NUCLEAIRE GENEESKUNDE

CENTRUM NUCLEAIRE GENEESKUNDE

ARTIKELS

ABSTRACT 1

The effects of ARBs, ACEis, and statins on clinical outcomes of COVID-19 infection among nursing home residents.

de Spiegeleer A, Bronselaer A, Teo J, Van de Wiele C, et al. Journal of the American Medical Directors Association, 2020, 21(7), 909-914

OBJECTIVE Angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs), and HMG-CoA reductase inhibitors ("statins") have been hypothesized to affect COVID-19 severity. However, up to now, no studies investigating this association have been conducted in the most vulnerable and affected population groups (ie, older adults residing in nursing homes). The objective of this study was to explore the association of ACEi/ARB and/or statins with clinical manifestations in COVID-19–infected older adults residing in nursing homes.

MATERIALS/METHODS We undertook a retrospective multicenter cohort study to analyze the association between ACEi/ARB and/or statin use with clinical outcome of COVID-19. The outcomes were (1) serious COVID-19 defined as long-stay hospital admission or death within 14 days of disease onset, and (2) asymptomatic (ie, no disease symptoms in the whole study period while still being diagnosed by polymerase chain reaction).

A total of 154 COVID-19-positive subjects were identified, residing in 1 of 2 Belgian nursing homes that experienced similar COVID-19 outbreaks.Logistic regression models were applied with age, sex, functional status, diabetes, and hypertension as covariates.

RESULTS We found a statistically significant association between statin intake and the absence of symptoms during COVID19 (odds ratio [OR] 2.91; confidence interval [CI] 1.27-6.71), which remained statistically significant after adjusting for covariates (OR 2.65; CI 1.13-6.68). Although the effects of statin intake on serious clinical outcome were in the same beneficial direction, these were not statistically significant (OR 0.75; CI 0.24-1.87). There was also no statistically significant association between ACEi/ARB and asymptomatic status (OR 2.72; CI 0.59-25.1) or serious clinical outcome (OR 0.48; CI 0.10-1.97). CONCLUSION Our data indicate that statin intake in older, frail adults could be associated with a considerable beneficial effect on COVID-19 clinical symptoms. The role of statins and renin-angiotensin system drugs needs to be further explored in larger observational studies as well as randomized clinical trials.

ABSTRACT 2

The role of imaging techniques to define a peri-prosthetic hip and knee joint infection: multidisciplinary consensus statements.

Romanò C, Petrosillo N, Argento G, Maes A, et al. Journal of Clinical Medicine, 2020, 9(8), 2548-2568

ABSTRACT Diagnosing a peri-prosthetic joint infection (PJI) remains challenging despite the availability of a variety of clinical signs, serum and synovial markers, imaging techniques, microbiological and histological findings. Moreover, the one and only true definition of PJI does not exist, which is reflected by the existence of at least six different definitions by independent societies. These definitions are composed of major and minor criteria for defining a PJI, but most of them do not include imaging techniques.

This paper highlights the pros and cons of available imaging techniques-X-ray, ultrasound, computed tomography (CT), Magnetic Resonance Imaging (MRI), bone scintigraphy, white blood cell scintigraphy (WBC), anti-granulocyte scintigraphy, and fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), discusses the added value of hybrid camera systems-single photon emission tomography/computed tomography (SPECT/CT), PET/ CT and PET/MRI and reports consensus answers on important clinical questions that were discussed during the Third European Congress on Inflammation/Infection Imaging in Rome, December 2019.

ABSTRACT 3

Characterization of FDG PET images using texture analysis in tumors of the gastro-intestinal tract: a review.

Deleu A, Sathekge M, Maes A, Van de Wiele C, et al. Biomedicines, 2020, 8(9), 304

ABSTRACT Radiomics or textural feature extraction obtained from positron emission tomography (PET) images through complex mathematical models of the spatial relationship between multiple image voxels is currently emerging as a new tool for assessing intra-tumoral heterogeneity in medical imaging. In this paper, available literature on texture analysis using FDG PET imaging in patients suffering from tumors of the gastro-intestinal tract is reviewed.

While texture analysis of FDG PET images appears clinically promising, due to the lack of technical specifications, a large variability in the implemented methodology used for texture analysis and lack of statistical robustness, at present, no firm conclusions can be drawn regarding the predictive or prognostic value of FDG PET texture analysis derived indices in patients suffering from gastro- enterologic tumors. In order to move forward in this field, a harmonized image acquisition and processing protocol as well as a harmonized protocol for texture analysis of tumor volumes, allowing multi-center studies excluding statistical biases should be considered. Furthermore, the complementary and additional value of CT-imaging, as part of the PET/CT imaging technique, warrants exploration.

ABSTRACT 4

Predictors of overall and disease-free survival in metastatic castration-resistant prostate cancer patients receiving 225 Ac-PSMA-617 radioligand therapy.

Sathekge M, Bruchertseifer F, Maes A, Van de Wiele C, et al. Journal of Nuclear Medicine, 2020, 61(1), 62-69

INTRODUCTION Metastatic prostate carcinoma overexpresses prostate-specific membrane antigen (PSMA), making this antigen a suitable target for radioligand therapy of the disease. Here we report on our experience with a series of 73 castration-resistant prostate carcinoma patients treated with 225Ac-PSMA-617, identifying variables predictive for overall survival (OS) and progression-free survival (PFS) after 225Ac-PSMA-617 treatment.

MATERIALS/METHODS 225Ac-PSMA-617 was administered to patients who had metastatic castration-resistant prostate carcinoma and who had exhausted available therapy options for their disease. Full blood count, glomerular filtration rate, and liver function test were obtained at baseline and on follow-up for evaluation of toxicity. 68Ga-PSMA PET/CT was obtained at baseline, before every treatment cycle, and on follow-up for selection of patients for treatment, to determine the activity of the treatment agent to be administered, and for response assessment. Serial prostate-specific antigen (PSA) was obtained for PSA response assessment.

RESULTS Seventy-three men (mean age, 69 y; range, 45-85 y) with metastatic castration-resistant prostate carcinoma were treated with 210 cycles of 225Ac-PSMA-617. In 70% of patients, a PSA decline of greater than or equal to 50% was obtained; 82% of patients had any PSA decline. In 29% of patients, all lesions on 68Ga-PSMA PET resolved in response to treatment. During follow-up, 23 patients experienced disease progression, whereas 13 patients died from their disease. The estimated median PFS and OS were 15.2 mo (95% CI, 13.1-17.4) and 18 mo (95% CI, 16.2-19.9), respectively. In univariate analyses, factors such as baseline PSA, any PSA decline, PSA decline of greater than or equal to 50%, prior chemotherapy, prior radiation therapy, and baseline hemoglobin level were associated with longer PFS and OS (all Ps < 0.05).

In multivariate analyses, there was a negative association between prior 177Lu-PSMA therapy and PFS, and a positive association between PSA decline of greater or equal to 50% and PFS. Only a PSA decline of greater than or equal to 50% remained significantly associated with OS on multivariate analyses. Xerostomia was seen in 85% of patients but was not severe enough to warrant discontinuing treatment. Anemia was seen in 27 patients; no patients had grade IV bone marrow toxicity. Renal failure of grade III or IV was seen in 5 patients with baseline renal impairment.

CONCLUSION In this study, a PSA decline of greater than or equal to 50% after treatment with 225Ac-PSMA-617 was proven by multivariate analyses to be significantly associated with OS and PFS. Furthermore, previous 177Lu-PSMA treatment was negatively associated with PFS in both univariate and multivariate analyses.

ABSTRACT 5

Quantification of 18F-fluorodeoxyglucose uptake to detect residual nodal disease in locally advanced head and neck squamous cell carcinoma after chemoradiotherapy: results from the ECLYPS study.

Helsen N, Maes A, Beels L, Debruyne P, Goethals L, et al. European Journal of Nuclear Medicine and Molecular Imaging, 2020, 47(5), 1075-1082

INTRODUCTION The Hopkins criteria were introduced for nodal response evaluation after therapy in head and neck cancer, but its superiority over quantification is not yet confirmed.

MATERIALS/METHODS SUVbody weight thresholds and lesion-to-background ratios were explored in a prospective multicenter study of standardized FDG-PET/CT 12 weeks after CRT in newly diagnosed locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients (ECLYPS). Reference standard was histology, negative FDG-PET/CT at 12 months after treatment or ≥ 2 years of negative follow-up. Area under the receiver operator characteristics curves (AUROC) were estimated and obtained thresholds were validated in an independent cohort of HNSCC patients (n = 127).

RESULTS In ECLYPS, 124 patients were available for quantification. With a median follow-up of 20.4 months, 23 (18.5%) nodal neck recurrences were observed. A SUV70 threshold of 2.2 (AUROC = 0.89; sensitivity = 79.7%; specificity = 80.8%) was identified as optimal metric to identify nodal recurrence within 1 year after therapy. For lesion-tobackground ratios, an SUV50/SUVliver threshold of 0.96 (AUROC = 0.89; sensitivity = 79.7%; specificity = 82.8%) had the best performance. Compared with Hopkins criteria (AUROC = 0.81), SUV70 and SUV50/SUVliver provided a borderline significant (p = 0.040 and p = 0.094, respectively) improvement. Validation of thresholds yielded similar AUROC values (SUV70 = 0.93, SUV50/SUVliver = 0.95), and were comparable to the Hopkins score (AUROC = 0.91; not statistically significant).

CONCLUSION FDG quantification detects nodal relapse in LAHNSCC patients. When using EARL standardized PET acquisitions and reconstruction, absolute SUV metrics (SUV70 threshold 2.2) prove robust, yet ratios (SUV50/SUVliver, threshold 0.96) may be more useful in routine clinical care. In this setting, the diagnostic value of quantification is comparable to the Hopkins criteria.

ABSTRACT 6

PSMA expression on neovasculature of solid tumors.

Van de Wiele C, Sathekge M, De Jonghe P, Debruyne P, Borms M, Beels L, Maes A, et al. Histology and Histopathology, 2020, 35(9), 919-927

ABSTRACT The use of prostate specific membrane antigen (PSMA) binding agents, labelled with diagnostic and therapeutic radio-isotopes is opening the potential for a new era of personalized management of prostate carcinoma. A wide variety of immunohistochemistry studies have shown PSMA also to be upregulated on the endothelial cells of the neovasculature of a wide variety of other solid tumors where it may facilitate endothelial cell sprouting and invasion through its regulation of lytic proteases that have the ability to cleave the extracellular matrix.

Similar to the introduction of PSMA-targeting theranostics in prostate carcinoma, overexpression of PSMA on newly formed tumor vessels may serve as a target for imaging and subsequent treatment of cancer through the use of agents that are capable of blocking PSMA in its function or through PSMA-mediated delivery of chemotherapeutics or radiation agents. In this review, the available data on PSMA expression on tumor neovasculature in human solid tumors assessed by using immunohistochemistry are discussed.

PRESENTATIES

ABSTRACT 7

Calibration of instrumentation for dosimetry: principles and applications.

Beels L

October 2020, 33rd Annual congress of the European Association of Nuclear Medicine, Online

ABSTRACT Radionuclide therapy uses radiopharmaceuticals that target specific tumours and therefore deliver radiation to lesions as part of a therapeutic strategy to cure, mitigate or control the tumour. The radiopharmaceuticals that are suited for radionuclide therapy are those that strongly bind with the tumour and transport targeted doses of radiation

directly to the tumour and its metastases, thereby minimizing normal healthy tissue radiation. The radionuclides best suited for therapy are those emitting ionizing radiation with short penetration into the tissue, such as α or ß emitters.

Radionuclide therapy is nowadays often given as a fixed activity instead of a patient-specific activity. Prospective, randomised trials with adequate methodology can provide the evidence that applied clinical dosimetry results in better patient outcome than is achieved with fixed activity dosing methods. Individual patient dosimetry has the following goals: • Establish individual minimum effective and maximum tolerated absorbed doses • Establish a dose-response relation to predict tumour response and normal organ toxicity on the basis of pre-therapy dosimetry • Compare the dose-response results of different radionuclide therapies or with the results obtained with external radiotherapy • Increase the knowledge of clinical radionuclide radiobiology Patient-specific treatment planning and dosimetry include the individual quantitative measurement of bio-kinetics in the patient, integration of the time-activity curves, calculation of the absorbed dose, inclusion of model-based predictions of toxicity, patient-specific prediction of the activities at which absorbed dose limits will be reached for organs at risk and determination if the tumour absorbed doses are sufficient to induce a significant therapeutic effect.

A very important step in individual patient dosimetry is quantitative imaging to obtain reliable absorbed doses. Calibration of non-imaging and imaging instrumentation in a nuclear medicine department is a prerequisite for quantitative imaging.

ABSTRACT 8

68Ga PSMA PET/CT in het PET-centrum West-Vlaanderen: wat kunnen we leren uit 2 jaar ervaring in een secundair centrum?

Dewulf K, Lesage K, Beels L, Van Bruwaene S, et al. February 2020, Elautprijs, Dendermonde - België

OBJECTIVE De beeldvorming van prostaatkanker kende recent een grote evolutie dankzij de komst van de 68Ga PSMA PET/ CT scan. Deze scan wordt aanbevolen door de European Association of Urology (EAU) bij biochemisch recidief na een behandeling met curatieve intentie bij prostaat specifiek antigen (PSA) ≥ 0,2 ng/mL. In augustus 2017 werd in het PET-centrum West-Vlaanderen gestart met 68Ga PSMA PET/CT. Het doel van deze studie is de indicatiestelling voor 68Ga PSMA PET/CT in secundaire centra onderzoeken en nagaan welk gevolg deze beeldvorming heeft voor de behandeling van prostaatkanker.

MATERIALS/METHODS Dit is een retrospectieve, multicentrische studie van 16 refererende centra naar het PET-centrum West-Vlaanderen tussen 08/2017 en 08/2019. Een interim analyse van 157 68Ga PSMA PET/CT scans in 145 patiënten werd uitge- voerd, 5 patiënten werden ge-ëxcludeerd. 15% van de scans werden uitgevoerd in de castratieresistente setting, 75% biochemisch recidief of persisterend PSA na behandeling met curatieve intentie, 7% was primaire staging van prostaatcarcinoom, 2% biochemisch recidief na oligo- metastatische behandeling en 1% PSA-stijging bij watchfull waiting. Verdere analyses werden uitgevoerd op 114 68Ga PSMA PET/CT scans in 104 patiënten met biochemisch recidief of persisterende PSA na behandeling met curatieve intentie. Goedkeuring van de commissie medische ethiek is aangevraagd onder nummer AZGS2019073.

RESULTS Mediane PSA voor 68Ga PSMA PET/CT scans was 0,95 ng/ mL (range 0,03 – 21,70). 41% van de scans waren negatief, 43% toonden oligometastasen (≤3 letsels), 16% heeft ≥ 4 PSMApositieve letsels. Univariate analyse toonde een hogere kans op een positieve 68Ga PSMA scan bij hogere PSA-waarde (p<0,0001). De EAU PSA-cutoff van 0,2 ng/ml resulteert in een positief predictieve waarde (PPV) van 62% en negatieve predictieve waarde (NPW) van 80%. Voor een cutoff van 0,5 ng/ml zou PPV 69% en NPW slechts 64% bedragen.

Er was geen relatie tussen kans op positieve 68Ga PSMA scan en PSA doubling time of EAU biochemical recurrence risk group (respectievelijk p=0,46 en p=0,89). In geval van een negatieve 68Ga PSMA scan kwamen nog 44 patiënten in aanmerking voor salvage radiotherapie wat slechts werd aangeboden in 45% van de gevallen. In geval van een positieve 68Ga PSMA scan betrof dit lokaal recidief in 17%, N1 in 32%, M1a in 17%, M1b in 31% en Mc1 in 3% (patiënten met meerdere letsels werden hierbij onderverdeeld in de hoogste categorie). In oligometastastische patiënten (≤3 letsels) werd slechts 4% behandeld met androgeen deprivatie monotherapie, 72% kreeg oligometastase-gerichte

therapie (34% heelkunde, 66% radio- therapie) en in 24% werd afwachtend beleid verkozen. In 92,5% van de patiënten met oligometastase-gerichte therapie werd een PSA-respons gezien (onduidelijk welk percentage conco- mittant ADT kreeg). Bij polymetastatische patiënten werd ADT monotherapie opgestart in 72% van de gevallen.

CONCLUSION Dankzij 68Ga PSMA PET/CT scans kunnen recidieven van prostaatkanker vroegtijdig worden gedetecteerd. De EAU PSA-cutoff van 0,2 ng/ml lijkt adequaat gezien hoge NPW (80%) en toch aanvaardbare PPW (62%). PSA doubling time of risicogroep had geen bijkomende waarde. Patiënten riskeren hun kans op salvage radiotherapie te ontlopen na/door negatieve 68Ga PSMA scan resultaten (45%). Oligometastase-gerichte behandeling, hoewel nog ex- perimenteel volgens de richtlijnen, lijkt in de regio ondertussen de standaardbehandeling (72%).