New PSMA-Targeting Ligands: Transformation from Diagnosis (Ga-68) to Radionuclide Therapy (Lu-177).

Prostate-specific membrane antigen (PSMA) is a promising target for the diagnosis and radionuclide therapy of prostate cancer. This study reports conversion of a previously reported 68Ga-imaging agent, [68Ga]Ga-P16-093, to a Lu-177 radionuclide therapeutic agent. Substitution of the HBED-CC metal chelating group with DOTA(GA)2 led to P17-087 (4) and P17-088 (7). Both agents showed excellent PSMA binding affinity (IC50 = 10-30 nM) comparable to that of recently FDA-approved [177Lu]Lu-PSMA-617 (Pluvicto). Biodistribution studies in PSMA expressing tumor bearing mice showed that [177Lu]Lu-4 exhibited very high tumor uptake and a fast blood clearance similar to those of [177Lu]Lu-PSMA-617. Conversely, [177Lu]Lu-7, containing an albumin binder, extended its blood half-life and exhibited significantly higher uptake and longer tumor residence time than [177Lu]Lu-4 and [177Lu]Lu-PSMA-617. The switch from chelator HBED-CC to DOTA(GA)2 and the switch from the imaging isotope gallium-68 to the therapeutic isotope lutetium-177 have successfully transformed a PSMA-targeting agent from diagnosis to promising radionuclide therapeutic agents.

Safety and efficacy of a novel iron chelator (HBED; (N,N'-Di(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid)) in equine (Equus caballus) as a model for black rhinoceros (Diceros bicornis).

While iron overload disorder (IOD) and related disease states are not considered a common occurrence in domestic equids, these issues appear prevalent in black rhinoceroses under human care. In addressing IOD in black rhinos, altering dietary iron absorption and excretion may be the most globally practical approach. A main option for treatment used across other species such as humans, is chelation therapy using iron-specific synthetic compounds. As horses may serve as an appropriate digestive model for the endangered rhinoceros, we evaluated the potential use of the oral iron chelator N,N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED) in horses for safety and efficacy prior to testing in black rhinoceros. Health and iron digestibility and dynamics were assessed in horses (n = 6) before, and after treatment with HBED (50 mg/kg body weight) for 8 days using a crossover design with serum, faecal and urine collection. A preliminary pharmacokinetic trial was also performed but no trace of HBED was found in serially sampled plasma through 8 h post-oral dosing. HBED increased urinary iron output in horses compared to control by 0.7% of total iron intake (p < 0.01), for an average of 27 mg urinary iron/day, similar to human chelation goals. Blood chemistry, blood cell counts and overall wellness were not affected by treatment. As healthy horses are able to regulate iron absorption, the lack of change in iron balance is unsurprising. Short-term HBED administration appeared to be safely tolerated by horses, therefore it was anticipated it would also be safe to administer to black rhinos for the management of iron overload.

[Target therapy and governance: the breast cancer PDTA of the Venetian Oncology Network.] / Target therapy e governance: il PDTA del tumore della mammella della Rete Oncologica Veneta.

Mutational oncology is becoming a fundamental element of diagnostic-therapeutic care pathways and requires new organizational models that allow for the aggregation of administrative, clinical and biomolecular data. From the experience of the Periplo Foundation in measuring the diagnostic and therapeutic care pathways (DTCP) indicators of almost 20 thousand women with breast cancer in five Italian regions, which showed the difficulty of measuring the efficiency of diagnostic-therapeutic care pathways based on the data available in the existing databases, the Foundation hopes for the creation of digital environments built with the aim of showing the greater/lesser efficiency of the health system.

Effect of 6,9,12,15-Hexadecatetraenoic Acid (C16:4n-1)-Ethyl Ester on Lipid Content and Fatty Acid Composition in the Blood and Organs of Mice.

The effects of 6,9,12,15-hexadecatetraenoic acid (C16:4n-1, HDTA), an n-1 polyunsaturated fatty acid (FA), on plasma and liver lipid content and distribution in blood and tissues were investigated. Mice were fed experimental diets containing 10% HDTA or eicosapentaenoic acid in ethyl ester form based on corn oil for four weeks. Dietary HDTA intake lowered plasma triacylglycerol content without affecting plasma total cholesterol content. HDTA barely accumulated in the epididymal white adipose tissue (eWAT), while C18:4n-1, an HDTA metabolite, was detected in small amounts (< 1% of total FAs) in the plasma, liver, and eWAT.

Complementary Role of 68Ga-Prostate-Specific Membrane Antigen and 18F-FDG PET/CT for Evaluation of Metastases and Treatment Response in Renal Cell Carcinoma.

ABSTRACT: We present a case of clear cell renal cell carcinoma, which demonstrates complementary FDG and prostate-specific membrane antigen (PSMA) uptake on metastases in PET/CT, as an example of tumor heterogeneity. The patient had non-FDG-avid lung and bone metastases with PSMA uptake, whereas metastatic cervical and axillary lymph nodes showed vice versa, and skeletal muscle metastasis to vastus lateralis, which is an unusual region for metastasis, showed both PSMA and FDG positivity. In response assessment, mix response was detected. It seems that 68Ga-PSMA and 18F-FDG may have a complementary role in demonstration of metastasis accurately and assessment of treatment response in clear cell renal cell carcinoma.

Antihormone treatment differentially regulates PSA secretion, PSMA expression and 68Ga-PSMA uptake in LNCaP cells.

BACKGROUND: In recent years, a variety of innovative therapeutics for castration-resistant prostate cancer have been developed, including novel anti-androgenic drugs, such as abiraterone or VPC-13566. Therapeutic monitoring of these pharmaceuticals is performed either by measuring PSA levels in serum or by imaging. PET using PSMA ligands labeled with Fluor-18 or Gallium-68 is the most sensitive and specific imaging modality for detection of metastases in advanced prostate cancer. To date, it remains unclear how PSMA expression is modulated by anti-hormonal treatment and how it correlates with PSA secretion. METHODS: We analyzed modulation of PSMA-mRNA and protein expression, 68Ga-PSMA uptake and regulation of PSA secretion by abiraterone or VPC-13566 in LNCaP cells in vitro. RESULTS: We found that abiraterone and VPC-13566 upregulate PSMA protein and mRNA expression but block PSA secretion in LNCaP cells. Both anti-androgens also enhanced 68Ga-PSMA uptake normalized by the number of cells, whereas abiraterone and VPC-13566 reduced 68Ga-PSMA uptake in total LNCaP monolayers treated due to cell death. CONCLUSION: Our data indicate that PSA secretion and PSMA expression are differentially regulated upon anti-androgen treatment. This finding might be important for the interpretation of 68Ga-PSMA PET images in monitoring therapies with abiraterone and VPC-13566 in prostate cancer patients, but needs to be validated in vivo.

[68Ga-PSMA-11 PET/mpMRI for local detection of primary prostate cancer in men with a negative prior biopsy]. / 68Ga-PSMA-11 PET/mpMRT zur Lokaldetektion des primären Prostatakarzinom bei Männern mit negativer Vorbiopsie.

INTRODUCTION AND OBJECTIVE: Multiparametric MRI (mpMRI) represents the current gold standard for the detection of primary prostate cancer (PC) after a negative biopsy. PSMA PET imaging has been introduced in the diagnostic work-up of PC with high accuracy, but is currently mainly utilised in the setting of biochemical recurrence. This study aimed to determine the efficacy of combined 68Ga-PSMA-11 PET/mpMRI imaging to detect PC in patients with previously negative prostate biopsies. METHODS: A total of 57 patients who had undergone at least one prior negative prostate biopsy were included in this retrospective analysis. All patients underwent 68Ga-PSMA-11 PET/mpMRI imaging of the prostate. mpMRI was evaluated according to the PIRADS classification system and 68Ga-PSMA-11 PET was rated on a 5-point Likert scale (1: PC highly unlikely; 2: PC unlikely; 3: presence of PC is equivocal; 4: PC likely; 5: PC highly likely). All patients received a systematic random biopsy as well as a targeted transrectal biopsy of lesions suspicious on imaging. Imaging and histological biopsy outcomes were compared on a per-patient basis. RESULTS: In the histological analysis, 35/57 (61.4 %) patients harboured PC lesions. In patients with biopsy-proven PC, 21/35 (60.0 %) had a PI-RADS 4 or 5 lesion on mpMRI and 28 /35 (80.0 %) had a PET rating of 4 or 5. Combined 68Ga-PSMA-11 PET/mpMRI missed only one patient with a Gleason score (GS) 7a tumour (rating of 1 or 2 in both PET and mpMRI). Limitations include the retrospective analysis as well as possible false negative biopsy results even in a fusion biopsy setting. CONCLUSION: In this initial analysis, the combined 68Ga-PSMA-11 PET/mpMRI proved to be a valuable imaging tool to guide prostate biopsies for the detection of PC in patients with a negative prior biopsy. In this approach, 68Ga-PSMA-11 PET and mpMRI show partially complementary findings that enhance the detection of PC lesions.

Comparison between 68Ga-PSMA-11 PET/CT and multiparametric magnetic resonance imaging in patients with biochemically recurrent prostate cancer following robot-assisted radical prostatectomy.

BACKGROUND/PURPOSE: We sought to compare the diagnostic performances of 68Ga-PSMA-11 PET/CT and prostate/whole-abdomen multiparametric magnetic resonance imaging (PWAmpMRI) in Taiwanese patients with biochemically recurrent prostate cancer following robot-assisted radical prostatectomy. METHODS: Between June 2017 and December 2018, we prospectively enrolled 34 patients. Upon review of all available clinical and imaging data, a best valuable comparator (BVC) was defined on an individual basis in the light of a consensus reached by a multidisciplinary tumor board. Diagnostic positivity was investigated in relation to the different lesion types. RESULTS: On a patient-based analysis, 68Ga-PSMA-11 PET/CT and PWAmpMRI showed a moderate agreement (kappa coefficient = 0.62). 68Ga-PSMA-11 PET/CT identified local recurrences, regional, and non-regional lymph node metastases, and bone metastases in 15, 10, 1, and 5 patients, respectively. Conversely, PWAmpMRI detected these lesions in 26, 8, 1, and 4 patients, respectively. When the BVC was used as reference standard, the positive diagnostic rates for local recurrences, regional lymph node metastases, non-regional lymph node metastases, and bone metastases were 57.7%, 90.9%, 100%, and 100%, respectively for 68Ga-PSMA-11 PET/CT, and 100%, 72.7%, 100%, and 80% for PWAmpMRI, respectively. The use of both PWAmpMRI and 68Ga-PSMA-11 PET/CT showed a complete diagnostic yield for detecting both local recurrence and systemic failure when PSA levels reached 0.5 ng/mL. CONCLUSION: Due to urine radioactivity, 68Ga-PSMA-11 PET/CT performs less than PWAmpMRI on local recurrences. However, it can have a complementary diagnostic role in the detection of lymph node metastases and in identifying non-axial bone metastases beyond the PWAmpMRI scanning field.

Can 68Ga-PSMA-11 Positron Emission Tomography/Computerized Tomography Predict Pathological Response of Primary Prostate Cancer to Neoadjuvant Androgen Deprivation Therapy? A Pilot Study.

PURPOSE: We explored the role of 68Ga-PSMA-11 positron emission/computerized tomography as a predictor of pathological response to neoadjuvant androgen deprivation therapy combined with abiraterone for high risk prostate cancer. MATERIALS AND METHODS: A total of 45 patients with localized high risk prostate cancer who had serial 68Ga-PSMA-11 positron emission tomography/computerized tomography scans before and after 6 months of androgen deprivation therapy plus abiraterone neoadjuvant treatment followed by radical prostatectomy were included in this study. Complete pathological response or minimal residual disease <5 mm on whole mount histopathology was defined as favorable pathological response. The diagnostic performance of prostate specific antigen response and positron emission tomography/computerized tomography response for favorable pathological response was calculated. Univariable and multivariable logistic regression analyses of clinical and imaging variables were also performed to identify favorable pathological response. RESULTS: Compared to the prostate specific antigen response, positron emission tomography/computerized tomography response had a significantly higher specificity in diagnosing favorable pathological response (89.7% vs 62.1%, p=0.043). Preoperative nadir prostate specific antigen (OR 0.121, 95% CI 0.028-0.529, p=0.005), posttreatment maximum standardized uptake value (OR 7.072, 95% CI 2.035-24.579, p=0.002) and posttreatment tumor volume (OR 7.896, 95% CI 1.415-44.054, p=0.018) measured on positron emission tomography/computerized tomography were significantly associated with favorable pathological response in univariable logistic regression analysis. On multivariable logistic regression analysis, only posttreatment maximum standardized uptake value was found to be an independent predictor of favorable pathological response (OR 9.69, 95% CI 1.439-65.242, p=0.020). CONCLUSIONS: 68Ga-PSMA positron emission tomography/computerized tomography has a better diagnostic performance of pathological response to neoadjuvant treatment compared with prostate specific antigen, with maximum standardized uptake value being an independent predictive factor. This pilot study suggests that prostate specific membrane antigen positron emission tomography/computerized tomography may serve as a potential predictor of pathological response to neoadjuvant treatment.

Novel strategies for the treatment of acetaminophen hepatotoxicity.

INTRODUCTION: Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the western world. Despite extensive investigations into the mechanisms of cell death, only a single antidote, N-acetylcysteine, is in clinical use. However, there have recently been more efforts made to translate mechanistic insight into identification of therapeutic targets and potential new drugs for this indication. AREAS COVERED: After a short review of the key events in the pathophysiology of APAP-induced liver injury and recovery, the pros and cons of targeting individual steps in the pathophysiology as therapeutic targets are discussed. While the re-purposed drug fomepizole (4-methylpyrazole) and the new entity calmangafodipir are most advanced based on the understanding of their mechanism of action, several herbal medicine extracts and their individual components are also considered. EXPERT OPINION: Fomepizole (4-methylpyrazole) is safe and has shown efficacy in preclinical models, human hepatocytes and in volunteers against APAP overdose. The safety of calmangafodipir in APAP overdose patients was shown but it lacks solid preclinical efficacy studies. Both drugs require a controlled phase III trial to achieve regulatory approval. All studies of herbal medicine extracts and components suffer from poor experimental design, which questions their clinical utility at this point.

Metabolic and mitochondrial treatments for severe paracetamol poisoning: a systematic review.

BACKGROUND: Paracetamol (acetaminophen) remains a leading cause of poisoning in Europe, North America, and Australia. For over four decades, acetylcysteine has been the antidote of choice. However, despite the use of acetylcysteine, some patients who ingest very large doses of paracetamol or who reach hospital late in the course of their poisoning, develop acute liver failure. Some will develop metabolic acidosis indicating mitochondrial toxicity. OBJECTIVE: We review the experimental and clinical data reported with the use of cimetidine, fomepizole, and calmangafodipir in the treatment of paracetamol toxicity to determine if these treatments alone or in combination with acetylcysteine might be of benefit. METHODS: We searched Ovid Medline 1946-2020, Embase 1947-2020, Scopus 2004-2020, Cochrane Databases of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov 1997-2020 for records including the concepts of paracetamol poisoning and cimetidine, fomepizole, calmangafodipir, and acetylcysteine. We included basic science studies in animals and all available study types in humans. We reviewed the reference lists of included articles to search for references missed in the original search. We registered the protocol in PROSPERO. RESULTS: We completed all search strategies on 20 August 2019, 27 January 2020, and 15 June 2020. These produced 6,826 citations. We identified and deleted 2,843 duplicate resulting in a total of 3,856 unique citations. After applying inclusion and exclusion criteria, 89 studies remained. The largest numbers of studies described the past use of cimetidine, and the more recent use of fomepizole.Cimetidine: There is good animal evidence that cimetidine blocks CYP 2E1 with the potential to inhibit the toxic metabolism of paracetamol. Early case reports were inconclusive regarding the benefit to humans in paracetamol poisoning. Two comparative trials found no benefit of cimetidine in paracetamol poisoning, but few patients had severe poisoning.Fomepizole: There is good animal evidence that fomepizole blocks CYP 2E1 with the potential to inhibit the toxic metabolism of paracetamol. There are no comparative trials of fomepizole for acute paracetamol poisoning. Case reports are inconclusive due to multiple other interventions including the use of acetylcysteine in all cases. The benefit of fomepizole as adjunct treatment has not been demonstrated.Calmangafodipir: Calmangafodipir, a drug mimicking superoxide dismutase, has emerged as a potential treatment for severe paracetamol toxicity because the formation of superoxide free radicals appears to explain part of the mitochondrial toxicity of extremely large paracetamol overdoses. Calmangafodipir has reached Phase I/II trial of safety in humans with acute paracetamol overdose. Planning for a Phase III study of efficacy is currently underway. CONCLUSIONS: The vast majority of patients with acute paracetamol overdose enjoy excellent outcomes with acetylcysteine alone. Although cimetidine and fomepizole inhibit CYP 2E1 in animals, there is insufficient evidence to recommend their use either as a primary treatment or adjunct therapy in paracetamol poisoning. Calmangafodipir remains investigational.

68 Ga-PSMA-PET/CT helps to select patients for salvage radical prostatectomy with local recurrence after primary radiotherapy for prostate cancer.

OBJECTIVE: To investigate the diagnostic performance of gallium-68 prostate-specific membrane antigen positron emission tomography/computed tomography (68 Ga-PSMA PET/CT) in patients with recurrent prostate cancer with regard to the presence of lymph node metastases (LNM) and local recurrences after primary radiotherapy. PATIENTS AND METHODS: We retrospectively reviewed 142 patients following salvage radical prostatectomy (sRP), 50 of which had a 68 Ga-PSMA PET/CT performed as a preoperative staging module. Predictive clinical parameters were analysed in a multivariate Cox regression analysis. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) and the accuracy of 68 Ga-PSMA PET/CT were analysed with regard to LNM and local recurrence. RESULTS: In all, 613 lymph nodes were resected in 40 patients and 23 lymph nodes had metastatic deposits in 14 patients. In all patients local recurrence could have been found with 68 Ga-PSMA PET/CT. Sensitivity, specificity, PPV and NPV and accuracy on a per lymph node basis were 34.78% (16.38-57.2%), 100% (99.38-100%), 100%, 97.52% (96.69-98.15%) and 97.55% (96.00-98.62%). For detecting local recurrence, the sensitivity and PPV were both 100% with an accuracy of 100% (92.89-100%). CONCLUSION: 68 Ga-PSMA PET/CT should be the standard imaging in biochemical recurrent prostate cancer. With this imaging module one detects first local recurrence and can detect locoregional and distant metastases more precisely than standard CT and bone scan.

Solitary rib lesions showing prostate-specific membrane antigen (PSMA) uptake in pre-treatment staging 68 Ga-PSMA-11 positron emission tomography scans for men with prostate cancer: benign or malignant?

OBJECTIVES: To determine the proportion of solitary rib lesions on pre-treatment 68 Gallium-labelled prostate-specific membrane antigen (PSMA)/computed tomography (CT) scans in men with prostate cancer that are malignant and examine any predictive factors. PATIENTS AND METHODS: This retrospective single tertiary referral institution cohort study of men reviewed the results of 68 Ga-PSMA-11 positron emission tomography (PET)/CT scans performed for primary staging prior to treatment of prostate cancer from July 2014 to September 2019. Men with PSMA uptake outside the prostate in only the rib lesion were included. A solitary rib lesion was considered to be malignant if it increased in size on follow-up imaging. A lesion was considered benign if the prostate-specific antigen (PSA) level remained <0.1 µg/L following a radical prostatectomy (RP), <2 µg/L above nadir following radiotherapy (RT) as per the Phoenix criteria, histology was benign on rib biopsy, or follow-up imaging showed no growth of the rib lesion. If a lesion did not meet these criteria it was considered indeterminate. RESULTS: A total of 62 men had PSMA uptake in a solitary rib lesion; 54 went on to have RPs and eight underwent RT. In all, 61 of the men (98.4%) met the criteria for a benign rib lesion. Only one man had a false-negative malignant lesion. This man had a rib lesion with a low maximum standardised uptake value (SUVmax ) of 2.21 reported as benign, but the postoperative PSA level was 0.67 µg/L and the rib lesion progressed on follow-up imaging, with development of widespread metastases. Of the benign rib lesions, there were four false positives reported as possible metastases. Three had percutaneous rib biopsies, two of which came back with benign histology and one was indeterminate. The indeterminate biopsy patient had a RP and his postoperative PSA level was <0.1 µg/L. A total of 43 (69.4%) men with benign rib lesions had a SUVmax greater than the SUVmax of the malignant lesion. CONCLUSION: To our knowledge, this is the first cohort study of men with PSMA-avid solitary rib lesions on pre-treatment 68 Ga-PSMA PET/CT staging scans for prostate cancer. Our results indicate that the vast majority of these lesions have low-intensity uptake and are benign. Intervention to confirm this is not usually required.

Potential Applications of 68Ga-PSMA-11 PET/CT in the Evaluation of Salivary Gland Uptake Function: Preliminary Observations and Comparison with 99mTcO4 - Salivary Gland Scintigraphy.

Purpose: To preliminarily evaluate the feasibility and potential of using 68Ga-PSMA-11 PET/CT in evaluating the function of salivary glands and lacrimal glands in comparison with 99mTc-pertechnetate (99mTcO4 -) salivary gland scintigraphy (SGS). Methods: A retrospective study was performed in 15 patients with different degrees of xerostomia and suspected salivary gland dysfunction. Each patient underwent 68Ga-PSMA-11 PET/CT first and SGS the next day, and the findings of both scans were compared. Results: The results of 68Ga-PSMA-11 PET/CT and SGS were consistent in 12/15 patients (80%) and were inconsistent in the remaining patients (20%). For 5 (33.3%) of 15 patients, 68Ga-PSMA-11 PET/CT provided more information than did SGS. Additionally, 68Ga-PSMA-11 PET/CT corrected the misdiagnosis by SGS for 1 patient. Conclusions: 68Ga-PSMA-11 PET/CT is a potentially useful imaging tool for evaluating the function of salivary glands and lacrimal glands. 68Ga-PSMA-11 PET/CT can be a promising supplement to SGS, and its clinical value deserves further study.

68Ga-PSMA-11 PET/CT in recurrent hormone-sensitive prostate cancer (HSPC): a prospective single-centre study in patients eligible for salvage therapy.

OBJECTIVES: The primary objective is to assess the efficacy of 68Ga-PSMA-11-PET/CT to detect recurrent location(s) in hormone-sensitive prostate cancer (PCa). Secondary objectives are (1) to evaluate changes in clinical management; (2) to determine which covariates independently predict positive scan; (3) to assess 68Ga-PSMA-11-PET/CT performance in different settings of PSA relapse. MATERIALS AND METHODS: Inclusion criteria include (1) histologically diagnosed PCa; (2) previous radical therapy; (3) proven biochemical recurrence (BCR) or biochemical persistence (BCP); (4) hormone-sensitive PCa (HSPC); (5) androgen deprivation therapy (ADT)-free for at least 6 months; (6) PSA < 1.5 ng/mL or any PSA in case of negative choline-PET/CT (n = 38). Changes in clinical management were defined by multidisciplinary tumour-board. Clinical settings were BCP (group-1, n = 25); first-time BCR (group-2, n = 121); BCR after salvage therapy (group-3, n = 77). RESULTS: Two hundred twenty-three (223) consecutive patients were enrolled: median PSA = 0.65 ng/mL (0.2-8.9) and median PSAdt = 9.3 months (0.4-144.6). 96.9% received RP as primary therapy. 68Ga-PSMA-11-PET/CT positivity rate was 39.9% (CI95% 33.5-46.7%). Disease confined to pelvis was detected in 23.3% of cases. At least one distant lesion was observed in 16.6% of cases. Secondary objectives are as follows: (1) changes in clinical management were observed in 34.5% of patients; (2) PSA, PSAdt and T stage > 3a were independent predictors (all p < 0.03); (3) 68Ga-PSMA-11-PET/CT positivity rate was 56% (in group 1, 36.3% in group 2, 40.3% in group 3. CONCLUSION: This study attested the overall good performance of 68Ga-PSMA-11-PET/CT to detect PCa locations in HSPC patients eligible for salvage therapy, influencing the therapy management in 35.4% of cases. Furthermore, patient characteristics are influencing factors of 68Ga-PSMA-11-PET/CT positivity rate and should be considered to reduce false negative scan.

Intraindividual comparison between 68Ga-PSMA-PET/CT and mpMRI for intraprostatic tumor delineation in patients with primary prostate cancer: a retrospective analysis in 101 patients.

PURPOSE: Accurate delineation of intraprostatic gross tumor volume (GTV) is mandatory for successful fusion biopsy guidance and focal therapy planning of prostate cancer (PCa). Multiparametric magnetic resonance imaging (mpMRI) is the current gold standard for GTV delineation; however, prostate-specific membrane antigen positron emission tomography (PSMA-PET) is emerging as a promising alternative. This study compares GTV delineation between mpMRI and 68Ga-PSMA-PET in a large number of patients using validated contouring approaches. METHODS: One hundred one patients with biopsy-proven primary PCa who underwent mpMRI and 68Ga-PSMA-PET within 3 months before primary treatment were retrospectively enrolled. Clinical parameters (age, PSA, Gleason score in biopsy) were documented. GTV based on MRI and PET images were delineated; volumes measured and laterality determined. Additionally, biopsy data from 77 patients was analyzed. Univariate and multivariate binary logistic regression analyses were performed using concordance in laterality as the endpoint. RESULTS: In total mpMRI and 68Ga-PSMA-PET detected 151 and 159 lesions, respectively. Median GTV-MRI (2.8 ml, 95% CI 2.31-3.38 ml) was significantly (p < 0.0001) smaller than median GTV-PET (4.9 ml, 95% CI 3.9-6.6 ml). 68Ga-PSMA-PET detected significantly more bilateral lesions than mpMRI (71 vs 57, p = 0.03). Analysis of patients with bilateral lesions in biopsy showed a significant higher concordance of laterality in 68Ga-PSMA-PET (p = 0.03). In univariate analysis, PSA level and volume of GTV-MRI had an impact on concordance in laterality (p = 0.02 and p = 0.01), whereas in multivariate analysis, only GTV-MRI volume remained significant (p = 0.04). CONCLUSION: MpMRI and 68Ga-PSMA-PET detect a similar amount of PCa lesions. However, GTV-PET had approximately twice the volume (median 4.9 ml vs 2.8 ml) and detected significantly more bilateral lesions than mpMRI. Thus, 68Ga-PSMA-PET gives highly important complementary information. Since we could not find any strong evidence for parameters to guide when 68Ga-PSMA-PET is dispensable, it should be performed additionally to MRI in patients with intermediate and high-risk PCa according to D'Amico classification to improve GTV delineation.

Efficacy and Safety of 177Lu-PSMA-617 Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer Patients.

PURPOSE: The aim of this study was to evaluate the efficacy and safety of Lu-PSMA-617 radioligand therapy in metastatic castration-resistant prostate cancer (mCRPC). METHODS: In this prospective, single-arm, single-institutional study, 90 mCRPC patients with progressive disease (PD) on second-line hormonal therapy and/or docetaxel chemotherapy were recruited for the study. All patients underwent diagnostic Ga-PSMA-HBED-CC PET/CT, prior to inclusion for therapy. Included patients underwent Lu-PSMA-617 therapy at 8- to 12-weekly intervals. The primary end point was to assess the overall survival. The secondary and cosecondary end points included biochemical response assessment as per the Prostate Cancer Working Group 3 criteria, progression-free survival, radiological and molecular response criteria, clinical response, safety profile, and disease control rates. All the outcome parameters were evaluated in 90 patients except for the radiographic and molecular response, which was evaluated in 69 patients. RESULTS: The median age of patients was 66.5 years (range, 30-88 years). The median activity administered per cycle was 3.7 to 8 GBq ranging from 1 to 7 cycles, and patients were followed up over a median duration of 28 months. At 2- to 3-month interval after the first therapy and the end of the assessment, greater than 50% decline in prostate-specific antigen was observed in 32.2% and 45.5%, respectively. Univariate analysis did not reveal any variables such as prior therapies, laboratory parameters, concomitant hormonal therapy, and SUV patient parameters associated with prostate-specific antigen decline. Radiographic response by diagnostic CT revealed partial remission in 23% (16/69), stable disease in 54% (37/69), and PD in 23% (16/69) of patients. Molecular tumor response by PET Response Criteria in Solid Tumor 1 criteria revealed 19 (27.5%) of 69 patients with partial remission, 30 (43.5%) of 69 with stable disease, and 20 (29%) of 69 with PD. The disease control rates according to the radiographic and molecular response were 77% and 71%, respectively. The median overall survival and median progression-free survivals were 14 and 11.8 months, respectively. Toxicities related to radioligand therapy were low and transient with no serious adverse effects. CONCLUSIONS: Lu-PSMA-617 radionuclide therapy is a safe and effective approach to the treatment of mCRPC patients.

Prospective study on the effect of short-term androgen deprivation therapy on PSMA uptake evaluated with 68Ga-PSMA-11 PET/MRI in men with treatment-naïve prostate cancer.

PURPOSE: Based on in vitro studies, it is known that androgen deprivation therapy (ADT) increases prostate-specific membrane antigen (PSMA) expression. Therefore, we hypothesised that ADT improves the performance of PSMA-PET imaging in primary staging of prostate cancer. The purpose of the study was to demonstrate the time course effect of ADT on PSMA uptake in different types of metastatic lesions evaluated with 68Ga-PSMA-11 PET/MRI. METHODS: Nine men with treatment-naïve prostate cancer were enrolled to a prospective, registered (NCT03313726) clinical trial. A 68Ga-PSMA-11 PET/MRI was performed once before and 3 times post-ADT (degarelix, Firmagon). Change of maximum standardised uptake values (SUVmax) in prostate, lymph nodes, bone metastases, and physiologically PSMA-avid organs were evaluated in a time frame of 1-8 weeks. RESULTS: All patients reached castration levels within 10 days, and 50% decrease in prostate-specific antigen (PSA) concentration was observed 14 days post-ADT. A heterogeneous increase in PSMA uptake was observed 3 to 4 weeks post-ADT. This phenomenon was definitively more evident in bone metastases: 13 (57%) of the metastasis, with a mean (range) SUVmax increase of 77% (8-238%). In one patient, already having bone metastases at baseline, three new bone metastases were observed post-ADT. Of lesions with reduced SUVmax, none disappeared. CONCLUSIONS: Both in patient and region level, increase in PSMA uptake post-ADT is heterogenous and is seen most evidently in bone metastases. Preliminary results on a small cohort of patients suggest the clinical impact of ADT on improving the performance of 68Ga-PSMA PET in staging seems to be minor. However, the optimal imaging time point might be 3 to 4 weeks post-ADT. Since none of the metastases with decreasing SUVmax disappeared, it seems that short-term usage of ADT does not interfere with the interpretation of 68Ga-PSMA PET. TRIAL REGISTRATION: NCT03313726, registered 18 October 2017; EUDRA-CT, 2017-002345-29.

Response assessment using [68 Ga]Ga-PSMA ligand PET in patients undergoing systemic therapy for metastatic castration-resistant prostate cancer.

BACKGROUND: To assess which parameters of [68 Ga]Ga-PSMA-11 positron emission tomography (PSMA-PET) predict response to systemic therapies in metastatic (m) castration-resistant prostate cancer (CRPC). In addition, to investigate which of these factors are associated with overall survival (OS). METHODS: We retrospectively assessed the following PSMA-PET parameters in 43 patients before and after systemic therapies for mCRPC: PSMA total tumor volume (TTV), mean standardized uptake value (SUVmean), SUVmax, and SUVpeak. prostate-specific antigen (PSA) levels and PSMA-PET/CT(magnetic resonance imaging [MRI]) imaging were both performed within 8 weeks before and 6 weeks after systemic therapy. PSMA-PET and CT (MRI) images were reviewed according to the modified PET Response Criteria in Solid Tumors (PERCIST) and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Results were compared to PSA response. Univariable survival analyses were performed. RESULTS: Overall, 43 patients undergoing 67 systemic therapies were included (9 patients radium-223, 12 cabazitaxel, 22 docetaxel, 6 abiraterone, and 18 enzalutamide). Median serum PSA level before any therapy was 11.3 ng/mL (interquartile range [IQR] = 3.3, 30.1). Delta (d) PSA after systemic therapies was -41%, dTTV 10.5%, dSUVmean -7.5%, dSUVmax -13.3%, dSUVpeak -12%, and dRECIST -13.3%. Overall, 31 patients had dPSA response (46.3%), 12 stable disease (17.9%), and 24 progressive disease (35.8%). All observed PET parameters, as well as the RECIST evaluation, were significantly associated with PSA response (dTTV P = .003, dSUVmean P = .003, dSUVmax P = .011, dSUVpeak P < 0001, dRECIST P = .012), while RECIST assessment was applicable in 37 out of 67 patients (55.2%). Within a median follow-up of 33 months (IQR = 26, 38), 10 patients (23.3%) died of PC. On univariable survival analyses, neither the investigated PET parameters nor PSA level or RECIST criteria were associated with OS. CONCLUSION: PSMA-PET provides reliable parameters for prediction of response to systemic therapies for mCRPC. These parameters, if confirmed, could enhance RECIST criteria, specifically concerning its limitations for sclerotic bone lesions.