Diagnostic effectiveness of [18F]Fluoroestradiol PET/CT in oestrogen receptor-positive breast cancer: the key role of histopathology. Evidence from an international multicentre prospective study.

INTRODUCTION: [18F]Fluoroestradiol ([18F]FES) PET/CT has been proposed as a tool for detecting the oestrogen receptor density in patients with metastatic breast cancer (BC) non-invasively across all disease localizations. However, its diagnostic potential in terms of the detection rate (DR) of metastases is unclear. In this study, we pitted this method against [18F]FDG PET/CT and tried to identify predictors of the diagnostic superiority of the [18F] FES-based method. MATERIALS AND METHODS: From a multicentre database, we enrolled all patients with metastatic BC who had undergone both [18F]FES PET/CT and [18F]FDG PET/CT. Two readers assessed both images independently and used a patient-based (PBA) and lesion-based analysis (LBA) to calculate the DR. Pathology-related and clinical factors were tested as predictors of [18F]FES PET/CT superiority using a multivariate model. RESULTS: 92 patients, bearing a total of 2678 metastases, were enrolled. On PBA, the DR of [18F]FDG and [18F]FES PET/CT was 97% and 86%, respectively (p = 0.018). On LBA, the [18F]FES method proved more sensitive than [18F]FDG PET/CT in lymph nodes, bone, lung and soft tissue (p < 0.01). This greater sensitivity was associated with lobular histology, both on PBA (Odds Ratio (OR) 3.4, 95%CI 1.0-12.3) and on LBA (OR 4.4, 95%CI 1.2-16.1 for lymph node metastases and OR 3.29, 95%CI 1.1-10.2 for bone localizations). CONCLUSIONS: The overall DR of [18F]FES PET/CT appears to be lower than that of [18F]FDG PET/CT on PBA. However, the [18F]FES method, if positive, can identify more lesions than [18F]FDG at most sites. The higher sensitivity of [18F]FES PET/CT was associated with lobular histology.

Heterogeneity of bone metastases as an important prognostic factor in patients affected by oestrogen receptor-positive breast cancer. The role of combined [18F]Fluoroestradiol PET/CT and [18F]Fluorodeoxyglucose PET/CT.

PURPOSE: To assess the prognostic role of different inter and intralesional expression (heterogeneity) of oestrogen receptor (ER) in bone metastases, as identified by the combined use of [18F]FES PET/CT and [18F]FDG PET/CT in patients with oestrogen receptor-positive (ER+) metastatic breast cancer (BC). METHODS: We analysed patients with a new diagnosis of bone metastases who were candidates for first-line systemic endocrine therapy. Before starting therapy, patients underwent baseline [18F]FES PET/CT and [18]FDG PET/CT. Semi-quantitative evaluation of whole-body bone metabolic burden (WB-B-MB) was performed on [18F]FES and [18F]FDG PET/CT in order to evaluate disease extent, tumour metabolism and ER heterogeneity. We used time-to-event analyses (Kaplan-Meier and Cox proportional-hazards methods) to estimate progression-free (PFS) and overall survival (OS), in order to assess the independent prognostic value of [18F]FES PET/CT and [18F]FDG PET/CT, alone and in combination. RESULTS: According to our criteria, we enrolled 49 patients. Over a median follow-up of 44.7 months, 35 patients suffered disease progression (71.4 %) and 15 died of disease (30.6 %). When the risk of disease progression was calculated by means of the Cox model, only [18F]FDG WB-B-MB was independently and directly associated to PFS (p = 0.02). On analysing the association between all prognostic parameters and survival, the Cox model showed that the only parameter associated with OS was the WB-B-MB FES/FDG ratio (p = 0.01). CONCLUSION: The combined use of [18F]FES-PET/CT and [18F]FDG-PET/CT can identify ER heterogeneity in BC bone metastases. This heterogeneity is significantly associated with survival. Moreover, the extension of the FDG-avid component correlates with the risk of disease progression.

Could short thyroid hormone withdrawal be an effective strategy for radioiodine remnant ablation in differentiated thyroid cancer patients?

PURPOSE: Current guidelines recommend thyroid hormone withdrawal (THW) of 3-4 weeks before radioiodine remnant ablation (RRA) of differentiated thyroid carcinoma (DTC). We aimed to evaluate (1) the reliability of a shorter THW (i.e., 14 days) to achieve adequate TSH levels (i.e., 30 mU/l), (2) the association between length of THW and response to therapy, and (3) the potential association between pre-ablation TSH levels and patients' outcome. METHODS: After thyroidectomy, all patients started LT4 therapy, which was subsequently discontinued in order to perform RRA. Patients were broken down into two groups according to the length of THW: group A, 2 weeks of THW, and group B, 3-4 weeks of THW. We used clinical, biochemical, and imaging data to evaluate patients' outcome. By means of univariate and multivariate analysis, including main DTC prognostic factors, we assessed the impact of THW length and TSH levels on patients' outcome. RESULTS: We evaluated 222 patients, 85 of whom were treated with RRA after a THW period of 2 weeks (group A). All other 137 patients underwent RRA after 3-4 weeks THW (group B). At the time of RRA all patients presented TSH levels ≥30 mU/l. After a median follow-up time of 3.4 years, we found 183 patients (82%) with excellent response to treatment and 39 patients (18%) showing incomplete response. Kaplan-Meier response to therapy curves showed that ablation-Tg, tumor size, and lymph node status were significantly associated with prognosis; no associations were found between THW length, TSH levels, and prognosis. Multivariate Cox model showed that only ablation-Tg was significantly associated with treatment response. CONCLUSIONS: Prior to RRA, a short 2-week THW is an effective method to stimulate TSH levels. No difference in terms of incomplete response to treatment was observed between DTC patients prepared for RRA with a short THW and those with the long THW.

Differentiated Thyroid Cancer lymph-node relapse. Role of adjuvant radioactive iodine therapy after lymphadenectomy.

PURPOSE: Our purpose as to evaluate the impact of adjuvant radioactive iodine therapy (RAI) on prognosis, as assessed by progression-free survival (PFS) and overall survival (OS), in patients affected by differentiated thyroid carcinoma (DTC) lymph-node relapse and previously treated with lymphadenectomy. METHODS: We retrospectively evaluated DTC patients treated with lymph-node dissection for disease relapse. All patients had previously undergone total thyroidectomy and radioiodine remnant ablation (RRA). We used clinical and histological data obtained during follow-up to assess response and outcome. By means of univariate and multivariate time-to-event analyses, we assessed the impact of RAI on outcome (PFS and OS) and the prognostic role of thyroglobulin (Tg) levels under suppression with levothyroxine (Tg-on) measured 1-3 months after lymphadenectomy and of other risk factors. RESULTS: We evaluated 113 patients (age at diagnosis: median 41 years, interquartile range: 31-59), 64 of whom were treated with RAI. Over a median follow-up time of 5.7 years, 27 patients showed disease progression and 13 died. Kaplan-Meier PFS and OS curves showed that age on diagnosis, tumor histology, tumor size, DTC aggressive variant, and Tg-on were associated with prognosis. Patients with Tg-on ≥1 ng/ml treated with RAI showed a better PFS (Log-rank pp 0.001) and OS (p = 0.005) than untreated patients, while no effect of RAI was observed in patients with Tg-on <1 ng/ml. Multivariate models showed that age, Tg-on (≥1 vs. < 1 ng/ml, HR: 18.2, 95% CI: 5.09-64.8, p = 0.001) and RAI (Yes vs. No, HR: 0.36,95%CI: 0.15-0. 9, p = 0.02) remained the only independent factors associated with PFS, but only age and Tg-on remained significantly associated with OS (HR: 8.31, 95%CI:1.56-44.3, p = 0.01). Nonetheless, patients treated with RAI showed a lower risk of mortality (HR: 0.34, 95%CI: 0.1-1.15 p = 0.08) than untreated patients. CONCLUSIONS: RAI after lymphadenectomy for DTC relapse is significantly associated with better PFS only in patients with Tg-on ≥1 ng/ml.

18F-FDG-PET/CT in Patients Affected by Differentiated Thyroid Carcinoma with Positive Thyroglobulin Level and Negative 131I Whole Body Scan. It's Value Confirmed by a Bicentric Experience.

BACKGROUND: 18F-FDG-PET/CT applications in the field of differentiated thyroid cancer (DTC) are continuously growing. OBJECTIVE: To retrospectively analyze in a wide population enrolled in two nuclear medicine centers the diagnostic value of 18F-FDG-PET/CT in patients treated with 131I and negative 131I-WBS but in presence of Tg levels higher than 1ng/ml after TSH stimulation. METHOD: From September 2005 to December 2014, 154 patients affected by DTC, treated with 131I with negative 131I-WBS and Tg&≥1ng/ml underwent 18F-FDG-PET/CT. RESULTS: 66 patients (43%) had a negative 18F-FDG-PET/CT (mean Tg=7.7ng/ml; SD=9.6) and 88 (57%) a positive scan (mean Tg=169.4; SD=294.6) documenting bone, pulmonary, lymph-node metastases and local recurrences. There was no statistically significant correlation between 18F-FDGPET/ CT results and sex, previous lymphadenectomy, the "on-" or "off-therapy" state; on the contrary, there was a statistically significant correlation between PET results and primary tumor size (T1-T2 vs. T3-T4). ROC analysis showed that the highest accuracy in terms of best compromise between sensitivity and specificity (sensitivity= 71,6%; specificity=92,4%; AUC area under the curve= 0.807) is achieved when the 12ng/mL is considered the Tg cut-off value to interpret the results. CONCLUSION: Our study confirm in a wide population that 18F-FDG-PET/CT is useful in evaluating patients affected by DTC, negative 131I-WBS and Tg>1ng/ml, identifying 12ng/ml as the Tg level cut-off over which is better to perform the study.

Heterogeneous response of cardiac sympathetic function to cardiac resynchronization therapy in heart failure documented by 11[C]-hydroxy-ephedrine and PET/CT.

INTRODUCTION: Cardiac resynchronization therapy (CRT) is an accepted treatment in patients with end-stage heart failure. PET permits the absolute quantification of global and regional homogeneity in cardiac sympathetic innervation. We evaluated the variation of cardiac adrenergic activity in patients with idiopathic heart failure (IHF) disease (NYHA III-IV) after CRT using (11)C-hydroxyephedrine (HED) PET/CT. METHODS: Ten IHF patients (mean age = 68; range = 55-81; average left ventricular ejection fraction 26 ± 4%) implanted with a resynchronization device underwent three HED PET/CT studies: PET 1 one week after inactive device implantation; PET 2, one week after PET 1 under stimulated rhythm; PET 3, at 3 months under active CRT. A dedicated software (PMOD 3.4 version) was used to estimate global and regional cardiac uptake of HED through 17 segment polar maps. RESULTS: At baseline, HED uptake was heterogeneously distributed throughout the left ventricle with a variation coefficient of 18 ± 5%. This variable markedly decreased after three months CRT (12 ± 5%, p < 0.01). Interestingly, subdividing the 170 myocardial segments (17 segments of each patient multiplied by the number of patients) into two groups, according to the median value of tracer uptake expressed as % of maximal myocardial uptake (76%), we observed a different behaviour depending on baseline innervation: HED uptake significantly increased only in segments with "impaired innervation" (SUV 2.61 ± 0.92 at PET1 and 3.05 ± 1.67 at three months, p < 0.01). CONCLUSION: As shown by HED PET/CT uptake and distribution, improvement in homogeneity of myocardial neuronal function reflected a selective improvement of tracer uptake in regions with more severe neuronal damage. ADVANCES IN KNOWLEDGE: These finding supported the presence of a myocardial regional variability in response of cardiac sympathetic system to CRT and a systemic response involving remote tissues with rich adrenergic innervation. IMPLICATION FOR PATIENT CARE: This work might contribute to identify imaging parameters that could predict the response to CRT therapy.

Multicentre study of 18F-FDG-PET/CT prostate incidental uptake.

AIM: The purpose of our study was to establish the prevalence and pathological nature of fluorine-18-fluorodeoxyglucose (18F-FDG) prostate incidental uptake (PIU) among patients studied for non-prostate-malignant purposes in three nuclear medicine centres. METHODS: We retrospectively evaluated 20,422 scans performed on male patients; all patients underwent 18F-FDG-PET/CT for purposes not related to prostate disease. RESULTS: Among 20,422 patients PIU was identified for 280 (1.4 %) with an average age of 70 ± 10.7 years. Sixty-three of the 280 patients with PIU (22.5 %) underwent PSA dosage and biopsy to determine the nature of the incidental uptake. Thirty-five of the 63 (55.5 %) PIU were malignant whereas 28/63 (44.5 %) were benign. The average value of PSA for patients with benign PIU was 3.7 ± 2.8 ng/ml whereas it was 7.8 ± 8.2 ng/ml in patients with malignant PIU; this difference was statistically significant. For malignant lesions, the average lesion-to-liver SUVmax ratio was 2.9 ± 2.5 and the average lesion-to-blood-pool SUVmax ratio was 3.7 ± 2.5. For benign lesions, the average lesion-to-liver SUVmax ratio was 2.5 ± 1.7 and the average lesion-to-blood-pool SUVmax ratio was 3.5 ± 2.4; there was no statistically significant difference between lesion-to-liver and lesion-to-blood-pool SUVmax ratios for benign and malignant lesions. CONCLUSION: Because PIU values are indicative of malignancy for a substantial percentage of patients, further investigation is required.

Added prognostic value of ischaemic threshold in radionuclide myocardial perfusion imaging: a common-sense integration of exercise tolerance and ischaemia severity.

PURPOSE: Reversible ischaemia at radionuclide myocardial perfusion imaging (MPI) accurately predicts risk of cardiac death and nonfatal myocardial infarction (major adverse cardiac events, MACE). This prognostic penetrance might be empowered by accounting for exercise tolerance as an indirect index of ischaemia severity. The present study aimed to verify this hypothesis integrating imaging assessment of ischaemia severity with exercise maximal rate pressure product (RPP) in a large cohort of patients with suspected or known coronary artery disease (CAD). METHODS AND RESULTS: We analysed 1,502 consecutive patients (1,014 men aged 59 ± 10 years) submitted to exercise stress/rest MPI. To account for exercise tolerance, the summed difference score (SDS) was divided by RPP at tracer injection providing a clinical prognostic index (CPI). Reversible ischaemia was documented in 357 patients (24 %) and was classified by SDS as mild (SDS 2-4) in 180, moderate (SDS 5-7) in 118 and severe (SDS >7) in 59. CPI values of ischaemic patients were clustered into tertiles with lowest and highest values indicating low and high risk, respectively. CPI modified SDS risk prediction in 119/357 (33 %) patients. During a 60-month follow-up, MACE occurred in 68 patients. Kaplan-Meier analysis revealed that CPI significantly improved predictive power for MACE incidence with respect to SDS alone. Multivariate Cox analysis confirmed the additive independent value of CPI-derived information. CONCLUSION: Integration of ischaemic threshold and ischaemia extension and severity can improve accuracy of exercise MPI in predicting long-term outcome in a large cohort of patients with suspected or known CAD.

Central antalgic activity of resveratrol.

A single dose of resveratrol (25 µg/10µl) was injected directly into the right lateral cerebral ventricle (icv) of Wistar rats via an implanted cannula in order to study the analgesic properties of the compound. A control group of rats received 10 µl NaCl 0.9%. The lengthening of the time to reaction to painful stimuli was assessed in the radiant heat tail-flick latency time test. In this study, the response to painful stimuli of the animals treated with resveratrol had a bimodal profile with hypoalgesia or hyperalgesia. In the selected experimental conditions, resveratrol had a definite analgesic effect; the increase in time to reaction ranged from 100-120% (8 rats) to 600-700% (9 rats). In this experiment resveratrol exerts evident central antalgic effects in the majority of rats, which are related to the individual level of excitation and vigilance at baseline. Antinociceptive induced by resveratrol icv injection was maximal at 4-10 min and lasted no longer than 15 min. The effect of resveratrol to produce analgesia after a single icv injection may be interesting for preventing chronic pain.

Analgesic resveratrol?

Resveratrol, a red wine and grape-derived phytoalexin, possesses diverse biochemical and physiological functions that are relevant to human health and disease. The emergent properties of resveratrol have forced us to rethink the biomedical significance of the wine culture. Novel observations point to the hypothesis that intracerebral resveratrol treatment diminishes the sensitivity of rats to pain, and that the said analgesic action of resveratrol is a central mechanism mediated by the inhibition of cycloxygenases I and II. This novel implication of resveratrol and perhaps red wine drinking warrants further studies.

A study of intrathecal self-injection of morphine by rats, and the difficulties entailed.

Rats were chronically implanted with an intrathecal cannula, through which they were taught to self-administer morphine. After a training period of 2 weeks, their self-injection behaviour was studied before, during and after nociceptive stimulation. In response to nociceptive stimulation the rats increased their intrathecal self-injection of morphine. This effect is specific for morphine, since under the same conditions rats did not increase NaCl self-injection. Acute naloxone pre-treatment was shown to block the analgesic effect of intrathecal morphine administration. In the present experiments, morphine never induced convulsions or epilepsy. This suggests, first that the mode action of intrathecally injected morphine is located in the spinal cord and second, that the low dose (20-30 micrograms) of self-injected morphine is not sufficient to induce symptoms of convulsions or epilepsy. Our results show that the rats behave as if deliberately reducing the painful sensation. This experimental situation is therefore similar to the therapeutic situation in humans. It might, therefore, be used for preclinical evaluation of the efficacy of an analgesic drug.

A study of intracerebroventricular self-administration of leucine or methionine enkephalin by rats in response to intermittent electric shocks.

Rats were taught to self-administer Leu-E (10, 25 and 100 micrograms/microliters) or Met-E (0.5, 10 and 100 micrograms/microliters) through a cannula implanted in the lateral cerebral ventricle (i.c.v.). Their self-injection behaviour was studied before, during and after nociceptive stimulation. In the course of the control period of the experiment, the rats rapidly learned lever pressing for self-injection of enkephalin but they did not increase their self-administration of Leu-E or Met-E during the nociceptive electrical stimulation period. Also studied were the acute effect of i.c.v. enkephalin and morphine on tail-flick latency (sec) and electrical threshold vocalization (mA). The analgesic effect of Leu-E and Met-E was of short duration (less than 2-6 min). The mean rise (i.e., analgesia) of the tail-flick threshold showed a significant difference after i.c.v. Met-E only. The acute i.c.v. effect of 20 or 30 micrograms of morphine induced a long-lasting analgesia, greater than 40 min. These results show that Leu-E and Met-E are not rewarding during a nociceptive stimulus. This may be due to the short and inconstant analgesic action of i.c.v. enkephalins.