Tumor-Derived Extracellular Vesicles Predict Clinical Outcomes in Oligometastatic Prostate Cancer and Suppress Antitumor Immunity.

PURPOSE: SABR has demonstrated clinical benefit in oligometastatic prostate cancer. However, the risk of developing new distant metastatic lesions remains high, and only a minority of patients experience durable progression-free response. Therefore, there is a critical need to identify which patients will benefit from SABR alone versus combination SABR and systemic agents. Herein we provide, to our knowledge, the first proof-of-concept of circulating prostate cancer-specific extracellular vesicles (PCEVs) as a noninvasive predictor of outcomes in oligometastatic castration-resistant prostate cancer (omCRPC) treated with SABR. METHODS AND MATERIALS: We analyzed the levels and kinetics of PCEVs in the peripheral blood of 79 patients with omCRPC at baseline and days 1, 7, and 14 after SABR using nanoscale flow cytometry and compared with baseline values from cohorts with localized and widely metastatic prostate cancer. The association of omCRPC PCEV levels with oncological outcomes was determined with Cox regression models. RESULTS: Levels of PCEVs were highest in mCRPC followed by omCRPC and were lowest in localized prostate cancer. High PCEV levels at baseline predicted a shorter median time to distant recurrence (3.5 vs 6.6 months; P = .0087). After SABR, PCEV levels peaked on day 7, and median overall survival was significantly longer in patients with elevated PCEV levels (32.7 vs 27.6 months; P = .003). This suggests that pretreatment PCEV levels reflect tumor burden, whereas early changes in PCEV levels after treatment predict response to SABR. In contrast, radiomic features of 11C-choline positron emission tomography and computed tomography before and after SABR were not predictive of clinical outcomes. Interestingly, PCEV levels and peripheral tumor-reactive CD8 T cells (TTR; CD8+ CD11ahigh) were correlated. CONCLUSIONS: This original study demonstrates that circulating PCEVs can serve as prognostic and predictive markers to SABR to identify patients with "true" omCRPC. In addition, it provides novel insights into the global crosstalk, mediated by PCEVs, between tumors and immune cells that leads to systemic suppression of immunity against CRPC. This work lays the foundation for future studies to investigate the underpinnings of metastatic progression and provide new therapeutic targets (eg, PCEVs) to improve SABR efficacy and clinical outcomes in treatment-resistant CRPC.

Pitfalls of a Mixed Metabolic Response at PET/CT.

Although the term mixed metabolic response is commonly used in PET/CT reports, it should be a red flag to reconsider the assumptions made by the PET scan reader. Fluorine 18 fluorodeoxyglucose (FDG) PET/CT is recognized as an accurate imaging method for detecting response to cancer therapies. Critical clinical decisions regarding therapy are dependent on accurate interpretation of findings. The use of standardized terminology for response assessment, such as that in the Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST), is highly recommended. With PERCIST, treatment response is categorized as complete metabolic response, partial metabolic response, stable metabolic disease, or progressive metabolic disease. Mixed metabolic response is not included in PERCIST. Rather, it is used colloquially to describe a scenario in which scanning performed after systemic cancer therapy reveals divergent findings, with some tumor foci responding and others not responding or even seen progressing. In PERCIST, mixed metabolic response should be described as stable metabolic disease or progressive metabolic disease. However, the PET/CT reader may also wish to suggest that individual tumors have heterogeneous genetic and/or other characteristics and consequently a mixed response to therapy. The concept of tumor heterogeneity is gaining momentum in cancer research and thus possibly leading to options for therapy targeted to oligometastases that are not responding. However, the authors suggest exercising extreme caution when PET/CT findings appear at first to reflect what some might call a mixed response. In addition, they have found that FDG PET/CT findings are often confounding owing to the simultaneous presence of two or more unrelated disease processes. Common examples include synchronous neoplasms, inflammatory processes, and treatment-related effects. Thus, an apparent mixed response is a red flag to reconsider whether all of the FDG-avid findings are actually metastases of the same cancer. Common mimics of a mixed metabolic response that do not represent true tumor heterogeneity are highlighted to improve the FDG PET/CT reader's recognition of these lesions.©RSNA, 2019.

Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis.

BACKGROUND: Cardiac transthyretin (ATTR) amyloidosis is a progressive and fatal cardiomyopathy for which several promising therapies are in development. The diagnosis is frequently delayed or missed because of the limited specificity of echocardiography and the traditional requirement for histological confirmation. It has long been recognized that technetium-labeled bone scintigraphy tracers can localize to myocardial amyloid deposits, and use of this imaging modality for the diagnosis of cardiac ATTR amyloidosis has lately been revisited. We conducted a multicenter study to ascertain the diagnostic value of bone scintigraphy in this disease. METHODS AND RESULTS: Results of bone scintigraphy and biochemical investigations were analyzed from 1217 patients with suspected cardiac amyloidosis referred for evaluation in specialist centers. Of 857 patients with histologically proven amyloid (374 with endomyocardial biopsies) and 360 patients subsequently confirmed to have nonamyloid cardiomyopathies, myocardial radiotracer uptake on bone scintigraphy was >99% sensitive and 86% specific for cardiac ATTR amyloid, with false positives almost exclusively from uptake in patients with cardiac AL amyloidosis. Importantly, the combined findings of grade 2 or 3 myocardial radiotracer uptake on bone scintigraphy and the absence of a monoclonal protein in serum or urine had a specificity and positive predictive value for cardiac ATTR amyloidosis of 100% (positive predictive value confidence interval, 98.0-100). CONCLUSIONS: Bone scintigraphy enables the diagnosis of cardiac ATTR amyloidosis to be made reliably without the need for histology in patients who do not have a monoclonal gammopathy. We propose noninvasive diagnostic criteria for cardiac ATTR amyloidosis that are applicable to the majority of patients with this disease.