Is cribriform pattern in prostate biopsy a risk factor for metastatic disease on 68Ga-PSMA-11 PET/CT?

INTRODUCTION: Cribriform growth pattern (CP) in prostate cancer (PCa) has been associated with different unfavourable oncological outcomes. This study addresses if CP in prostate biopsies is an independent risk factor for metastatic disease on PSMA PET/CT. METHODS: Treatment-naive patients with ISUP GG ≥ 2 staged with 68Ga-PSMA-11 PET/CT diagnosed from 2020 to 2021 were retrospectively enrolled. To test if CP in biopsies was an independent risk factor for metastatic disease on 68Ga-PSMA PET/CT, regression analyses were performed. Secondary analyses were performed in different subgroups. RESULTS: A total of 401 patients were included. CP was reported in 252 (63%) patients. CP in biopsies was not an independent risk factor for metastatic disease on the 68Ga-PSMA PET/CT (p = 0.14). ISUP grade group (GG) 4 (p = 0.006), GG 5 (p = 0.003), higher PSA level groups per 10 ng/ml until > 50 (p-value between 0.02 and > 0.001) and clinical EPE (p > 0.001) were all independent risk factors. In the subgroups with GG 2 (n = 99), GG 3 (n = 110), intermediate-risk group (n = 129) or the high-risk group (n = 272), CP in biopsies was also not an independent risk factor for metastatic disease on 68Ga-PSMA PET/CT. If the EAU guideline recommendation for performing metastatic screening was applied as threshold for PSMA PET/CT imaging, in 9(2%) patients, metastatic disease was missed, and 18% fewer PSMA PET/CT would have been performed. CONCLUSION: This retrospective study found that CP in biopsies was not an independent risk factor for metastatic disease on 68Ga-PSMA PET/CT.

Optimization of injected 68Ga-PSMA activity based on list-mode phantom data and clinical validation.

Optimization of injected gallium-68 (68Ga) activity for 68Ga-prostate-specific membrane antigen positron emission tomography/computed tomography (68Ga-PSMA PET/CT) studies is relevant for image quality, radiation protection, and from an economic point of view. However, no clear guidelines are available for 68Ga-PSMA studies. Therefore, a phantom study is performed to determine the highest coefficient of variation (COV) acceptable for reliable image interpretation and quantification.To evaluate image interpretation, the relationship of COV and contrast-to-noise ratio (CNR) was studied. The CNR should remain larger than five, according to the Rose criterion. To evaluate image quantification, the effect of COV on the percentage difference (PD) between quantification results of two studies was analyzed. Comparison was done by calculating the PD of the SUVmax. The maximum allowable PDSUVmax was set at 20%. The highest COV at which both criteria are still met is defined as COVmax. Of the NEMA Image Quality phantom, a 20 min/bed (2 bed positions) scan was acquired in list-mode PET (Philips Gemini TF PET/CT). The spheres to background activity ratio was approximately 9:1. To obtain images with different COV, lower activity was mimicked by reconstructions with acquisition times of 10 min/bed to 5 s/bed. Pairs of images were obtained by reconstruction of two non-overlapping parts of list-mode data.For the 10-mm diameter sphere, a COV of 25% still meets the criteria of CNRSUVmean ≥ 5 and PDSUVmax ≤ 20%. This phantom scan was acquired with an acquisition time of 116 s and a background activity concentration of 0.71 MBq/kg. Translation to a clinical protocol results in a clinical activity regimen of 3.5 MBq/kg min at injection. To verify this activity regimen, 15 patients (6 MBq/kg min) with a total of 22 lesions are included. Additional reconstructions were made to mimic the proposed activity regimen. Based on the CNRSUVmax, no lesions were missed with this proposed activity regimen.For our institution, a clinical activity regimen of 3.5 MBq/kg min at injection is acceptable, which indicates that activity can be reduced by almost 50% compared with the current code of practice. Our proposed method could be used to obtain an objective activity regimen for other PET/CT systems and tracers.

Diffuse bone metastases on (68)Ga-PSMA PET-CT in a patient with prostate cancer and normal bone scan.

A 75-year-old patient was diagnosed with a Gleason 9 prostate carcinoma. His PSA level was 50.4 ng/ml. Routine bone scintigraphy was negative for metastasis (a). Due to the high tumour grading and relatively high PSA level, (68)Ga-PSMA PET-CT was ordered to rule out distant metastases. This scan showed numerous skeletal lesions with high tracer accumulation as sign of diffuse osseous metastases (b). On low-dose CT there were no signs of sclerosis (c). (68)Ga-PSMA PET-CT also showed high uptake in the prostate and in para-iliac and para-aortal lymph nodes, without lymph node enlargement. No bone biopsy was obtained to confirm the metastases. Due to this result, the treatment plan was changed to systemic therapy, instead of local therapy.

Imaging the inflammatory activity of sarcoidosis: sensitivity and inter observer agreement of (67)Ga imaging and (18)F-FDG PET.

AIM: The aim of this study was to investigate sensitivity of 67Ga imaging and 18F-FDG PET for sarcoidosis activity and their inter observer variability. METHODS: Thirty-four newly diagnosed, histologically proven sarcoidosis patients were analyzed prospectively. (67)Ga imaging and (18)F-FDG PET were performed, the presence of pulmonary and extra pulmonary lesions was evaluated and inter observer variability of both techniques was assessed. RESULTS: Overall sensitivity to detect active sarcoidosis was 88% for (67)Ga imaging and 97% for (18)F-FDG PET. Although these results were not significantly different, 18F-FDG PET detected more lesions in the mediastinum (P<0.05), hila (P<0.05), lymph nodes (P<0.001) and extra pulmonary regions in general (P<0.001). Inter observer agreement was poor to moderate for (67)Ga imaging (kappa 0.19-0.59) and good to very good for (18)F-FDG PET (kappa 0.65-1.00). CONCLUSION: (18)F-FDG PET is more sensitive than (67)Ga imaging in the assessment of sarcoidosis activity with regard to the mediastinum, hila, lymph nodes and extra pulmonary lesions in general. Furthermore, (18)F-FDG PET demonstrates a very good inter observer agreement in contrast with (67)Ga imaging and (18)F-FDG PET is therefore the nuclear imaging technique of choice in sarcoidosis assessment.

Cortical serotonin transporter density and verbal memory in individuals who stopped using 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy"): preliminary findings.

BACKGROUND: Although the popular drug 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") has been shown to damage brain serotonin (5-HT) neurons in animals, the fate and functional consequences of 5-HT neurons after MDMA injury are not known in humans. We investigated the long-term effects of MDMA use on cortical 5-HT neurons in humans and memory function, because brain 5-HT has been implicated in memory function. METHODS: Twenty-two recent MDMA users, 16 ex-MDMA users who had stopped using MDMA for more than 1 year, and 13 control subjects. The effects of MDMA use on cortical 5-HT neurons was studied by means of single-photon emission computed tomography with iodine 123-labeled 2beta-carbomethoxy-3beta-(4-iodophenyl) tropane ([(123)I]beta-CIT) by quantification of brain 5-HT transporter densities. Verbal memory performance was assessed with the Rey Auditory Verbal Learning Test. RESULTS: Mean cortical [(123)I]beta-CIT-labeled 5-HT transporter density was significantly lower in recent MDMA users than in controls (1.17 vs. 1.28 [-9%]) but not in ex-MDMA users (1.24 vs. 1.28 [-3%]). Recent and ex-MDMA users recalled significantly fewer words than did controls on the immediate recall (47.0 and 48.0 vs 60.0, respectively; P =.001) as well as the delayed recall (9.8 and 10.1 vs. 13.1, respectively; P =.003). Greater use of MDMA was associated with greater impairment in immediate verbal memory. However, memory performance was not associated with [(123)I]beta-CIT binding to cortical 5-HT transporters or duration of abstinence from MDMA. CONCLUSION: The present study suggests that, while the neurotoxic effects of MDMA on 5-HT neurons in the human cortex may be reversible, the effects of MDMA on memory function may be long-lasting.

Higher occupancy of muscarinic receptors by olanzapine than risperidone in patients with schizophrenia. A[123I]-IDEX SPECT study.

RATIONALE: In vitro data have shown anticholinergic properties of the atypical antipsychotic drug olanzapine. Substantial occupancy of muscarinic receptors may be an explanation for the low incidence of extrapyramidal side effects induced by olanzapine. OBJECTIVES: To obtain an in vivo measurement of muscarinic receptor occupancy by olanzapine compared with risperidone in patients with schizophrenia stabilised on medication. METHODS: Five patients with schizophrenia treated with olanzapine and five patients treated with risperidone were studied. Muscarinic receptor occupancy in the striatum and cortex was studied in vivo with SPECT using [123I]-IDEX as a radioligand. SPECT data were compared with those of six healthy subjects. RESULTS: Patients stabilised on olanzapine showed significantly lower mean (+/-SD) striatal and cortical (1.50+/-0.21 and 1.51+/-0.22, respectively) muscarinic receptor binding ratios of [123I]-IDEX (reflecting higher levels of muscarinic receptor occupancy) than controls (3.91+/-0.61 and 3.65+/-0.70, respectively). Furthermore, [123I]-IDEX binding ratios in patients treated with risperidone were slightly lower than controls, reaching significance only in the striatum (2.99+/-0.27 versus 3.91+/-0.61, for risperidone and controls). CONCLUSIONS: The substantial occupancy of muscarinic receptors in the striatum and cortex by olanzapine may be an explanation for the low incidence and severity of extrapyramidal side effects of this antipsychotic drug. Furthermore, it may also explain the anticholinergic side effects of olanzapine.

Dopamine transporter density in patients with tardive dyskinesia: a single photon emission computed tomography study.

RATIONALE: Tardive dyskinesia occurs frequently in schizophrenic patients chronically treated with classical antipsychotic medication. It may be caused by loss of dopaminergic cells, due to free radicals as a product of high synaptic dopamine levels. OBJECTIVE: To evaluate dopamine transporter density in the striatum in patients with tardive dyskinesia. METHODS: Striatal [123I]FP-CIT binding was measured with SPECT in seven schizophrenic patients with tardive dyskinesia and eight healthy controls. RESULTS: No significant difference was found between striatal [123I]FP-CIT binding ratios in patients with tardive dyskinesia and controls. CONCLUSIONS: This preliminary study indicates no change in striatal dopamine transporter density in schizophrenic patients with tardive dyskinesia. This finding does not support the hypothesis that tardive dyskinesia is caused by dopaminergic cell loss.

Dopamine transporter density in young patients with schizophrenia assessed with [123]FP-CIT SPECT.

Disturbances in the dopamine (DA) system are thought to play a major role in schizophrenia. Amphetamine-induced release of endogenous DA is shown to be enhanced in schizophrenia, as is striatal [18F]FDOPA uptake in the striatum. It is not clear if the density of DA neurons is altered in schizophrenia. By studying the DA transporter with [123I]FP-CIT single photon emission computed tomography (SPECT), the density of nigrostriatal dopaminergic cells can be studied. Using [123I]FP-CIT SPECT, DA transporter density in the striatum was studied in 36 young patients with schizophrenia. Ten patients were antipsychotic (AP)-naive, 15 were treated with olanzapine, eight with risperidone and three were AP-free. A control group of 10 age-matched volunteers was included. Striatal [123I]FP-CIT binding was not significantly different between AP-naive patients (2.87), patients treated with olanzapine (2.76), patients treated with risperidone (2.76), AP-free patients (2.68) and controls (2.82) (F=0.07,p=0.98). Unexpectedly, striatal [123I]FP-CIT binding in females was significantly higher than in males (3.29 and 2.70, respectively; t=-2.56, p=0.014).Concluding, functional changes in the dopaminergic system in schizophrenia are not likely to be reflected in a change in DA transporter density. Moreover, DA transporter density does not seem to be altered by AP medication.

Addition of a 5-HT receptor agonist to methylphenidate potentiates the reduction of [123I]FP-CIT binding to dopamine transporters in rat frontal cortex and hippocampus.

The neurotoxic potential of amphetamine and related drugs is well documented. However, methylphenidate, an amphetamine derivative used in the treatment of attention deficit hyperactivity disorder, and known to increase synaptic dopamine (DA) levels, seems to lack neurotoxic potential. It is hypothesized that both dopaminergic and serotonergic systems are involved in the neurotoxicity of amphetamine derivatives. The purpose of the present study was to evaluate the neurotoxic potential of methylphenidate and to test whether stimulation of the serotonergic system may confer neurotoxic properties to methylphenidate for DA or serotonin (5-HT) neurons. In addition, the present study was undertaken to evaluate the necessity to perform future SPECT studies in individuals using both methylphenidate and 5-HT-acting agents. We therefore measured monoaminergic transporters in rat brain using radioligands suitable for SPECT imaging ([123I]beta-CIT and [123I]FP-CIT). Groups of rats were treated with methylphenidate or saline for 4 days. Additional groups were treated with the selective 5-HT(2) receptor agonist quipazine or the selective 5-HT reuptake blocker fluoxetine, alone or in combination with methylphenidate. Binding studies were performed 5 days after the last treatment. In a second experiment, methylphenidate in combination with quipazine, along with a control group, was retested. In this experiment, monoaminergic terminal density was estimated 2 weeks (rather than 5 days) after drug treatment. Five days, but not 2 weeks, after treatment a significant reduction in specific [123I]FP-CIT binding was observed in the frontal cortex and hippocampus of rats treated with methylphenidate in combination with quipazine. These changes probably do not reflect neurotoxic changes of frontal cortex and hippocampal DA terminal markers, but a compensatory downregulation of DA transporters. These findings suggest potential harmful effects of concomitant use of drugs directly activating 5-HT2 receptors in patients using methylphenidate.

Effect of age and gender on dopamine transporter imaging with [123I]FP-CIT SPET in healthy volunteers.

Dopamine transporter imaging is a valuable tool to investigate the integrity of the dopaminergic neurons. To date, several reports have shown an age-associated decline in dopamine transporters in healthy volunteers. Although animal studies suggest an effect of gender on dopamine transporter density, this gender effect has not yet been confirmed in human studies. To study the influence of age and gender on dopamine transporter imaging in healthy volunteers, we performed single-photon emission tomography imaging with [123I]FP-CIT to quantify dopamine transporters. Forty-five healthy volunteers (23 males and 22 females) were included, ranging in age from 18 to 83 years. SPET imaging was performed 3 h after injection of +/-110 MBq [123I]FP-CIT. An operator-independent volume of interest analysis was used for quantification of [123I]FP-CIT binding in the striatum. The ratio of specific striatal to non-specific [123I]FP-CIT binding was found to decrease significantly with age. Moreover, we found a high variance in [123I]FP-CIT binding in young adults. Finally, females were found to have significantly higher [123I]FP-CIT binding ratios than males. This effect of gender on [123I]FP-CIT binding ratios was not related to age. The results of this study are consistent with findings from previous studies, which showed that dopamine transporter density declines with age. The intriguing finding of a higher dopamine transporter density in females than in males is in line with findings from animal studies.

Subjective experience and striatal dopamine D(2) receptor occupancy in patients with schizophrenia stabilized by olanzapine or risperidone.

OBJECTIVE: The authors' goal was to study the relationship between subjective experience during treatment with olanzapine or risperidone and dopamine D(2) receptor occupancy in stabilized patients with schizophrenia. METHOD: Subjective experience, psychopathology, and extrapyramidal symptoms were assessed, and D(2) receptor occupancy was determined with [(123)I]iodobenzamide single photon emission computed tomography, in 22 patients whose schizophrenia was stabilized by olanzapine or risperidone. RESULTS: Subjective experience, depression, and negative symptoms were related to dopamine D(2) receptor occupancy, but extrapyramidal symptoms were not. CONCLUSIONS: These results provide preliminary evidence that negative subjective experience is related to high D(2) receptor occupancy. Longitudinal study is required because this relationship may have implications for dosing strategies.

[123I]FP-CIT binding in rat brain after acute and sub-chronic administration of dopaminergic medication.

The recently developed radioligand [123I]FP-CIT is suitable for clinical single-photon emission tomography (SPET) imaging of the dopamine (DA) transporter in vivo. To date it has remained unclear whether dopaminergic medication influences the striatal [123I]FP-CIT binding. The purpose of this study was to investigate the influence of this medication on [123I]FP-CIT binding in the brain. We used an animal model in which we administered dopaminomimetics, antipsychotics and an antidepressant. In vivo [123I]FP-CIT binding to the DA and serotonin transporters was evaluated after subchronic and acute administration of the drugs. The administered medication induced small changes in striatal [123I]FP-CIT binding which were not statistically significant. As expected, the DA reuptake blocker GBR 12,909 induced a significant decrease in [123I]FP-CIT binding. [123I]FP-CIT binding in the serotonin-rich hypothalamus was decreased only after acute administration of fluvoxamine. The results of this study suggest that dopaminergic medication will not affect the results of DA transporter SPET imaging with [123I]FP-CIT.

Comparative in vivo study of iodine-123-labeled beta-CIT and nor-beta-CIT binding to serotonin transporters in rat brain.

Both iodine-123-labeled beta-CIT (2beta-carbomethoxy-3beta-(4-iodophenyl)tropane) and nor-beta-CIT (2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane) have shown to be suitable radioligands for imaging serotonin (5-HT) transporters. [(123)I]nor-beta-CIT has the highest in vitro affinity for 5-HT transporters among beta-CIT analogs reported so far. However, no direct comparison-studies of these two radiotracers as to their in vivo binding to 5-HT transporters have been reported so far. Therefore, it is still unclear which of the two radiotracers is more suitable for single photon emission computed tomography (SPECT) imaging of 5-HT transporters. The purpose of this study was to compare directly in a controlled design the in vivo [(123)I]beta-CIT and [(123)I]nor-beta-CIT binding to 5-HT transporters under the same conditions in rats with the focus on brain kinetic characteristics by means of a two-compartment analysis. We observed that [(123)I]beta-CIT has a higher binding potential and faster kinetics for 5-HT transporters than [(123)I]nor-beta-CIT, suggesting that [(123)I]beta-CIT may be a more suitable radioligand than [(123)I]nor-beta-CIT for imaging 5-HT transporters with SPECT.

Dopamine D2 receptor occupancy by olanzapine or risperidone in young patients with schizophrenia.

A crucial characteristic of antipsychotic medication is the occupancy of the dopamine (DA) D2 receptor. We assessed striatal DA D2 receptor occupancy by olanzapine and risperidone in 36 young patients [31 males, 5 females; mean age 21.1 years (16-28)] with first episode schizophrenia, using [123I]iodobenzamide (IBZM) SPECT. The occupancy of DA D2 receptors was not significantly different between olanzapine and risperidone. However, in subgroups of most prescribed doses, DA D2 occupancy was higher in the risperidone 4-mg group (79%) compared to the olanzapine 15-mg group (62%). [123I]IBZM binding ratios decreased with olanzapine dose (r = -0.551; P < 0.01), indicating higher DA D2 receptor occupancy with higher olanzapine dose. Akathisia and positive symptoms were correlated with [123I]IBZM binding ratio (r = -0.442; P < 0.01; and r = -0.360; P < 0.05, respectively). Prolactin (PRL) levels were elevated in the risperidone, but not in the olanzapine group, at comparable D2 receptor occupancy levels. In the olanzapine group, PRL levels were correlated with [123I]IBZM binding ratio (r = -0.551; P < 0.01). In conclusion, both olanzapine and risperidone induce a high striatal D2 receptor occupancy, dependent on dose and group formation. The lower incidence of prolactin elevation with olanzapine, compared to risperidone, may not be attributed to a lower D2 receptor occupancy.

Implementation of technetium-99m MIBI SPECT imaging guidelines: optimizing the two day stress-rest protocol.

OBJECTIVES: In a previous study in 460 patients, we found that in patients with suspected or known coronary artery disease undergoing stress-rest technetium-99m sestamibi (MIBI) SPECT myocardial perfusion imaging, rest SPECT imaging could be withhold in approximately 20% of patients because of a completely normal stress study. The present study was set up to evaluate the consequences of the implementation of this finding in a subsequent population of patients, and to set standards for the variety of protocols now used for MIBI SPECT imaging. METHODS: Within a period of 4 months, 235 consecutive patients referred for MIBI SPECT scintigraphy were studied. All patients had stable cardiac chest pain and underwent symptom-limited exercise MIBI SPECT perfusion imaging. The stress SPECT images were reconstructed and evaluated immediately after acquisition of the images. In case of a clearly normal stress SPECT study, rest imaging was cancelled. RESULTS: Twenty-six of 235 patients (11%) had a completely normal stress MIBI SPECT study and the rest SPECT imaging procedure could be subsequently cancelled. In 20 patients (9%) the stress SPECT was inconclusive, and in 189 (80%) of patients stress imaging was clearly abnormal. In the first month of the study, the nuclear medicine physicians and cardiologists would interprete only 6% of the stress images as normal, while this number increased to 13% after 9 weeks, with a mean of 11% for the whole investigation period of 4 months. CONCLUSION: In patients undergoing stress MIBI SPECT imaging, it was found justified to cancel rest MIBI SPECT imaging in at least 11% of patients because of a completely normal stress SPECT. As 9% of the images were inconclusive, the number of normal stress images could theoretically increase to 20% if reliable measures are taken to improve reading accuracy. This number is in close agreement with the number of normal stress studies previously reported by our institution and would lead to a considerable reduction of radiation dose, costs, and increased convenience for an important subset of patients.