The additional value of 68Ga-PSMA PET/CT SUVmax in predicting ISUP GG ≥ 2 and ISUP GG ≥ 3 prostate cancer in biopsy.

BACKGROUND: Prebiopsy magnetic resonance imaging (MRI) increases the detection rate of clinically significant prostate cancer (csPCa). Prostate-specific membrane antigen-positron emission tomography/computed tomography (PSMA PET/CT) maximum standardized uptake value (SUVmax) of the prostate may offer additional value in predicting the likelihood of csPCa in biopsy. METHODS: A single-center cohort study involving patients with biopsy-proven PCa who underwent both MRI and PSMA PET/CT between 2020 and 2021. Logistic regression models were developed for International Society of Urological Pathology (ISUP) Grade Group (GG) ≥ 2 and GG ≥ 3 using noninvasive prebiopsy parameters: age, (log-)prostate-specific antigen (PSA) density, PI-RADS 5 lesion presence, extraprostatic extension (EPE) on MRI, and SUVmax of the prostate. Models with and without SUVmax were compared using Likelihood ratio tests and area under the curve (AUC). DeLong's test was used to compare the AUCs. RESULTS: The study included 386 patients, with 262 (68%) having ISUP GG ≥ 2 and 180 (47%) having ISUP GG ≥ 3. Including SUVmax significantly improved both models' goodness of fit (p < 0.001). The GG ≥ 2 model had a higher AUC with SUVmax 89.16% (95% confidence interval [CI]: 86.06%-92.26%) than without 87.34% (95% CI: 83.93%-90.76%) (p = 0.026). Similarly, the GG ≥ 3 model had a higher AUC with SUVmax 82.51% (95% CI: 78.41%-86.6%) than without 79.33% (95% CI: 74.84%-83.83%) (p = 0.003). The SUVmax inclusion improved the GG ≥ 3 model's calibration at higher probabilities. CONCLUSION: SUVmax of the prostate on PSMA PET/CT potentially improves diagnostic accuracy in predicting the likelihood of csPCa in prostate biopsy.

Advances in Radionuclide Therapies for Patients with Neuro-endocrine Tumors.

PURPOSE OF REVIEW: To provide insights into the role of peptide receptor radionuclide therapy (PRRT) in patients with advanced neuroendocrine tumors (NET) and an overview of possible strategies to combine PRRT with locoregional and systemic anticancer treatments. RECENT FINDINGS: Research on combining PRRT with other treatments encompasses a wide variety or treatments, both local (transarterial radioembolization) and systemic therapies, chemotherapy (i.e., capecitabine and temozolomide), targeted therapies (i.e., olaparib, everolimus, and sunitinib), and immunotherapies (e.g., nivolumab and pembrolizumab). Furthermore, PRRT shows promising first results as a treatment prior to surgery. There is great demand to enhance the efficacy of PRRT through combination with other anticancer treatments. While research in this area is currently limited, the field is rapidly evolving with numerous ongoing clinical trials aiming to address this need and explore novel therapeutic combinations.

Extrahepatic perfusion and incomplete hepatic perfusion after hepatic arterial infusion pump implantation: incidence and clinical implications.

INTRODUCTION: This study investigates the incidence of extrahepatic perfusion and incomplete hepatic perfusion at intraoperative methylene blue testing and on postoperative nuclear imaging in patients undergoing hepatic arterial infusion pump (HAIP) chemotherapy. METHODS: The first 150 consecutive patients who underwent pump implantation in the Netherlands were included. All patients underwent surgical pump implantation with the catheter in the gastroduodenal artery. All patients underwent intraoperative methylene blue testing and postoperative nuclear imaging (99mTc-Macroaggregated albumin SPECT/CT) to determine perfusion via the pump. RESULTS: Patients were included between January-2018 and December-2021 across eight centers. During methylene blue testing, 29.3% had extrahepatic perfusion, all successfully managed intraoperatively. On nuclear imaging, no clinically relevant extrahepatic perfusion was detected (0%, 95%CI: 0.0-2.5%). During methylene blue testing, 2.0% had unresolved incomplete hepatic perfusion. On postoperative nuclear imaging, 8.1% had incomplete hepatic perfusion, leading to embolization in only 1.3%. CONCLUSION: Methylene blue testing during pump placement for intra-arterial chemotherapy identified extrahepatic perfusion in 29.3% of patients, but could be resolved intraoperatively in all patients. Postoperative nuclear imaging found no clinically relevant extrahepatic perfusion and led to embolization in only 1.3% of patients. The role of routine nuclear imaging after HAIP implantation should be studied in a larger cohort.

Feasibility of clinical studies of chemical exchange saturation transfer magnetic resonance imaging of prostate cancer at 7 T.

Chemical exchange saturation transfer (CEST) has been explored for differentiation between tumour and benign tissue in prostate cancer (PCa) patients. With ultrahigh field strengths such as 7-T, the increase of spectral resolution and sensitivity could allow for selective detection of amide proton transfer (APT) at 3.5 ppm and a group of compounds that resonate at 2 ppm (i.e., [poly]amines and/or creatine). The potential of 7-T multipool CEST analysis of the prostate and the detection of PCa was studied in patients with proven localised PCa who were scheduled to undergo robot-assisted radical prostatectomy (RARP). Twelve patients were prospectively included (mean age 68.0 years, mean serum prostate-specific antigen 7.8ng/mL). A total of 24 lesions larger than 2 mm were analysed. Used were 7-T T2-weighted (T2W) imaging and 48 spectral CEST points. Patients received 1.5-T/3-T prostate magnetic resonance imaging and galium-68-prostate-specific membrane antigen-positron emission tomography/computerised tomography to determine the location of the single-slice CEST. Based on the histopathological results after RARP, three regions of interest were drawn on the T2W images from a known malignant zone and benign zone in the central and peripheral zones. These areas were transposed to the CEST data, from which the APT and 2-ppm CEST were calculated. The statistical significance of the CEST between the central zone, the peripheral zone, and tumour was calculated using a Kruskal-Wallis test. The z-spectra showed that APT and even a distinct pool that resonated at 2 ppm were detectable. This study showed a difference trend in the APT levels, but no difference in the 2-ppm levels when tested between the central zone, the peripheral zone, and tumour (H(2) = 4.8, p = 0.093 and H(2) = 0.86, p = 0.651, respectively). Thus, to conclude, we could most likely detect APT and amines and/or creatine levels noninvasively in prostate using the CEST effect. At group level, CEST showed a higher level of APT in the peripheral versus the central zone; however, no differences of APT and 2-ppm levels were observed in tumours.

Current research topics in FAPI theranostics: a bibliometric analysis.

PURPOSE: The study aimed to provide a comprehensive bibliometric overview of the current scientific publications on fibroblast activation protein inhibitor (FAPI) positron emission tomography imaging and radionuclide therapy. METHODS: A PubMed search was performed to identify all MEDLINE-indexed publications on FAPI imaging and radionuclide therapy. The last update was performed on 31 May 2022. An online database of this literature was created, and hierarchical topic-related tags were subsequently assigned to all relevant studies. Frequency analysis was used to evaluate the distribution of the following characteristics: first author's country of origin, journal of publication, study design, imaging techniques and radiopharmaceutical used, histopathological correlation, the type of cancer, and benign disease/uptake types evaluated. RESULTS: A total of 294 relevant publications on original studies were identified, consisting of 209 (71%) case reports/series and 85 cohort studies (29%). The majority of studies focused on imaging topics, predominantly comparing uptake on FAPI-PET/CT with 2-[18F]FDG-PET/CT, anatomical imaging, and/or histopathology results. 68% of studies focused on malignancies, with gastro-intestinal cancer, hepato-pancreato-biliary cancer, mixed cancers/metastases, lung cancer, sarcoma, head and neck cancer, and breast cancer being the most frequently reported. 42% of studies focused on benign disease categories, with cardiovascular, musculoskeletal, HPB, head and neck, and IgG4-related disease as most common categories. 16/294 (5%) studies focused on radionuclide therapy, with preliminary reports of acceptable toxicity profiles, tumour activity retention, and suggestion of disease control. CONCLUSION: FAPI research is rapidly expanding from diagnostic studies in malignancies and benign diseases to the first reports of salvage radionuclide therapy. The research activity needs to shift now from low-level-of-evidence case reports and series to prospectively designed studies in homogenous patient groups to provide evidence on how and in which clinical situations FAPI theranostics can be of added value to clinical care. We have provided an overview of current research topics to build upon.

[18F]mFBG PET-CT for detection and localisation of neuroblastoma: a prospective pilot study.

PURPOSE: Meta-[18F]fluorobenzylguanidine ([18F]mFBG) is a positron emission tomography (PET) radiotracer that allows for fast and high-resolution imaging of tumours expressing the norepinephrine transporter. This pilot study investigates the feasibility of [18F]mFBG PET-CT for imaging in neuroblastoma. METHODS: In a prospective, single-centre study, we recruited children with neuroblastoma, referred for meta-[123I]iodobenzylguanidine ([123I]mIBG) scanning, consisting of total body planar scintigraphy in combination with single-photon emission computed tomography-CT (SPECT-CT). Within two weeks of [123I]mIBG scanning, total body PET-CTs were performed at 1 h and 2 h after injection of [18F]mFBG (2 MBq/kg). Detected tumour localisations on scan pairs were compared. Soft tissue disease was quantified by number of lesions and skeletal disease by SIOPEN score. RESULTS: Twenty paired [123I]mIBG and [18F]mFBG scans were performed in 14 patients (median age 4.9 years, n = 13 stage 4 disease and n = 1 stage 4S). [18F]mFBG injection was well tolerated and no related adverse events occurred in any of the patients. Mean scan time for [18F]mFBG PET-CT (9.0 min, SD 1.9) was significantly shorter than for [123I]mIBG scanning (84.5 min, SD 10.5), p < 0.01. Most tumour localisations were detected on the 1 h versus 2 h post-injection [18F]mFBG PET-CT. Compared to [123I]mIBG scanning, [18F]mFBG PET-CT detected a higher, equal, and lower number of soft tissue lesions in 40%, 55%, and 5% of scan pairs, respectively, and a higher, equal, and lower SIOPEN score in 55%, 30%, and 15% of scan pairs, respectively. On average, two more soft tissue lesions and a 6-point higher SIOPEN score were detected per patient on [18F]mFBG PET-CT compared to [123I]mIBG scanning. CONCLUSION: Results of this study demonstrate feasibility of [18F]mFBG PET-CT for neuroblastoma imaging. More neuroblastoma localisations were detected on [18F]mFBG PET-CT compared to [123I]mIBG scanning. [18F]mFBG PET-CT shows promise for future staging and response assessment in neuroblastoma. TRIAL REGISTRATION: Dutch Trial Register NL8152.

Tolerability of concurrent external beam radiotherapy and [177Lu]Lu-PSMA-617 for node-positive prostate cancer in treatment naïve patients, phase I study (PROQURE-I trial).

BACKGROUND: Prostate cancer patients with locoregional lymph node disease at diagnosis (N1M0) still have a limited prognosis despite the improvements provided by aggressive curative intent multimodal locoregional external beam radiation therapy (EBRT) with systemic androgen deprivation therapy (ADT). Although some patients can be cured and the majority of patients have a long survival, the 5-year biochemical failure rate is currently 29-47%. [177Lu]Lu-PSMA-617 has shown impressive clinical and biochemical responses with low toxicity in salvage setting in metastatic castration-resistant prostate cancer. This study aims to explore the combination of standard EBRT and ADT complemented with a single administration of [177Lu]Lu-PSMA-617 in curative intent treatment for N1M0 prostate cancer. Hypothetically, this combined approach will enhance EBRT to better control macroscopic tumour localizations, and treat undetected microscopic disease locations inside and outside EBRT fields. METHODS: The PROQURE-I study is a multicenter prospective phase I study investigating standard of care treatment (7 weeks EBRT and 3 years ADT) complemented with one concurrent cycle (three, six, or nine GBq) of systemic [177Lu]Lu-PSMA-617 administered in week two of EBRT. A maximum of 18 patients with PSMA-positive N1M0 prostate cancer will be included. The tolerability of adding [177Lu]Lu-PSMA-617 will be evaluated using a Bayesian Optimal Interval (BOIN) dose-escalation design. The primary objective is to determine the maximum tolerated dose (MTD) of a single cycle [177Lu]Lu-PSMA-617 when given concurrent with EBRT + ADT, defined as the occurrence of Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 grade three or higher acute toxicity. Secondary objectives include: late toxicity at 6 months, dosimetric assessment, preliminary biochemical efficacy at 6 months, quality of life questionnaires, and pharmacokinetic modelling of [177Lu]Lu-PSMA-617. DISCUSSION: This is the first prospective study to combine EBRT and ADT with [177Lu]Lu-PSMA-617 in treatment naïve men with N1M0 prostate cancer, and thereby explores the novel application of [177Lu]Lu-PSMA-617 in curative intent treatment. It is considered likely that this study will confirm tolerability as the combined toxicity of these treatments is expected to be limited. Increased efficacy is considered likely since both individual treatments have proven high anti-tumour effect as mono-treatments. TRIAL REGISTRATION: ClinicalTrials, NCT05162573 . Registered 7 October 2021.

Dose finding study for unilobar radioembolization using holmium-166 microspheres to improve resectability in patients with HCC: the RALLY protocol.

BACKGROUND: High dose unilobar radioembolization (also termed 'radiation lobectomy')-the transarterial unilobar infusion of radioactive microspheres as a means of controlling tumour growth while concomitantly inducing future liver remnant hypertrophy-has recently gained interest as induction strategy for surgical resection. Prospective studies on the safety and efficacy of the unilobar radioembolization-surgery treatment algorithm are lacking. The RALLY study aims to assess the safety and toxicity profile of holmium-166 unilobar radioembolization in patients with hepatocellular carcinoma ineligible for surgery due to insufficiency of the future liver remnant. METHODS: The RALLY study is a multicenter, interventional, non-randomized, open-label, non-comparative safety study. Patients with hepatocellular carcinoma who are considered ineligible for surgery due to insufficiency of the future liver remnant (< 2.7%/min/m2 on hepatobiliary iminodiacetic acid scan will be included. A classical 3 + 3 dose escalation model will be used, enrolling three to six patients in each cohort. The primary objective is to determine the maximum tolerated treated non-tumourous liver-absorbed dose (cohorts of 50, 60, 70 and 80 Gy). Secondary objectives are to evaluate dose-response relationships, to establish the safety and feasibility of surgical resection following unilobar radioembolization, to assess quality of life, and to generate a biobank. DISCUSSION: This will be the first clinical study to assess the unilobar radioembolization-surgery treatment algorithm and may serve as a stepping stone towards its implementation in routine clinical practice. TRIAL REGISTRATION: Netherlands Trial Register NL8902 , registered on 2020-09-15.

Evaluating the Targeting of a Staphylococcus-aureus-Infected Implant with a Radiolabeled Antibody In Vivo.

Implant infections caused by Staphylococcus aureus are difficult to treat due to biofilm formation, which complicates surgical and antibiotic treatment. We introduce an alternative approach using monoclonal antibodies (mAbs) targeting S. aureus and provide evidence of the specificity and biodistribution of S.-aureus-targeting antibodies in a mouse implant infection model. The monoclonal antibody 4497-IgG1 targeting wall teichoic acid in S. aureus was labeled with indium-111 using CHX-A"-DTPA as a chelator. Single Photon Emission Computed Tomography/computed tomographyscans were performed at 24, 72 and 120 h after administration of the 111In-4497 mAb in Balb/cAnNCrl mice with a subcutaneous implant that was pre-colonized with S. aureus biofilm. The biodistribution of this labelled antibody over various organs was visualized and quantified using SPECT/CT imaging, and was compared to the uptake at the target tissue with the implanted infection. Uptake of the 111In-4497 mAbs at the infected implant gradually increased from 8.34 %ID/cm3 at 24 h to 9.22 %ID/cm3 at 120 h. Uptake at the heart/blood pool decreased over time from 11.60 to 7.58 %ID/cm3, whereas the uptake in the other organs decreased from 7.26 to less than 4.66 %ID/cm3 at 120 h. The effective half-life of 111In-4497 mAbs was determined to be 59 h. In conclusion, 111In-4497 mAbs were found to specifically detect S. aureus and its biofilm with excellent and prolonged accumulation at the site of the colonized implant. Therefore, it has the potential to serve as a drug delivery system for the diagnostic and bactericidal treatment of biofilm.

Dose-response relationship after yttrium-90-radioembolization with glass microspheres in patients with neuroendocrine tumor liver metastases.

BACKGROUND: In radioembolization, response is achieved through the irradiation and damaging of tumor DNA. For hepatic metastases of neuroendocrine tumors, a dose-response relationship has not been established yet. This study assesses whether increasing tumor-absorbed doses lead to increased response rates. METHODS: We included all patients who underwent yttrium-90 (90Y) glass microspheres radioembolization in our center if both pre- and post-treatment contrast-enhanced CT and post-injection PET/CT were available. Up to five hepatic tumors and the healthy hepatic tissue were delineated, and absorbed dose was quantified using post-injection PET/CT. Response was measured according to RECIST 1.1 on patient and tumor level. Linear mixed models were used to study the relationship between absorbed dose and response on tumor level. Logistic regression analysis was used on patient level to study dose-response and hepatic dose-toxicity relationships. RESULTS: A total of 128 tumors in 26 patients (31 procedures) were included in the response analysis. While correcting for confounding by tumor volume, a significant effect of response on dose was found (p = 0.0465). Geometric mean of absorbed dose for responding tumors was 170 Gy, for stable disease 101 Gy, and for progressive disease 67 Gy. No significant dose-toxicity relationship could be identified. CONCLUSION: In patients with neuroendocrine tumor liver metastases, treated with 90Y-radioembolization, a clear dose-response relationship was found. We propose to perform 90Y-radioembolization with an absolute minimum planned tumor-absorbed dose of 150 Gy.

A compact and mobile hybrid C-arm scanner for simultaneous nuclear and fluoroscopic image guidance.

PURPOSE: This study evaluates the performance of a mobile and compact hybrid C-arm scanner (referred to as IXSI) that is capable of simultaneous acquisition of 2D fluoroscopic and nuclear projections and 3D image reconstruction in the intervention room. RESULTS: The impact of slightly misaligning the IXSI modalities (in an off-focus geometry) was investigated for the reduction of the fluoroscopic and nuclear interference. The 2D and 3D nuclear image quality of IXSI was compared with a clinical SPECT/CT scanner by determining the spatial resolution and sensitivity of point sources and by performing a quantitative analysis of the reconstructed NEMA image quality phantom. The 2D and 3D fluoroscopic image of IXSI was compared with a clinical CBCT scanner by visualizing the Fluorad A+D image quality phantom and by visualizing a reconstructed liver nodule phantom. Finally, the feasibility of dynamic simultaneous nuclear and fluoroscopic imaging was demonstrated by injecting an anthropomorphic phantom with a mixture of iodinated contrast and 99mTc. CONCLUSION: Due to the divergent innovative hybrid design of IXSI, concessions were made to the nuclear and fluoroscopic image qualities. Nevertheless, IXSI realizes unique image guidance that may be beneficial for several types of procedures. KEY POINTS: • IXSI can perform time-resolved planar (2D) simultaneous fluoroscopic and nuclear imaging. • IXSI can perform SPECT/CBCT imaging (3D) inside the intervention room.

Factors modulating 99m Tc-MAA planar lung dosimetry for 90 Y radioembolization.

PURPOSE: To investigate the accuracy and biases of predicted lung shunt fraction (LSF) and lung dose (LD) calculations via 99m Tc-macro-aggregated albumin (99m Tc-MAA) planar imaging for treatment planning of 90 Y-microsphere radioembolization. METHODS AND MATERIALS: LSFs in 52 planning and LDs in 44 treatment procedures were retrospectively calculated, in consecutive radioembolization patients over a 2 year interval, using 99m Tc-MAA planar and SPECT/CT imaging. For each procedure, multiple planar LSFs and LDs were calculated using different: (1) contours, (2) views, (3) liver 99m Tc-MAA shine-through compensations, and (4) lung mass estimations. The accuracy of each planar-based LSF and LD methodology was determined by calculating the median (range) absolute difference from SPECT/CT-based LSF and LD values, which have been demonstrated in phantom and patient studies to more accurately and reliably quantify the true LSF and LD values. RESULTS: Standard-of-care LSF using geometric mean of lung and liver contours had median (range) absolute over-estimation of 4.4 percentage points (pp) (0.9 to 11.9 pp) from SPECT/CT LSF. Using anterior views only decreased LSF errors (2.4 pp median, -1.1 to +5.7 pp range). Planar LD over-estimations decreased when using single-view versus geometric-mean LSF (1.3 vs. 2.6 Gy median and 7.2 vs. 18.5 Gy maximum using 1000 g lung mass) but increased when using patient-specific versus standard-man lung mass (2.4 vs. 1.3 Gy median and 11.8 vs. 7.2 Gy maximum using single-view LSF). CONCLUSIONS: Calculating planar LSF from lung and liver contours of a single view and planar LD using that same LSF and 1000 g lung mass was found to improve accuracy and minimize bias in planar lung dosimetry.

Dosing Therapeutic Radiopharmaceuticals in Obese Patients.

The prevalence of obesity has increased dramatically in the Western population. Obesity is known to influence not only the proportion of adipose tissue but also physiological processes that could alter drug pharmacokinetics. Yet, there are no specific dosing recommendations for radiopharmaceuticals in this patient population. This could potentially lead to underdosing and thus suboptimal treatment in obese patients, while it could also lead to drug toxicity due to high levels of radioactivity. In this review, relevant literature is summarized on radiopharmaceutical dosing and pharmacokinetic properties, and we aimed to translate these data into practical guidelines for dosing of radiopharmaceuticals in obese patients. For radium-223, dosing in obese patients is well established. Furthermore, for samarium-153-ethylenediaminetetramethylene (EDTMP), dose-escalation studies show that the maximum tolerated dose will probably not be reached in obese patients when dosing on MBq/kg. On the other hand, there is insufficient evidence to support dose recommendations in obese patients for rhenium-168-hydroxyethylidene diphosphonate (HEDP), sodium iodide-131, iodide 131-metaiodobenzylguanidine (MIBG), lutetium-177-dotatate, and lutetium-177-prostate-specific membrane antigen (PSMA). From a pharmacokinetic perspective, fixed dosing may be appropriate for these drugs. More research into obese patient populations is needed, especially in the light of increasing prevalence of obesity worldwide.

Use of an anti-reflux catheter to improve tumor targeting for holmium-166 radioembolization-a prospective, within-patient randomized study.

PURPOSE: The objective of this study was to investigate whether the use of an anti-reflux catheter improves tumor targeting for colorectal cancer patients with unresectable, chemorefractory liver metastases (mCRC) treated with holmium-166 (166Ho)-radioembolization. MATERIALS AND METHODS: In this perspective, within-patient randomized study, left and right hepatic perfusion territories were randomized between infusion with a Surefire® anti-reflux catheter or a standard microcatheter. The primary outcome was the difference in tumor to non-tumor (T/N) activity distribution. Secondary outcomes included the difference in infusion efficiency, absorbed doses, predictive value of 166Ho-scout, dose-response relation, and survival. RESULTS: Twenty-one patients were treated in this study (the intended number of patients was 25). The median T/N activity concentration ratio with the use of the anti-reflux catheter was 3.2 (range 0.9-8.7) versus 3.6 (range 0.8-13.3) with a standard microcatheter. There was no difference in infusion efficiency (0.04% vs. 0.03% residual activity for the standard microcatheter and anti-reflux catheter, respectively) (95%CI - 0.05-0.03). No influence of the anti-reflux catheter on the dose-response rate was found. Median overall survival was 7.8 months (95%CI 6-13). CONCLUSION: Using a Surefire® anti-reflux catheter did not result in a higher T/N activity concentration ratio in mCRC patients treated with 166Ho-radioembolization, nor did it result in improved secondary outcomes measures. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT02208804.

Normal imaging findings after aortic valve implantation on 18F-Fluorodeoxyglucose positron emission tomography with computed tomography.

BACKGROUND: To determine the normal perivalvular 18F-Fluorodeoxyglucose (18F-FDG) uptake on positron emission tomography (PET) with computed tomography (CT) within one year after aortic prosthetic heart valve (PHV) implantation. METHODS: Patients with uncomplicated aortic PHV implantation were prospectively included and underwent 18F-FDG PET/CT at either 5 (± 1) weeks (group 1), 12 (± 2) weeks (group 2) or 52 (± 8) weeks (group 3) after implantation. 18F-FDG uptake around the PHV was scored qualitatively (none/low/intermediate/high) and quantitatively by measuring the maximum Standardized Uptake Value (SUVmax) and target to background ratio (SUVratio). RESULTS: In total, 37 patients (group 1: n = 12, group 2: n = 12, group 3: n = 13) (mean age 66 ± 8 years) were prospectively included. Perivalvular 18F-FDG uptake was low (8/12 (67%)) and intermediate (4/12 (33%)) in group 1, low (7/12 (58%)) and intermediate (5/12 (42%)) in group 2, and low (8/13 (62%)) and intermediate (5/13 (38%)) in group 3 (P = 0.91). SUVmax was 4.1 ± 0.7, 4.6 ± 0.9 and 3.8 ± 0.7 (mean ± SD, P = 0.08), and SUVratio was 2.0 [1.9 to 2.2], 2.0 [1.8 to 2.6], and 1.9 [1.7 to 2.0] (median [IQR], P = 0.81) for groups 1, 2, and 3, respectively. CONCLUSION: Non-infected aortic PHV have similar low to intermediate perivalvular 18F-FDG uptake with similar SUVmax and SUVratio at 5, 12, and 52 weeks after implantation.

Additional holmium-166 radioembolisation after lutetium-177-dotatate in patients with neuroendocrine tumour liver metastases (HEPAR PLuS): a single-centre, single-arm, open-label, phase 2 study.

BACKGROUND: In patients with metastatic neuroendocrine neoplasms, the liver is the most commonly affected organ and a crucial factor for prognosis and survival. Peptide receptor radionuclide therapy can prolong progression-free survival in these patients. Additional treatment of liver disease might further improve outcomes. We aimed to investigate the safety and efficacy of additional holmium-166 (166Ho) radioembolisation after peptide receptor radionuclide therapy in patients with metastatic liver neuroendocrine neoplasms. METHODS: The Holmium Embolization Particles for Arterial Radiotherapy Plus 177Lu-Dotatate in Salvage Neuroendocrine Tumour Patients (HEPAR PLuS) study was a single-centre, phase 2 study done at the University Medical Center Utrecht (Utrecht, Netherlands). Patients, aged at least 18 years, with histologically proven grade 1 or 2 neuroendocrine neoplasms of all origins, an Eastern Cooperative Oncology Group performance status of 0-2, and three or more measurable liver metastases according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 criteria received 166Ho-radioembolisation within 20 weeks after four cycles of peptide receptor radionuclide therapy (lutetium-177-dotatate [177Lu-dotatate]). The primary endpoint was objective liver tumour response in the treated liver volume, defined as complete response (disappearance of all lesions) or partial response (≥30% decrease in the sum of the longest diameters of the target lesions, compared with baseline measurements), according to RECIST 1.1, analysed per protocol at 3 months. Safety was assessed in all patients who received treatment. This study is registered with ClinicalTrials.gov, NCT02067988. Recruitment is completed and long-term follow-up is ongoing. FINDINGS: From Oct 15, 2014, to Sept 12, 2018, 34 patients were assessed for eligibility. 31 patients received treatment and 30 (97%) patients were available for primary endpoint assessment and completed 6 months of follow-up. Three (9%) patients were excluded at screening and one (3%) patient was treated and died before the primary endpoint and was replaced. According to the per-protocol analysis 13 (43%; 95% CI 26-63) of 30 patients achieved an objective response in the treated volume. The most frequently reported Common Terminology Criteria for Adverse Events (CTCAE) grade 3-4 clinical and laboratory toxicities within 6 months included abdominal pain (three [10%] of 31 patients), increased γ-glutamyl transpeptidase (16 [54%]), and lymphocytopenia (seven [23%]). One (3%) fatal treatment-related serious adverse event occurred (radioembolisation-induced liver disease). Two (6%) patients had serious adverse events deemed to be unrelated to treatment (gastric ulcer and perforated cholecystitis). INTERPRETATION: 166Ho-radioembolisation, as an adjunct to peptide receptor radionuclide therapy in patients with neuroendocrine neoplasm liver metastases, is safe and efficacious. Radioembolisation can be considered in patients with bulky liver disease, including after peptide receptor radionuclide therapy. A future randomised, controlled study should investigate the added benefit of this treatment on progression-free survival. FUNDING: None.

A prospective observational registry evaluating clinical outcomes of Radium-223 treatment in a nonstudy population.

The ALSYMPCA study established a 3.6 month Overall Survival (OS) benefit in metastatic Castration Resistant Prostate Cancer (mCRPC) patients treated with Radium-223 dichloride (Ra-223) over placebo. Here we report clinical outcomes of Ra-223 treatment in a nonstudy population. In this prospective registry, patients from 20 Dutch hospitals were included prior to Ra-223 treatment. Clinical parameters collected included previous treatments and Adverse Events. Primary outcome was 6 months Symptomatic Skeletal Event (SSE)-free survival, while secondary outcomes included Progression-Free Survival (PFS) and Overall Survival (OS). Of the 305 patients included, 300 were evaluable. The mean age was 73.6 years, 90% had ≥6 bone metastases and 74.1% were pretreated with Docetaxel, 19.5% with Cabazitaxel and 80.5% with Abiraterone and/or Enzalutamide. Of all patients, 96.7% were treated with Ra-223 and received a median of 5 cycles. After a median follow-up of 13.2 months, 6 months SSE-free survival rate was 83%, median PFS was 5.1 months and median OS was 15.2 months. Six months SSE-free survival rate and OS were comparable with those reported in ALSYMPCA. "Previous Cabazitaxel treatment" and "bone-only metastases" were independent predictors of a shorter and longer PFS, respectively, while above-median LDH and "bone-only metastases" were independent predictors of shorter and longer OS, respectively. Toxicity was similar as reported in the ALSYMPCA trial. These results suggest that in a nonstudy population, Ra-223 treatment is well-tolerated, equally effective as in the ALSYMPCA population and that patients not previously treated with Cabazitaxel benefit most from Ra-223.

PSMA PET/CT Identifies Intrapatient Variation in Salivary Gland Toxicity From Iodine-131 Therapy.

INTRODUCTION: Xerostomia is a well-known complication after iodine-131 (131I) therapy for thyroid carcinoma. It is currently insufficiently understood how the dose and biodistribution of 131I relates to salivary gland toxicity, and whether this is consistent for all salivary glands within a single patient. Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) was recently introduced as a new tool to evaluate the relative loss of vital acinar cells in individual salivary glands. We aimed to assess gland-specific salivary gland toxicity after 131I-therapy using PSMA PET/CT. METHODS: Five patients with differentiated thyroid cancer underwent [68Ga]Ga-PSMA-11 PET/CT to evaluate their eligibility for peptide radioligand therapy with [177Lu]Lu-PSMA-617. Uptake patterns in salivary glands were evaluated visually and quantitatively as an indicator of vital acinar cell loss after prior 131I-therapy. RESULTS: Four of 5 patients demonstrated significant lowered uptake in at least one salivary gland, after receiving at least 2 131I-treatments. Asymmetric loss of vital acinar cells occurred by gland type (parotid/submandibular) and location (right/left). The other salivary glands in these patients and all salivary glands in the fifth patient showed normal uptake, demonstrating high intrapatient and interpatient variability. CONCLUSIONS: 131I-therapy can induce salivary gland toxicity with high inter- but also high intrapatient variation among separate gland locations, which can be assessed with PSMA PET/CT. This new technique offers potential to guide further development and evaluation of protective measures in patients receiving 131I-therapy.

Prospective Validation of Gallium-68 Prostate Specific Membrane Antigen-Positron Emission Tomography/Computerized Tomography for Primary Staging of Prostate Cancer.

PURPOSE: Prospective validation of 68Ga prostate specific membrane antigen positron emission tomography/computerized tomography is lacking in initial staging of prostate cancer. In this study we evaluated the diagnostic accuracy of 68Ga prostate specific membrane antigen positron emission tomography/computerized tomography for detecting lymph node metastasis in patients with intermediate-high risk prostate cancer. MATERIALS AND METHODS: Patients with newly diagnosed prostate cancer and negative bone scan findings at greater than 10% MSKCC (Memorial Sloan Kettering Cancer Center) risk for lymph node metastasis were prospectively included in study from October 2017 to October 2018. In candidates for extended pelvic lymph node dissection 68Ga prostate specific membrane antigen positron emission tomography/computerized tomography was performed prior to planned surgery. Scan results were evaluated in a second tumor board meeting to assess a potential change of management. Sensitivity, specificity, and positive and negative predictive value for detecting lymph node metastasis were calculated per patient and per resection template using histopathology as the reference. A positron emission tomography based change of management was also reported. RESULTS: A total of 103 patients were eligible for analysis and 97 extended pelvic lymph node dissections were performed. In 41 patients (42.3%) there was a total of 85 lymph node metastases. Positron emission tomography was positive in 17 patients, resulting in 41.5% patient based sensitivity (95% CI 26.7-57.8) for detecting lymph node metastasis. The patient based specificity rate was 90.9% (95% CI 79.3-96.6), and positive and negative predictive values were 77.3% (95% CI 54.2-91.3) and 67.6% (95% CI 55.6-77.7), respectively. A positron emission tomography based change of treatment was observed in 13 patients (12.6%). CONCLUSIONS: In patients with newly diagnosed prostate cancer at greater than 10% MSKCC risk for lymph node involvement 68Ga prostate specific membrane antigen positron emission tomography/computerized tomography detected lymph node metastasis with high specificity and moderate sensitivity. This led to a treatment change in 12.6% of patients.

The superior predictive value of 166Ho-scout compared with 99mTc-macroaggregated albumin prior to 166Ho-microspheres radioembolization in patients with liver metastases.

PURPOSE: As an alternative to technetium-99m-macroaggregated albumin (99mTc-MAA), a scout dose of holmium-166 (166Ho) microspheres can be used prior to 166Ho-radioembolization. The use of identical particles for pre-treatment and treatment procedures may improve the predictive value of pre-treatment analysis of distribution. The aim of this study was to analyze the agreement between 166Ho-scout and 166Ho-therapeutic dose in comparison with the agreement between 99mTc-MAA and 166Ho-therapeutic dose. METHODS: Two separate scout dose procedures were performed (99mTc-MAA and 166Ho-scout) before treatment in 53 patients. First, qualitative assessment was performed by two blinded nuclear medicine physicians who visually rated the agreement between the 99mTc-MAA, 166Ho-scout, and 166Ho-therapeutic dose SPECT-scans (i.e., all performed in the same patient) on a 5-point scale. Second, agreement was measured quantitatively by delineating lesions and normal liver on FDG-PET/CT. These volumes of interest (VOIs) were co-registered to the SPECT/CT images. The predicted absorbed doses (based on 99mTc-MAA and 166Ho-scout) were compared with the actual absorbed dose on post-treatment SPECT. RESULTS: A total of 23 procedures (71 lesions, 22 patients) were included for analysis. In the qualitative analysis, 166Ho-scout was superior with a median score of 4 vs. 2.5 for 99mTc-MAA (p < 0.001). The quantitative analysis showed significantly narrower 95%-limits of agreement for 166Ho-scout in comparison with 99mTc-MAA when evaluating lesion absorbed dose (- 90.3 and 105.3 Gy vs. - 164.1 and 197.0 Gy, respectively). Evaluation of normal liver absorbed dose did not show difference in agreement between both scout doses and 166Ho-therapeutic dose (- 2.9 and 5.5 Gy vs - 3.6 and 4.1 Gy for 99mTc-MAA and 166Ho-scout, respectively). CONCLUSIONS: In this study, 166Ho-scout was shown to have a superior predictive value for intrahepatic distribution in comparison with 99mTc-MAA.