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Prospective Comparison of PET Imaging with PSMA-Targeted 18F-DCFPyL Versus Na18F for Bone Lesion Detection in Patients with Metastatic Prostate Cancer.
Rowe, SP, Li, X, Trock, BJ, Werner, RA, Frey, S, DiGianvittorio, M, Bleiler, JK, Reyes, DK, Abdallah, R, Pienta, KJ, et al
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2020;(2):183-188
Abstract
Bone metastases in prostate cancer (PCa) have important prognostic significance, and imaging modalities used for PCa staging should have high sensitivity for detecting such lesions. Prostate-specific membrane antigen (PSMA)-targeted PET radiotracers are promising new agents for imaging PCa. We undertook a head-to-head comparison of PSMA-targeted 2-(3-{1-carboxy-5-[(6-18F-fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyL) PET to Na18F PET to determine which modality was more sensitive for the detection of lesions suggestive of bone metastases in a group of patients with metastatic PCa. Methods: Patients with progressive, metastatic PCa were prospectively imaged with both 18F-DCFPyL and Na18F PET/CT, with both scans occurring within 24 h of each other. A consensus 2-reader central review was performed to identify all bone lesions suggestive of sites of PCa involvement on both scans, and maximized SUVs corrected for body weight (SUVmax) and lean body mass (SULmax) were recorded. Soft-tissue lesions were also noted on both scans, and SUVmax, SULmax, and PSMA reporting and data system (RADS) version 1.0 scores were recorded. Data from the 2 scans were compared using a generalized estimating equation. Results: In total, 16 patients meeting all inclusion criteria were enrolled in this study, and 15 of the 16 (93.8%) were imaged with both PET radiotracers. In total, 405 bone lesions suggestive of sites of PCa were identified on at least 1 scan. On 18F-DCFPyL PET/CT, 391 (96.5%) were definitively positive, 4 (1.0%) were equivocally positive, and 10 (2.5%) were negative. On Na18F PET/CT, the corresponding values were 388 (95.8%), 4 (1.0%), and 13 (3.2%). Of the definitively negative lesions on 18F-DCFPyL PET, 8 of 10 (80.0%) were sclerotic and 2 of 10 (20.0%) were infiltrative or marrow-based. Additionally, 12 of 13 (92.3%) of the definitively negative lesions on Na18F PET were infiltrative or marrow-based and 1 of 13 (7.7%) was lytic. Also identified were 78 PSMA-RADS-4, 17 PSMA-RADS-5, and 1 PSMA-RADS-3C soft-tissue lesions. Conclusion: PET/CT imaging using 18F-DCFPyL and Na18F PET had nearly identical sensitivities for the detection of bone lesions in patients with metastatic PCa. As would be expected, PSMA-targeted PET provides more information on soft-tissue disease. There may be little additional value to imaging PCa patients with Na18F after a PSMA-targeted PET scan has already been performed.
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Intraindividual Comparison of 18F-PSMA-1007 and 18F-DCFPyL PET/CT in the Prospective Evaluation of Patients with Newly Diagnosed Prostate Carcinoma: A Pilot Study.
Giesel, FL, Will, L, Lawal, I, Lengana, T, Kratochwil, C, Vorster, M, Neels, O, Reyneke, F, Haberkon, U, Kopka, K, et al
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2018;(7):1076-1080
Abstract
The introduction of 18F-labeled prostate-specific membrane antigen (PSMA)-targeted PET/CT tracers, first 18F-DCFPyL (2-(3-{1-carboxy-5-[(6-18F-fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid) and more recently 18F-PSMA-1007 (((3S,10S,14S)-1-(4-(((S)-4-carboxy-2-((S)-4-carboxy-2-(6-18F-fluoronicotinamido)butanamido)butanamido)methyl)phenyl)-3-(naphthalen-2-ylmethyl)-1,4,12-trioxo-2,5,11,13-tetraazahexadecane-10,14,16-tricarboxylic acid)), have demonstrated promising results for the diagnostic workup of prostate cancer. This clinical study presents an intraindividual comparison to evaluate tracer-specific characteristics of 18F-DCFPyL versus 18F-PSMA-1007. Methods: Twelve prostate cancer patients, drug-naïve or before surgery, received similar activities of about 250 MBq of 18F-DCFPyL and 18F-PSMA-1007 48 h apart and were imaged 2 h after injection on the same PET/CT scanner using the same reconstruction algorithm. Normal-organ biodistribution and tumor uptake were quantified using SUVmaxResults: PSMA-positive lesions were detected in 12 of 12 prostate cancer patients. Both tracers, 18F-DCFPyL and 18F-PSMA-1007, detected the same lesions. No statistical significance could be observed when comparing the SUVmax of 18F-DCFPyL and 18F-PSMA-1007 for local tumor, lymph node metastases, and bone metastases. With regard to normal organs, 18F-DCFPyL had statistically significant higher uptake in kidneys, urinary bladder, and lacrimal gland. Vice versa, significantly higher uptake of 18F-PSMA-1007 in muscle, submandibular and sublingual gland, spleen, pancreas, liver, and gallbladder was observed. Conclusion: Excellent imaging quality was achieved with both 18F-DCFPyL and 18F-PSMA-1007, resulting in identical clinical findings for the evaluated routine situations. Nonurinary excretion of 18F-PSMA-1007 might present some advantage with regard to delineation of local recurrence or pelvic lymph node metastasis in selected patients; the lower hepatic background might favor 18F-DCFPyL in late stages, when rare cases of liver metastases can occur.
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Ammonia control in children with urea cycle disorders (UCDs); phase 2 comparison of sodium phenylbutyrate and glycerol phenylbutyrate.
Lichter-Konecki, U, Diaz, GA, Merritt, JL, Feigenbaum, A, Jomphe, C, Marier, JF, Beliveau, M, Mauney, J, Dickinson, K, Martinez, A, et al
Molecular genetics and metabolism. 2011;(4):323-9
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UNLABELLED Twenty four hour ammonia profiles and correlates of drug effect were examined in a phase 2 comparison of sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB or HPN-100), an investigational drug being developed for urea cycle disorders (UCDs). STUDY DESIGN Protocol HPN-100-005 involved open label fixed-sequence switch-over from the prescribed NaPBA dose to a PBA-equimolar GPB dose with controlled diet. After 7 days on NaPBA or GPB, subjects underwent 24-hour blood sampling for ammonia and drug metabolite levels as well as measurement of 24-hour urinary phenyacetylglutamine (PAGN). Adverse events (AEs), safety labs and triplicate ECGs were monitored. RESULTS Eleven subjects (9 OTC, 1 ASS, 1 ASL) enrolled and completed the switch-over from NaPBA (mean dose=12.4 g/d or 322 mg/kg/d; range=198-476 mg/kg/d) to GPB (mean dose=10.8 mL or 0.284 mL/kg/d or 313 mg/kg/d; range=192-449 mg/kg/d). Possibly-related AEs were reported in 2 subjects on NaPBA and 4 subjects on GPB. All were mild, except for one moderate AE of vomiting on GPB related to an intercurrent illness. No clinically significant laboratory or ECG changes were observed. Ammonia was lowest after overnight fast, peaked postprandially in the afternoon to early evening and varied widely over 24h with occasional values >100 μmol/L without symptoms. Ammonia values were ~25% lower on GPB vs. NaPBA (p≥0.1 for ITT and p<0.05 for per protocol population). The upper 95% confidence interval for the difference between ammonia on GPB vs. NaPBA in the ITT population (95% CI 0.575, 1.061; p=0.102) was less than the predefined non-inferiority margin of 1.25 and less than 1.0 in the pre-defined per-protocol population (95% CI 0.516, 0.958; p<0.05). No statistically significant differences were observed in plasma phenylacetic acid and PAGN exposure during dosing with GPB vs. NaPBA, and the percentage of orally administered PBA excreted as PAGN (66% for GPB vs. 69% for NaPBA) was very similar. GPB and NaPBA dose correlated best with urinary-PAGN. CONCLUSIONS These findings suggest that GPB is at least equivalent to NaPBA in terms of ammonia control, has potential utility in pediatric UCD patients and that U-PAGN is a clinically useful biomarker for dose selection and monitoring.
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N-carbamylglutamate markedly enhances ureagenesis in N-acetylglutamate deficiency and propionic acidemia as measured by isotopic incorporation and blood biomarkers.
Tuchman, M, Caldovic, L, Daikhin, Y, Horyn, O, Nissim, I, Nissim, I, Korson, M, Burton, B, Yudkoff, M
Pediatric research. 2008;(2):213-7
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N-acetylglutamate (NAG) is an endogenous essential cofactor for conversion of ammonia to urea in the liver. Deficiency of NAG causes hyperammonemia and occurs because of inherited deficiency of its producing enzyme, NAG synthase (NAGS), or interference with its function by short fatty acid derivatives. N-carbamylglutamate (NCG) can ameliorate hyperammonemia from NAGS deficiency and propionic and methylmalonic acidemia. We developed a stable isotope (13)C tracer method to measure ureagenesis and to evaluate the effect of NCG in humans. Seventeen healthy adults were investigated for the incorporation of (13)C label into urea. [(13)C]urea appeared in the blood within minutes, reaching maximum by 100 min, whereas breath (13)CO(2) reached a maximum by 60 min. A patient with NAGS deficiency showed very little urea labeling before treatment with NCG and normal labeling thereafter. Correspondingly, plasma levels of ammonia and glutamine decreased markedly and urea tripled after NCG treatment. Similarly, in a patient with propionic acidemia, NCG treatment resulted in a marked increase in urea labeling and decrease in glutamine, alanine, and glycine. These results provide a reliable method for measuring the effect of NCG on nitrogen metabolism and strongly suggest that NCG could be an effective treatment for inherited and secondary NAGS deficiency.
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Survival after treatment with phenylacetate and benzoate for urea-cycle disorders.
Enns, GM, Berry, SA, Berry, GT, Rhead, WJ, Brusilow, SW, Hamosh, A
The New England journal of medicine. 2007;(22):2282-92
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BACKGROUND The combination of intravenous sodium phenylacetate and sodium benzoate has been shown to lower plasma ammonium levels and improve survival in small cohorts of patients with historically lethal urea-cycle enzyme defects. METHODS We report the results of a 25-year, open-label, uncontrolled study of sodium phenylacetate and sodium benzoate therapy (Ammonul, Ucyclyd Pharma) in 299 patients with urea-cycle disorders in whom there were 1181 episodes of acute hyperammonemia. RESULTS Overall survival was 84% (250 of 299 patients). Ninety-six percent of the patients survived episodes of hyperammonemia (1132 of 1181 episodes). Patients over 30 days of age were more likely than neonates to survive an episode (98% vs. 73%, P<0.001). Patients 12 or more years of age (93 patients), who had 437 episodes, were more likely than all younger patients to survive (99%, P<0.001). Eighty-one percent of patients who were comatose at admission survived. Patients less than 30 days of age with a peak ammonium level above 1000 micromol per liter (1804 microg per deciliter) were least likely to survive a hyperammonemic episode (38%, P<0.001). Dialysis was also used in 56 neonates during 60% of episodes and in 80 patients 30 days of age or older during 7% of episodes. CONCLUSIONS Prompt recognition of a urea-cycle disorder and treatment with both sodium phenylacetate and sodium benzoate, in conjunction with other therapies, such as intravenous arginine hydrochloride and the provision of adequate calories to prevent catabolism, effectively lower plasma ammonium levels and result in survival in the majority of patients. Hemodialysis may also be needed to control hyperammonemia, especially in neonates and older patients who do not have a response to intravenous sodium phenylacetate and sodium benzoate.
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Use of [14C]-sodium bicarbonate/urea to measure physical activity induced increases in total energy expenditure in free-living healthy males.
Roffey, DM, Luscombe, ND, Byrne, NM, Hills, AP, Bellon, M, Tsopelas, C, Kirkwood, ID, Wittert, GA
Asia Pacific journal of clinical nutrition. 2005;(1):83-90
Abstract
The aim of this study was to evaluate the utility of the [(14)C]-sodium bicarbonate/urea technique to detect physical activity-induced increases in total energy expenditure in free-living healthy men. Thirteen healthy males aged 34.1 +/- 11.7 yrs with body mass index 24.1 +/- 3.1 kg/m(2) were studied on three separate occasions, during which [(14)C]-bicarbonate was infused over 48-hours and urine was collected during the second 24-hours. On three separate occasions and in random order, subjects either remained sedentary, or performed a bout of physical activity on an electro-magnetically braked cycle ergometer sufficient to increase energy expenditure by 7% or 11% above predicted sedentary total energy expenditure. Urine samples were analyzed to evaluate the amount of [(14)C]-bicarbonate incorporated into urinary urea, thereby reflecting the amount of CO(2) produced per day, and upon conversion, the number of kilojoules of energy expended in 24-hours. All 13 subjects successfully completed the two physical activity treatments and there were no adverse events. As measured by the [(14)C]-urea assay, mean total energy expenditure values were not significantly different between sedentary activity (17902 +/- 905 kJ/day), the physical activity treatment designed to increase TEE by 7% (17701 +/- 594 kJ/day) and the physical activity treatment designed to increase TEE by 11% (18538 +/- 485 kJ/day) (P=0.668). In conclusion, although the [(14)C]-sodium bicarbonate/urea technique was well tolerated and did not interfere with normal daily activities, it was not able to accurately measure physical activity-induced increases in EE in the range of 7-11% above predicted sedentary total energy expenditure.
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Postprandial metabolic utilization of wheat protein in humans.
Bos, C, Juillet, B, Fouillet, H, Turlan, L, Daré, S, Luengo, C, N'tounda, R, Benamouzig, R, Gausserès, N, Tomé, D, et al
The American journal of clinical nutrition. 2005;(1):87-94
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BACKGROUND The quality of cereal protein has been little studied in humans despite its quantitative importance in the diet, particularly in developing countries. OBJECTIVE The objective of this study was to determine the nutritional value of wheat protein in humans as assessed by the measurement of their real ileal digestibility and postprandial retention. DESIGN Healthy young adults (n = 14) were fitted with an intestinal tube to allow the collection of intestinal fluid in the duodenum or terminal ileum. Subjects received a mixed meal of 136 g wheat toast that contained 24.6 g uniformly and intrinsically [(15)N]-labeled wheat protein. Intestinal fluid, blood, and urine were collected for 8 h postprandially. RESULTS The real ileal digestibility of dietary wheat nitrogen amounted to 90.3 +/- 4.3%. The cumulative amount of dietary nitrogen transferred to the deamination pools reached a plateau at 8 h of 24.7 +/- 6.8% of the amount ingested. The urinary excretion of dietary nitrogen in ammonia was high (0.8 +/- 0.3% of ingested dose). The incorporation of dietary nitrogen into serum protein reached 7.0 +/- 1.9% of the meal. Postprandial wheat protein retention was 66.1 +/- 5.8%. CONCLUSIONS Our results show that wheat proteins had the same true ileal digestibility as did most of the plant proteins already studied in humans, but also that they had a lower postprandial nitrogen retention value. However, this low value was higher than that predicted from the calculation of indispensable amino acid scores, ie, 89% rather than 30-40% of the nutritional value of milk proteins.
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Ureagenesis: evidence for a lack of hepatic regulation of acid-base equilibrium in humans.
Hosch, M, Muser, J, Hulter, HN, Krapf, R
American journal of physiology. Renal physiology. 2004;(1):F94-9
Abstract
Ureagenesis in the liver consumes up to 1,000 mmol of HCO3-/day in humans as a result of 2NH4+ + 2HCO3- --> urea + CO2 + 3H2O. Whether the liver contributes to the regulation of acid-base equilibrium by controlling the rate of ureagenesis and, therefore, HCO3- consumption in response to changes in plasma acidity has not been adequately evaluated in humans. Rates of ureagenesis were measured in eight healthy volunteers during control, chronic metabolic acidosis (induced by oral administration of CaCl2 3.2 mmol.kg body wt-1.day-1 for 11 days), and recovery as well as during bicarbonate infusion (200 mmol over 240 min; acute metabolic alkalosis). Rates of ureagenesis were correlated negatively with plasma HCO3- concentration both during adaption to metabolic acidosis and during the chronic, steady-state phase. Thus ureagenesis, an acidifying process, increased rather than decreased in metabolic acidosis. During bicarbonate infusion, rates of ureagenesis decreased significantly. Thus ureagenesis did not appear to be involved in the regulated elimination of excess HCO3-. The finding of a negative correlation between ureagenesis and plasma HCO3- concentration over a wide range of HCO3- concentrations, altered both chronically and acutely, suggests that the ureagenic process per se is maladaptive for acid-base regulation and that ureagenesis has no discernible homeostatic effect on acid-base equilibrium.
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13C urea breath test (UBT) in the diagnosis of Helicobacter pylori: why does it work better with acid test meals?
Pantoflickova, D, Scott, DR, Sachs, G, Dorta, G, Blum, AL
Gut. 2003;(7):933-7
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BACKGROUND Acid test meals may improve the accuracy of the (13)C urea breath test (UBT). This has been attributed to changes in gastric emptying rather than to the effects of gastric pH on Helicobacter pylori urease. AIMS To determine whether enhancement of (13)CO(2) excretion in the UBT in H pylori infected volunteers by acidification of a test meal is due to a delay in gastric emptying. METHODS Urease activity in vitro was measured in intact bacteria and in bacterial homogenates. Urease activity in vivo was assessed by means of the UBT. Eleven H pylori infected subjects underwent UBTs with neutral Ensure (pH 7.0), acidified Ensure (pH 3.0), and apple juice (pH 3.0). Gastric emptying was assessed by (13)C sodium acetate breath test. RESULTS From pH 7 to pH 3, the in vitro urease activity of intact bacteria increased sixfold. In contrast, urease activity of bacterial homogenates was inactivated by low pH. In vivo, urease activity, as measured by the UBT 20 minutes after meal ingestion, was higher with apple juice (delta (13)CO(2)=21.1; p=0.03) and acidified Ensure (delta (13)CO(2)=25.5; p=0.01) than with neutral Ensure (delta (13)CO(2)=12.5). Gastric emptying was faster with apple juice (T(max)=36.7 (8) minutes) but not with acidified Ensure (T(max)=63.3 (5) minutes; p=0.06) than with neutral Ensure (T(max)=65.0 (3) minutes; p=0.04). CONCLUSIONS The higher UBT found with acidified compared with neutral test meals was independent of the emptying rates of the test meals but may have been due to medium acidity dependent activation of intra-bacterial urease in intact H pylori.
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Estimating phosphate removal in haemodialysis: an additional tool to quantify dialysis dose.
Gutzwiller, JP, Schneditz, D, Huber, AR, Schindler, C, Gutzwiller, F, Zehnder, CE
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2002;(6):1037-44
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BACKGROUND Half of the dialysis population suffers from hyperphosphataemia, which is now recognized as a major factor of haemodialysis (HD) morbidity and mortality. Current control is focussed on reducing dietary phosphate intake and diminishing absorption using phosphate binders, whereas control and quantification of phosphate removal by HD is undervalued. The aim of this prospective study was to develop a simple, bedside formula to estimate dialytic phosphate removal in stable HD patients. METHODS This was a prospective, randomized trial. Phosphate and urea elimination were assessed in a representative group of patients at two dialysis centres using randomly different dialysers (1.3-2.4 m(2)). Quantification was performed by partial dialysate collection, concentration measurements in blood and effluent dialysate spot samples, and Kt/V(urea) during standard high-flux HD. Multiple linear regression analyses were used in 77% of all data sets to generate an equation to predict phosphate removal. The formula was validated in the remaining 23% of data sets, in the same group of patients using a large capillary filter, and in diabetic patients treated with a small dialyser at different blood flows (200, 250, and 300 ml/min). RESULTS A formula allowing quantification of phosphate removal within one HD session was developed in 18 of 74 patients during 41 treatments (137 out of 177 data sets) and was determined as: M(PO4pred)=0.1t -17+50c(ds60)+11c(b60), where t is treatment time in min, c(ds60) and c(b60) are phosphate concentrations in dialysate and plasma measured 60 min into HD in mmol/l, and M(PO4pred) is estimated phosphate removed in mmol. The precision was remarkable (r(2)=0.92-0.94). The comparison of phosphate and Kt/V(urea) showed a significant association (r(2)=0.28), albeit with remarkable scatter. CONCLUSIONS We present the first approach to quantify phosphate removal during high-flux HD by a bedside formula. Only 28% of the variation in phosphate removal was explained by Kt/V(urea). It appears that other factors not adequately accounted for by Kt/V(urea) affect phosphate removal. Therefore, we propose an individual control and quantification of phosphate removal in HD.