patients with DTC and extra-thyroid 99mTc-pertechnetate uptake. The clinical features, location, location count and extra-thyroid 99mTc-pertechnetate uptake distribution were analysed, combined with the uptake rate, stimulated thyroglobulin (sTg) level, post-therapy whole-body scan and curative effect. RESULTS: A total of 38 patients were enrolled in the study and 65 extra-thyroid 99mTc-pertechnetate foci were detected. Thirty-four patients showed abnormal 99mTc-pertechnetate uptake in the lymph nodes (26 of 38; 68.4%), lungs (four of 38; 10.5%) and bones (four of 38; 10.5%). The corresponding uptake rates were 0.2%, 0.2% and 0.8%, respectively. The uptake rate and sTg were significantly positively correlated (r = 0.36). 131I uptake was found in 36 patients at the 99mTc-pertechnetate uptake site. The number of iodine uptake foci was significantly higher than that of 99mTc-pertechnetate uptake foci. The sTg value and pathological staging significantly differed between the excellent and nonexcellent response groups (Z = -2.947 and Z = -2.348, respectively). CONCLUSION: Extra-thyroid 99mTc-pertechnetate uptake mostly indicated metastases with specific clinical features, which may have prognostic value for the judgment of iodine uptake function and the RAI therapy plan.

Role of oncogene PIM-1 in the development and progression of papillary thyroid carcinoma: Involvement of oxidative stress.

In this study, we aimed to clarify the role of PIM-1 in papillary thyroid carcinoma (PTC) in vitro and investigate the relationship between PIM-1 and redox proteins (NOX4, SOD2, and GPX2) at the tissue and cellular levels. As a PIM-1 inhibitor, SGI-1776 inhibited cell proliferation, colony formation, migration and induced an increase in apoptosis and reactive oxygen species in two PTC cell lines (BCPAP and TPC-1). The expressions of PIM-1, SOD2 and GPX2 were downregulated after siNOX4 exposure. Immunohistochemistry in 120 PTC patients showed that all four proteins exhibited higher expression levels in PTC tissues than in adjacent normal tissues. PIM-1 expression was related to NOX4, SOD2, and GPX2 expressions. The Cancer Genome Atlas database analysis showed the significant correlation between the expression of NOX4 and PIM-1. Our results demonstrated that PIM-1 played an important oncogenic role in PTC carcinogenesis that may be related to oxidative stress.

A review on the mechanism of iodide metabolic dysfunction in differentiated thyroid cancer.

The incidence of differentiated thyroid cancer (DTC) has been increasing rapidly worldwide, and the risk factors remain unclear. With the growing number of patients with DTC, the related issues have been gradually highlighted. 131Iodide (131I) is an important treatment for DTC and has the potential to reduce the risk of recurrence. 131I is also an effective treatment for distant metastases of thyroid carcinoma. However, iodide metabolism dysfunction in metastatic foci causes patients to lose the opportunity of 131I treatment. This article reviews the related mechanisms of iodide metabolism dysfunction in DTC cells and summarizes the clinical transformation progression.

Inhibition of autophagy enhances the targeted therapeutic effect of sorafenib in thyroid cancer.

The multi-target kinase inhibitor sorafenib has been approved for the treatment of patients with advanced differentiated thyroid cancer. However, different sensitivities to sorafenib have been observed, and few patients have benefited from sorafenib treatment in the long term. In the event of acquired resistance to sorafenib it is not beneficial to continue treatment in most patients. Autophagy can be induced in a variety of cancer treatments and plays an important role in cancer treatment. The role of autophagy in sorafenib treatment of thyroid cancer has not been fully demonstrated. The present study investigated whether autophagy is activated by sorafenib during the treatment of thyroid cancer, examined the underlying mechanisms, and explored potential strategies to enhance the therapeutic sensitivity of sorafenib. Chloroquine (CQ) is an autophagy inhibitor that has been reported to increase sensitivity to various cancer treatments. Thyroid cancer xenograft model mice were treated with sorafenib, CQ, or a combination of sorafenib and CQ. We observed that CQ or sorafenib treatment suppressed tumor growth, while mice treated with the combination of sorafenib and CQ displayed significantly reduced tumor growth compared with those treated with sorafenib or CQ alone. Western blotting results indicated that sorafenib concurrently inhibited the activities of the MAPK and AKT/mTOR pathways in thyroid cancer. Autophagy was activated by sorafenib in thyroid cancer, both in vitro and in vivo, which was at least in part due to suppression of the AKT/mTOR pathway. Combination treatment including CQ could inhibit the autophagic flux induced by sorafenib. Silencing the key autophagy gene ATG5 using small interfering RNA also increased the anticancer effect of sorafenib. In summary, the present study revealed that inhibition of autophagy enhances the anticancer effect of sorafenib, and the combination of CQ with sorafenib treatment represents a potential therapeutic strategy for treating advanced differentiated thyroid cancer.

Inhibition of the AKT/mTOR Pathway Augments the Anticancer Effects of Sorafenib in Thyroid Cancer.

BACKGROUND: Sorafenib is a multikinase inhibitor that has been approved for the treatment of patients with advanced 131iodine (131I) refractory differentiated thyroid cancer (DTC). However, the progression-free survival of patients with advanced 131I refractory DTC is short, and most DTC patients eventually acquire resistance to sorafenib. Therefore, new therapeutic strategies need to be developed. MATERIALS AND METHODS: The thyroid cancer cell lines 8505C and FTC133 were treated with sorafenib in the presence or absence of BEZ235 or small interfering RNA (siRNA) directed against AKT. A CCK8 kit was used to evaluate cell viability. Protein expression levels of relevant genes were determined by Western blotting analysis, whereas messenger RNA expression levels were determined by real-time PCR analysis. Flow cytometry was performed to assess the number of apoptotic cells. RESULTS: The results indicate that sorafenib simultaneously inhibited the activities of the MAPK and PI3K/AKT/mTOR pathways in thyroid cancer cells. Treatment of 8505C and FTC133 cells with NVP-BEZ235, siRNA against AKT, or sorafenib induced tumor cell apoptosis and led to reduced tumor cell proliferation. Sorafenib in combination with PI3K/AKT/mTOR inhibition by NVP-BEZ235 or AKT siRNA enhanced apoptosis and proliferation suppression. CONCLUSIONS: The evidence of this study suggests that a combinatorial approach that inhibits both the MAPK and PI3K/AKT/mTOR pathways exerts a greater antitumor effect than sorafenib alone in thyroid cancer cell lines.

Assessment of radioiodine therapy efficacy for treatment of differentiated thyroid cancer patients with pulmonary metastasis undetected by chest computed tomography.

Radioiodine therapy (RAI) has proven effective for the treatment of patients exhibiting differentiated thyroid cancer (DTC) with pulmonary metastases. However, the early detection of metastasis remains challenging, and various studies have reported variations in radioiodine treatment efficacy. The present study investigated whether RAI is an effective method for the treatment of DTC with pulmonary metastases undetected by computed tomography (CT). A retrospective study was performed, analyzing iodine-131 (131I) therapy in 21 DTC patients with lung metastases that were undetected by CT. All 21 patients were initially treated with radioiodine ablation of thyroid remnants. Routine chest CT was performed prior to 131I treatment without diagnostic radioiodine whole-body scanning (DxWBS), and post-therapeutic WBS was performed 3-5 days subsequent to oral administration of 131I. The overall effectiveness rate was 95.2% (20/21). The rates for complete response (CR), partial response and no response were 23.8 (5/21), 71.4 (15/21) and 4.8% (1/21), respectively. There were 12 patients with diffuse uptake, and the remaining 9 patients demonstrated focused and low uptake. The difference in CR rate between diffuse uptake and focused uptake patients was not statistically significant (P=0.123). A correlation was observed between thyroglobulin (Tg) levels and extrapulmonary metastases. All patients exhibited extrapulmonary metastases when Tg levels were >87.5 ng/ml (area under receiver operating characteristic curve, 1.0; P<0.001). Overall, DTC patients with lung metastases undetected by CT imaging responded well to 131I radiotherapy and demonstrated a positive prognosis. Serum Tg levels prior to 131I treatment may correlate with metastasis, and this may suggest a requirement for the performance of DxWBS prior to radiotherapy.

Combined use of radioiodine therapy and radiofrequency ablation in treating postsurgical thyroid remnant of differentiated thyroid carcinoma.

PURPOSE: To determine whether postoperative radioiodine (RAI) combined with radiofrequency ablation (RFA) is an effective, safe, and feasible method for elimination of excessive postsurgical thyroid remnant for differentiated thyroid carcinoma (DTC). MATERIALS AND METHODS: We took a prospective study and treated 12 DTC patients (4 males, 8 females, age 20-78 years) who underwent thyroidectomy for RFA followed by 131 I ablation. The pretreatment requires iodine-free diet and thyroid hormone withdrawal for 3-4 week. All the patients showed the level of serum thyroid-stimulating hormone (TSH) <30 mU/L, and obvious thyroid remnant in 99m Technetium (99m Tc) imaging. Serum TSH level was determined 1 day before RFA and on days 1, 7, 14 after RFA, and 99m Tc imaging was performed on day 14 after RFA. Subsequently, the patients were given an oral dosage of 3700 MBq 131 I for remnant ablation, and posttreatment whole body scan was performed on day 5 after ablation. Efficacy evaluation was done 4-6 months after treatment. The changes of variants before and after RFA were analyzed using Wilcoxon signed rank sum test. RESULTS: Serum TSH was <30 µIU/ml (mean value 10.27 ± 6.16 µIU/ml) before RFA, and increased to more than 30 µIU/ml (34.73 ± 3.93 µIU/ml) 2 weeks later (P = 0.002, Wilcoxon rank sum test). The 99m Tc uptake ratio on day 14 postRFA was (0.31 ± 0.12)%, which is significantly lower than before RFA (0.80 ± 0.16)% (P = 0.002, Wilcoxon rank sum test). The success rate of thyroid remnant ablation was 91.7% (11/12), which was assessed 4-6 months after treatment. All patients reported neck discomfort and some are self-limiting, with no hoarseness, choking, or radiation thyroiditis symptoms. Five patients had puncture area pain, among which one patient had neck edema, which was relieved after prednisone treatment. CONCLUSION: Combined use of RAI therapy and radiofrequency ablation in treating excessive postsurgical thyroid remnant of DTC can be an effective approach and avoids re-operation. Long-term efficacy monitoring would further determine its feasibility.

Autophagy: A potential target for thyroid cancer therapy (Review).

The sharply increasing incidence of thyroid cancer has attracted considerable attention over the last few years. The combination of surgery, radioiodine ablation and thyroid-stimulating hormone suppression is usually efficient for the majority of thyroid tumors. However, advanced thyroid cancer that is recurrent, metastatic and 131I-refractory, or medullary thyroid cancer, pose a therapeutic challenge. Autophagy is a process that metabolizes damaged cytoplasmic organelles and long-lived proteins in order to recycle cellular materials and maintain homeostasis. It has been confirmed that autophagy plays a dual role during cancer development, progression and treatment, mainly depending on the type and stage of the tumor. Autophagy modulation has become a potential therapeutic target for diverse diseases. The mechanism of thyroid tumorigenesis and cancer progression was largely demonstrated to be correlated with the dysregulation of the Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase and the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathways, as well as with abnormal epigenetic modifications. Those mechanisms are associated with autophagy regulation and may be beneficial for the treatment of advanced thyroid cancer. However, the number of available studies on the role of autophagy in thyroid cancer development, progression and treatment outcome, is currently limited. The aim of this review was to elaborate on the relevant knowledge and future prospectives of autophagy in the treatment of thyroid cancer.

MicroRNA-18a upregulates autophagy and ataxia telangiectasia mutated gene expression in HCT116 colon cancer cells.

Autophagy is an evolutionarily conserved, multi-step lysosomal degradation process in which a cell degrades its own long-lived proteins and damaged organelles. Ataxia telangiectasia mutated (ATM) has recently been shown to upregulate the process of autophagy. Previous studies showed that certain microRNAs, including miR-18a, potentially regulate ATM in cancer cells. However, the mechanisms behind the modulation of ATM by miR-18a remain to be elucidated in colon cancer cells. In the present study, we explored the impact of miR-18a on the autophagy process and ATM expression in HCT116 colon cancer cells. To determine whether a preliminary link exists between autophagy and miR-18a, HCT116 cells were irradiated and quantitative (q) PCR was performed to measure miR-18a expression. HCT116 cells were transfected with an miR-18a mimic to study its impact on indicators of autophagy. Western blotting and luciferase assays were implemented to explore the impact of miR-18a on ATM gene expression in HCT116 cells. The results showed that miR-18a expression was strongly stimulated by radiation. Ectopic overexpression of miR-18a in HCT116 cell lines potently enhanced autophagy and ionizing radiation-induced autophagy. Moreover, miR-18a overexpression led to the upregulation of ATM expression and suppression of mTORC1 activity. Results of the present study pertaining to the role of miR-18a in regulating autophagy and ATM gene expression in colon cancer cells revealed a novel function for miR-18a in a critical cellular event and on a crucial gene with significant impacts in cancer development, progression, treatment and in other diseases.