Efficacy of Empirical 131 I Radioiodine Therapy in Well-Differentiated Thyroid Carcinoma Patients With Thyroglobulin-Elevated Negative Iodine Scintigraphy Syndrome : A Systematic Review and Meta-analysis.

OBJECTIVES: This study aimed to perform a systematic review and meta-analysis on the efficacy of empirical high-dose radioiodine therapy in treating differentiated thyroid cancer patients with thyroglobulin (Tg)-elevated negative iodine scintigraphy (TENIS) syndrome. METHODS: We searched PubMed, EMBASE, and the Cochrane Library to identify relevant studies published until April 2022. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist and registered in an international prospective register of systematic reviews (PROSPERO). Meta-analyses of proportions and odds ratios were performed to assess the beneficial effect of empirical high-dose radioiodine therapy in patients with TENIS syndrome. Subgroup analysis was also performed according to the presence of micrometastasis or macrometastasis. RESULTS: We identified 14 studies including 690 patients who received empirical high-dose radioiodine therapy for TENIS syndrome. Those who had micrometastasis exhibited additional lesions not previously observed on diagnostic whole-body scan (prop = 0.64, 95% confidence interval [CI], 0.51-0.77) and had reduced serum Tg levels (prop = 0.69; 95% CI, 0.52-0.84) after empirical radioiodine treatment. No such findings were observed among patients with macrometastasis. Moreover, we found that the empirical radioiodine treatment group had lower serum Tg levels than did controls (odds ratio = 0.27; 95% CI, 0.09-0.87), which suggests a lower risk of disease progression. CONCLUSIONS: Our findings indicate that empirical high-dose radioiodine therapy promoted beneficial effects and could be recommended for patients with TENIS syndrome, especially those with micrometastasis.

Comparison of Recombinant Human Thyroid-Stimulating Hormone and Thyroid Hormone Withdrawal for 131 I Therapy in Patients With Intermediate- to High-Risk Thyroid Cancer : A Systematic Review and Meta-analysis.

BACKGROUND: This meta-analysis and systematic review aimed to evaluate the therapeutic efficacy and advantages associated with the use of recombinant human thyroid-stimulating hormone (rhTSH) for radioactive iodine (RAI) therapy in patients with intermediate- to high-risk differentiated thyroid cancer. PATIENTS AND METHODS: MEDLINE, EMBASE, and Cochrane databases were searched to identify relevant articles reporting clinical outcomes of rhTSH compared with thyroid hormone withdrawal (THW) in patients with intermediate- to high-risk differentiated thyroid cancer published between January 2012 and June 2023. Meta-analyses were performed (PROSPERO registration number: CRD42022340915) to assess the success rate of radioiodine remnant ablation (RRA) in patients with intermediate to high risk and determine the disease control rate among patients with distant metastases, evaluated using the RECIST criteria. RESULTS: Thirteen studies involving 1858 patients were included in the meta-analysis. Pooled analyses revealed significantly higher overall RRA success rate in the rhTSH group compared with the THW group, with a risk ratio (RR) of 1.12 (95% confidence interval [CI], 1.01-1.25). However, in the subgroup analysis of high-risk patients, pooled analyses showed no significant differences in RRA success rate between the rhTSH group compared with the THW group with a pooled RR of 1.05 (95% CI, 0.88-1.24). In patients with distant metastases, there were no significant differences in the disease control rate between groups, with a pooled RR of 1.06 (95% CI, 0.78-1.44). CONCLUSIONS: rhTSH for RAI therapy is a practical option for RAI therapy in patients with intermediate- to high-risk thyroid cancer, including those with distant metastases.

Clinical Implications of Adding SPECT/CT to Radioiodine Whole-Body Scan in Patients With Differentiated Thyroid Cancer: A Systematic Review and Meta-analysis.

PURPOSE: This study aimed to determine the usefulness of adding SPECT/CT to radioiodine whole-body scans (WBSs) for the treatment of differentiated thyroid cancer (DTC). PATIENTS AND METHODS: A systematic review and meta-analysis were performed following the PRISMA guidelines (PROSPERO registration: CRD42022341732) to compare the feasibility of conclusive readings and the frequency of changes in treatment plans in patients with DTC undergoing WBS + SPECT/CT versus WBS. MEDLINE, EMBASE, and Cochrane databases were searched to identify relevant articles concerning thyroid cancer, radioactive iodine, and SPECT/CT or SPECT, published before August 16, 2023. Studies not comparing WBS + SPECT/CT with WBS, those lacking target outcomes, and those not involving human subjects were excluded. The risk of bias was assessed using the RoBANS 2.0 (Risk of Bias Assessment Tool for Nonrandomized Studies) tool. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system was used to evaluate the quality of evidence and strength of recommendations. RESULTS: A total of 30 studies (prospective n = 9, retrospective n = 21) were included in the meta-analyses. Adding SPECT/CT to WBS was shown to increase conclusive readings for cervical lesions, extracervical lesions, and all regions. Lesion-based analyses showed improvements of 14%, 20%, and 18%, respectively, whereas scan-based analyses showed improvements of 27%, 9%, and 34%. The addition of SPECT/CT to WBS led to changes in 30% of treatment plans after diagnostic scans and 9% of treatment plans after posttherapeutic scans. The quality of evidence and strength of recommendations were low. CONCLUSIONS: Compelling evidence demonstrates that the addition of SPECT/CT to WBS improves lesion localization, diagnostic performance, and therapy plan for patients with DTC.

The Diagnostic Value of 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Differentiated Thyroid Cancer Patients with Elevated Thyroglobulin/Thyroglobulin Antibody Levels and Negative Iodine Scintigraphy: A Systematic Review and Meta-Analysis.

Background: The objective of this study is to evaluate the diagnostic accuracy of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in detecting recurrence in patients with differentiated thyroid cancer (DTC) who have negative whole-body scans (WBSs) but elevated serum thyroglobulin (Tg) or thyroglobulin antibody (TgAb) levels. Methods: This systematic review/meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis for Diagnostic Test Accuracy criteria (International Prospective Register of Systematic Reviews registration number: CRD42022340924). A comprehensive search of the MEDLINE, EMBASE, and Cochrane databases identified articles reporting the diagnostic accuracy of FDG PET/CT for the detection of recurrence in patients with DTC with negative WBS and elevated serum Tg or TgAb levels published between January 2012 and June 2023. Meta-analyses were performed to determine the diagnostic accuracy of FDG PET/CT on the total target population as well as on subgroups stratified by serum Tg or TgAb, and thyrotropin (TSH) stimulation status at the time of FDG PET/CT. The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework was applied to evaluate the quality of evidence and the strength of recommendations to facilitate translation of the meta-analysis results into practical recommendations for clinical guidelines. Results: A total of 24 studies involving 1988 patients were included for analysis. The overall pooled sensitivity and specificity values were 0.87 (95% confidence interval [CI] = 0.83-0.92; I2 = 75%) and 0.84 (CI = 0.80-0.89; I2 = 44%), respectively. Subgroup analyses revealed no significant differences in the diagnostic accuracy of FDG PET/CT in patients stratified by serum Tg or TgAb levels, and TSH stimulation status at the time of PET/CT. Treatment plans were changed following FDG PET/CT imaging in 40% (CI = 34-47%; I2 = 39%) of cases. The quality level of evidence for using FDG PET/CT was moderate in both sensitivity and specificity according to the GRADE system. Conclusion: There is moderate quality evidence demonstrating the high diagnostic accuracy of FDG PET/CT in detecting recurrence in patients with DTC with negative WBS and elevated serum Tg or TgAb levels. This evidence corroborates the current guidelines' endorsement of FDG PET/CT as a diagnostic tool in such patients.

Thyroid segmentation using perithyroidal halo layer on 99mTc-pertechnetate thyroid SPECT/CT: An easy and reliable method for accurate quantification of thyroid activity.

OBJECTIVE: In previous fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) studies, tumor segmentation using peritumoral halo layer (PHL; SegPHL) was shown to be reliable and accurate segmentation method in various malignant tumors. We found that the halo layer also was observed on the 99mTc-pertechnetate (99mTcO4) thyroid single photon emission computed tomography (SPECT)/CT. In the present study, we attempted to apply thyroid segmentation using the perithyroidal halo layer (PTHL; SegPTHL) on 99mTcO4 thyroid SPECT/CT and compared SegPTHL with CT-based thyroid segmentation (SegCT). SUBJECTS AND METHODS: A total of 33 patients (19 females, 14 males; mean age, 46.91±15.7 years old) were enrolled in this study. For SegCT, three-dimensional volume of interest (VOI) of the thyroid was generated via multiple 2-dimensional regions of interest (ROI) along the thyroid margin on transaxial CT images that were manually drawn slice by slice. The PTHL was easily identified by an abrupt increase in layer thickness with minimal or mild distortion of the main thyroid contour, and the thyroid margin for SegPTHL was determined at the innermost portion of PTHL. An automated VOI generation for SegPTHL was performed using the Q. Volumetrix software. The correlation and reliability tests were performed between the quantification parameters of SegPTHL and SegCT. RESULTS: The PTHL threshold adjusted according to maximal SUV of thyroid were similar to the results of previous SegPHLstudies of 18F-FDG PET/CT. A good correlation was observed between the thyroid volumes of SegCT and SegPTHL (r=0.725; P<0.0001), although the thyroid volume of SegPTHL was slightly larger than that of SegCT (P=0.0017). The % thyroid uptake (TcTU), total lesion activity (TLA), and mean standardized uptake value (SUVmean) of SegPTHL correlated well with those of SegCT (r=0.9877, 0.9883, 0.9875, respectively; P<0.0001). No significant error was observed between the parameters (i.e., TcTU, TLA, and SUVmean) of SegPTHL and SegCT. CONCLUSION: Thyroid segmentation PTHL may be a useful method for reliable quantification of thyroid uptake, because the SPECT/CT parameters of SegPTHL were strongly correlated with those of SegCT, as well as the process of SegPTHL is easier and faster than that of SegCT.

CRIF1 siRNA-Encapsulated PLGA Nanoparticles Suppress Tumor Growth in MCF-7 Human Breast Cancer Cells.

Mitochondrial oxidative phosphorylation (OXPHOS) system dysfunction in cancer cells has been exploited as a target for anti-cancer therapeutic intervention. The downregulation of CR6-interacting factor 1 (CRIF1), an essential mito-ribosomal factor, can impair mitochondrial function in various cell types. In this study, we investigated whether CRIF1 deficiency induced by siRNA and siRNA nanoparticles could suppress MCF-7 breast cancer growth and tumor development, respectively. Our results showed that CRIF1 silencing decreased the assembly of mitochondrial OXPHOS complexes I and II, which induced mitochondrial dysfunction, mitochondrial reactive oxygen species (ROS) production, mitochondrial membrane potential depolarization, and excessive mitochondrial fission. CRIF1 inhibition reduced p53-induced glycolysis and apoptosis regulator (TIGAR) expression, as well as NADPH synthesis, leading to additional increases in ROS production. The downregulation of CRIF1 suppressed cell proliferation and inhibited cell migration through the induction of G0/G1 phase cell cycle arrest in MCF-7 breast cancer cells. Similarly, the intratumoral injection of CRIF1 siRNA-encapsulated PLGA nanoparticles inhibited tumor growth, downregulated the assembly of mitochondrial OXPHOS complexes I and II, and induced the expression of cell cycle protein markers (p53, p21, and p16) in MCF-7 xenograft mice. Thus, the inhibition of mitochondrial OXPHOS protein synthesis through CRIF1 deletion destroyed mitochondrial function, leading to elevated ROS levels and inducing antitumor effects in MCF-7 cells.

The relative isoform expression levels of isocitrate dehydrogenase in breast cancer: IDH2 is a potential target in MDA-MB-231 cells.

PURPOSE: The isocitrate dehydrogenase (IDH) family plays an essential role in metabolism and energy production. The relative expression levels of IDH isoforms (IDH1, IDH2, and IDH3) have prognostic significance in several malignancies, including breast carcinoma. However, the IDH isozyme expression levels in different cancer stages and types have not been determined in breast carcinoma tissues. METHODS: We analyzed the messenger RNA (mRNA) and protein levels of IDH (IDH1, IDH2, and IDH3A) and α-ketoglutarate (α-KG) in 59 breast carcinoma tissues. RESULTS: The mRNA level of IDH2 was significantly increased at stages 2 and 3 in triple-negative and (ER-/PR-/HER+) breast cancers. However, the elevated α-KG level was only observed in stages 2 and 3, with no differences in the various breast carcinoma types. Western blotting analysis showed that IDH2 protein expression increased in the patient tissues and cell lines. An in vitro study showed IDH2 downregulation in the triple-negative breast cancer cell line MDA-MB-231 that inhibited cell proliferation and migration and induced cell cycle arrest in the G0/G1 phase. CONCLUSION: These findings suggest that different from IDH1 and IDH3, IDH2 is more highly expressed in stages 2 and 3 breast cancer tissues, especially in triple-negative breast cancer. IDH2 potentially serves as a target to detect unknown mechanisms in breast cancer.

Meta-analysis of meta-analyses in oncologic positron emission tomography.

OBJECTIVES: As PET has become a standard of treatment in patients with cancer, publications of oncologic PET have grown sharply. We aimed to organize the data of meta-analyses of oncologic PET and assess the quality of studies. MATERIALS AND METHODS: The inclusion criteria were studies that meta-analyzed to combine the data from multiple studies of oncologic PET. We used the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) to assess the reporting quality of the included studies. RESULTS: A total of 254 meta-analyses were eligible for inclusion in the study. The peak number of publications increased up to 42 in 2014. Lung (n=39, 15.4%) is the most common site of tumor included in meta-analysis with oncologic PET. Overall, 84% of studies were categorized into diagnostic test accuracy reviews (n=214). Studies published in 2010 or later (n=213) showed higher PRISMA scores than those published in 2009 or before. CONCLUSION: A large number of meta-analyses are published in the field of oncologic PET. Meta-analyses in oncologic PET seem to be cited more often than regular research papers. The overall quality of studies is low; however, they showed improvement after PRISMA statement.

Accurate FDG PET tumor segmentation using the peritumoral halo layer method: a study in patients with esophageal squamous cell carcinoma.

BACKGROUND: In a previous study, FDG PET tumor segmentation (SegPHL) using the peritumoral halo layer (PHL) was more reliable than fixed threshold methods in patients with thyroid cancer. We performed this study to validate the reliability and accuracy of the PHL method in patients with esophageal squamous cell carcinomas (ESCCs), which can be larger and more heterogeneous than thyroid cancers. METHODS: A total of 121 ESCC patients (FDG avid = 85 (70.2%); FDG non-avid = 36 (29.8%)) were enrolled in this study. In FDG avid ESCCs, metabolic tumor length (ML) using SegPHL (MLPHL), fixed SUV 2.5 threshold (ML2.5), and fixed 40% of maximum SUV (SUVmax) (ML40%) were measured. Regression and Bland-Altman analyses were performed to evaluate associations between ML, endoscopic tumor length (EL), and pathologic tumor length (PL). A comparison test was performed to evaluate the absolute difference between ML and PL. Correlation with tumor threshold determined by the PHL method (PHL tumor threshold) and SUVmax was evaluated. RESULTS: MLPHL, ML2.5, and ML40% correlated well with EL (R2 = 0.6464, 0.5789, 0.3321, respectively; p < 0.001) and PL (R2 = 0.8778, 0.8365, 0.6266, respectively; p < 0.001). However, ML2.5 and ML40% showed significant proportional error with regard to PL; there was no significant error between MLPHL and PL. MLPHL showed the smallest standard deviation on Bland-Altman analyses. The absolute differences between ML and PL were significantly smaller for MLPHL and ML40% than for ML2.5 (p < 0.0001). The PHL tumor threshold showed an inverse correlation with SUVmax (σ = - 0.923, p < 0.0001). CONCLUSIONS: SegPHL was more accurate than fixed threshold methods in ESCC. The PHL tumor threshold was adjusted according to SUVmax of ESCC.