Thyroglobulin-Based Risk Factor Repositioning for Determining Radioactive Iodine Activity in Patients with Papillary Thyroid Carcinoma: a Multicenter Retrospective Cohort Study.

Purpose: We aimed to investigate the impact of various factors including radioactive iodine (RAI) activity on the therapeutic response according to the range of serum thyroglobulin (Tg) in patients with papillary thyroid carcinoma (PTC). Methods: A total of 2809 patients were retrospectively enrolled from 24 hospitals. They were divided into four subgroups according to their serum Tg (stimulated Tg, sTg) or anti-Tg antibody (TgAb) levels, measured just before RAI therapy: sTg < 2 ng/mL, 2 ≤ sTg < 10 ng/mL, sTg ≥ 10 ng/mL, and TgAb > 100 IU/mL. The clinicopathologic factors for therapeutic responses, which were classified as acceptable response (AR) or non-AR, were compared in each subgroup. Results: Clinical impact of the pN category on therapeutic response was different among subgroups based on sTg levels (subgroups with sTg < 2 ng/mL (P = 0.057), 2 ≤ sTg < 10 ng/mL (P = 0.032), and sTg ≥ 10 ng/mL (P = 0.001)). The pN category was also a significant factor in the subgroup with TgAb > 100 IU/mL (P = 0.006). The pT category was not associated with therapeutic response regardless of the sTg level. High activities of RAI (≥ 3.70 GBq) were associated with favorable therapeutic responses in only the subgroup with sTg ≥ 10 ng/mL (P = 0.044). Conclusion: Risk factors for response prediction could be repositioned based on the serum Tg before RAI therapy. RAI activity should be determined while considering the serum Tg-aided remnant thyroid or malignant tissues as well as conventional factors. Supplementary Information: The online version contains supplementary material available at 10.1007/s13139-022-00756-4.

In vivo imaging of invasive aspergillosis with 18F-fluorodeoxysorbitol positron emission tomography.

Invasive aspergillosis is a critical complication in immunocompromised patients with hematologic malignancies or with viral pneumonia caused by influenza virus or SARS­CoV­2. Although early and accurate diagnosis of invasive aspergillosis can maximize clinical outcomes, current diagnostic methods are time-consuming and poorly sensitive. Here, we assess the ability of 2-deoxy-2-18F-fluorosorbitol (18F-FDS) positron emission tomography (PET) to specifically and noninvasively detect Aspergillus infections. We show that 18F-FDS PET can be used to visualize Aspergillus fumigatus infection of the lungs, brain, and muscles in mouse models. In particular, 18F-FDS can distinguish pulmonary aspergillosis from Staphylococcus aureus infection, both of which induce pulmonary infiltrates in immunocompromised patients. Thus, our results indicate that the combination of 18F-FDS PET and appropriate clinical information may be useful in the differential diagnosis and localization of invasive aspergillosis.

A Stepwise Approach Using Metastatic Lymph Node Ratio-Combined Thyroglobulin for Customization of [18F]FDG-PET/CT Indication to Detect Persistent Disease in Patients with Papillary Thyroid Cancer.

We investigated whether an indication for [18F]FDG-PET/CT to detect FDG-avid persistent disease (PD) could be identified precisely using the extent of metastatic lymph nodes (MLNs) and serum thyroglobulin (Tg) in papillary thyroid cancer (PTC) patients. This retrospective study included 429 PTC patients who underwent surgery and radioactive iodine (RAI) therapy. [18F]FDG-PET/CT and serum Tg were evaluated just before RAI therapy. The MLN ratio (LNR) was defined as the ratio of the number of MLNs to the number of removed LNs. To derive the LNR-combined criteria, different Tg cut-off values for identifying the PET/CT-indicated group for PD detection were applied individually to subgroups initially classified based on LNR cut-off values. The cut-off values for serum Tg, the number of MLNs, and LNR for a PET/CT indication were 6.0 ng/mL, 5, and 0.51, respectively. Compared to a single parameter (serum Tg, total number of MLNs, and LNR), the LNR-combined criteria showed significantly superior diagnostic performance in detecting FDG-avid PD (p < 0.001). The diagnostic performance of PET/CT in detecting FDG-avid PD was significantly improved when the PET/CT-indicated group was identified through the LNR-combined criteria in a stepwise manner; this can contribute to a customized PET/CT indication in PTC patients.

Clinical impact of radioactive iodine dose selection based on the number of metastatic lymph nodes in patients with papillary thyroid carcinoma: A multicenter retrospective cohort study.

OBJECTIVE: The aim of this study is to investigate whether the number of metastatic lymph nodes (LNs) could be used as a basis in the radioactive iodine (RAI) dose selection for patients with papillary thyroid carcinoma (PTC). PATIENTS: A total of 595 patients with PTC who received first RAI therapy after total or near-total thyroidectomy and had no evidence of disease in treatment response assessment were retrospectively enroled from five hospitals. The patients were classified into two subgroups based on the number of metastatic LNs (>5). The multivariate Cox-proportional hazard model was performed to identify the significant factors for recurrence prediction in each group as well as all enroled patients. RESULTS: Overall, 22 (3.7%) out of 595 patients had the recurrent disease during the follow-up period. The number of metastatic LNs (>5) was only a significant factor for recurrence prediction in all enroled patients (odds ratio: 7.834, p < .001). In the subgroup with ≤5 metastatic LNs, the presence of extrathyroidal extension was only associated with recurrence (odds ratio: 7.333, p = .024) in multivariate analysis. RAI dose was significantly associated with recurrence rate in which the patients with high-dose RAI (3.7 GBq or higher) had less incidence of recurrence than those with low-dose RAI (1.11 GBq) in the subgroup with more than five metastatic LNs (odds ratio: 6.533, p = .026). CONCLUSIONS: High-dose RAI (≥3.7 GBq) therapy significantly lowered the recurrence rate in patients with more than five metastatic LNs. Therefore, RAI dose should be determined based on the number of metastatic LNs as well as conventional risk factors.

Change of Therapeutic Response Classification According to Recombinant Human Thyrotropin-Stimulated Thyroglobulin Measured at Different Time Points in Papillary Thyroid Carcinoma.

PURPOSE: We investigated whether response classification after total thyroidectomy and radioactive iodine (RAI) therapy could be affected by serum levels of recombinant human thyrotropin (rhTSH)-stimulated thyroglobulin (Tg) measured at different time points in a follow-up of patients with papillary thyroid carcinoma (PTC). METHODS: A total of 147 PTC patients underwent serum Tg measurement for response assessment 6 to 24 months after the first RAI therapy. Serum Tg levels were measured at 24 h (D1Tg) and 48-72 h (D2-3Tg) after the 2nd injection of rhTSH. Responses were classified into three categories based on serum Tg corresponding to the excellent response (ER-Tg), indeterminate response (IR-Tg), and biochemical incomplete response (BIR-Tg). The distribution pattern of response classification based on serum Tg at different time points (D1Tg vs. D2-3Tg) was compared. RESULTS: Serum D2-3Tg level was higher than D1Tg level (0.339 ng/mL vs. 0.239 ng/mL, P < 0.001). The distribution of response categories was not significantly different between D1Tg-based and D2-3Tg-based classification. However, 8 of 103 (7.8%) patients and 3 of 40 (7.5%) patients initially categorized as ER-Tg and IR-Tg based on D1Tg, respectively, were reclassified to IR-Tg and BIR-Tg based on D2-3Tg, respectively. The optimal cutoff values of D1Tg for the change of response categories were 0.557 ng/mL (from ER-Tg to IR-Tg) and 6.845 ng/mL (from IR-Tg to BIR-Tg). CONCLUSION: D1Tg measurement was sufficient to assess the therapeutic response in most patients with low level of D1Tg. Nevertheless, D2-3Tg measurement was still necessary in the patients with D1Tg higher than a certain level as response classification based on D2-3Tg could change.

Differences in diagnostic impact of dual-tracer PET/computed tomography according to the extrahepatic metastatic site in patients with hepatocellular carcinoma.

OBJECTIVES: We compared the diagnostic performance of C-11 acetate and F-18 fluorodeoxyglucose (FDG) PET/computed tomography (CT) for the detection of extrahepatic metastasis in patients with hepatocellular carcinoma (HCC) and evaluated whether the improvement in the diagnostic performance of dual tracer PET/CT differs by the metastatic site. METHODS: Fifty-eight patients who had extrahepatic metastasis on either C-11 acetate or F-18 FDG PET/CT were enrolled, and 193 metastatic lesions were analyzed in this retrospective study. The metastatic lesions were categorized based on six sites of involvement. According to each involved site, the tracer avidity of the metastatic lesions was compared using the maximum standardized uptake value (SUVmax). RESULTS: Bone was the most frequent categorized metastatic site (44.8%), followed by lymph node (39.7%), lung (34.5%), soft tissue (27.6%), adrenal gland (6.9%), and vascular category (3.4%). C-11 acetate PET/CT showed a higher SUVmax than F-18 FDG PET/CT in metastatic bone lesions (P = 0.003). F-18 FDG uptake was significantly higher than C-11 acetate uptake in metastatic lymph node lesions (P < 0.001). The detection rate of dual tracer PET/CT was significantly higher in the metastatic lung (93.6%) and soft tissue (100%) lesions. However, the diagnostic performance of dual tracer PET/CT was limited in the metastatic bone and lymph node lesions because each tracer's detection rate was very high (bone: 94.6% in C-11 acetate, lymph node: 94.1% in F-18 FDG). CONCLUSIONS: The tracer avidity of metastatic lesions differed according to the involved site. This difference affected the complementary role of dual tracer PET/CT in the diagnosis of extrahepatic metastases in patients with HCC.

Shy Girl, a kiwifruit suppressor of feminization, restricts gynoecium development via regulation of cytokinin metabolism and signalling.

Kiwifruit (Actinidia chinensis) is a dioecious, long-living woody perennial vine. Reduced generation time and induction of hermaphroditism can accelerate crop improvement and facilitate alternative farming for better food security in the face of climate change. Previous studies identified that CENTRORADIALIS genes CEN and CEN4 act to repress flowering, whilst the male-specific Shy Girl (SyGl) gene with homology to type-C cytokinin response regulators could repress gynoecium development in model plants. Here we use CRISPR/Cas9 to mutagenize CEN, CEN4 and SyGl in the male kiwifruit A. chinensis 'Bruce'. Biallelic mutations of CEN and CEN4 generated rapid-flowering male plants, and simultaneous targeting of CEN4 and SyGl gave rise to rapid-flowering hermaphrodites with restored gynoecial function and viable pollen, providing functional evidence for the role of SyGl in suppression of feminization. Analysis of ovary tissues identified genes that contribute to carpel development and revealed that SyGl affected both cytokinin profiles and the expression of genes involved in cytokinin metabolism and signalling. The plant lines generated by CEN4/SyGl knockout could self-pollinate and produce fast-flowering offspring. These results establish that SyGI acts as the suppressor of feminization in kiwifruit and demonstrate the potential for accelerated breeding in an outcrossing horticultural woody perennial.

Clinical Impact of F-18 FDG PET-CT on Biopsy Site Selection in Patients with Suspected Bone Metastasis of Unknown Primary Site.

PURPOSE: We investigated the clinical role of F-18 fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) in the identification of the primary site and the selection of the optimal biopsy site in patients with suspected bone metastasis of unknown primary site. METHODS: The patients with suspected bone metastasis who underwent PET-CT for evaluation of primary site were enrolled in this study. The primary sites were identified by the histopathologic or imaging studies and were classified according to the FDG uptake positivity of the primary site. To evaluate the guiding capability of PET-CT in biopsy site selection, we statistically analyzed whether the biopsy site could be affected according to the presence of extra-skeletal FDG uptake. RESULTS: Among 74 enrolled patients, 51 patients had a metastatic bone disease. The primary site was identified in 48 of 51 patients (94.1%). Forty-six patients were eligible to test the association of clinical choice of biopsy site with PET positivity of extra-skeletal lesion. The extra-skeletal biopsies were done in 42 out of 43 patients with positive extra-skeletal uptake lesions. Bone biopsies were inevitably performed in the other three patients without extra-skeletal uptake lesions. The association came out to be significant (Fisher's exact test, P < 0.001). CONCLUSION: F-18 FDG PET-CT significantly contributed not only to identify the primary site but also to suggest optimal biopsy sites in patients with suspected bone metastasis.

Combined role of lymph node ratio and serum thyroglobulin levels in predicting prognosis of papillary thyroid carcinoma.

OBJECTIVES: The aim of this study was to evaluate a prognostic value of the extent of metastatic lymph node combined with TSH-stimulated serum thyroglobulin (sTg) measured just before radioactive iodine (RAI) therapy in patients with papillary thyroid cancer (PTC). METHODS: The retrospective study included 468 patients with PTC who underwent total thyroidectomy with neck dissection and postoperative RAI therapy. The extent of metastatic lymph node was evaluated with the lymph node ratio (LNR) which was defined as the number of metastatic lymph nodes out of the number of total removed lymph nodes. We investigated which factors could significantly predict persistent or recurrent disease (PRD). RESULTS: LNR ≥0.4 (P = 0.002) and sTg ≥6.0 ng/mL (P < 0.001) were associated with PRD in univariate analysis. In multivariate analysis, only male [hazard ratio: 2.35, 95% confidence interval (CI): 1.18-4.66, P = 0.014] and sTg (hazard ratio: 9.35, 95% CI: 4.44-19.67, P < 0.001) were associated with PRD prediction. When we divided patients into two groups (patients with sTg level < 6.0 ng/mL and those with sTg level ≥ 6.0 ng/mL), LNR (≥0.4) was a significant predictor of PRD in patients with sTg <6.0 ng/mL (hazard ratio: 4.38, 95% CI: 1.22-15.72, P = 0.024). CONCLUSIONS: LNR ≥0.4 was a significant predictor of PRD when the sTg level was <6.0 ng/mL. LNR should be used in combination with a relatively low level of serum sTg to predict the prognosis of patients with PTC.

Optimization of serum thyroglobulin measured at different time points for prognostic evaluation in differentiated thyroid carcinoma patients.

Although serum thyroglobulin (Tg) is a reliable differentiated thyroid carcinoma (DTC) prognostic marker, its cutoff values can be affected by TSH stimulation status. Serum Tg prognostic values measured at different time points before and after radioactive iodine (RAI) therapy prepared with recombinant human TSH (rhTSH) in DTC patients, were investigated.This study included 160 DTC patients who underwent surgery followed by rhTSH-aided RAI therapy. Their serum Tg levels were measured 7 days before (D-7Tg), on the day of (D0Tg), and 2 days after (D2Tg) the RAI therapy. For response evaluation, the patients were classified into 2 groups: acceptable response and non-acceptable response (non-AR). Optimal Tg level cutoff values measured at different time points were evaluated for persistent or recurrent disease (PRD) prediction, as well as therapeutic response.Multivariate analysis showed that D-7Tg, D0Tg, and D2Tg significantly predicted non-AR (P < .05, for all). Optimal Tg level cutoff values for non-AR prediction were 0.6, 2.6, and 3.7 ng/mL for D-7Tg, D0Tg, and D2Tg, respectively. Cox regression analysis showed that Tg levels were significantly associated with PRD free survival with D-7Tg, D0Tg, and D2Tg cutoff values of 0.8, 4.0, and 6.0 ng/mL, respectively (D-7Tg, P = .010; D0Tg, P = .005; D2Tg, P = .011).Serum Tg levels measured at the different time points could predict PRD free survival as well as therapeutic response with different cutoff values in DTC patients who underwent rhTSH-aided RAI therapy.

Optimization of Predictive Performance for the Therapeutic Response Using Iodine Scan-Corrected Serum Thyroglobulin in Patients with Differentiated Thyroid Carcinoma.

We investigated whether the performance of serum thyroglobulin (Tg) for response prediction could be improved based on the iodine uptake pattern on the post-therapeutic I-131 whole body scan (RxWBS) and the degree of thyroid tissue damage with radioactive iodine (RAI) therapy. A total of 319 patients with differentiated thyroid carcinoma who underwent total thyroidectomy and RAI therapy were included. Based on the presence/absence of focal uptake at the anterior midline of the neck above the thyroidectomy bed on RxWBS, patients were classified into positive and negative uptake groups. Serum Tg was measured immediately before (D0Tg) and 7 days after RAI therapy (D7Tg). Patients were further categorized into favorable and unfavorable Tg groups based on the prediction of excellent response (ER) using scan-corrected Tg developed through the stepwise combination of D0Tg with ratio Tg (D7Tg/D0Tg). We investigated whether the predictive performance for ER improved with the application of scan-corrected Tg compared to the single Tg cutoff. The combined approach using scan-corrected Tg showed better predictive performance for ER than the single cutoff of D0Tg alone (p < 0.001). Therefore, scan-corrected Tg can be a promising biomarker to predict the therapeutic responses after RAI therapy.

A Stepwise Approach to Identify the Clinical Role of 18F-FDG PET/CT in Patients With Suspicious Bone Metastasis From an Unknown Primary Site.

In patients with suspicious bone metastasis, the clinical impact of PET/CT for differential diagnosis and primary lesion identification could differ according to F-FDG uptake patterns. We report the findings in patients with suspicious bone metastasis who underwent PET/CT for the evaluation of the primary lesion site and were classified in a stepwise manner, first based on the multiplicity of positive bone uptake and then the presence of extraskeletal uptake.

Mutagenesis of kiwifruit CENTRORADIALIS-like genes transforms a climbing woody perennial with long juvenility and axillary flowering into a compact plant with rapid terminal flowering.

Annualization of woody perennials has the potential to revolutionize the breeding and production of fruit crops and rapidly improve horticultural species. Kiwifruit (Actinidia chinensis) is a recently domesticated fruit crop with a short history of breeding and tremendous potential for improvement. Previously, multiple kiwifruit CENTRORADIALIS (CEN)-like genes have been identified as potential repressors of flowering. In this study, CRISPR/Cas9- mediated manipulation enabled functional analysis of kiwifruit CEN-like genes AcCEN4 and AcCEN. Mutation of these genes transformed a climbing woody perennial, which develops axillary inflorescences after many years of juvenility, into a compact plant with rapid terminal flower and fruit development. The number of affected genes and alleles and severity of detected mutations correlated with the precocity and change in plant stature, suggesting that a bi-allelic mutation of either AcCEN4 or AcCEN may be sufficient for early flowering, whereas mutations affecting both genes further contributed to precocity and enhanced the compact growth habit. CRISPR/Cas9-mediated mutagenesis of AcCEN4 and AcCEN may be a valuable means to engineer Actinidia amenable for accelerated breeding, indoor farming and cultivation as an annual crop.

Response Prediction of Altered Thyroglobulin Levels After Radioactive Iodine Therapy Aided by Recombinant Human Thyrotropin in Patients with Differentiated Thyroid Cancer.

PURPOSE: Thyroglobulin (Tg) may be released from damaged residual thyroid tissues after radioactive iodine (RAI) therapy in patients with differentiated thyroid carcinoma (DTC). We investigated whether altered levels of serum Tg after recombinant human thyrotropin (rhTSH)-aided RAI therapy could be a prognostic marker in patients with DTC. METHODS: We evaluated 68 patients who underwent RAI therapy after total thyroidectomy. Serum Tg levels were measured just before RAI administration (D0Tg) and 7 days after RAI therapy (D7Tg). Patients with a D0Tg level greater than 2.0 ng/mL were excluded to more precisely evaluate the injury effect of RAI in small remnant tissues. The ratioTg was defined as the D7Tg level divided by that on D0Tg. The therapeutic responses were classified as acceptable or non-acceptable. Finally, we investigated which clinicopathologic parameters were associated with therapeutic response. RESULTS: At the follow-up examination, an acceptable response was observed in 50 patients (73.5%). Univariate analysis revealed significant differences in N stage (P = 0.003) and ratioTg (acceptable vs. non-acceptable responses, 21.9 ± 33.6 vs. 3.8 ± 6.5; P = 0.006). In multivariate analysis, only ratioTg significantly predicted an acceptable response (odds ratio 1.104; 95% confidence interval 1.005-1.213; P = 0.040). A ratioTg above 3.5 predicted an acceptable response with a sensitivity of 66.0%, specificity of 83.3%, and accuracy of 70.6% (area under the curve = 0.718; P = 0.006). CONCLUSIONS: Altered levels of serum Tg after RAI therapy, calculated as the ratioTg (D7Tg/D0Tg), significantly predicted an acceptable response in patients with DTC.