Nuclear medicine in the assessment and prevention of cancer therapy-related cardiotoxicity: prospects and proposal of use by the European Association of Nuclear Medicine (EANM).

Cardiotoxicity may present as (pulmonary) hypertension, acute and chronic coronary syndromes, venous thromboembolism, cardiomyopathies/heart failure, arrhythmia, valvular heart disease, peripheral arterial disease, and myocarditis. Many of these disease entities can be diagnosed by established cardiovascular diagnostic pathways. Nuclear medicine, however, has proven promising in the diagnosis of cardiomyopathies/heart failure, and peri- and myocarditis as well as arterial inflammation. This article first outlines the spectrum of cardiotoxic cancer therapies and the potential side effects. This will be complemented by the definition of cardiotoxicity using non-nuclear cardiovascular imaging (echocardiography, CMR) and biomarkers. Available nuclear imaging techniques are then presented and specific suggestions are made for their application and potential role in the diagnosis of cardiotoxicity.

Automated Analysis vs. Expert Reading in Nuclear Cardiology: Correlations with the Angiographic Score.

Background and Objectives: Myocardial perfusion imaging (MPI) has an important role in the non-invasive investigation of coronary artery disease. The interpretation of MPI studies is mainly based on the visual evaluation of the reconstructed images, while automated quantitation methods may add useful data for each patient. However, little evidence is currently available regarding the actual incremental clinical diagnostic performance of automated MPI analysis. In the present study, we aimed to assess the correlation between automated measurements of Summed Stress Score (SSS), Summed Rest Score (SRS) and Summed Difference Score (SDS), with the corresponding expert reading values, using coronary angiography as the gold standard. Materials and Methods: The study was conducted at the Nuclear Medicine Laboratory of the University Hospital of Larissa, Larissa, Greece, οver an one-year period (January 2019-January 2020). 306 patients, with known or suspected coronary artery disease, were enrolled in the study. Each participant underwent a coronary angiography, prior to or after the scintigraphic study (within a three-month period). Either symptom-limited treadmill test, or pharmacologic testing using adenosine or regadenoson, was performed in all participants, and the scintigraphic studies were carried out using technetium 99m (99mTc) tetrofosmin (one-day stress/rest protocol). Coronary angiographies were scored according to a 4-point scoring system (angiographic score; O: normal study, 1: one-vessel disease, 2: two-vessel disease, 3: three-vessel disease). Moreover, automated measurements of SSS, SRS and SDS were derived by three widely available software packages (Emory Cardiac Toolbox, Myovation, Quantitative Perfusion SPECT). Results: Interclass Correlation Coefficients of SSS, SRS and SDS between expert reading and software packages were moderate to excellent. Visually defined SSS, SRS and SDS were significantly correlated with the corresponding results of all software packages. However, visually defined SSS, SRS and SDS were more strongly correlated with the angiographic score, indicating a better performance of expert reading when compared to automated analysis. Conclusions: Based on our results, visual evaluation continues to have a crucial role for the interpretation of MPI images. Software packages can provide automated measurements of several parameters, particularly contributing to the investigation of cases with ambiguous scintigraphic findings.

Effect of adiponectin on estradiol and progesterone secretion from human luteinized granulosa cells in vitro.

Ιnformation on the role of adiponectin in human ovarian steroidogenesis is limited. The present study aimed to investigate the effect of different doses of adiponectin on the secretion of estradiol and progesterone by human luteinized granulosa cells in culture. Granulosa cells, obtained from women undergoing in vitro fertilization (IVF) treatment, were pre-incubated for 24 h and then cultured for 48 h. Adiponectin was used in 3 doses, i.e., 5, 10, and 100 µg/ml alone and in combinations with FSH (10 and 100 ng/ml). Estradiol and progesterone were measured by radioimmunoassays in culture supernatants at 24 h and 48 h. Adiponectin after 48 h of culture stimulated the secretion of estradiol and, to a lesser extent, progesterone in a dose-dependent manner. FSH showed a variable effect on steroidogenesis. However, when the low dose FSH was combined with adiponectin, estradiol, and progesterone secretion were increased disproportionally to the dose of adiponectin. With the high dose FSH, the positive effect of adiponectin on FSH-induced estradiol secretion was less pronounced, while the effect on progesterone secretion was negligible. This study shows for the first time a stimulatory effect of adiponectin on the secretion of estradiol and progesterone by human luteinized granulosa cells in vitro. It is suggested that adiponectin plays a paracrine role in human ovarian steroidogenesis by sensitizing the granulosa cells to FSH.

Fahr's syndrome due to hypoparathyroidism revisited: A case of parkinsonism and a review of all published cases.

INTRODUCTION: Fahr's syndrome due to hypoparathyroidism refers to bilateral basal ganglia (BG) calcifications and manifests with movement disorders, seizures, cognitive and behavioral symptoms. CASE PRESENTATION: We report a case of a 74-year-old woman, who presented with parkinsonism due to post-surgical hypoparathyroidism and normal DaT scan, despite extensive calcifications of the BG, periventricular white matter, and cerebellum. METHODS: A comprehensive literature review of all reported cases of Fahr's syndrome due to hypoparathyroidism was conducted in the electronic databases PubMed and Web of science. Moreover, demographic and clinical characteristics of the patients overall were calculated and associated with radiological findings. RESULTS: We reviewed a total of 223 cases with Fahr's syndrome due to hypoparathyroidism (124 female, 99 male). Mean age on presentation was 44.6 ± 17.7 years. Thirty nine percent of patients had idiopathic hypoparathyroidism, 35.4 % acquired and 25.6 % pseudohypoparathyroidism. Almost half of the patients had tetany, seizures or a movement disorder and approximately 40 % neuropsychiatric symptoms. The patients with a movement disorder had a 2.23 likelihood of having neuropsychiatric symptoms as well (OR 2.23, 95 % CI 1.29-3.87). Moreover, there was a statistically significant association between the phenotype severity (i.e. the presence of more than one symptom) and the extent of brain calcifications (χ2 = 32.383, p = 0.009). CONCLUSION: Fahr's syndrome is a rare disorder, which nonetheless manifests with several neurological symptoms. A head CT should be considered for patients with hypoparathyroidism and neurological symptoms. More studies using DaT scan are needed to elucidate the effects of calcifications on the dopaminergic function of the BG.

HPA axis responses to acute exercise differ in smokers and non-smokers.

Physical exercise has been proposed as an adjunct in addiction treatment, including tobacco cigarette smoking. The physiological and biochemical mechanisms that could be affected by physical exercise in smokers and that could help quit smoking have not been investigated yet. OBJECTIVE: To investigate whether the effects of acute exercise on smoking behavior and HPA axis activation in smokers are intensity-dependent. METHODS: Healthy, non-systematically exercising individuals [25 smokers (age: 33±1.4 years) and 10 non-smokers (age: 34±2.1 years)] underwent three trials [moderate intensity (MI), high intensity (HI) exercise, control (C)] in a counterbalanced order, after an overnight fast and smoking abstinence, separated by at least six days. MI involved cycling at 50-60% of Heart Rate Reserve (HRR) for 30 min, HI involved cycling at 65-75% HRR for 30 min, while in C participants rested for 30 min. Time till the first cigarette following each trial was recorded. Smoking urge was evaluated and blood samples, [analyzed for ß-endorphin (ß-E), adrenocorticotropic hormone (ACTH), cortisol and catecholamines], were obtained prior to and immediately after each trial. RESULTS: ß-E, ACTH, catecholamines and cortisol responses to exercise were intensity-dependent and differed in smokers and non-smokers. Resting ß-E levels were 2-2.5 times lower in smokers compared to non-smokers. HI resulted in increased ß-E levels in both groups, with smokers exhibiting similar levels to that observed in non-smokers. Although smoking urge did not change post-exercise in smokers, time till first cigarette increased following both MI (64.6%) and HI (77.9%) compared to C. CONCLUSIONS: HPA axis activation in response to exercise may differ between smokers and non-smokers. Smokers have lower resting levels of ß-E compared to non-smokers and, since HI exercise increases ß-E to similar levels to those of non-smokers and delays smoking, this may be used as an adjunct in smoking cessation.

Human white-fat thermogenesis: Experimental and meta-analytic findings.

White adipose tissue (WAT) thermogenic activity may play a role in whole-body energy balance and two of its main regulators are thought to be environmental temperature (Tenv) and exercise. Low Tenv may increase uncoupling protein one (UCP1; the main biomarker of thermogenic activity) in WAT to regulate body temperature. On the other hand, exercise may stimulate UCP1 in WAT, which is thought to alter body weight regulation. However, our understanding of the roles (if any) of Tenv and exercise in WAT thermogenic activity remains incomplete. Our aim was to examine the impacts of low Tenv and exercise on WAT thermogenic activity, which may alter energy homeostasis and body weight regulation. We conducted a series of four experimental studies, supported by two systematic reviews and meta-analyses. We found increased UCP1 mRNA (p = 0.03; but not protein level) in human WAT biopsy samples collected during the cold part of the year, a finding supported by a systematic review and meta-analysis (PROSPERO review protocol: CRD42019120116). Additional clinical trials (NCT04037371; NCT04037410) using Positron Emission Tomography/Computed Tomography (PET/CT) revealed no impact of low Tenv on human WAT thermogenic activity (p > 0.05). Furthermore, we found no effects of exercise on UCP1 mRNA or protein levels (p > 0.05) in WAT biopsy samples from a human randomized controlled trial (Clinical trial: NCT04039685), a finding supported by systematic review and meta-analytic data (PROSPERO review protocol: CRD42019120213). Taken together, the present experimental and meta-analytic findings of UCP1 and SUVmax, demonstrate that cold and exercise may play insignificant roles in human WAT thermogenic activity. Abbreviations: WAT:White adipose tissue; Tenv: Environmental temperature; UCP1: Uncoupling protein one; BAT: Brown adipose tissue; BMI:Body mass index; mRNA: Messenger ribonucleic acid; RCT: Randomized controlled trial; WHR: Waist-to-hip ratio; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-analyses; PET/CT: Positron Emission Tomography and Computed Tomography; REE: Resting energy expenditure; 18F-FDG: F18 fludeoxyglucose; VO2peak:Peak oxygen consumption; 1RM: One repetition maximum; SUVmax: Maximum standardized uptake value; Std: Standardized mean difference.

Detection of Extramedullary Hematopoietic Tissue in a Patient with Beta-Thalassemia Major on Tc99m-Sestamibi Parathyroid Scintigraphy.

A 50-year-old man with beta-thalassemia major underwent Tc-99m sestamibi parathyroid scintigraphy due to elevated parathyroid hormone and calcium serum levels. Single-photon emission computed tomography imaging of neck and thorax revealed a parathyroid adenoma, as well as increased tracer uptake in a paraspinal region in the right hemithorax, where X-ray and computed tomography of the thorax had shown previously a mass compatible with extramedullary hematopoietic tissue.

The effect of a GnRH antagonist on follicle maturation in normal women.

RESEARCH QUESTION: Ganirelix is a gonadotrophin-releasing hormone (GnRH) antagonist used for the prevention of premature LH surge during ovarian stimulation. What is the impact of ganirelix on follicle maturation in normal women? DESIGN: Ten normally cycling women were investigated during two menstrual cycles, i.e. cycle 1 (control) and cycle 2 (ganirelix). During both cycles, daily blood samples were taken from day 2, while transvaginal ultrasound scans were performed on cycle days 8 and 10 and daily thereafter. During cycle 2, all women were given 0.25 mg/day subcutaneous injections of the GnRH antagonist ganirelix from day 2 until the day of the endogenous LH surge onset in cycle 1. RESULTS: During treatment with ganirelix, serum FSH and oestradiol concentrations remained stable, while those of LH decreased significantly on days 3, 4, 7 and 9 (P < 0.05) compared with controls. Nevertheless, there was no significant within-cycle variation in LH concentrations. From day 10 onwards, no follicle maturation was observed in cycle 2, in contrast to cycle 1. Ovulation occurred in 9 of 10 women in cycle 1. In cycle 2, ovulation was delayed by at least 1 week in eight women. Follicle growth and ovulation occurred in only one woman while on ganirelix treatment. CONCLUSIONS: This study demonstrates for the first time that in normal women dominant follicle selection failed during treatment with ganirelix. As there was a similar gonadotrophin profile in the two cycles, it is suggested that ganirelix interferes with the process of follicle selection by acting in the ovary.

Effect of resistin on estradiol and progesterone secretion from human luteinized granulosa cells in culture.

Information on the role of resistin on steroidogenesis is limited to animal studies. The aim of this study was to investigate the effect of various doses of resistin on estradiol and progesterone secretion from human luteinized granulosa cells in culture. Granulosa cells were obtained from follicular fluid aspirated from 50 women undergoing in vitro fertilization (IVF) treatment. The cells were cultured for 48 h after a 24 h pre-incubation period. The effect of resistin at dosages 1, 10 and 100 ng/ml alone or in combinations with FSH (10 and 100 ng/ml) on steroidogenesis was investigated. Estradiol and progesterone were measured by radioimmunoassays in culture supernatants at 24 h and 48 h. FSH treatment increased both estradiol and progesterone secretion. Resistin suppressed basal estradiol (at 1 ng/ml) and progesterone secretion (at all concentrations tested). When resistin (all concentrations) was combined with FSH (100 ng/ml), it eliminated the stimulatory effect of FSH on the secretion of estradiol and progesterone. This study indicates an inhibitory effect of resistin on the secretion of estradiol and progesterone by human luteinized granulosa cells in vitro. It is likely that this adipokine locally affects ovarian function in women. Abbreviations: 3ß-HSD: 3ß-hydroxysteroid dehydrogenase; CAP1: cyclase-associated protein 1; DCN: decorin; FIZZ: Found in Inflammatory Zones; hCG: human chorionic gonadotropin; IGF1: insulin-like growth factor type 1; IVF: in vitro fertilization; PCOS: polycystic ovary syndrome; RIA: radioimmunoassay; ROR1: receptor tyrosine kinase-like orphan receptor-1; TLR4: Toll-like receptor 4.

Evaluation of the Performance of 18F-Fluorothymidine Positron Emission Tomography/Computed Tomography (18F-FLT-PET/CT) in Metastatic Brain Lesions.

18F-fluorothymidine (18F-FLT) is a radiolabeled thymidine analog that has been reported to help monitor tumor proliferation and has been studied in primary brain tumors; however, knowledge about 18F-FLT positron emission tomography/computed tomography (PET/CT) in metastatic brain lesions is limited. The purpose of this study is to evaluate the performance of 18F-FLT-PET/CT in metastatic brain lesions. A total of 20 PET/CT examinations (33 lesions) were included in the study. Semiquantitative analysis was performed: standard uptake value (SUV) with the utilization of SUVmax, tumor-to-background ratio (T/B), SUVpeak, SUV1cm³, SUV0.5cm³, SUV50%, SUV75%, PV50% (volume × SUV50%), and PV75% (volume × SUV75%) were calculated. Sensitivity, specificity, and accuracy for each parameter were calculated. Optimal cutoff values for each parameter were obtained. Using a receiver operating characteristic (ROC) curve analysis, the optimal cutoff values of SUVmax, T/B, and SUVpeak for discriminating active from non-active lesions were found to be 0.615, 4.21, and 0.425, respectively. In an ROC curve analysis, the area under the curve (AUC) is higher for SUVmax (p-value 0.017) compared to the rest of the parameters, while using optimal cutoff T/B shows the highest sensitivity and accuracy. PVs (proliferation × volumes) did not show any significance in discriminating positive from negative lesions. 18F-FLT-PET/CT can detect active metastatic brain lesions and may be used as a complementary tool. Further investigation should be performed.

A study on ghrelin and LH secretion after short fasting and on ghrelin levels at perioestrual period in dairy cattle.

In two experiments, we studied (a) the changes of LH secretion in heifers under different feeding schedules and (b) total ghrelin concentration at oestrus in cows and heifers. In experiment one, synchronized heifers were allocated in three groups (R, regularly fed controls; F, fasted; and F-F fasted-fed). One day after the completion of the oestrous induction protocol, group F and F-F animals stayed without feed for 24 hr; thereafter, feed was provided to R and F-F cattle; 2 hr later, GnRH was administered to all animals. Blood samples were collected for ghrelin, progesterone, LH and cortisol concentrations. Fasting caused increased ghrelin concentrations in groups F and F-F, while in response to GnRH, LH surge was significantly attenuated in groups F and F-F compared to R. In experiment 2, lactating cows and heifers were used. On day 9 of a synchronized cycle, PGF2α was administered, and blood samples were collected twice daily until the third day after oestrus and analysed for progesterone, estradiol, ghrelin, glucose and BHBA concentrations. No difference was recorded between groups in steroids and BHBA concentrations. In comparison to mid-luteal values, ghrelin concentrations significantly increased at perioestrual period in cows, but not in heifers. This study provides evidence that starving-induced elevated ghrelin concentrations can have suppressing effect on LH secretion, even after ghrelin's restoration to basal values and that during oestrus, ghrelin secretion is differently regulated in cows and heifers, likely being independent from oestradiol concentrations. Further research is required to identify the determining factors that drive the different regulation of ghrelin secretion in cows and heifers.

The Effect of Metformin on the Endometrium of Women with Polycystic Ovary Syndrome.

OBJECTIVES: To investigate the effect of metformin on endometrial receptivity in women with polycystic ovary syndrome (PCOS). METHODS: Twenty volunteer women with polycystic ovaries and oligomenorrhea were prospectively investigated. All women were treated with exogenous estradiol and progesterone to simulate a normal menstrual cycle (28-day duration) after GnRH-induced pituitary desensitization. Ten of the women received no other medication (group A, control), while the remaining 10 received metformin (group B, metformin). Endometrial biopsy was performed in all women on day 21 of the 2 simulated cycles. RESULTS: The expression of corticotropin - releasing hormone and urocortin in the endometrium was investigated. There was no significant difference between the 2 groups. A 3-day delay in the secretory maturation of the glandular epithelium relatively to the stroma was observed in 7 out of 10 women of group B (70%) as compared to only 1 out of 10 women of group A (10%, p = 0.02). CONCLUSIONS: It is shown for the first time that metformin administration to women with PCOS did not affect the expression of endometrial receptivity markers but delayed histological glandular maturation. It is suggested that metformin may have an impact on the function of the endometrium in PCOS.

Enhanced erythrocyte antioxidant status following an 8-week aerobic exercise training program in heavy drinkers.

Alcohol-induced oxidative stress is involved in the development and progression of various pathological conditions and diseases. On the other hand, exercise training has been shown to improve redox status, thus attenuating oxidative stress-associated disease processes. The purpose of the present study was to evaluate the effect of an exercise training program that has been previously reported to decrease alcohol consumption on blood redox status in heavy drinkers. In a non-randomized within-subject design, 11 sedentary, heavily drinking men (age: 30.3 ± 3.5 years; BMI: 28.4 ± 0.86 kg/m2) participated first in a control condition for 4 weeks, and then in an intervention where they completed an 8-week supervised aerobic training program of moderate intensity (50-60% of the heart rate reserve). Blood samples were collected in the control condition (pre-, post-control) as well as before, during (week 4 of the training program), and after intervention (week 8 of the training program). Samples were analyzed for total antioxidant capacity (TAC), thiobarbituric acid reactive substances (TBARS), protein carbonyls (PC), uric acid (UA), bilirubin, reduced glutathione (GSH), and catalase activity. No significant change in indices of redox status in the pre- and post-control was observed. Catalase activity increased (p < 0.05) after 8 weeks of intervention compared to week 4. GSH increased (p < 0.05) after 8 weeks of intervention compared to the control condition and to week 4 of intervention. TAC, UA, bilirubin, TBARS, and PC did not significantly change at any time point. Moreover, concentrations of GSH, TBARS, and catalase activity negatively correlated with alcohol consumption. In conclusion, an 8-week aerobic training program enhanced erythrocyte antioxidant status in heavy drinkers, indicating that aerobic training may attenuate pathological processes caused by alcohol-induced oxidative stress.

Radiolabeled mAbs as Molecular Imaging and/or Therapy Agents Targeting PSMA.

Molecular imaging and therapy is a rapidly evolving field in research and clinical medicine. The use of the exciting and attractive properties of radioisotopes for imaging and therapy has made Nuclear Medicine very significant when it comes to molecular imaging/therapy. Monoclonal Antibodies (mAbs) on the other hand are very important targeting biomolecules with high affinity that can "carry" the radioisotope of choice. Herein we make a brief overview of the radiolabeled mAbs that target prostate specific membrane antigen (PSMA) and their use in the management of patients with prostate cancer (PCa).

Myocardial perfusion and left ventricular quantitative parameters obtained using gated myocardial SPECT: Comparison of three software packages.

BACKGROUND: The aim of the present study was to compare Emory Cardiac Toolbox, Myovation, and Quantitative Gated SPECT software regarding the automatic measurements of perfusion and functional left ventricular (LV) quantitative parameters, summed stress score (SSS), perfusion defect score, LV ejection fraction (LVEF), end-diastolic volume, and end-systolic volume (ESV). METHODS AND RESULTS: 99mTc-tetrofosmin gated SPECT studies were performed in 634 consecutive patients based on the one-day stress/rest protocol. Participants were divided into subgroups according to heart size (ESV cut-off value: 25 mL), perfusion (SSS >/≤3), and other patient/protocol-related factors. LVEF was categorized as normal (≥50%), mildly moderately impaired (35-49%), and severely abnormal (<35%). The concordance between the packages was good to excellent, in overall population, ESV ≤25 mL, ESV >25 mL, and SSS >3 subgroups (intraclass correlation coefficients, ICCs 0.73-0.93). In SSS ≤3 subgroup, the correlation was excellent for LV functional parameters, but suboptimal for perfusion variables (ICCs 0.30-0.83). LVEF categorization revealed similar variability (discordance 18.1 and 11.1% for stress/rest LVEF values, respectively). Pair comparisons demonstrated considerable differences concerning all parameters for all patient subgroups. The statistical significance of our findings by ESV and SSS classifications was evaluated. CONCLUSIONS: Despite the significant concordance between software packages, considerable differences in mean values of myocardial perfusion and LV functional parameters were demonstrated.

18F-fluorothymidine PET imaging in gliomas: an update.

Brain neoplasms constitute a group of tumors with discrete differentiation grades, and therefore, course of disease and prognosis. Magnetic resonance imaging (MRI) remains the gold standard method for the investigation of central nervous system tumors. However, MRI suffers certain limitations, especially if radiation therapy or chemotherapy has been previously applied. On the other hand, given the development of newer radiopharmaceuticals, positron emission tomography (PET) aims to a better investigation of brain tumors, assisting in the clinical management of the patients. In the present review, the potential contribution of radiolabeled fluorothymidine (FLT) imaging for the evaluation of brain tumors will be discussed. In particular, we will present the role of FLT-PET imaging in the depiction of well and poorly differentiated lesions, the assessment of patient prognosis and treatment response, and the recognition of disease recurrence. Moreover, related semi-quantitative and kinetic parameters will be discussed.