Immunohistochemical ERG positivity is associated with decreased PSMA expression and lower visibility in corresponding [68Ga]Ga-PSMA-11 PET scans of primary prostate cancer.

PURPOSE: TMPRSS2:ERG gene fusion negatively regulates PSMA expression in prostate adenocarcinoma (PCa) cell lines. Therefore, immunohistochemical (IHC) ERG expression, a surrogate for an underlying ERG rearrangement, and PSMA expression patterns in radical prostatectomy (RPE) specimens of primary PCa, including corresponding PSMA-PET scans were investigated. METHODS: Two cohorts of RPE samples (total n=148): In cohort #1 (n=62 patients) with available RPE and preoperative [68Ga]Ga-PSMA-11 PET, WHO/ISUP grade groups, IHC-ERG (positive vs. negative) and IHC-PSMA expression (% PSMA-negative tumour area, PSMA%neg) were correlated with the corresponding SUVmax. In the second cohort #2 (n=86 patients) including RPE only, same histopathological parameters were evaluated. RESULTS: Cohort #1: PCa with IHC-ERG expression (35.5%) showed significantly lower IHC-PSMA expression and lower SUVmax values on the corresponding PET scans. Eight of 9 PCa with negative PSMA-PET scans had IHC-ERG positivity, and confirmed TMPRSS2::ERG rearrangement. In IHC-PSMA positive PCa, IHC-ERG positivity was significantly associated with lower SUVmax values. In cohort #2, findings of higher IHC-PSMA%neg and IHC-ERG expression was confirmed with only 0-10% PSMA%neg tumour areas in IHC-ERG-negative PCa. CONCLUSION: IHC-ERG expression is significantly associated with more heterogeneous and lower IHC-PSMA tissue expression in two independent RPE cohorts. There is a strong association of ERG positivity in RPE tissue with lower [68Ga]Ga-PSMA-11 uptake on corresponding PET scans. Results may serve as a base for future biomarker development to enable tumour-tailored, individualized imaging approaches.

PSMA-positive prostatic volume prediction with deep learning based on T2-weighted MRI.

PURPOSE: High PSMA expression might be correlated with structural characteristics such as growth patterns on histopathology, not recognized by the human eye on MRI images. Deep structural image analysis might be able to detect such differences and therefore predict if a lesion would be PSMA positive. Therefore, we aimed to train a neural network based on PSMA PET/MRI scans to predict increased prostatic PSMA uptake based on the axial T2-weighted sequence alone. MATERIAL AND METHODS: All patients undergoing simultaneous PSMA PET/MRI for PCa staging or biopsy guidance between April 2016 and December 2020 at our institution were selected. To increase the specificity of our model, the prostatic beds on PSMA PET scans were dichotomized in positive and negative regions using an SUV threshold greater than 4 to generate a PSMA PET map. Then, a C-ENet was trained on the T2 images of the training cohort to generate a predictive prostatic PSMA PET map. RESULTS: One hundred and fifty-four PSMA PET/MRI scans were available (133 [68Ga]Ga-PSMA-11 and 21 [18F]PSMA-1007). Significant cancer was present in 127 of them. The whole dataset was divided into a training cohort (n = 124) and a test cohort (n = 30). The C-ENet was able to predict the PSMA PET map with a dice similarity coefficient of 69.5 ± 15.6%. CONCLUSION: Increased prostatic PSMA uptake on PET might be estimated based on T2 MRI alone. Further investigation with larger cohorts and external validation is needed to assess whether PSMA uptake can be predicted accurately enough to help in the interpretation of mpMRI.

Is There a Role of Interim PSMA PET in Chemotherapy of Prostate Cancer?

While RECIST 1.1 is well established in radiological response assessment, it is of limited use in prostate cancer (PCa) considering that the disease is often seen only as sclerotic bone changes on conventional imaging. Therefore, a molecular imaging-based response assessment including bone scans has been proposed and used in clinical trials, however, due to the flare phenomenon on bone scans this assessment leads to substantial delays in the detection of progression. Indeed, a robust and reliable imaging tool to assess response to chemotherapy in PCa is still warranted. Whether Positron Emission Tomography (PET) targeting the Prostate-Specific Membrane Antigen (PSMA) could achieve this, is still controversial. In this review, we summarized the available data on cytotoxic agents and their impact on PSMA expression, as well as the available data on PSMA PET imaging for response assessment.

Relaxed fibronectin: a potential novel target for imaging endometriotic lesions.

BACKGROUND: Endometriosis is characterized by the ectopic occurrence of endometrial tissue. Though considered benign, endometriotic lesions possess tumor-like properties such as tissue invasion and remodeling of the extracellular matrix. One major clinical hurdle concerning endometriosis is its diagnosis. The diagnostic modalities ultrasound and MRI are often unable to detect all lesions, and a clear correlation between imaging and clinical symptoms is still controversial. Therefore, it was our aim to identify a potential target to image active endometriotic lesions. RESULTS: For our studies, we employed the preclinical radiotracer [111In]In-FnBPA5, which specifically binds to relaxed fibronectin-an extracellular matrix protein with key functions in homeostasis that has been implicated in the pathogenesis of diseases such as cancer and fibrosis. We employed this tracer in biodistribution as well as SPECT/CT studies in mice and conducted immunohistochemical stainings on mouse uterine tissue as well as on patient-derived endometriosis tissue. In biodistribution and SPECT/CT studies using the radiotracer [111In]In-FnBPA5, we found that radiotracer uptake in the myometrium varies with the estrous cycle of the mouse, leading to higher uptake of [111In]In-FnBPA5 during estrogen-dependent phases, which indicates an increased abundance of relaxed fibronectin when estrogen levels are high. Finally, immunohistochemical analysis of patient samples demonstrated that there is preferential relaxation of fibronectin in the proximity of the endometriotic stroma. CONCLUSION: Estrous cycle stages characterized by high estrogen levels result in a higher abundance of relaxed fibronectin in the murine myometrium. This finding together with a first proof-of-concept study employing human endometriosis tissues suggests that relaxed fibronectin could be a potential target for the development of a diagnostic radiotracer targeting endometriotic lesions. With [111In]In-FnBPA5, the matching targeting molecule is in preclinical development.

Evaluating the biodistribution for [68Ga]Ga-PSMA-11 and [18F]F-PSMA-1007 PET/CT with an inter- and intrapatient based analysis.

BACKGROUND: Liver uptake in [68Ga]Ga-PSMA-11 PET is used as an internal reference in addition to clinical parameters to select patients for [177Lu]Lu-PSMA-617 radioligand therapy (RLT). Due to increased demand, [68Ga]Ga-PSMA-11 was replaced by [18F]F-PSMA-1007, a more lipophilic tracer with different biodistribution and splenic uptake was suggested as a new internal reference. We compared the intra-patient tracer distribution between [68Ga]Ga-PSMA-11 and [18F]F-PSMA-1007. METHODS: Fifty patients who underwent PET examinations in two centers with both [18F]F-PSMA-1007 and [68Ga]Ga-PSMA-11 within one year were included. Mean standardized uptake values (SUVmean) were obtained for liver, spleen, salivary glands, blood pool, and bone. Primary tumor, local recurrence, lymph node, bone or visceral metastasis were also assessed for intra- and inter-individual comparison. RESULTS: Liver SUVmean was significantly higher with [18F]F-PSMA-1007 (11.7 ± 3.9) compared to [68Ga]Ga-PSMA-11 (5.4 ± 1.7, p < .05) as well as splenic SUVmean (11.2 ± 3.5 vs.8.1 ± 3.5, p < .05). The blood pool was comparable between the two scans. Malignant lesions did not show higher SUVmean on [18F]F-PSMA-1007. Intra-individual comparison of liver uptake between the two scans showed a linear association for liver uptake with SUVmean [68Ga]Ga-PSMA-11 = 0.33 x SUVmean [18F]F-PSMA-1007 + 1.52 (r = .78, p < .001). CONCLUSION: Comparing biodistribution of [68Ga]Ga and [18F]F tracers, liver uptake on [68Ga]Ga-PSMA-11 PET is the most robust internal reference value. Liver uptake of [18F]F-PSMA-1007 was significantly higher, but so was the splenic uptake. The strong intra-individual association of hepatic accumulation between the two scans may allow using of a conversion factor for [18F]F-PSMA-1007 as a basis for RLT selection.

Single-nucleus transcriptomics identifies separate classes of UCP1 and futile cycle adipocytes.

Adipose tissue can recruit catabolic adipocytes that utilize chemical energy to dissipate heat. This process occurs either by uncoupled respiration through uncoupling protein 1 (UCP1) or by utilizing ATP-dependent futile cycles (FCs). However, it remains unclear how these pathways coexist since both processes rely on the mitochondrial membrane potential. Utilizing single-nucleus RNA sequencing to deconvolute the heterogeneity of subcutaneous adipose tissue in mice and humans, we identify at least 2 distinct subpopulations of beige adipocytes: FC-adipocytes and UCP1-beige adipocytes. Importantly, we demonstrate that the FC-adipocyte subpopulation is highly metabolically active and utilizes FCs to dissipate energy, thus contributing to thermogenesis independent of Ucp1. Furthermore, FC-adipocytes are important drivers of systemic energy homeostasis and linked to glucose metabolism and obesity resistance in humans. Taken together, our findings identify a noncanonical thermogenic adipocyte subpopulation, which could be an important regulator of energy homeostasis in mammals.