eLIMS: Ensemble Learning-Based Spatial Segmentation of Mass Spectrometry Imaging to Explore Metabolic Heterogeneity.

Spatial segmentation is an essential processing method for image analysis aiming to identify the characteristic suborgans or microregions from mass spectrometry imaging (MSI) data, which is critical for understanding the spatial heterogeneity of biological information and function and the underlying molecular signatures. Due to the intrinsic characteristics of MSI data including spectral nonlinearity, high-dimensionality, and large data size, the common segmentation methods lack the capability for capturing the accurate microregions associated with biological functions. Here we proposed an ensemble learning-based spatial segmentation strategy, named eLIMS, that combines a randomized unified manifold approximation and projection (r-UMAP) dimensionality reduction module for extracting significant features and an ensemble pixel clustering module for aggregating the clustering maps from r-UMAP. Three MSI datasets are used to evaluate the performance of eLIMS, including mouse fetus, human adenocarcinoma, and mouse brain. Experimental results demonstrate that the proposed method has potential in partitioning the heterogeneous tissues into several subregions associated with anatomical structure, i.e., the suborgans of the brain region in mouse fetus data are identified as dorsal pallium, midbrain, and brainstem. Furthermore, it effectively discovers critical microregions related to physiological and pathological variations offering new insight into metabolic heterogeneity.

Multicenter Randomized Double-Blind Phase III Trial of Donafenib in Progressive Radioactive Iodine-Refractory Differentiated Thyroid Cancer.

PURPOSE: The phase II/III study of donafenib was initiated when there was no available treatment indicated for Chinese patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC). Donafenib, an oral tyrosine kinase inhibitor (TKI), showed good efficacy and tolerability in the phase II study. We aimed to further evaluate the antitumor activity and safety of donafenib in Chinese patients with RAIR-DTC. PATIENTS AND METHODS: This multicenter, double-blind, placebo-controlled, phase III study enrolled 191 patients with progressive RAIR-DTC and randomized in a ratio of 2:1 to donafenib (300 mg twice daily, n = 128) or matched placebo (n = 63). An open-label donafenib treatment period was allowed upon disease progression. The primary endpoint was progression-free survival (PFS) assessed by the independent review committee. The second endpoints include objective response rate (ORR), disease control rate (DCR), safety, etc. RESULTS: Donafenib demonstrated prolonged median PFS over placebo [12.9 vs. 6.4 months; hazard ratio (HR), 0.39; 95% confidence interval (CI), 0.25-0.61; P < 0.0001] in Chinese patients with RAIR-DTC. Improved ORR (23.3% vs. 1.7%; P = 0.0002) and DCR (93.3% vs. 79.3%; P = 0.0044) were observed in the donafenib group over placebo. For donafenib, the most common grade ≥ 3 treatment-related adverse events (AE) included hypertension (13.3%) and hand-foot syndrome (12.5%), 42.2% underwent dose reduction or interruption, and 6.3% experienced discontinuation. CONCLUSIONS: Donafenib was well-tolerated and demonstrated clinical benefit in terms of improved PFS, ORR, and DCR in patients with RAIR-DTC. The results suggest that donafenib could be a new treatment option for patients with RAIR-DTC.

Differential distribution and prognostic value of CD4+ T cell subsets before and after radioactive iodine therapy in differentiated thyroid cancer with varied curative outcomes.

Differentiated thyroid cancer is the most frequently diagnosed endocrine tumor. While differentiated thyroid cancers often respond to initial treatment, little is known about the differences in circulating immune cells amongst patients who respond differently. A prospective study of 39 patients with differentiated thyroid cancer was conducted. Serum thyroglobulin levels and thyroid and immunological functions were tested before and after radioactive iodine treatment (RAIT). Efficacy assessments were performed 6 to 12 months after radioactive iodine treatment. Most patients showed an excellent response to radioactive iodine treatment. Before radioactive iodine treatment, the excellent response group had considerably fewer circulating CD4+ T cell subsets than the non-excellent response group. Both the excellent response and non-excellent response groups had considerably lower circulating CD4+ T lymphocyte subsets 30 days after radioactive iodine treatment, but those of the excellent response group were still lower than those of the non-excellent response group. All circulating CD4+ T cell subsets in the excellent response group rose by varying degrees by the 90th day, but only Treg cell amounts increased in the non-excellent response group. Interestingly, in the non-excellent response group, we noticed a steady drop in Th1 cells. However, the bulk of circulating CD4+ T cell subsets between the two groups did not differ appreciably by the 90th day. Finally, we discovered that CD4+ T cell subsets had strong predictive potential, and we thus developed high-predictive-performance models that deliver more dependable prognostic information. In conclusion, in individuals with differentiated thyroid cancer, there is great variation in circulating immune cells, resulting in distinct treatment outcomes. Low absolute CD4+ T cell counts is linked to improved clinical outcomes as well as stronger adaptive and resilience capacities.

Dynamic Immune Function Changes Before and After the First Radioactive Iodine Therapy After Total Resection of Differentiated Thyroid Carcinoma.

The effects of total thyroidectomy or radioactive iodine therapy on immune activation and suppression of the tumor microenvironment remain unknown. We aimed to investigate the effects of these treatments on the immune function in patients with differentiated thyroid carcinoma (DTC). Our cohort included 45 patients with DTC treated with total thyroidectomy and radioactive iodine therapy (RAIT). Immune function tests were performed by flow cytometry at 0, 30, and 90 days post-RAIT. Both the percentage and absolute number of circulating regulatory T cells were significantly lower in the postoperative DTC compared to the healthy controls. Notably, the absolute number of multiple lymphocyte subgroups significantly decreased at 30 days post-RAIT compared to those pre-RAIT. The absolute counts of these lymphocytes were recovered at 90 days post-RAIT, but not at pre-RAIT levels. Additionally, the Th17 cell percentage before RAIT was positively correlated with thyroglobulin (Tg) levels after RAIT. The tumor burden might contribute to increased levels of circulating Tregs. In conclusion, RAIT caused transient radiation damage in patients with DTC and the percentage of Th17 cells before RAIT could be a significant predictor of poor prognosis in patients with DTC.

Radiosynthesis and evaluation of N5-(2-18F-fluoropropanyl) ornithine as a potential agent for tumor PET imaging.

OBJECTIVE: Studies have confirmed that tumorigenesis is related to an imbalance of polyamine metabolism and over-expression of oncogenes resulting in the up-regulation of ornithine decarboxylase (ODC, the first rate-limiting enzyme for regulating intracellular polyamines biosynthesis), which has become a target for anti-tumor therapy. In this study, an ornithine derivative, N5-(2-[18F]fluoropropionyl) ornithine (N5-[18F]FPO), has been prepared and its potential utility for tumor PET imaging evaluated. METHODS: N5-[18F]FPO was successfully prepared via a nucleophilic fluorination reaction and a subsequent efficient deprotection step. The in vitro and in vivo stability were determined by HPLC conducted in fetal bovine serum, saline and rat urine. Cellular uptake studies were conducted in HepG2 cells and the biodistribution and micro-PET/CT imaging performed in normal ICR mice and three tumor-bearing mice models, respectively. RESULTS: Total synthesis time of N5-[18F]FPO was about 80 min with a radiochemical yield of 15% ± 6% (uncorrected, based on 18F-, n = 6) and a high radiochemical stability can be seen in vitro and vivo. The N5-[18F]FPO exhibited fast uptake in HepG2 cells and the cellular uptake ability of N5-[18F]FPO can be inhibited by L-ornithine and DFMO, which indicated that the transport pathway of N5-[18F]FPO is similar to that of L-ornithine, interacting with ODC after being transported into the cell. The biodistribution and micro-PET/CT images demonstrate that N5-[18F]FPO was excreted by the urinary system, and excellent tumor visualization with high tumor-to-background ratios can be observed in the three tumor-bearing mice models studied. CONCLUSION: All the above results suggest that N5-[18F]FPO has the potential to be a novel radiotracer for imaging ODC expression in solid tumors.

[Radioiodine-131 therapy improves sex hormones and sexual function in male patients with Graves' disease].

OBJECTIVE: To observe the changes of sex hormones and sexual function in male patients with Graves' disease (GD) after Radioiodine-131 (I-131) therapy. METHODS: Thirty-four male GD patients, aged 21 -40 (32.3 +/- 6.7) years, were treated with I-131 at the dose of 111 - 407 (237.8 +/- 51.8) MBq. The levels of serum sex hormones were measured, and the patients'scores on erectile function (IIEF-5) were obtained before and 3 and 6 months after the treatment. Another 20 healthy men aged 25 - 37 (31 +/- 3.1) years were enlisted as controls. RESULTS: The baseline levels of estrogen (E2), testosterone (T) and luteinizing hormone (LH) were (132.5 +/- 40.4) pmol/L, (21.6 +/- 4.6) nmol/L and (10.1 +/- 4.4) IU/L in the GD patients, significantly higher than (80.4 +/- 31.2) pmol/L, (14.5 +/- 4.2) nmol/L and (6.2 +/- 1.9) IU/L in the healthy controls (P < 0.05). The E2, T and LH levels showed a significant decrease in the GD patients after 3 months of treatment ([110.2 +/- 20.6] pmol/L, [17.7 +/- 5.5] nmol/L and (9.4 +/- 3.9) IU/L, P < 0.05), but exhibited no statistically significant differences from the healthy controls at 6 months ([82.6 +/- 30.1] pmol/L, [13.8 +/- 3.4 ] nmol/L and [6.6 +/- 1.5] IU/L, P > 0.05). The IIEF-5 score of the GD patients was 5 - 25 (15.5 +/- 3.5) before I-131 treatment, significantly lower than that of the controls (19 - 25, 24 +/- 0.5) (P < 0.05), and it was 8 - 25 (19.5 +/- 1.0) at 3 months and 10 - 25 (23.5 +/- 1.5) at 6 months, significantly higher in the latter than in the former (P < 0.05), and with no significant difference between the 6-month treated patients and the healthy controls (P > 0.05). CONCLUSION: The E2, T and LH levels are increased while the IIEF-5 score decreased markedly in male GD patients. Six-month treatment with I-131 can not only restore the E2, T and LH levels to normal but also significantly improve the patient's sexual function.