Predictive value of intratumoral-metabolic heterogeneity derived from 18F-FDG PET/CT in distinguishing microsatellite instability status of colorectal carcinoma.

Purpose/background: Microsatellite instability (MSI) status is a significant biomarker for the response to immune checkpoint inhibitors, response to 5-fluorouracil-based adjuvant chemotherapy, and prognosis in colorectal carcinoma (CRC). This study investigated the predictive value of intratumoral-metabolic heterogeneity (IMH) and conventional metabolic parameters derived from 18F-FDG PET/CT for MSI in patients with stage I-III CRC. Methods: This study was a retrospective analysis of 152 CRC patients with pathologically proven MSI who underwent 18F-FDG PET/CT examination from January 2016 to May 2022. Intratumoral-metabolic heterogeneity (including heterogeneity index [HI] and heterogeneity factor [HF]) and conventional metabolic parameters (standardized uptake value [SUV], metabolic tumor volume [MTV], and total lesion glycolysis [TLG]) of the primary lesions were determined. MTV and SUVmean were calculated on the basis of the percentage threshold of SUVs at 30%-70%. TLG, HI, and HF were obtained on the basis of the above corresponding thresholds. MSI was determined by immunohistochemical evaluation. Differences in clinicopathologic and various metabolic parameters between MSI-High (MSI-H) and microsatellite stability (MSS) groups were assessed. Potential risk factors for MSI were assessed by logistic regression analyses and used for construction of the mathematical model. Area under the curve (AUC) were used to evaluate the predictive ability of factors for MSI. Results: This study included 88 patients with CRC in stages I-III, including 19 (21.6%) patients with MSI-H and 69 (78.4%) patients with MSS. Poor differentiation, mucinous component, and various metabolic parameters including MTV30%, MTV40%, MTV50%, and MTV60%, as well as HI50%, HI60%, HI70%, and HF in the MSI-H group were significantly higher than those in the MSS group (all P < 0.05). In multivariate logistic regression analyses, post-standardized HI60% by Z-score (P = 0.037, OR: 2.107) and mucinous component (P < 0.001, OR:11.394) were independently correlated with MSI. AUC of HI60% and our model of the HI60% + mucinous component was 0.685 and 0.850, respectively (P = 0.019), and the AUC of HI30% in predicting the mucinous component was 0.663. Conclusions: Intratumoral-metabolic heterogeneity derived from 18F-FDG PET/CT was higher in MSI-H CRC and predicted MSI in stage I-III CRC patients preoperatively. HI60% and mucinous component were independent risk factors for MSI. These findings provide new methods to predict the MSI and mucinous component for patients with CRC.

Quantitative assessment of renal functions using 68Ga-EDTA dynamic PET imaging in renal injury in mice of different origins.

Background: Early detection of kidney diseases can be challenging as conventional methods such as blood tests or imaging techniques (computed tomography (CT), magnetic resonance imaging (MRI), or ultrasonography) may be insufficient to assess renal function. A single-photon emission CT (SPECT) renal scan provides a means of measuring glomerular filtration rates (GFRs), but its diagnostic accuracy is limited due to its planar imaging modality and semi-quantification property. In this study, we aimed to improve the accuracy of GFR measurement by preparing a positron emission tonometry (PET) tracer 68Ga-Ethylenediaminetetraacetic acid (68Ga-EDTA) and comprehensively evaluating its performance in healthy mice and murine models of renal dysfunction. Methods: Dynamic PET scans were performed in healthy C57BL/6 mice and in models of renal injury, including acute kidney injury (AKI) and unilateral ureter obstruction (UUO) using 68Ga-EDTA. In a 30-min dynamic scan, PET images and time-activity curves (TACs) were acquired. Renal function and GFR values were measured using renograms and validated through serum renal function parameters, biodistribution results, and pathological staining. Results: 68Ga-EDTA dynamic PET imaging quantitatively captured the tracer elimination process. The calculated GFR values were 0.25 ± 0.02 ml/min in healthy mice, 0.01 ± 0.00 ml/min in AKI mice, and 0.25 ± 0.04, 0.29 ± 0.03 and 0.24 ± 0.01 ml/min in UUO mice, respectively. Furthermore, 68Ga-EDTA dynamic PET imaging and GFRPET were able to differentiate mild renal impairment before serum parameters indicated any changes. Conclusions: Our findings demonstrate that 68Ga-EDTA dynamic PET provides a reliable and precise means of evaluating renal function in two murine models of renal injury. These results hold promise for the widespread clinical application of 68Ga-EDTA dynamic PET in the near future.

Corrigendum: Predictive value of intratumoral-metabolic heterogeneity derived from 18F-FDG PET/CT in distinguishing microsatellite instability status of colorectal carcinoma.

[This corrects the article DOI: 10.3389/fonc.2023.1065744.].

Glomerular filtration rate calculation based on 68Ga-EDTA dynamic renal PET.

Positron emission tomography (PET) can accurately locate and quantify radioactivity over traditional single photon emission computed tomography (SPECT), encouraging its application in kidney function evaluation and glomerular filtration rate (GFR) measurement. 68Ga-ethylenediamine-tetraacetic acid (68Ga-EDTA) is a novel PET tracer for renal scan but a mature GFR calculation method still pending establishment. Herein, we aim to investigate the imaging performance of 68Ga-EDTA dynamic PET in healthy C57BL/6 mice, establish quantitative methods to calculate GFR, and evaluate its feasibility in mice with kidney dysfunction. Dynamic PET of 68Ga-EDTA successfully visualized the whole process of tracer elimination. GFR values were measured by the integral method (253.80±40.11 µL/min) and the Patlak Plot method (22.69±9.75 µL/min), while blood clearance rate of the tracer was found at 787.46±70.86 µL/min. The PET-based GFR values correlate well with the GFRblood (R2=0.7468, R2=0.8793). The Integral method provides better accuracy than Patlak Plot method. Further application of GFR measurement in kidney-diseased mice proves better performance of the Integral method for defining split renal function.

Mutated SASH1 promotes Mitf expression in a heterozygous mutated SASH1 knock­in mouse model.

The SAM and SH3 domain­containing 1 (SASH1) genes have been identified as the causal genes of dyschromatosis universalis hereditaria (DUH); these genes cause the pathological phenotypes of DUH, and SASH1 variants have been shown to regulate the abnormal pigmentation phenotype in human skin in various genodermatoses. However, investigations into the mutated SASH1 gene have been limited to in vitro studies. In the present study, to recapitulate the molecular pathological phenotypes of individuals with DUH induced by SASH1 mutations, a heterozygous BALB/c mouse model, in which the human SASH1 c.1654 T>G (p. Tyr 551Asp, Y551D) mutation was knocked in was first generated. The in vivo functional experiments on Y551D SASH1 indicated that the increased expression of microphthalmia­associated transcription factor (Mitf) was uniformly induced in the tails of heterozygous BALB/c mice, and an increased quantity of Mitf­positive epithelial cells was also detected. An increased expression of Mitf­ and Mitf­positive cells was also demonstrated in the epithelial tissues of Y551D­SASH1 affected individuals. In the present study, Mitf expression was also found to be increased by Y551D SASH1 in vitro. Taken together, these findings indicate that the upregulation of Mitf is the bona fide effector of the Y551D SASH1­mediated melanogenesis signaling pathway in vivo. SASH1 may function as a scaffold molecule for the assembly of a SASH1­Mitf molecular complex to regulate Mitf expression in the cell nucleus and thus to promote the hyperpigmented phenotype in the pathogenesis of DUH and other genodermatoses related to pigment abnormalities.