Molecular Imaging and Theragnostics of Thyroid Cancers

SIMPLE SUMMARY: According to the American Cancer Society, approximately 53,000 new cases of thyroid cancer were diagnosed and more than 2200 people died from the disease in 2020. New developments in molecular imaging are significantly improving thyroid cancer diagnostics and therapy. Continuous research in molecular imaging techniques additionally contributes to an understanding of a variety of diseases and enables more efficient care of thyroid cancer patients. Molecular imaging-based personalized therapy has been a fascinating concept for individualized therapeutic strategy, which is able to attain the highest efficacy and reduce adverse effects in certain patients. Theragnostics, which integrates diagnostic testing to detect molecular targets for particular therapeutic modalities, is one of the key technologies that contributes to the success of personalized medicine. This review details the inception of molecular imaging and theragnostic applications for thyroid cancer management. ABSTRACT: Molecular imaging plays an important role in the evaluation and management of different thyroid cancer histotypes. The existing risk stratification models can be refined, by incorporation of tumor-specific molecular markers that have theranostic power, to optimize patient-specific (individualized) treatment decisions. Molecular imaging with varying radioisotopes of iodine (i.e., (131)I, (123)I, (124)I) is an indispensable component of dynamic and theragnostic risk stratification of differentiated carcinoma (DTC) while [(18)F]F-fluorodeoxyglucose ([(18)F]FDG) positron emission tomography/computed tomography (PET/CT) helps in addressing disease aggressiveness, detects distant metastases, and risk-stratifies patients with radioiodine-refractory DTC, poorly differentiated and anaplastic thyroid cancers. For medullary thyroid cancer (MTC), a neuroendocrine tumor derived from thyroid C-cells, [(18)F]F-dihydroxyphenylalanine (6-[(18)F]FDOPA) PET/CT and/or [(18)F]FDG PET/CT can be used dependent on serum markers levels and kinetics. In addition to radioiodine therapy for DTC, some theragnostic approaches are promising for metastatic MTC as well. Moreover, new redifferentiation strategies are now available to restore uptake in radioiodine-refractory DTC while new theragnostic approaches showed promising preliminary results for advanced and aggressive forms of follicular-cell derived thyroid cancers (i.e., peptide receptor radiotherapy). In order to help clinicians put the role of molecular imaging into perspective, the appropriate role and emerging opportunities for molecular imaging and theragnostics in thyroid cancer are discussed in our present review

Systematic evaluation of 99mTc-tetrofosmin versus 99mTc-sestamibi to study murine myocardial perfusion in small animal SPECT/CT

Background: The “back-translation” of clinically available protocols to measure myocardial perfusion to preclinical imaging in mouse models of human disease is attractive for basic biomedical research. With respect to singlephoton emission computed tomography (SPECT) approaches, clinical myocardial perfusion imaging protocols are established with different 99mTc-labeled perfusion tracers; however, studies evaluating and optimizing protocols for these tracers in high-resolution pinhole SPECT in mice are lacking. This study aims at evaluating two clinically available 99mTc-labeled myocardial perfusion tracers (99mTc-sestamibi vs. 99mTc-Tetrofosmin) in mice using four different imaging protocols. Methods: Adult C57BL/6 male mice were injected with 99mTc-sestamibi (MIBI) or 99mTc-Tetrofosmin (TETRO) (4 MBq/g body weight) either intravenously through the tail vein (n = 5) or retroorbitally (n = 5) or intraperitoneally (i. p.) under anesthesia (n = 3) or i.p. in an awake state (n = 3) at rest. Immediately after injection, a multi-frame singlephoton emission computed tomography/computed tomography (SPECT/CT) acquisition was initiated with six subsequent time frames of 10 min each. Reconstructed images of the different protocols were assessed and compared by visual analysis by experts and by time-activity-curves generated from regions-of-interest for various organs (normalized uptake values). Results: Visually assessing overall image quality, the best image quality was found for MIBI for both intravenous injection protocols, whereas TETRO only had comparable image quality after retroorbital injections. These results were confirmed by quantitative analysis where left ventricular (LV) uptake of MIBI after tail vein injections was found significantly higher for all time points accompanied with a significantly slower washout of 16% for MIBI vs. 33% for TETRO (p = 0.009) from 10 to 60 min post injection (PI). Interestingly, LV washout from 10 to 60 min PI was significantly higher for TETRO when applied by tail vein injections when compared to retroorbital injections (22%, p = 0.008). However, liver uptake was significant and comparable for both tracers at all time points. Radioactivity concentration in the lungs was negligible for all time points and both tracers. Conclusion: Intravenous MIBI injection (both tail vein and retroorbital) results in the best image quality for assessing myocardial perfusion of the murine heart by SPECT/CT. TETRO has a comparable image quality only for the retroorbital injection route

Intraoperative 3-D mapping of parathyroid adenoma using freehand SPECT

Background: Freehand single photon emission computed tomography (fSPECT) is a three-dimensional (3-D) tomographic imaging modality based on data acquisition with a handheld detector that is moved freely, in contrast to conventional, gantry-mounted gamma camera systems. In this pilot study, we evaluated the feasibility of fSPECT for intraoperative 3-D mapping in patients with parathyroid adenomas. Methods: Three patients (range 30 to 45 years) diagnosed with hyperparathyroidism (one primary and two tertiary) underwent parathyroid scintigraphy with technetium-99m sestamibi (99mTc-MIBI) to localize parathyroid adenomas. Two patients were referred with persistent hyperparathyroidism after conventional parathyroidectomy. In all three patients, a planar scintigraphy of the neck was performed 10 min after injection (p.i.) followed by SPECT/CT (Symbia T2, Siemens Healthcare) and a correlative ultrasound 2 h p.i. 99mTc-MIBI scan was performed the day before surgery in two patients and at the same day in one patient. fSPECT images were acquired intraoperatively using declipse SPECT (SurgicEyeTM). Results: A total of five parathyroid adenomas were successfully located with SPECT/CT. fSPECT allowed intraoperative detection of all adenomas, and successful parathyroidectomy was accomplished. Parathyroid hormone level decreased intraoperatively in all three patients, on average, by 79% (range 72% to 91%). Conclusion: In this preliminary study, we could demonstrate that intraoperative localization of parathyroid adenomas is feasible using the freehand SPECT technology, thus allowing an image-guided parathyroidectomy

Molecular Theranostics in Radioiodine-Refractory Differentiated Thyroid Cancer

Differentiated thyroid cancer (DTC) is the most common subtype of thyroid cancer and has an excellent overall prognosis. However, metastatic DTC in certain cases may have a poor prognosis as it becomes radioiodine-refractory. Molecular imaging is essential for disease evaluation and further management. The most commonly used tracers are [18F]FDG and isotopes of radioiodine. Several other radiopharmaceuticals may be used as well, with different diagnostic performances. This review article aims to summarize radiopharmaceuticals used in patients with radioiodine-refractory DTC (RAI-R DTC), focusing on their different molecular pathways. Additionally, it will demonstrate possible applications of the theranostics approach to this subgroup of metastatic DTC

PSMA-PET/CT-guided salvage radiotherapy in recurrent or persistent prostate cancer and PSA < 0.2 ng/ml.

PURPOSE The purpose of this retrospective, multicenter study was to assess efficacy of PSMA-PET/CT-guided salvage radiotherapy (sRT) in patients with recurrent or persistent PSA after primary surgery and PSA levels < 0.2 ng/ml. METHODS The study included patients from a pooled cohort (n = 1223) of 11 centers from 6 countries. Patients with PSA levels > 0.2 ng/ml prior to sRT or without sRT to the prostatic fossa were excluded. The primary study endpoint was biochemical recurrence-free survival (BRFS) and BR was defined as PSA nadir after sRT + 0.2 ng/ml. Cox regression analysis was performed to assess the impact of clinical parameters on BRFS. Recurrence patterns after sRT were analyzed. RESULTS The final cohort consisted of 273 patients; 78/273 (28.6%) and 48/273 (17.6%) patients had local or nodal recurrence on PET/CT. The most frequently applied sRT dose to the prostatic fossa was 66-70 Gy (n = 143/273, 52.4%). SRT to pelvic lymphatics was delivered in 87/273 (31.9%) patients and androgen deprivation therapy was given to 36/273 (13.2%) patients. After a median follow-up time of 31.1 months (IQR: 20-44), 60/273 (22%) patients had biochemical recurrence. The 2- and 3-year BRFS was 90.1% and 79.2%, respectively. The presence of seminal vesicle invasion in surgery (p = 0.019) and local recurrences in PET/CT (p = 0.039) had a significant impact on BR in multivariate analysis. In 16 patients, information on recurrence patterns on PSMA-PET/CT after sRT was available and one had recurrent disease inside the RT field. CONCLUSION This multicenter analysis suggests that implementation of PSMA-PET/CT imaging for sRT guidance might be of benefit for patients with very low PSA levels after surgery due to promising BRFS rates and a low number of relapses within the sRT field

The prognostic significance of a negative PSMA-PET scan prior to salvage radiotherapy following radical prostatectomy.

AIM The optimal management for early recurrent prostate cancer following radical prostatectomy (RP) in patients with negative prostate-specific membrane antigen positron-emission tomography (PSMA-PET) scan is an ongoing subject of debate. The aim of this study was to evaluate the outcome of salvage radiotherapy (SRT) in patients with biochemical recurrence with negative PSMA PET finding. METHODS This retrospective, multicenter (11 centers, 5 countries) analysis included patients who underwent SRT following biochemical recurrence (BR) of PC after RP without evidence of disease on PSMA-PET staging. Biochemical recurrence-free survival (bRFS), metastatic-free survival (MFS) and overall survival (OS) were assessed using Kaplan-Meier method. Multivariable Cox proportional hazards regression assessed predefined predictors of survival outcomes. RESULTS Three hundred patients were included, 253 (84.3%) received SRT to the prostate bed only, 46 (15.3%) additional elective pelvic nodal irradiation, respectively. Only 41 patients (13.7%) received concomitant androgen deprivation therapy (ADT). Median follow-up after SRT was 33 months (IQR: 20-46 months). Three-year bRFS, MFS, and OS following SRT were 73.9%, 87.8%, and 99.1%, respectively. Three-year bRFS was 77.5% and 48.3% for patients with PSA levels before PSMA-PET ≤ 0.5 ng/ml and > 0.5 ng/ml, respectively. Using univariate analysis, the International Society of Urological Pathology (ISUP) grade > 2 (p = 0.006), metastatic pelvic lymph nodes at surgery (p = 0.032), seminal vesicle involvement (p 0.5 ng/ml (p = 0.004), and lack of concomitant ADT (p = 0.023) were significantly associated with worse bRFS. On multivariate Cox proportional hazards, seminal vesicle infiltration (p = 0.007), ISUP score >2 (p = 0.048), and pre SRT PSA level > 0.5 ng/ml (p = 0.013) remained significantly associated with worse bRFS. CONCLUSION Favorable bRFS after SRT in patients with BR and negative PSMA-PET following RP was achieved. These data support the usage of early SRT for patients with negative PSMA-PET findings

Development and Validation of a Multi-institutional Nomogram of Outcomes for PSMA-PET-Based Salvage Radiotherapy for Recurrent Prostate Cancer.

IMPORTANCE Prostate-specific antigen membrane positron-emission tomography (PSMA-PET) is increasingly used to guide salvage radiotherapy (sRT) after radical prostatectomy for patients with recurrent or persistent prostate cancer. OBJECTIVE To develop and validate a nomogram for prediction of freedom from biochemical failure (FFBF) after PSMA-PET-based sRT. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study included 1029 patients with prostate cancer treated between July 1, 2013, and June 30, 2020, at 11 centers from 5 countries. The initial database consisted of 1221 patients. All patients had a PSMA-PET scan prior to sRT. Data were analyzed in November 2022. EXPOSURES Patients with a detectable post-radical prostatectomy prostate-specific antigen (PSA) level treated with sRT to the prostatic fossa with or without additional sRT to pelvic lymphatics or concurrent androgen deprivation therapy (ADT) were eligible. MAIN OUTCOMES AND MEASURES The FFBF rate was estimated, and a predictive nomogram was generated and validated. Biochemical relapse was defined as a PSA nadir of 0.2 ng/mL after sRT. RESULTS In the nomogram creation and validation process, 1029 patients (median age at sRT, 70 years [IQR, 64-74 years]) were included and further divided into a training set (n = 708), internal validation set (n = 271), and external outlier validation set (n = 50). The median follow-up was 32 months (IQR, 21-45 months). Based on the PSMA-PET scan prior to sRT, 437 patients (42.5%) had local recurrences and 313 patients (30.4%) had nodal recurrences. Pelvic lymphatics were electively irradiated for 395 patients (38.4%). All patients received sRT to the prostatic fossa: 103 (10.0%) received a dose of less than 66 Gy, 551 (53.5%) received a dose of 66 to 70 Gy, and 375 (36.5%) received a dose of more than 70 Gy. Androgen deprivation therapy was given to 325 (31.6%) patients. On multivariable Cox proportional hazards regression analysis, pre-sRT PSA level (hazard ratio [HR], 1.80 [95% CI, 1.41-2.31]), International Society of Urological Pathology grade in surgery specimen (grade 5 vs 1+2: HR, 2.39 [95% CI, 1.63-3.50], pT stage (pT3b+pT4 vs pT2: HR, 1.91 [95% CI, 1.39-2.67]), surgical margins (R0 vs R1+R2+Rx: HR, 0.60 [95% CI, 0.48-0.78]), ADT use (HR, 0.49 [95% CI, 0.37-0.65]), sRT dose (>70 vs ≤66 Gy: HR, 0.44 [95% CI, 0.29-0.67]), and nodal recurrence detected on PSMA-PET scans (HR, 1.42 [95% CI, 1.09-1.85]) were associated with FFBF. The mean (SD) nomogram concordance index for FFBF was 0.72 (0.06) for the internal validation cohort and 0.67 (0.11) in the external outlier validation cohort. CONCLUSIONS AND RELEVANCE This cohort study of patients with prostate cancer presents an internally and externally validated nomogram that estimated individual patient outcomes after PSMA-PET-guided sRT

Impact of MR-safe headphones on PET attenuation in combined PET/MRI scans

Background: MR headphones are attenuation sources affecting PET quantification in hybrid PET/MRI. Despite potentially better patient communication, usage in PET/MRI scans is not approved by the vendor. This study aims to determine the impact of headphones on PET by means of phantom and patient scans. Additionally, the perceived benefit of using headphones was evaluated. Findings: A cylinder phantom was scanned without and with dedicated MR headphones in a PET/CT scanner. Headphone attenuation was additionally assessed in a clinical setup in 10 patients on a PET/MR scanner using F-18-fluoro-deoxy-glucose. The difference in tracer uptake with and without headset was determined for the various brain regions. Additionally, the patients were asked for differences in noise levels, patient comfort, communication quality, and preference. CT data revealed headphone attenuation values of 350–500 HU. Neglecting headphone attenuation leads to a decrease in PET values between the earcups of about 11 % when compared to the correctly reconstructed data. Regions further away from the headphones were less affected. Patient images demonstrated a decrease of 11 % on average in the cerebellum and temporal lobes, while other regions were less affected. No visual artefacts in the images were noticed. On average, no advantage in terms of noise and patient comfort and only slightly better quality of communication were imparted by the patients. Conclusions: Using headphones during PET/MR acquisition leads to a negative bias in brain uptake values without introducing obvious image artefacts. Since they lack benefits for the patients, they should be avoided if PET quantification of the brain is needed

Coronary artery calcium burden, carotid atherosclerotic plaque burden, and myocardial blood flow in patients with end-stage renal disease: A non-invasive imaging study combining PET/CT and 3D ultrasound

Background!#!Imaging-based measures of atherosclerosis such as coronary artery calcium score (CACS) and coronary flow reserve (CFR) as well as carotid atherosclerotic plaque burden (cPB) are predictors of cardiovascular events in the general population. The objective of this study was to correlate CACS, cPB, myocardial blood flow (MBF), and CFR in patients with end-stage renal disease (ESRD).!##!Methods and results!#!39 patients (mean age 53 ± 12 years) with ESRD prior to kidney transplantation were enrolled. MBF and CFR were quantified at baseline and under hyperemia by !##!Conclusions!#!CACS, cPB, and MB

Higher thyroid hormone levels and cancer

Purpose: This narrative review aims to summarize the relationship between hyperthyroidism, upper reference range thyroid hormone (TH) levels, and cancer, and to address the clinical management of hyperthyroidism in cancer patients. Methods: A comprehensive search was performed by an independent reviewer through Google Scholar and PubMed Electronic databases. All searches were restricted to English language manuscripts published between 2000 and 2020. Results: Numerous in vitro, in vivo, and population-based studies suggest cancer-stimulating effect of triiodothyronine and thyroxin. THs are presented as mediators for tumor growth, proliferation, and progression. Many population and case–control studies suggest an increased risk of several solid but also hematologic malignancies in relation to hyperthyroidism and upper normal range TH levels. However, results are not unambiguous. In this review, we will summarize population and case–control studies that investigated the relationship between hyperthyroidism, upper reference range TH levels, lower thyrotropin (TSH) levels, lower reference range TSH levels with cancer risk, cancer prognosis, and cancer outcome. The vast majority of evidence suggests an association between clinical and subclinical hyperthyroidism with the risk of developing several types of cancer. Furthermore, hyperthyroidism is also linked with a poorer cancer prognosis. In this review, we will also discuss the diagnosis of hyperthyroidism in patients with pre-existing cancer and cover the management of hyperthyroidism in cancer patients, with special attention on the role of nuclear medicine. Conclusions: It is crucial to emphasize the importance of the rapid establishment of euthyroidism, and consequently, the importance of radioiodine therapy, as the therapy of choice in most cancer patients. We want to show that in this day and age there still is a high relevance for I-131 to achieve a permanent solution and thus likely reduce the risk of adverse influence of hyperthyroidism on the occurrence of new and course of existing cancer cases