Rationale and design of the RAPID-WATER-FLOW trial: Radiolabeled perfusion to identify coronary artery disease using water to evaluate responses of myocardial FLOW.

OBJECTIVES: The objective of this study was to determine the diagnostic performance of 15O-water positron emission tomography (PET) myocardial perfusion imaging to detect coronary artery disease (CAD) using the truth-standard of invasive coronary angiography (ICA) with fractional flow reserve (FFR) or instantaneous wave-Free Ratio (iFR) or coronary computed tomography angiogram (CCTA). BACKGROUND: 15O-water has a very high first-pass extraction that allows accurate quantification of myocardial blood flow and detection of flow-limiting CAD. However, the need for an on-site cyclotron and lack of automated production at the point of care and relatively complex image analysis protocol has limited its clinical use to date. METHODS: The RAPID WATER FLOW study is an open-label, multicenter, prospective investigation of the accuracy of 15O-water PET to detect obstructive angiographic and physiologically significant stenosis in patients with suspected CAD. The study will include the use of an automated system for producing, dosing, and injecting 15O-water and enrolling approximately 215 individuals with suspected CAD at approximately 10 study sites in North America and Europe. The primary endpoint of the study is the diagnostic sensitivity and specificity of the 15O-water PET study using the truth-standard of ICA with FFR or iFR to determine flow-limiting stenosis, or CCTA to rule out CAD and incorporating a quantitative analytic platform developed for the 15O-water PET acquisitions. Sensitivity and specificity are to be considered positive if the lower bound of the 95% confidence interval is superior to the threshold of 60% for both, consistent with prior registration studies. Subgroup analyses include assessments of diagnostic sensitivity, specificity, and accuracy in female, obese, and diabetic individuals, as well as in those with multivessel disease. All enrolled individuals will be followed for adverse and serious adverse events for up to 32 hours after the index PET scan. The study will have >90% power (one-sided test, α = 0.025) to test the hypothesis that sensitivity and specificity of 15O-water PET are both >60%. CONCLUSIONS: The RAPID WATER FLOW study is a prospective, multicenter study to determine the diagnostic sensitivity and specificity of 15O-water PET as compared to ICA with FFR/iFR or CCTA. This study will introduce several novel aspects to imaging registration studies, including a more relevant truth standard incorporating invasive physiologic indexes, coronary CTA to qualify normal individuals for eligibility, and a more quantitative approach to image analysis than has been done in prior pivotal studies. CLINICAL TRIAL REGISTRATION INFORMATION: Clinical-Trials.gov (#NCT05134012).

A review on the fate of micro and nano plastics (MNPs) and their implication in regulating nutrient cycling in constructed wetland systems.

This review discusses the micro-nano plastics (MNPs) and their interaction with physical, chemical and biological processes in a constructed wetland (CW) system that is typically used as a nature-based tertiary wastewater treatment for municipal as well as industrial applications. Individual components of the CW system such as substrate, microorganisms and plants were considered to assess how MNPs influence the CW processes. One of the main functions of a CW system is removal of nutrients like nitrogen (N) and phosphorus (P) and here we highlight the pathways through which the MNPs influence CW's efficacy of nutrient removal. The presence of morphologically (size and shape) and chemically different MNPs influence the growth rate of microorganisms important in N and P cycling, invertebrates, decomposers, and the plants which affect the overall efficiency of a CW treatment system. Certain plant species take up the MNPs, and some toxicity has been observed. This review focuses on two significant aspects: (1) the presence of MNPs in a significant concentration affects the efficiency of N and P removal, and (2) the removal of MNPs. Because MNPs reduce the enzyme activities in abundance and overproduction of ROS oxidizes the enzyme active sites, resulting in the depletion of proteins, ultimately inhibiting nitrogen and phosphorus removal within the substrate layer. The review found that the majority of the studies used sand-activated carbon (SAC), granular-activated carbon (GAC), rice straw, granular limestone, and calcium carbonate, as a substrate for CW treatment systems. Common plant species used in the CW include Phragmites, Arabidopsis thaliana, Lepidium sativum, Thalia dealbata, and Canna indica, which were also found to be dominant in the uptake of the MNPs in the CWs. The MNPs were found to affect earthworms such as Eisenia fetida, Caenorhabditis elegans, and, Enchytraeus crypticus, whereas Metaphire vulgaris were found unaffected. Though various mechanisms take place during the removal process, adsorption and uptake mechanism effectively emphasize the removal of MNPs and nitrogen and phosphorus in CW. The MNPs characteristics (type, size, and concentration) play a crucial role in the removal efficiency of nano-plastics (NPs) and micro-plastics (MPs). The enhanced removal efficiency of NPs compared to MPs can be attributed to their smaller size, resulting in a faster reaction rate. However, NPs dose variation showed fluctuating removal efficiency, whereas MPs dose increment reduces removal efficiency. MP and NPs dose variation also affected toxicity to plants and earthworms as observed from data. Understanding the fate and removal of microplastics in wetland systems will help determine the reuse potential of wastewater and restrict the release of microplastics. This study provides information on various aspects and highlights future gaps and needs for MNP fate study in CW systems.

Prior Resection of the Primary Tumor Prolongs Survival After Peptide Receptor Radionuclide Therapy of Advanced Neuroendocrine Neoplasms.

OBJECTIVE: The aim of the study was to compare impact on survival after resection of primary tumors (PTs) after peptide receptor radionuclide therapy (PRRT). BACKGROUND: PRRT is a highly effective therapeutic option to treat locally advanced or metastatic neuroendocrine neoplasms (NENs). METHODS: We retrospectively analyzed the data of 889 patients with advanced NEN (G1-G3, stage IV) treated with at least 1 cycle of PRRT. In 486 of 889 patients (55%, group 1), PT had been removed before PRRT. Group 2 constituted 403 patients (45%) with no prior PT resection. Progression-free survival (PFS) and overall survival (OS) was determined by 68Ga SSTR-PET/CT in all patients applying RECIST and EORTC. RESULTS: Most patients had their PT in pancreas (n = 335; 38%) and small intestine (n = 284; 32%). Both groups received a mean of 4 cycles of PRRT (P = 0.835) with a mean cumulative administered radioactivity of 21.6 ±â€Š11.7 versus 22.2 ±â€Š11.2 GBq (P = 0.407). Median OS in group 1 was 134.0 months [confidence interval (CI): 118-147], whereas OS in group 2 was 67.0 months (CI: 60-80; hazard ratio 2.79); P < 0.001. Likewise, the median progression-free survival after first PRRT was longer in group 1 with 18.0 (CI: 15-20) months as compared to group 2 with 14.0 (CI: 15-18; hazard ratio 1.21) months; P = 0.012. CONCLUSIONS: A previous resection of the PT before PRRT provides a significant survival benefit in patients with NENs stage IV.

Prior therapies as prognostic factors of overall survival in metastatic castration-resistant prostate cancer patients treated with [177Lu]Lu-PSMA-617. A WARMTH multicenter study (the 617 trial).

INTRODUCTION: The impact of prior therapies, especially chemotherapy, on overall survival (OS) in patients with castration-resistant prostate cancer (CRPC) receiving [177Lu]Lu-PSMA-617 therapy has been the subject of controversy. Therefore, WARMTH decided to plan a multicenter retrospective analysis (the "617 trial") to evaluate response rate and OS as well as the impact of prior therapies on OS in more than 300 patients treated with 177Lu-PSMA-617. MATERIALS AND METHODS: The data of 631 metastatic CRPC (mCRPC) patients from 11 different clinics were evaluated. According to the inclusion and exclusion criteria, all patients had to have received at least abiraterone or enzalutamide prior to [177Lu]Lu-PSMA-617 therapy. The patients were divided into three groups: patients who had received prior chemotherapy, patients who avoided chemotherapy, and patients for whom a chemotherapy was contraindicated. RESULTS: The analysis included the data of 416 patients, with a median age of 71.9 years. At the time of analysis, 87 patients (20,9%) were still alive. A total of 53.6% of patients had received both abiraterone and enzalutamide; 75.5% and 26.4% had a history of chemotherapy with docetaxel and cabazitaxel, respectively. A total of 20.4% had had Ra-223. The median OS was 11.1 months. Prior chemotherapy, the existence of bone and liver metastases, as well as Eastern Cooperative Oncology Group (ECOG) status, were significant prognosticators of worse overall survival in both univariate and multivariate analyses. Patients without any prior chemotherapy showed a significantly longer OS (14.6 months). The median OS in patients who received one or two lines of chemotherapy with docetaxel or docetaxel followed by cabazitaxel, respectively, was 10.9 months and 8.9 months. There was no difference in OS between patients who had not received chemotherapy and patients for whom chemotherapy was contraindicated. The other prior therapies did not have any significant impact on OS. CONCLUSION: In the present multicenter analysis, chemotherapy-naïve mCRPC patients receiving [177Lu]Lu-PSMA-617 therapy had a significantly longer OS than patients with a history of chemotherapy. This remained independent in the multivariate analysis besides presence of bone and liver metastases as negative prognosticators for survival, whereas an ECOG of 0-1 is associated with a longer OS.

Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors.

BACKGROUND: Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. METHODS: We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. RESULTS: At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. CONCLUSIONS: Treatment with 177Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .).

Optimizing PSMA Radioligand Therapy for Patients with Metastatic Castration-Resistant Prostate Cancer. A Systematic Review and Meta-Analysis.

The aim of the review was to evaluate patient and treatment characteristics for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with PSMA radioligand therapy (PRLT) associated with above-average outcome. The systematic review and meta-analysis followed recommendations by the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA). We searched for publications in PubMed, Embase, and ClinicalTrials.gov up to 31 September 2020. Thirty-six publications and four duplicates reported 2346 patients. Nearly two-thirds of the patients had bone metastases. Median overall survival (OS) was 16 months. Asymptomatic patients and patients with only lymph node metastases lived longer than symptomatic patients and patients with more extensive metastases. Patients treated with an intensified schedule of 177Lu PRLT lived longer than those treated with a conventional schedule. Half of the patients obtained a PSA decline ≥ 50% and these patients lived longer than those with less PSA decline. Approximately 10% of the patients developed hematologic toxicity with anemia grade 3 as the most severe adverse effect. Characteristics for patients, cancer, restaging, and PRLT predict above average overall survival following treatment with PRLT.

Morphological and Functional Imaging for Detecting and Assessing the Resectability of Neuroendocrine Liver Metastases.

This review evaluates the diagnostic efficacy of different morphological and functional imaging modalities (ultrasound [US], computed tomography [CT], magnetic resonance [MR] imaging, scintigraphy, and positron emission tomography [PET]) in detecting neuroendocrine liver metastases (NELM), assessing vascular and biliary involvement, and the presence of extrahepatic disease. MR imaging is superior for depicting NELM compared to US, CT, and somatostatin receptor scintigraphy. Diffusion-weighted MR imaging is more sensitive for detecting NELM than both T2-weighted and dynamic gadolinium-enhanced MR sequences, and should be systematically performed. Similarly, gadoxetic acid-enhanced MR imaging is more sensitive for detecting liver metastases than conventional extracellular gadolinium chelate-enhanced MR sequences. Its role in detecting NELM remains investigational but appears promising. Somatostatin receptor-targeted PET/CT is a highly effective approach in assessing the resectability of well-differentiated NELM due to very high specificity (and high sensitivity) and its ability to detect small volume extrahepatic disease; this molecular imaging modality is becoming increasingly available in and outside Europe after the recent approval of 6868-DOTATATE in the US. In addition, the information from multiphase, contrast-enhanced CT with 3D reconstruction - obtained concurrently with the information on somatostatin receptor expression of the metastases - is very helpful in planning the extent and type of resection of NELM.

Investigating Fluorescent Organic-Matter Composition as a Key Predictor for Arsenic Mobility in Groundwater Aquifers.

Dissolved organic matter (DOM) is linked to the heterogeneous distribution of elevated arsenic (As) in groundwater used for drinking and irrigation purposes, but the relationship between DOM characteristics and arsenic mobility has yet to be fully understood. Here, DOM from groundwater sampled in the Bengal Basin region was characterized using both conventional bulk emission-excitation (EEM) spectroscopy and high-performance size-exclusion chromatography coupled to spectroscopy (HPSEC-EEM). Notably, application of the novel HPSEC-EEM approach permitted the total fluorescence of individual samples to be independently resolved into its underlying components. This allowed the external validation of the bulk-sample fluorescence decomposition and offered insight into the molecular size distribution of fluorescent DOM. Molecular size distributions were similar for the UVA fluorescent (C310 and C340) as well as the three visible fluorescent (C390, C440, and C500) components. There was a greater visible fluorescence in shallow aquifer samples (10-33 m) with high As (SH, up to 418 µg/L) than in samples from the same depth with lower As (up to 40 µg/L). This indicated a link between DOM quality and As mobility within the shallow aquifer. The deep aquifer samples (170-200 m) revealed DOM characteristics similar to SH samples but had low As concentrations (<4 µg/L), signifying that the deep aquifer is potentially vulnerable to As contamination. These findings pave the way for a more comprehensive assessment of the susceptibility of drinking water aquifers, thereby supporting the management of groundwater resources.

Water Recovery from Advanced Water Purification Facility Reverse Osmosis Concentrate by Photobiological Treatment Followed by Secondary Reverse Osmosis.

Reverse osmosis (RO)-based desalination and advanced water purification facilities have inherent challenges associated with concentrate management and disposal. Although enhanced permeate recovery and concentrate minimization are desired, membrane scaling due to inorganic constituents, such as silica, calcium, phosphate, and iron, hinders the process. To solve this problem, a new diatom-based photobiological process has been developed to remove these scaling constituents by biological uptake and precipitation. In this study, RO concentrate samples were collected from a full-scale advanced water reclamation facility in California and were treated in 3.8 and 57 L photobioreactors inoculated with a brackish water diatom  Pseudostaurosira trainorii PEWL001 using light-emitting diode bulbs or natural sunlight as a light source. The photobiological treatment removed 95% of reactive silica and 64% of calcium and enabled additional water recovery using a secondary RO at a recovery rate up to 66%. This represents 95% overall recovery, including 85% recovery in the primary RO unit. In addition to the scaling constituents, the photobiological treatment removed 12 pharmaceuticals and personal care products, as well as N-nitrosodimethylamine, from RO concentrate samples primarily via photolysis. This novel approach has a strong potential for application to brackish water desalination and advanced water purification in arid and semiarid areas.

Preclinical and first clinical experience with the gastrin-releasing peptide receptor-antagonist [68Ga]SB3 and PET/CT.

PURPOSE: Gastrin-releasing peptide receptors (GRPR) represent attractive targets for tumor diagnosis and therapy because of their overexpression in major human cancers. Internalizing GRPR agonists were initially proposed for prolonged lesion retention, but a shift of paradigm to GRPR antagonists has recently been made. Surprisingly, radioantagonists, such as [(99m)Tc]DB1 ((99m)Tc-N4'-DPhe(6),Leu-NHEt(13)]BBN(6-13)), displayed better pharmacokinetics than radioagonists, in addition to their higher inherent biosafety. We introduce here [(68)Ga]SB3, a [(99m)Tc]DB1 mimic-carrying, instead of the (99m)Tc-binding tetraamine, the chelator DOTA for labeling with the PET radiometal (68)Ga. METHODS: Competition binding assays of SB3 and [(nat)Ga]SB3 were conducted against [(125)I-Tyr(4)]BBN in PC-3 cell membranes. Blood samples collected 5 min postinjection (pi) of the [(67)Ga]SB3 surrogate in mice were analyzed using high-performance liquid chromatography (HPLC) for degradation products. Likewise, biodistribution was performed after injection of [(67)Ga]SB3 (37 kBq, 100 µL, 10 pmol peptide) in severe combined immunodeficiency (SCID) mice bearing PC-3 xenografts. Eventually, [(68)Ga]SB3 (283 ± 91 MBq, 23 ± 7 nmol) was injected into 17 patients with breast (8) and prostate (9) cancer. All patients had disseminated disease and had received previous therapies. PET/CT fusion images were acquired 60-115 min pi. RESULTS: SB3 and [(nat)Ga]SB3 bound to the human GRPR with high affinity (IC50: 4.6 ± 0.5 nM and 1.5 ± 0.3 nM, respectively). [(67)Ga]SB3 displayed good in vivo stability (>85 % intact at 5 min pi). [(67)Ga]SB3 showed high, GRPR-specific and prolonged retention in PC-3 xenografts (33.1 ± 3.9%ID/g at 1 h pi - 27.0 ± 0.9%ID/g at 24 h pi), but much faster clearance from the GRPR-rich pancreas (≈160%ID/g at 1 h pi to <17%ID/g at 24 h pi) in mice. In patients, [(68)Ga]SB3 elicited no adverse effects and clearly visualized cancer lesions. Thus, 4 out of 8 (50 %) breast cancer and 5 out of 9 (55 %) prostate cancer patients showed pathological uptake on PET/CT with [(68)Ga]SB3. CONCLUSION: [(67)Ga]SB3 showed excellent pharmacokinetics in PC-3 tumor-bearing mice, while [(68)Ga]SB3 PET/CT visualized lesions in about 50 % of patients with advanced and metastasized prostate and breast cancer. We expect imaging with [(68)Ga]SB3 to be superior in patients with primary breast or prostate cancer.

Peptide receptor radionuclide therapy with (90)Y/ (177)Lu-labelled peptides for inoperable head and neck paragangliomas (glomus tumours).

PURPOSE: Head and neck paragangliomas (HNPGLs) are rare tumours arising from autonomic nervous system ganglia. Although surgery offers the best chance of complete cure, there is associated morbidity due to the crucial location of these tumours. Radiotherapy arrests tumour growth and provides symptomatic improvement, but has long-term consequences. These tumours express somatostatin receptors (SSTR) and hence peptide receptor radionuclide therapy (PRRT) is now a treatment option. We assessed the molecular, morphological and clinical responses of inoperable HNPGLs to PRRT. METHODS: Nine patients with inoperable HNPGL assessed between June 2006 and June 2014 were included. Four patients had a solitary lesion, four had multifocal involvement and one had distant metastases (bone and lungs). The patients were treated with PRRT using (90)Y/(177)Lu-labelled peptides after positive confirmation of SSTR expression on (68)Ga-DOTATOC PET/CT. All patients received two to four courses of PRRT. Subsequent serial imaging with (68)Ga-DOTATOC PET/CT was carried out every 6 months to assess response to treatment. Clinical (symptomatic) response was also assessed. RESULTS: Based on molecular response (EORTC) criteria, four of the nine patients showed a partial molecular response to treatment seen as significant decreases in SUVmax, accompanied by a reduction in tumour size. Five patients showed stable disease on both molecular and morphological criteria. Six out of nine patients were symptomatic at presentation with manifestations of cranial nerve involvement, bone destruction at the primary site and metastatic bone pain. Molecular responses were correlated with symptomatic improvement in four out of these six patients; while two patients showed small reductions in tumour size and SUVmax. The three asymptomatic patients showed no new lesions or symptomatic worsening. CONCLUSION: PRRT was effective in all patients, with no disease worsening seen, either in the form of neurological symptoms or distant spread. Though these are preliminary results, PRRT shows promise as a good treatment option for HNPGL, and hence study in a larger patient cohort is essential to establish its place in the management algorithm.

Immune Response to Molecular Radiotherapy with 177Lu-DOTATOC: Predictive Value of Blood Cell Counts for Therapy Outcome.

Purpose: In a prior, retrospective study, 76% of patients with advanced neuroendocrine tumors undergoing 177Lu-DOTATOC molecular radiotherapy (MRT) showed their best response within 8 months from the first MRT cycle. In 24% of patients, latency was much greater up to >22 months after the first cycle, and long after near-complete decay of 177Lu from the last cycle. An immune response induced by MRT seems a likely explanation. As a crude measure of immunocompetence, the authors investigated whether blood cell counts (BCCs) may have predictive value for MRT outcome with 177Lu-DOTATOC. Methods: 56 Patients with neuroendocrine tumors (NET) were administered 177Lu-DOTATOC (mean 2.1 cycles; range 1-4) with median radioactivity of 7.0 GBq/cycle at 3-month intervals. Patients' BCCs were evaluated for four responder categories: CR, PR, SD, and PD (RECIST 1.1). Furthermore, baseline BCCs were correlated with progression-free survival (PFS). Finally, BCCs of patients with (PMT+) and without prior medical therapy (PMT-) were compared. Results: Significant differences between responder categories were found for baseline hemoglobin (Hb), erythrocytes, neutrophils, lymphocytes, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and LEHN-score, integrating lymphocyte, erythrocyte, and neutrophil counts, and Hb level, but not for leukocytes and platelets. LEHN-score yielded an almost complete separation between CR and PD groups. In analogy, PFS times showed significant correlations with baseline Hb, erythrocytes, neutrophils, lymphocytes, NLR, PLR, and LEHN-score, the LEHN-score showing the strongest correlation, but not with leukocytes and platelets. For PMT- patients, median PFS was 34.5 months, compared with 20.8 months in PMT+ patients, with corresponding baseline lymphocyte (32.1 ± 9.6% vs. 24.5 ± 11.6%, p = 0.028) and neutrophil (54.9 ± 11.6% vs. 63.5 ± 13.7%, p = 0.039) counts. Conclusion: These findings emphasize the significance of an immune response to MRT for obtaining optimal therapy efficacy and support concepts to enhance the immune response of less immunocompetent patients before MRT. It seems advisable to avoid prior or concomitant immunosuppressant medical therapy.

Rare metastases detected by (68)Ga-somatostatin receptor PET/CT in patients with neuroendocrine tumors.

AIM: The most common sites of metastasis in neuroendocrine tumors are liver, lymph nodes, and bone. The aim of this study is to determine the prevalence and location of other sites of metastasis. METHODS: 4,210 Ga-68 somatostatin-receptor PET/CT studies were performed at our center between July 2004 and December 2009. We retrospectively reviewed the reports of patients to check rare sites of metastasis other than liver, bone, and lymph nodes. Lesions were confirmed on follow-up and/or other imaging methods (MRI, echocardiography, and ultrasound). RESULTS: The different sites of metastasis according to frequency of occurrence were: cardiac (n = 29), breast (n = 21), retro-orbital (n = 9), uterus (n = 7), skin (n = 8), brain (n = 6), spleen (n = 3), testes (n = 1), seminal vesicle (n = 1), and intramuscular in psoas muscle (n = 4). CONCLUSIONS: Cardiac and breast metastases appear to be not infrequent in neuroendocrine tumor patients. Ga-68 somatostatin-receptor PET/CT enables detection of these and other rare sites of metastasis.

Peptide receptor radionuclide therapy with (177)Lu labeled somatostatin analogs DOTATATE and DOTATOC: contrasting renal dosimetry in the same patient.

AIM: The aim of this study is to correlate the uptake, residence time, and resulting mean absorbed dose in the kidneys with the posttherapy effect on renal function using the two most commonly used somatostatin analogs, (177)Lu-DOTATATE and (177)Lu-DOTATOC, during consecutive cycles of peptide receptor radionuclide therapy (PRRNT) in the same patient. METHODS: 22 patients with metastatic neuroendocrine tumors underwent PRRNT with (177)Lu-DOTATATE and (177)Lu-DOTATOC. Dosimetry (MIRD scheme) was performed using OLINDA software. The patients were followed up for 6-12 months with serum creatinine, BUN, tubular extraction rate (TER) using (99m)Tc-MAG3, and glomerular filtration rate (GFR) using (99m)Tc-DTPA before and after therapy. Age, hypertension, and diabetes mellitus were the associated risk factors for renal toxicity, which were taken into account. RESULTS: Uptake, residence time, and mean absorbed dose to the kidney were slightly, but significantly, higher for DOTATATE (actual absorbed dose 1.9-9.2 Gy) as compared with DOTATOC (dose 2.3-7.8 Gy) in 19 out of the 22 (86%) patients (p < 0.05). The tumor-to-kidney ratio was higher for DOTATOC in 23 out of 43 (53%) of the lesions analyzed; however, this difference was not statistically significant. There were no statistically significant changes in serum creatinine, BUN, TER or GFR pre and post-therapy with either DOTATATE or DOTATOC. Five of the 22 patients had mildly elevated serum creatinine after PRRNT, of whom 3 had history of hypertension, 1 had diabetes, and 1 was more than 65 years of age. CONCLUSIONS: (177)Lu-DOTATATE and (177)Lu-DOTATOC are safe radiopharmaceuticals concerning renal toxicity. (177)Lu-DOTATOC delivers a slightly, but significantly, lower renal dose.

High uptake of (68)Ga-DOTATOC in spleen as compared to splenosis: measurement by PET/CT.

AIM: The aim of this study is to ascertain the high somatostatin receptor (SSTR) uptake in spleen and to compare the uptake in spleen and splenosis using SSTR PET/CT using( 68)Ga-DOTATOC. MATERIALS AND METHODS: SUV(max) of spleen on (68)Ga-DOTATOC SSTR PET/CT (acquired for initial staging) in 10 patients with known neuroendocrine neoplasm of pancreatic tail was analyzed. All patients underwent left pancreatectomy and splenectomy. Diagnosis of splenosis was confirmed on CT, and SUV(max) was noted on follow-up SSTR PET/CT. RESULTS: SUV(max)was 28.8 ± 12.5 in normal spleen and 10.5 ± 4.3 in splenosis. CONCLUSION: The high uptake of( 68)Ga-DOTATOC (which has a high affinity to SSTR 2) in the spleen as compared to splenosis, which has a different histology, suggests white pulp as the probable site of high SSTR 2 expression.

Is there a correlation between peptide receptor radionuclide therapy-associated hematological toxicity and spleen dose?

AIM: The spleen receives a high mean absorbed radiation dose during peptide receptor radionuclide therapy (PRRNT). The aim of this study is to correlate the radiation dose to spleen with the effect on blood cell count after PRRNT. METHODS: Fifty-three neuroendocrine tumor (NET) patients were treated with 3.8-8.5 GBq (177)Lu-DOTATATE or (177)Lu-DOTATOC. Dosimetry was performed according to MIRD scheme. Eleven NET patients who had undergone splenectomy before PRRNT and who received 4.7-7.6 GBq (177)Lu-DOTATATE or (177)Lu-DOTATOC were selected as controls. RBC, WBC (total and differential), and platelet counts before and after each cycle of PRRNT were documented. RESULTS: The median dose to the spleen in the study group was 6.34 Gy (2.32-20.06 Gy). There was no significant difference in the posttherapy changes in the blood cell counts (RBC, WBC, or platelets) between the study group and the control group. Mild hematological toxicity was found in 7 of the 53 (13.2%) patients in the study group and in 1 out of the 11 patients (9.1%) in the control group. However, there was no correlation between the incidence or grade of hematological toxicity and the dose to the spleen. CONCLUSION: This study demonstrates for the first time that hematological toxicity after PRRNT is not related to the radiation dose to the spleen.

The Bad Berka dose protocol: comparative results of dosimetry in peptide receptor radionuclide therapy using (177)Lu-DOTATATE, (177)Lu-DOTANOC, and (177)Lu-DOTATOC.

PURPOSE: The objective of this study is to analyze the in vivo behavior of the (177)Lu-labeled peptides DOTATATE, DOTANOC, and DOTATOC used for peptide receptor radionuclide therapy (PRRNT) of neuroendocrine tumors (NETs), by measuring organ and tumor kinetics and by performing dosimetric calculations. METHODS: Two hundred fifty-three patients (group 1) with metastasized NET who underwent PRRNT were examined. Out of these, 185 patients received (177)Lu-DOTATATE, 9 were treated with (177)Lu-DOTANOC, and 59 with (177)Lu-DOTATOC. Additionally, 25 patients receiving, in consecutive PRRNT cycles, DOTATATE followed by DOTATOC (group 2) and 3 patients receiving DOTATATE and DOTANOC (group 3) were analyzed. Dosimetric calculations (according to MIRD scheme) were performed using OLINDA software. RESULTS: In group 1, DOTATOC exhibited the lowest and DOTANOC the highest uptake and therefore mean absorbed dose in normal organs (whole body, kidney, and spleen). In group 2, there was a significant difference between DOTATATE and DOTATOC concerning kinetics and normal organ doses. (177)Lu-DOTATOC had the lowest uptake/dose delivered to normal organs and highest tumor-to-kidney ratio. There were no significant differences between the three peptides concerning tumor kinetics and mean absorbed tumor dose. CONCLUSIONS: The study demonstrates a correlation between high affinity of DOTANOC in vitro and high uptake in normal organs/whole body in vivo, resulting in a higher whole-body dose. DOTATOC exhibited the lowest uptake and dose delivered to normal tissues and the best tumor-to-kidney ratio. Due to large interpatient variability, individual dosimetry should be performed for each therapy cycle.

Peptide Receptor Radionuclide Therapy in Patients With Advanced Progressive Medullary Thyroid Cancer: Efficacy, Safety, and Survival Predictors.

PURPOSE: Progressive metastatic medullary thyroid carcinoma (MTC) is often characterized by rapid disease progression and poor prognosis, with only few therapeutic options available. Peptide receptor radionuclide therapy (PRRT) has demonstrated remarkable success in the management of gastroenteropancreatic neuroendocrine tumors and has also been suggested to treat MTC. However, evidence on its effectiveness and long-term outcome for this indication is still limited. The objective of this study was to assess the safety and efficacy of PRRT in patients with advanced, progressive MTC and to determine survival. Potential predictors of survival were also evaluated. METHODS: From September 2003 to June 2019, 28 patients (15 men and 13 women; mean age, 49 ± 14 years) with progressive, somatostatin receptor-positive advanced MTC received PRRT with 177Lu- or 90Y-labeled somatostatin analogs at Zentralklinik Bad Berka, Germany. Toxicity was graded according to Common Terminology Criteria for Adverse Events version 5.0. Treatment response was evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) 1.1, as well as molecular imaging criteria (European Organisation for Research and Treatment of Cancer). Kaplan-Meier analysis was used to calculate progression-free survival (PFS) and overall survival (OS), defined from the start of PRRT. Univariate and multivariate Cox regression analyses were performed to identify parameters associated with PFS and OS. RESULTS: Seventy-seven cycles of PRRT were administered (mean cumulative administered activity, 16.0 ± 7.8 GBq). No acute or long-term grade 3/4 toxicity was recorded with a follow-up of 3 to 140 months, except for 1 patient (4%) who suffered from grade 3 anemia (possibly related to disease progression). According to the RECIST criteria, the disease control rate after 3 to 4 months of PRRT was 56% (partial remission, 12%; stable disease, 44%). The disease control rate (72%) was higher by molecular response evaluation. Median OS and PFS were 63.7 and 10.1 months, respectively. The annual OS rates were 84% at 1 year, 65% at 3 years, 57% at 5 years, and 18% at 10 years. The annual PFS rates were 42% at 1 year, 21% at 2 years, and 13% at 5 years. Patients with bone metastases had poorer OS and PFS than those without metastases (median OS, 58.7 vs 92.3 months [P = 0.035; hazard ratio, 2.7; 95% confidence interval, 0.92-7.84]; median PFS, 8.5 vs 12.8 months [P = 0.592; hazard ratio, 1.2; 95% confidence interval, 0.56-2.76]). CONCLUSIONS: Peptide receptor radionuclide therapy was well tolerated and effective in patients with advanced, aggressive MTC. Bone metastasis was an independent adverse prognostic factor for OS.

Prostate-Specific Membrane Antigen Radioligand Therapy Using 177Lu-PSMA I&T and 177Lu-PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer: Comparison of Safety, Biodistribution, and Dosimetry.

The objective of this study was to determine the safety, kinetics, and dosimetry of the 177Lu-labeled prostate-specific membrane antigen (PSMA) small molecules 177Lu-PSMA I&T and 177Lu-PSMA-617 in a large cohort of patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing PSMA radioligand therapy (PRLT). Methods: In total, 138 patients (mean age, 70 ± 9 y; age range, 46-90 y) with progressive mCRPC and PSMA expression verified by 68Ga-PSMA-11 PET/CT underwent PRLT. Fifty-one patients received 6.1 ± 1.0 GBq (range, 3.4-7.6 GBq) of 177Lu-PSMA I&T, and 87 patients received 6.5 ± 1.1 GBq (range, 3.5-9.0 GBq) of 177Lu-PSMA-617. Dosimetry was performed on all patients using an identical protocol. The mean absorbed doses were estimated with OLINDA software (MIRD Scheme). Treatment-related adverse events were graded according to the Common Terminology Criteria for Adverse Events, version 5.0, of the National Cancer Institute. Results: The whole-body half-lives were shorter for 177Lu-PSMA I&T (35 h) than for 177Lu-PSMA-617 (42 h). The mean whole-body dose of 177Lu-PSMA-617 was higher than that of 177Lu-PSMA I&T (0.04 vs. 0.03 Gy/GBq, P < 0.00001). Despite the longer half-life of 177Lu-PSMA-617, the renal dose was lower for 177Lu-PSMA-617 than for 177Lu-PSMA I&T (0.77 vs. 0.92 Gy/GBq, P = 0.0015). Both PSMA small molecules demonstrated a comparable dose to the parotid glands (0.5 Gy/GBq, P = 0.27). Among all normal organs, the lacrimal glands exhibited the highest mean absorbed doses, 5.1 and 3.7 Gy/GBq, for 177Lu-PSMA-617 and 177Lu-PSMA I&T, respectively. All tumor metastases exhibited a higher initial uptake when using 177Lu-PSMA I&T than when using 177Lu-PSMA-617, as well as a shorter tumor half-life (P < 0.00001). The mean absorbed tumor doses were comparable for both 177Lu-PSMA I&T and 177Lu-PSMA-617 (5.8 vs. 5.9 Gy/GBq, P = 0.96). All patients tolerated the therapy without any acute adverse effects. After 177Lu-PSMA-617 and 177Lu-PSMA I&T, there was a small, statistically significant reduction in hemoglobin, leukocyte counts, and platelet counts that did not need any clinical intervention. No nephrotoxicity was observed after either 177Lu-PSMA I&T or 177Lu-PSMA-617 PRLT. Conclusion: Both 177Lu-PSMA I&T and 177Lu-PSMA-617 PRLT demonstrated favorable safety in mCRPC patients. The highest absorbed doses among healthy organs were in the lacrimal and parotid glands-not, however, resulting in any significant clinical sequel. 177Lu-PSMA-617 demonstrated a higher absorbed dose to the whole-body and lacrimal glands but a lower renal dose than did 177Lu-PSMA I&T. The mean absorbed tumor doses were comparable for both 177Lu-PSMA I&T and 177Lu-PSMA-617. There was a large interpatient variability in the dosimetry parameters. Therefore, individual patient-based dosimetry seems favorable for personalized PRLT.

Salivary Gland Toxicity of PSMA-Targeted Radioligand Therapy with 177Lu-PSMA and Combined 225Ac- and 177Lu-Labeled PSMA Ligands (TANDEM-PRLT) in Advanced Prostate Cancer: A Single-Center Systematic Investigation.

Purpose: PSMA-targeted radioligand therapy (PRLT) is a promising treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). However, a high uptake of the radiopharmaceutical in the salivary glands (SG) can lead to xerostomia and becomes dose-limiting for 225Ac-PSMA-617. This study investigated the sialotoxicity of 177Lu-PSMA-I&T/-617 monotherapy and co-administered 225Ac-PSMA-617 and 177Lu-PSMA-617 (Tandem-PPRLT). Methods: Three patient cohorts, that had undergone 177Lu-PSMA-I&T/-617 monotherapy or Tandem-PRLT, were retrospectively analyzed. In a short-term cohort (91 patients), a xerostomia assessment (CTCAE v.5.0), a standardized questionnaire (sXI), salivary gland scintigraphy (SGS), and SG SUVmax and the metabolic volume (MV) on 68Ga-PSMA-11-PET/CT were obtained before and after two cycles of 177Lu-PSMA-I&T/-617. In a long-term cohort, 40 patients were similarly examined. In a Tandem cohort, the same protocol was applied to 18 patients after one cycle of Tandem-PRLT. Results: Grade 1 xerostomia in the short-term follow-up was observed in 22 (24.2%) patients with a worsening of sXI from 7 to 8 at (p < 0.05). In the long-term cohort, xerostomia grades 1 to 2 occurred in 16 (40%) patients. SGS showed no significant changes, but there was a decline of the MV of all SGs. After Tandem-PRLT, 12/18 (66.7%) patients reported xerostomia grades 1 to 2, and the sXI significantly worsened from 9.5 to 14.0 (p = 0.005), with a significant reduction in the excretion fraction (EF) and MV of all SGs. Conclusion: 177Lu-PSMA-I&T/-617 causes only minor SG toxicity, while one cycle of Tandem-PRLT results in a significant SG impairment. This standardized protocol may help to objectify and quantify SG dysfunction.