(18)F-FAMT PET showed higher specificity for detecting malignant lesions than (18)F-FDG PET. The uptake of (18)F-FAMT by OSCC cells can be determined by the presence of LAT1 expression and tumour cell proliferation.

Ferroptosis is a newly recognized mechanism of regulated cell death. It was reported to be highly associated with immune therapy and chemotherapy. However, its mechanism of regulation in the tumor microenvironment (TME) and influence on oral squamous cell carcinoma (OSCC) therapy are unknown. We identified a ferroptosis-specific gene-expression signature, an FPscore, developed by a principal component analysis (PCA) algorithm to evaluate the ferroptosis regulation patterns of individual tumor. Multi-omics analysis of ferroptosis regulation patterns was conducted. Three distinct ferroptosis regulation subtypes, which linked to outcomes and the clinical relevance of each patient, were established. A high FPscore of patients with OSCC was associated with a favorable prognosis, a ferroptosis-related immune-activation phenotype, potential sensitivities to the chemotherapy and immunotherapy. Importantly, a high FPscore correlated with a low gene copy number burden and high immune checkpoint expressions. We validated the prognostic value of the FPscore using independent immunotherapy and pan-cancer cohorts. Comprehensive evaluation of individual tumors with distinct ferroptosis regulation patterns provides new mechanistic insights, which may be clinically relevant for the application of combination therapies in OSCC.

The accurate depiction of both biologic and anatomic profiles of tumors has long been a challenge in PET imaging. An inflammation, which is innate in the carcinogenesis of oral squamous cell carcinoma (OSCC), frequently complicates the image analysis because of the limitations of 18 F-FDG and maximum standardized uptake values (SUV max ). New PET parameters, metabolic tumor volume (MTV) and total lesion glycolysis (TLG), as well as 18 Ffluoro-α-methyltyrosine ( 18 F-FAMT), a malignancy-specific amino acid-based PET radiotracer, are considered more comprehensive in tumor image analysis. Here, we showed the substantial effects of the intratumoral inflammatory process on 18 F-FDG uptake and further study the possibility of MTV and TLG to predict both tumor biology (proliferation activity) and anatomy (pathologic tumor volume). Methods: 18 F-FDG and 18 F-FAMT PET images from 25 OSCC patients were analyzed. SUV max on the tumor site was obtained. PET volume computerized-assisted reporting was used to generate a volume of interest to obtain MTV and TLG for 18 F-FDG and total lesion retention (TLR) for 18 F-FAMT. The whole tumor dissected from surgery was measured and sectioned for pathologic analysis of tumor inflammation grade and Ki-67 labeling index. Results: The high SUV max of 18 F-FDG was related to the high inflammation grade. The SUV max ratio of 18 F-FDG to 18 F-FAMT was higher in inflammatory tumors (P , 0.05) whereas the corresponding value in tumors with a low inflammation grade was kept low. All 18 F-FAMT parameters were correlated with Ki-67 labeling index (P , 0.01). Pathologic tumor volume predicted from MTV of 18 F-FAMT was more accurate (R 5 0.90, bias 5 3.4 ± 6.42 cm 3 , 95% confidence interval 5 0.77-6.09 cm 3 ) than that of 18 F-FDG (R 5 0.77, bias 5 8.1 ± 11.17 cm 3 , 95% confidence interval 5 3.45-12.67 cm 3 ). Conclusion: 18 F-FDG uptake was overestimated by additional uptake related to the intratumoral inflammatory process, whereas 18 F-FAMT simply accumulated in tumors according to tumor activity as evaluated by Ki-67 labeling index in OSCC.

(18)F-FAMT PET/CT was useful and more specific than MRI or (18)F-FDG PET/CT in the detection of bone marrow invasion of OSCC and may contribute to minimize the extent of resection in oral surgery patient.

Purpose To evaluate the expression of alanine-serine-cysteine-transporter 2 (ASCT2) and L-type amino acid transporter1 (LAT1) in prostate cancer (PCa) and their impact on uptake of 18 F-1-amino-3-fluorocyclobutane-1-carboxylic acid ( 18 F-fluciclovine) which is approved for the detection of recurrent PCa. Methods Twenty-five hormone-naïve patients with histologically confirmed PCa underwent PET/CT before prostatectomy. Dynamic imaging was performed immediately after injection of 368 ± 10 MBq of 18 F-fluciclovine and the uptake in PCa was expressed as SUV max at six sequential 4-min time frames and as tracer distribution volume ( V T ) using Logan plots over 0–24 min. The expression of ASCT2 and LAT1 was studied with immunohistochemistry (IHC) on a tissue microarray (TMA) containing three cores per carcinoma lesion. The TMA slides were scored independently by two trained readers based on visual intensity of ASCT2/LAT1 expression on a four-tiered scale. The correlations between ASCT2/LAT1 staining intensity, SUVmax/ V T , and Gleason grade group (GGG) were assessed using Spearman’s rank correlation coefficient ( ρ ). Results Forty tumor foci (> 0.5 mm in diameter, max. 3 per patient) were available for TMA. In visual scoring, low, moderate, and high staining intensity of ASCT2 was observed in 4 (10%), 24 (60%), and 12 (30%) tumors, respectively. No tumors showed high LAT1 staining intensity while moderate intensity was found in 10 (25%), 25 (63%) showed low, and the remaining 5 (12%) were negative for staining with LAT1. Tumors with GGG > 2 showed significantly higher uptake of 18 F-fluciclovine and higher LAT1 staining intensity ( p < 0.05). The uptake of 18 F-fluciclovine correlated significantly with LAT1 expression ( ρ = 0.39, p = 0.01, for SUV max at 2 min and ρ = 0.39, p = 0.01 for V T ). No correlation between ASCT2 expression and 18 F-fluciclovine uptake or GGG was found. Conclusions Our findings suggest that LAT1 is moderately associated with the transport of 18 F-fluciclovine in local PCa not exposed to hormonal therapy. Both high and low Gleason grade tumors express ASCT2 while LAT1 expression is less conspicuous and may be absent in some low-grade tumors. Our observations may be of importance when using 18 F-fluciclovine imaging in the planning of focal therapies for PCa.