Intra-Individual Comparison of Physiologic [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 Uptake in Ganglia in Patients with Prostate Cancer: A Retrospective, Monocentric Analysis.

BACKGROUND: Several studies indicate, particularly in the case of [18F]PSMA-1007, a relatively high rate of detection of ganglia in PSMA PET imaging. Ganglia are an integral part of the sympathetic portion of the autonomous nervous system. To date, no studies have directly compared [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 ganglionic uptake intra-individually and analyzed the underlying molecular and physical mechanisms of different detection rates. With this monocentric retrospective study, we sought to evaluate the intra-individual physiological ganglion uptake of these different PSMA ligands in evidence-based imaging for prostate cancer. METHODS: Our cohort consists of 19 male patients (median age 72 ± 9 with a range of 56-85) with biochemical recurrence of prostate cancer who underwent both [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 PET/CT in our clinic on the same scanner per standard care between March 2015 and March 2022. Tracer uptake was quantified according to maximum standardized uptake value (SUVmax) for both [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 PET/CT scans. Ganglia-to-background ratios (GBRs) were determined to quantify the image contrast through dividing the SUVmax of the ganglia by the background value (SUVmax of blood pool in the descending aorta, fatty tissue, and skeletal muscle in gluteal region). We used descriptive analyses for demographics and tumor characteristics and performed two-way repeated-measures ANOVA (analysis of variance) for SUV metrics including GBR measurements. RESULTS: In total, we examined 101 ganglia with [18F]PSMA-1007 scanning, localized mostly in pairs as stellate, coeliac, and sacral, of which 76 were also detected with [68Ga]Ga-PSMA-11 PET/CT scanning. There was no statistically significant difference in PSMA uptake in terms of SUVmax between [18F]PSMA-1007 and [68Ga]Ga-PSMA-11 (p value: 0.052). In contrast, the comparison of GBRs revealed a higher detectability rate of ganglia with [18F]PSMA-1007 imaging (p < 0.001). Furthermore, a separate comparison of ganglia with respect to their anatomical location also demonstrated statistically significant differences both within and between [18F]PSMA-1007 and [68Ga]Ga-PSMA-11 PET/CT scans. CONCLUSION: Given the impression of more accentuated [18F]PSMA-1007 uptake in ganglia compared with 68Ga-labelled counterparts, our study demonstrated that the better detectability of ganglia is not due to more intense [18F]PSMA-1007 uptake by these small structures but to much more favorable physical properties of the radionuclide 18F. The most relevant limitations of our study are its retrospective design and the small patient cohort.

Head-to-Head Intra-Individual Comparison of Biodistribution and Tumor Uptake of [18F]FAPI-74 with [18F]FDG in Patients with PDAC: A Prospective Exploratory Study.

BACKGROUND: Radiolabeled fibroblast activation protein (FAP) ligands, a novel class of tracers for PET/CT imaging, have demonstrated very promising results in various oncological, as well as in some benign, diseases with long-term potential to supplant the current pan-cancer agent [18F]FDG in some cancer types. Pancreatic ductal carcinoma (PDAC) belongs to the group of epithelial malignancies with a strong so-called "desmoplastic reaction", leading to a prominent tumor stroma with cancer-associated fibroblasts that exhibit a marked overexpression of fibroblast activation protein (FAP). The first clinical experiences in PDAC with 68Ga-labeled FAP ligands suggested superior sensitivity to [18F]FDG. However, there is limited data with 18F-labeled FAP derivatives, i.e. [18F]FAPI-74, yet prospective single- and multicenter trials are already ongoing. In this proof-of-concept study, we sought to evaluate the biodistribution, tumor uptake, and lesion detectability in patients with PDAC using [18F]FAPI-74 PET/CT as compared to [18F]FDG PET/CT scans for staging. METHODS: This study includes 7 patients (median age 69) who underwent both [18F]FDG PET/CT with contrast-enhancement and [18F]FAPI-74 PET with low-dose CT for primary staging (n = 3) and therapy response control after neoadjuvant (n = 1) or re-staging after palliative therapy (n = 3). The mean interval between PET scans was 11 ± 4 days (range 1-15 days). The [18F]FDG and [18F]FAPI-74 PET/CT scans were acquired at 64 ± 4.1 min (range 61-91 min) and 66.4 ± 6.3 min (range 60-76 min), respectively, after administration of 200 ± 94 MBq (range 79-318 MBq) and 235 ± 88 MBq (range 90-321 MBq), respectively. Quantification of tracer uptake was determined with SUVmax and SUVmean. Furthermore, the tumor-to-background ratio (TBR) was derived by dividing the SUVmax of tumor lesions by the SUVmax of adipose tissue, skeletal muscle, and blood pool. RESULTS: Overall, 32 lesions were detected in 7 patients including primary (n = 7), lung (n = 7), bone (n = 3), lymph node (n = 13), and peritoneal metastases (n = 2). [18F]FAPI-74 detected 22% more lesions compared with [18F]FDG with a better TBR and visual lesion delineation. In one patient the primary lesion could be detected unequivocally with [18F]FAPI-74 but was missed by [18F]FDG imaging. Altogether, most of the lesions demonstrated markedly elevated uptake of [18F]FAPI-74 with a simultaneous lower uptake in the background, providing a very high visual contrast. CONCLUSION: To the best of our knowledge, this is the first, prospective, intra-individual investigation comparing [18F]FAPI-74 with [18F]FDG imaging in PDAC with encouraging results. These pivotalresults supporta larger, multicentric, prospective study to determine the value of [18F]FAPI-74 in detecting and staging PDAC in comparison with current standard of care imaging.

A Role of Non-FDG Tracers in Lung Cancer?

Since the introduction of PET/CT hybrid imaging about two decades ago the landscape of oncological imaging has fundamentally changed, opening a new era of molecular imaging with emphasis on functional characterization of biological processes such as metabolism, cellular proliferation, hypoxia, apoptosis, angiogenesis and immune response. The most commonly assessed functional hallmark of cancer is the increased metabolism in tumor cells due to well-known Warburg effect, because of which FDG has been the most employed radiotracer, the so-called pan-cancer agent, in oncological imaging. However, several limitations such as low specificity and low sensitivity for several histopathological forms of lung cancer as well as high background uptake in the normal tissue of FDG imaging lead to numerous serious pitfalls. This restricts its utilization and diagnostic value in lung cancer imaging, even though this is currently considered to be the method of choice in pulmonary cancer imaging. Accurate initial tumor staging and therapy response monitoring with respect to the TNM criteria plays a crucial role in therapy planning and management in patients with lung cancer. To this end, many efforts have been made for decades to develop novel PET radiopharmaceuticals with innovative approaches that go beyond the assessment of increased glycolytic activity alone. Radiopharmaceuticals targeting DNA synthesis, amino acid metabolism, angiogenesis, or hypoxia have been extensively studied, leading to the emergence of indications for specific clinical questions or as a complementary imaging tool alongside existing conventional or FDG imaging. Nevertheless, despite some initial encouraging results, these tracers couldn't gain a widespread use and acceptance in clinical routine. However, given its mechanism of action and some initial pilot studies regarding lung cancer imaging, FAPI has emerged as a very promising alternative tool that could provide superior or comparable diagnostic performance to FDG imaging in lung cancer entities. Thus, in this review article, we summarized the current PET radiopharmaceuticals, different imaging approaches and discussed the potential benefits and clinical applications of these agents in lung cancer imaging.

Evaluation of Intraoperative Frozen Section Analysis with Final Histopathology Results for Sentinel Lymph Node Biopsy: Z0011 Criteria Eligible Versus Ineligible Breast Cancer Patients.

Background Intraoperative frozen section analysis (FSA) of sentinel lymph nodes (SLNs) declined in the post American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011) trial era. However, for those patients who do not meet the ACOSOG Z0011 criteria, FSA continues to be a valuable tool in intraoperative decision-making for axillary lymph node dissection (ALND). The aim of this study was therefore to retrospectively evaluate the benefit and accuracy of FSA of Z0011 criteria eligible versus ineligible patients and identify possible predictive factors for false negative results. Methods Intraoperative FSA was performed on SLNs of 522 cT1-T3 breast cancer patients between 2008 and 2013. Clinicopathologic characteristics were retrospectively assessed by chart review. Results Overall FSA sensitivity and specificity was 67.8% and 100%. Sensitivity was generally higher for macrometastasis than for micrometastasis. The Z0011 eligible group showed a sensitivity and specificity of 72.7% and 100% versus 62.1% and 100% in the Z0011 ineligible group. Importantly, subgroup analysis of ≤ 2 versus > 2 positive SLNs of the Z0011 eligible group demonstrated both a 100% specificity and sensitivity. Several clinicopathologic factors were associated with a higher rate of false negative results in the Z0011 ineligible patient group. FSA was beneficial for 22.2% of Z0011 ineligible patients and for only 0.6% of Z0011 eligible patients regarding intraoperative decision-making for ALND. Conclusions FSA continues to be especially beneficial in the intraoperative assessment of SLNs in the Z0011 ineligible group to prevent second stage ALND. Despite an overall lower FSA sensitivity in the Z0011 eligible patient group, FSA offers in both groups a comparable high sensitivity and diagnostic accuracy for macrometastasis.

Boosted dopamine and blunted serotonin in Tourette syndrome - evidence from in vivo imaging studies.

The precise cortical and subcortical mechanisms of Tourette syndrome (TS) are still not fully understood. In the present retrospective analysis, adolescent and adult medication-naïve patients showed increased DA transporter (DAT) binding in nucleus caudate (CAUD), putamen (PUT) and/or whole neostriatum (NSTR). D2 receptor (R) binding and DA release were not different from controls throughout the nigrostriatal and mesolimbocortical system. When patients were medication-free (either medication-naïve or under withdrawal), DAT was still increased in PUT, but not different from controls in CAUD, NSTR and ventral striatum (VSTR). SERT was unaltered in midbrain/pons (MP), but decreased in PUT, thalamus (THAL) and hypothalamus. D2R was unaltered throughout the nigrostriatal and mesolimbocortical system, while DA release was not different from controls in PUT, CAUD and NSTR, but elevated in VSTR. 5-HT2AR binding was unaltered in neocortex and cingulate. In acutely medicated adults, DAT was unaltered in PUT, but still increased in CAUD, whereas DA release remained unaltered throughout the nigrostriatal and mesolimbocortical system. When part of the patients was acutely medicated, vesicular monoamine transporter (VMAT2), DAT, SERT and DA synthesis were not different from controls in striatal regions, whereas D2R was decreased in NSTR, THAL, frontal cortex and limbic regions. Conversely, 5-HT2AR binding was unaltered in striatal regions and THAL, but increased in neocortical and limbic areas. It may be hypothesized that both the DA surplus and the 5-HT shortage in key regions of the nigrostriatal and mesolimbic system are relevant for the bouts of motor activity and the deficiencies in inpulse control.

Is there a diagnostic benefit of late-phase abdomino-pelvic PET/CT after urination as part of whole-body 68 Ga-PSMA-11 PET/CT for restaging patients with biochemical recurrence of prostate cancer after radical prostatectomy?

BACKGROUND: To assess the diagnostic value of an additional late-phase PET/CT scan after urination as part of 68 Ga-PSMA-11 PET/CT for the restaging of patients with biochemically recurrent prostate cancer (BCR). METHODS: This retrospective trial included patients with BCR following radical prostatectomy, who underwent standard whole-body early-phase PET/CT performed 105 ± 45 min and an additional late-phase PET/CT performed 159 ± 13 min after injection of 68 Ga-PSMA-11. Late-phase PET/CT covered a body volume from below the liver to the upper thighs and was conducted after patients had used the bathroom to empty their urinary bladder. Early- and late-phase images were evaluated regarding lesion count, type, localisation, and SUVmax. Reference standard was histopathology and/or follow-up imaging. RESULTS: Whole-body early-phase PET/CT detected 93 prostate cancer lesions in 33 patients. Late-phase PET/CT detected two additional lesions in two patients, both local recurrences. In total, there were 57 nodal, 28 bone, and 3 lung metastases, and 7 local recurrences. Between early- and late-phase PET/CT, lymph node metastases showed a significant increase of SUVmax from 14.5 ± 11.6 to 21.5 ± 17.6 (p = 0.00007), translating to a factor of + 1.6. Benign lymph nodes in the respective regions showed a significantly lower increase of SUVmax of 1.4 ± 0.5 to 1.7 ± 0.5 (p = 0.0014, factor of + 1.2). Local recurrences and bone metastases had a SUVmax on late-phase PET/CT that was + 1.7 and + 1.1 times higher than the SUVmax on early-phase PET/CT, respectively. CONCLUSION: In patients with BCR following radical prostatectomy, an additional abdomino-pelvic late-phase 68 Ga-PSMA-11 PET/CT scan performed after emptying the urinary bladder may help to detect local recurrences missed on standard whole-body 68 Ga-PSMA-11 PET/CT. Lymph node metastases show a higher SUVmax and a stronger increase of SUVmax than benign lymph nodes on late-phase PET/CT, hence, biphasic 68 Ga-PSMA-11 PET/CT might help to distinguish between malignant and benign nodes. Bone metastases, and especially local recurrences, also demonstrate a metabolic increase over time.

FAP and FAPI-PET/CT in Malignant and Non-Malignant Diseases: A Perfect Symbiosis?

A fibroblast activation protein (FAP) is an atypical type II transmembrane serine protease with both endopeptidase and post-proline dipeptidyl peptidase activity. FAP is overexpressed in cancer-associated fibroblasts (CAFs), which are found in most epithelial tumors. CAFs have been implicated in promoting tumor cell invasion, angiogenesis and growth and their presence correlates with a poor prognosis. However, FAP can generally be found during the remodeling of the extracellular matrix and therefore can be detected in wound healing and benign diseases. For instance, chronic inflammation, arthritis, fibrosis and ischemic heart tissue after a myocardial infarction are FAP-positive diseases. Therefore, quinoline-based FAP inhibitors (FAPIs) bind with a high affinity not only to tumors but also to a variety of benign pathologic processes. When these inhibitors are radiolabeled with positron emitting radioisotopes, they provide new diagnostic and prognostic tools as well as insights into the role of the microenvironment in a disease. In this respect, they deliver additional information beyond what is afforded by conventional FDG PET scans that typically report on glucose uptake. Thus, FAP ligands are considered to be highly promising novel tracers that offer a new diagnostic and theranostic potential in a variety of diseases.