Androgen Deprivation therapy for Oligo-recurrent Prostate cancer in addition to radioTherapy (ADOPT): study protocol for a randomised phase III trial.

BACKGROUND: More than 60% of oligo-recurrent prostate cancer (PCa) patients treated with metastasis-directed radiotherapy (MDRT) develop biochemical recurrence within 2 years. This recurrence rate emphasises the need for improved treatment and patient selection. In line with the treatment of primary PCa, the efficacy of MDRT may be enhanced when combined with androgen-deprivation therapy (ADT). Furthermore, the availability of PSMA PET/CT offers an excellent tool for optimal patient selection for MDRT. This phase III randomised controlled trial will investigate the role of the addition of ADT to MDRT in oligo-recurrent PCa patients selected with PSMA PET/CT to enhance oncological outcome. METHODS: Two hundred and eighty patients will be randomised in a 1:1 ratio to the standard treatment arm (MDRT alone) or the experimental arm (MDRT + 6 months ADT). Patients with biochemical recurrence after primary treatment of PCa presenting with ≤ 4 metastases will be included. The primary endpoint is the 2.5-year metastases progression-free survival (MPFS). Secondary endpoints are acute and late toxicity, quality of life, biochemical progression-free survival, overall survival, and the sensitivity of the PSMA PET/CT for detecting oligometastases at low PSA-levels. So far, between March 2020 and December 2021, one hundred patients have been included. DISCUSSION: This phase III randomised controlled trial will assess the possible benefit of the addition of 6 months ADT to MDRT on metastases progression-free survival, toxicity, QoL and survival in PCa patients with 1-4 recurrent oligometastatic lesions. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04302454 . Registered 10 March 2020.

Phase III randomised controlled trial on PSMA PET/CT guided hypofractionated salvage prostate bed radiotherapy of biochemical failure after radical prostatectomy for prostate cancer (PERYTON-trial): study protocol.

BACKGROUND: Salvage external beam radiotherapy (sEBRT) for patients with a biochemical recurrence (BCR) after radical prostatectomy provides a 5-year biochemical progression-free survival up to 60%. Multiple studies have shown that dose escalation to the primary prostate tumour improves treatment outcome. However, data is lacking on the role of dose escalation in the recurrent salvage setting. The main objective of the PERYTON-trial is to investigate whether treatment outcome of sEBRT for patients with a BCR after prostatectomy can be improved by increasing the biological effective radiation dose using hypofractionation. Moreover, patients will be staged using the PSMA PET/CT scan, which is superior to conventional imaging modalities in detecting oligometastases. METHODS: The PERYTON-study is a prospective multicentre open phase III randomised controlled trial. We aim to include 538 participants (269 participants per treatment arm) with a BCR after prostatectomy, a PSA-value of < 1.0 ng/mL and a recent negative PSMA PET/CT scan. Participants will be randomised in a 1:1 ratio between the conventional fractionated treatment arm (35 × 2 Gy) and the experimental hypofractionated treatment arm (20 × 3 Gy). The primary endpoint is the 5-year progression-free survival after treatment. The secondary endpoints include toxicity, quality of life and disease specific survival. DISCUSSION: Firstly, the high rate of BCR after sEBRT may be due to the presence of oligometastases, for which local sEBRT is inappropriate. With the use of the PSMA PET/CT before sEBRT, patients with oligometastases will be excluded from intensive local treatment to avoid unnecessary toxicity. Secondly, the currently applied radiation dose for sEBRT may be too low to achieve adequate local control, which may offer opportunity to enhance treatment outcome of sEBRT by increasing the biologically effective radiotherapy dose to the prostate bed. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (Identifier: NCT04642027 ). Registered on 24 November 2020 - Retrospectively registered. The study protocol was approved by the accredited Medical Ethical Committee (METc) of all participating hospitals (date METc review: 23-06-2020, METc registration number: 202000239). Written informed consent will be obtained from all participants.

Patients with left bundle branch block pattern and high cardiac risk myocardial SPECT: does the current management suffice?

INTRODUCTION: Myocardial perfusion SPECT (MPS) is frequently used for cardiovascular risk stratification. The significance of MPS in patients with abnormal electrical ventricular activation is often questionable. This review assesses the value of MPS for risk stratification of patients with intrinsic left bundle branch block or that due to right ventricular apical pacing. METHODS: We reviewed the literature by a search of the MEDLINE database (January 1980 to September 2010). The terms prognosis or prognostic value were combined with SPECT and LBBB or pacing or pacemakers. MPS was categorised as low and high risk according to the original definitions. RESULTS: We identified 11 studies suitable for review. A low-risk MPS is associated with a low risk of cardiac events whereas high-risk MPS carries a 4.8-fold increased risk, 95% CI [3.2 - 7.2] (p < 0.0001). Despite secondary prevention and an improved medical and interventional care, these figures have hardly changed over time. CONCLUSION AND CLINICAL IMPLICATIONS: A low-risk MPS permits a policy of watchful waiting whereas a high-risk MPS requires further analysis and treatment. The persistent high cardiac death and acute myocardial infarction rate after a high-risk MPS suggest that the current management of these patients does not suffice and needs reconsideration.

18F-FDG PET in sarcoidosis: an observational study in 12 patients treated with infliximab.

BACKGROUND: 18F-FDG PET is a promising technique in sarcoidosis imaging, although it is not incorporated in routine activity assessment. The purpose of this study was to correlate 18F-FDG PET with standard sarcoidosis activity parameters during infliximab treatment. METHODS: Twelve patients with refractory sarcoidosis were treated with 6 cycles of infliximab. Pre- and post-therapy 18F-FDG PET was visually evaluated and SUVmax was measured. In addition, the effect of infliximab was evaluated by changes in symptoms, angiotensin converting enzyme (ACE), soluble interleukin-2 receptor (sIL-2R), vital capacity (VC), diffusion capacity of the lung for carbon monoxide (DLCO) and chest radiography. SUVmax and conventional parameters were correlated. RESULTS: Clinical improvement as judged by conventional parameters was seen in all patients, though with a minor response in one. Symptoms improved in 11/12 patients while chest radiographic stages did not change. The decrease in ACE was 39% and in sIL-2R 47% (p<0.01). Improvement of VC and DLCO was 5.4% and 3.3% (p<0.05), respectively. 18F-FDG PET revealed either improvement or normalization in 11/12 (92%) clinically responding patients. The overall decrease in SUVmax was 55% (p<0.01); the patient with a limited response showed a 34% increase. A decrease in SUVmax of the lung parenchyma correlated with an improvement of VC (r=-0.75, p<0.01). No significant correlation between SUVmax and other parameters was found. CONCLUSION: Changes imaged by 18F-FDG PET during infliximab treatment in sarcoidosis patients correlate with signs of clinical improvement to a considerate extent, which supports the hypothesis that 18F-FDG uptake represents disease activity.

[Not Available]. / PSMA-PET voor prostaatkanker en eventuele metastasen.

(68)Gallium (Ga)-PSMA PET/CT (PSMA stands for "prostate-specific membrane antigen") is a new diagnostic tool for patients with prostate cancer or with prostate cancer metastases. PET/CT is a combination scan which uses the physiological information of the PET scan and the anatomic information of the CT scan. The radioligand (68)Ga-PSMA is a radioactively labelled peptide that binds to the membrane protein PSMA. Prostate cancer cells in the primary tumour and in metastases express increased levels of PSMA in the plasma membrane. A number of studies have shown that (68)Ga-PSMA PET/CT is sensitive in detecting primary prostate cancer and metastases in lymph nodes and bone. In the same patient, (68)Ga-PSMA PET/CT detects more metastases in an earlier phase, i.e. at a lower PSA level, than fluorine-18 choline PET/CT. Furthermore, the (68)Ga-PSMA can be produced in the investigating hospital with a gallium generator. The expectation is that the use of (68)Ga-PSMA PET/CT will increase to a major extent over the coming years in patients with prostate cancer.

Inadequate exercise leads to suboptimal imaging. Thallium-201 myocardial perfusion imaging after dipyridamole combined with low-level exercise unmasks ischemia in symptomatic patients with non-diagnostic thallium-201 scans who exercise submaximally.

This study was undertaken to establish the additional value of 201TI imaging after dipyridamole in combination with low-level exercise in 15 symptomatic patients with non-diagnostic 201TI scans, who exercised submaximally. Most patients had angina, ST-segment depression and even exertional hypotension and were referred for stress 201TI testing for determining the functional significance of known coronary artery disease. Six patients with a normal exercise 201TI test and one patient with an apical defect only were found to have 37 segments (of 105 segments) with reversible perfusion defects after dipyridamole infusion. One patient showing two reversible defects after exercise had five reversible segments after dipyridamole. Seven patients with fixed defects in 28 segments after exercise and two with small areas of border zone ischemia in seven additional (sub)segments, demonstrated fixed in defects in only nine segments but reversible defects in 40 segments after dipyridamole. Quantitative analysis resulted in 24.8 +/- 28.5 (mean value) sample points below -2 s.d. of the mean normal uptake after exercise, which increased to 72 +/- 26.5 after dipyridamole infusion (p less than 0.005). The washout analysis resulted in a mean value of 5.5 +/- 8.1 sample points below -2 s.d. after exercise, increasing to 33.3 +/- 22.1 after dipyridamole (p less than 0.005). Thallium-201 myocardial perfusion imaging after dipyridamole combined with low-level upright bicycle exercise may unmask scintigraphic evidence for ischemia in symptomatic patients who would otherwise have non-diagnostic imaging studies during submaximal exercise.

Head-to-head comparison between technetium-99m-sestamibi and thallium-201 tomographic imaging for the detection of coronary artery disease using combined dipyridamole-exercise stress.

AIM: The purpose of this study was a head-to-head comparison of tomographic imaging (SPECT) with technetium-99m (Tc-99m)-sestamibi and thallium-201 (Tl-201) using dipyridamole-low-level bicycle exercise stress for the assessment of coronary artery disease. METHODS: We studied 38 consecutive patients referred for the evaluation of chest pain who had undergone coronary angiography. The patients were randomly allocated to Tc-99m-sestamibi SPECT followed by Tl-201 SPECT or vice versa. The accuracy of both tracers in detecting significant coronary artery disease (> 50% luminal stenosis) was 87% (95% confidence interval 72-96%). Only two patients were classified differently by the two methods. RESULTS: On a segmental basis, good agreement was found between Tc-99m-sestamibi and Tl-201 for both the localization and the nature of perfusion defects (reversible or persistent) identified (Cohen's kappa = 0.67). CONCLUSION: No clinically relevant differences in diagnostic accuracy were demonstrated between Tc-99m-sestamibi and Tl-201 SPECT using combined dipyridamole-exercise stress for the evaluation of coronary artery disease.

Ischemic ST-segment changes after dipyridamole infusion.

Thirty consecutive patients were studied by thallium-201 myocardial imaging after dipyridamole infusion and by coronary angiography because of syndromes of chest pain. Eight patients (27%) had ischemic ST-segment changes after the infusion of dipyridamole. They all had significant coronary arterial disease. It is suggested that the combination of visual analysis of myocardial imaging and analysis of ST-segment changes be used after dipyridamole infusion to improve the sensitivity of this non-invasive test.

Quantitative thallium-201 myocardial exercise scintigraphy in normal subjects and patients with normal coronary arteries.

Quantitative thallium-201 myocardial exercise scintigraphy was tested in two patient populations representing alternative standards for cardiac normality: group I comprised 18 male uncatheterized patients with a low likelihood of coronary artery disease (CAD); group II contained 41 patients with normal coronary arteriograms. Group I patients were younger, they achieved a higher rate-pressure product than group II patients; all had normal findings by physical examination and electrocardiography at rest and exercise. Group II patients comprised 21 females, 11 patients showed abnormal electrocardiography at rest, and five patients showed ischemic ST depression during exercise. Twelve patients had signs of minimal CAD. Twelve patients revealed abnormal visual and quantitative thallium findings, three of these patients had minimal CAD. Profiles of uptake and washout of thallium-201 were derived from both patient groups, and compared with normal limits developed by Maddahi et al. Furthermore, low likelihood and angiographically normal patients may differ substantially, and both sets of normal patients should be considered when establishing criteria for abnormality in exercise thallium imaging. When commercial software containing normal limits for quantitative analysis of exercise thallium-201 imaging is used in clinical practice, it is mandatory to compare these with normal limits of uptake and washout of thallium-201, derived from the less heterogeneous group of low-likelihood subjects, which should be used in selecting a normal population to define normality.

99Tcm-sestamibi SPECT with combined dipyridamole and exercise stress in coronary artery disease.

In order to evaluate the clinical value of 99Tcm-methoxyisobutylisonitrile (sestamibi) single photon emission computed tomography (SPECT) after dipyridamole infusion in combination with low level bicycle exercise for the assessment of the presence, localization and extent of coronary artery disease (CAD), myocardial perfusion imaging was performed in 76 patients. Low level bicycle exercise was used to supplement the standard dipyridamole infusion protocol because of the lower incidence of non-cardiac side effects. The results were compared to arteriographic findings obtained within 3 months of the SPECT studies. The overall sensitivity of detection of coronary artery disease (i.e. a luminal stenosis > 50%) was 81%, specificity 80%, positive predictive value 96%, negative predictive value 40% and accuracy 82%. The diagnostic values for the detection of significant stenoses in the three major coronary arteries were: left anterior descending artery sensitivity 72%, specificity 87% and accuracy 76%; right coronary artery sensitivity 75%, specificity 90% and accuracy 80%; left circumflex coronary artery sensitivity 57%, specificity 85% and accuracy 71%. Scintigraphic evidence of multivessel disease was found in 31 (65%) patients with two- or three-vessel involvement assessed by arteriography. False negative test results were mainly found in patients with relatively mild CAD (one-vessel disease, branch and distal disease). 99Tcm-sestamibi SPECT after dipyridamole infusion in combination with low level bicycle exercise is shown to be a valuable diagnostic tool for the evaluation of CAD.

99Tcm-SESTAMIBI for planar myocardial perfusion imaging; not as ideal as the physical properties.

99Tcm-methoxyisobutyl isonitrile (Tc-SESTAMIBI) has recently been introduced as a new myocardial perfusion agent which exhibits ideal physical properties for imaging with the gamma camera. To assess the diagnostic accuracy of planar Tc-SESTAMIBI, myocardial perfusion imaging was performed in 60 consecutive patients at rest and during exercise. The results were compared with coronary angiographic findings, obtained within 3 months of the exercise test. Planar 201Tl images were also performed on the same day and to the same level of stress as the Tc-SESTAMIBI exercise. Exact segmental agreement between Tc-SESTAMIBI and 201Tl was 77%. Nineteen per cent of all 900 segments demonstrated ischaemia with Tc-SESTAMIBI and 20% with 201Tl. The overall sensitivity for detecting haemodynamically significant coronary artery disease with Tc-SESTAMIBI was 86% and specificity was 78%; with 201Tl the values were 89 and 78%, respectively (differences not significant). Vessel-specific comparative detection rates revealed no statistical significant differences between both radiopharmaceuticals. Intra-observer variability for Tc-SESTAMIBI images was 12% and for 201Tl it was 14%. Inter-observer variability for Tc-SESTAMIBI was 14% and for 201Tl 17%. Although the physical characteristics of Tc-SESTAMIBI allow crisp and clear high-count density imaging, no significant differences are found when planar images are compared with 201Tl and are well within observer variabilities.

Potential for imaging cerebral amyloid deposits using 123I-labelled serum amyloid P component and SPET.

The systemic and cerebral accumulation of 123I-labelled serum amyloid P component (123I-SAP) was studied in patients with hereditary cerebral amyloid angiopathy-Dutch type (HCHWA-D) to determine the usefulness of 123I-SAP imaging in cerebral amyloidosis. Whole-body and SPET scintigraphic imaging was performed in two patients with HCHWA-D and four controls after the intraveous injection of 123I-SAP. Venous 123I-SAP clearance was also determined. Accumulation of the tracer was observed in the cerebral cortex of both patients, whereas no accumulation was seen in the controls. Blood clearance of radioactivity was similar in the patients and controls, suggesting that the amount of uptake of 123I-SAP in the cerebral amyloid deposits is relatively small. We believe this to be the first demonstration of cerebral amyloid deposits in vivo. Our findings indicate that 123I-SAP scintigraphy has possibilities for the diagnosis of patients with cerebral amyloid diseases, in addition to its use in patients with systemic amyloid deposition.

Comparison of adenosine and high-dose dipyridamole both combined with low-level exercise stress for 99Tcm-MIBI SPET myocardial perfusion imaging.

Intravenously administered adenosine and high-dose dipyridamole, both combined with low-level exercise stress, were compared in a head-to-head fashion using 99Tcm-methoxyisobutyl isonitrile (99Tcm-MIBI) single photo emission tomography (SPET) myocardial perfusion imaging. Thirty-nine consecutive patients who had undergone coronary arteriography underwent 99Tcm-MIBI (740 Mbq) SPET after dipyridamole (0.84 mg kg-1) and after adenosine (0.84 mg kg-1), both combined with low-level exercise (30 W load), and under resting conditions. Our results demonstrate that adenosine and dipyridamole combined with exercise have comparable haemodynamic effects, with a low incidence of side-effects. The time of recovery from the stress protocol was not significantly different: adenosine, 5.7 +/- 3.9 min; dipyridamole, 6.6 +/- 4.9 min. However, aminophylline was significantly (P < 0.05) more often administered to reverse side-effects using the dipyridamole protocol (36% of patients) compared with the adenosine protocol (8% of patients). The results of 99Tcm-MIBI SPET imaging were highly concordant and demonstrated a high diagnostic accuracy for identifying coronary artery disease (CAD). The sensitivity was 90% (95% confidence intervals 79-100%) with adenosine SPET and 93% (95% confidence intervals 84-100%) with dipyridamole SPET for identifying patients with CAD (i.e. luminal stenosis > 50%); their specificities were both 100% (95% confidence intervals 66-100%). The sensitivity of identifying angiographically diseased vessels was 81% (95% confidence intervals 70-92%) using adenosine SPET and 85% (95% confidence intervals 75-95%) using dipyridamole; the specificity for both stress modalities was 94% (95% confidence intervals 89-100%). The combination of exercise with adenosine and high-dose dipyridamole appears to be a feasible and safe method to alleviate some of the undesirable A1-receptor-mediated side-effects of adenosine. The choice of the pharmacological stress will depend on local expertise and availability.