Tomomi W. Nobashi

Objective The primary role of ¹⁸F-FDG PET/CT at the initial diagnosis of breast cancer is to detect distant metastases. This study aimed to investigate locoregional characteristics associated with distant metastasis, based on clinicopathological factors, standard-of-care (SOC) imaging, and ¹⁸F-FDG PET/CT—including a novel PET parameter, subcutaneous/cutaneous uptake (SCU). Methods This retrospective study included patients with newly diagnosed, unilateral invasive breast cancer who underwent pretreatment ¹⁸F-FDG PET/CT. Associations between distant metastasis and the following parameters—including age, SOC imaging-based clinical T and N stage, histology, histological grade, and subtype, as well as tumor SUVmax, subareolar SUV ratio (sSUVr), and subcutaneous/cutaneous uptake (SCU) on PET—were assessed using the Mann–Whitney U test, Fisher’s exact test, and logistic regression. Subgroup analyses were also performed after stratifying patients by locoregional clinical stage (I–IIIA vs. IIIB–C). Results Among 197 women (mean age, 56 ± 14 years), distant metastasis was identified in 23 (11.6%). The prevalence of distant metastasis at each locoregional stage in SCU-positive versus SCU-negative patients was as follows: 0% vs. 0% for stage I; 22% vs. 1% for stage IIA; 25% vs. 14% for stage IIB; 25% vs. 13% for stage IIIA; 25% vs. 33% for stage IIIB; and 50% vs. 50% for stage IIIC, with a statistically significant difference observed at stage IIA. In the total cohort, univariate analysis showed that clinical T stage (p = .005), clinical N stage (p < .001), sSUVr (p = .002), and SCU (p < .001) were significantly associated with distant metastasis. In multivariate analysis, only clinical N stages (Odd ratio [OR], 6.5–32.6; p < .001-0.02) remained independent predictors. In the stage I–IIIA subgroup, SCU (OR, 4.86; p = .048) independently predicted distant metastasis, along with age (OR, 1.07; p = .01) and clinical N stages (OR, 8.40–30.26; p = .002–0.008). In the stage IIIB–C subgroup, none of the explanatory variables had significant associations with distant metastasis. Conclusions Age, clinical N stages, and SCU were associated with an elevated risk of distant metastasis in the stage I–IIIA disease. SCU may serve as a novel imaging marker of systemic disease and aid in the diagnosis of distant metastasis—particularly in patients with early-stage breast cancer, where such findings can critically influence treatment strategy.

Objective Subcutaneous/cutaneous uptake (SCU) is occasionally observed in the cancer-affected breast, apart from the primary tumor. This study aimed to explore the prognostic value of SCU on preoperative Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) in patients with stage I–III non-inflammatory breast cancer. Additional objectives were to assess the association between SCU and subcutaneous edema (SE) on magnetic resonance imaging (MRI), as well as between SCU and lymphovascular invasion (LVI) on pathology. Methods This retrospective single-center study included patients with newly diagnosed unilateral stage I-III non-inflammatory breast cancer who underwent preoperative ¹⁸F-FDG PET/CT followed by surgery between January 2012 and March 2021. SCU was visually assessed by independent board-certified nuclear medicine physicians and quantified using the subareolar standardized uptake value ratio (sSUVr), calculated as the maximum standardized uptake value (SUVmax) ratio of the nipple–areolar–subareolar region in the affected breast to that in the contralateral breast. Inter-reader agreement for SCU and agreement between SCU and SE were evaluated using the kappa coefficient. Associations between SCU and LVI were assessed using Fisher’s exact test. Cox regression and long-rank tests were used to evaluate associations between clinicopathological and imaging variables—including tumor size, nodal metastasis, histology, molecular subtype, primary tumor SUVmax, SCU, sSUVr, skin thickness on CT, and SE on MRI—and survival outcomes, including invasive disease-free survival (iDFS) and overall survival (OS). Results Among 168 women (mean age: 55 years, range: 23–85), SCU was visually positive in 24 patients (14.3%), with high inter-reader agreement (κ = 0.76). SCU showed moderate concordance with SE (κ = 0.66). Dermal LVI was absent in all SCU-negative cases but detected in 2 of 7 SCU-positive cases (28.6%) (p = .005). Both visually positive SCU and sSUVr > 1.3 were associated with worse iDFS and OS (p < .05 for each). In multivariate analysis, sSUVr > 1.3 was associated with worse iDFS and OS (hazard ratio [HR] 2.80, p = .04; HR 5.74, p = .02, respectively). Conclusions SCU on preoperative ¹⁸F-FDG PET/CT was associated with poorer iDFS and OS in patients with stage I–III breast cancer and was moderately correlated with SE on MRI.

Graft-versus-host disease (GvHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT), mediated primarily by donor T cells that become activated and attack host tissues. Noninvasive strategies detecting T-cell activation would allow for early diagnosis and possibly more effective management of HCT recipients. PET imaging is a sensitive and clinically relevant modality ideal for GvHD diagnosis, and there is a strong rationale for the use of PET tracers that can monitor T-cell activation and expansion with high specificity. The TNF receptor superfamily member OX40 (CD134) is a cell surface marker that is highly specific for activated T cells, is upregulated during GvHD, and mediates disease pathogenesis. We recently reported the development of an antibody-based activated T-cell imaging agent targeting OX40. In the present study, we visualize the dynamics of OX40 expression in an MHC-mismatch mouse model of acute GvHD using OX40-immunoPET. This approach enabled visualization of T-cell activation at early stages of disease, prior to overt clinical symptoms with high sensitivity and specificity. This study highlights the potential utility of the OX40 PET imaging as a new strategy for GvHD diagnosis and therapy monitoring.Significance:OX40-immunoPET imaging is a promising noninvasive strategy for early detection of GvHD, capable of detecting signs of GvHD pathology even prior to the development of overt clinical symptoms.

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