Preclinical Assessment Addressing Intravenous Administration of a [68Ga]Ga-PSMA-617 Microemulsion: Acute In Vivo Toxicity, Tolerability, PET Imaging, and Biodistribution.

It has been herein presented that a microemulsion, known to be an effective and safe drug delivery system following intravenous administration, can be loaded with traces of [68Ga]Ga-PSMA-617 without losing its properties or causing toxicity. Following tolerated IV injections the capability of the microemulsion in altering [68Ga]Ga-PSMA-617 distribution was presented at 120 min post injection based on its ex vivo biodistribution results.

The meta-analysis of the effect of 68Ga-PSMA-PET/CT diagnosis of prostatic cancer compared with bone scan.

BACKGROUND: 68Ga-PSMA-PET/CT (positron emission tomography/computed tomography) is a promising method for prostate cancer (PC) detection. However, the ability of 68Ga-PSMA-PET/CT to detect malignant bone lesions, and whether this method is superior to the existing bone imaging methods are still lack of systematic analysis. PURPOSE: To evaluate the value of 68Ga-PSMA-PET/CT and bone scan in clinical diagnosis of prostatic cancer from the perspective of evidence-based medicine. METHODS: PubMed, The Cochrane Library, EMBASE, Springer Link, Sinomed, CNKI, Wanfang database, and CQVIP database were searched to find the satisfactory studies that needed systematic review of trials and compared the value of 68Ga-PSMA-PET/CT and bone scan. All studies published from inception to March 31, 2020. According to the inclusion and exclusion criteria, 2 reviewers independently evaluated and extracted the literature. Review Manager 5.3 was applied to evaluate the included literature quality. The heterogeneity of the included literature was tested by Meta Disc 1.4, and the effect model was selected according to the heterogeneity test results, and the sensitivity (SEN), specificity (SPE), PLR, NLR and diagnostic odds ratio (DOR) were analyzed. After testing the heterogeneity results of literature by using the 95% confidence interval and the forest map. RESULTS: A total of 4 studies were eligible for inclusion in the meta-analysis, which included 318 patients, 120 cases with bone metastasis and 198 cases without bone metastasis. The results of summary evaluation for 68Ga-PSMA-PET/CT and bone scan in diagnosis of prostatic cancer as follow respectively: The SEN were 0.97 and 0.86; the SPE were 1.00 and 0.87; the DOR were 1468.33 and 36.23; PLR were 88.45 and 6.67; NLR were 0.05 and 0.19; and the area under curve (AUC) and 95% CI were 0.9973 (1.0000-0.9927) and 0.8838 (0.9584-0.8092). CONCLUSION: By comparing the diagnostic results of 68Ga-PSMA-PET/CT and bone scan imaging diagnosis methods, the 68Ga-PSMA-PET/CT has a higher SEN and SPE than bone scan, and it has a higher diagnostic efficiency for prostate cancer bone metastasis, which is worthy of clinical application.

Wheat flour fortification with iron and other micronutrients for reducing anaemia and improving iron status in populations.

BACKGROUND: Anaemia is a condition where the number of red blood cells (and consequently their oxygen-carrying capacity) is insufficient to meet the body's physiological needs. Fortification of wheat flour is deemed a useful strategy to reduce anaemia in populations. OBJECTIVES: To determine the benefits and harms of wheat flour fortification with iron alone or with other vitamins and minerals on anaemia, iron status and health-related outcomes in populations over two years of age. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, 21 other databases and two trials registers up to 21 July 2020, together with contacting key organisations to identify additional studies. SELECTION CRITERIA: We included cluster- or individually-randomised controlled trials (RCTs) carried out among the general population from any country, aged two years and above. The interventions were fortification of wheat flour with iron alone or in combination with other micronutrients. We included trials comparing any type of food item prepared from flour fortified with iron of any variety of wheat DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results and assessed the eligibility of studies for inclusion, extracted data from included studies and assessed risks of bias. We followed Cochrane methods in this review. MAIN RESULTS: Our search identified 3538 records, after removing duplicates. We included 10 trials, involving 3319 participants, carried out in Bangladesh, Brazil, India, Kuwait, Philippines, South Africa and Sri Lanka. We identified two ongoing studies and one study is awaiting classification. The duration of interventions varied from 3 to 24 months. One study was carried out among adult women and one trial among both children and nonpregnant women. Most of the included trials were assessed as low or unclear risk of bias for key elements of selection, performance or reporting bias. Three trials used 41 mg to 60 mg iron/kg flour, three trials used less than 40 mg iron/kg and three trials used more than 60 mg iron/kg flour. One trial used various iron levels based on type of iron used: 80 mg/kg for electrolytic and reduced iron and 40 mg/kg for ferrous fumarate. All included studies contributed data for the meta-analyses. Iron-fortified wheat flour with or without other micronutrients added versus wheat flour (no added iron) with the same other micronutrients added Iron-fortified wheat flour with or without other micronutrients added versus wheat flour (no added iron) with the same other micronutrients added may reduce by 27% the risk of anaemia in populations (risk ratio (RR) 0.73, 95% confidence interval (CI) 0.55 to 0.97; 5 studies, 2315 participants; low-certainty evidence). It is uncertain whether iron-fortified wheat flour with or without other micronutrients reduces iron deficiency (RR 0.46, 95% CI 0.20 to 1.04; 3 studies, 748 participants; very low-certainty evidence) or increases haemoglobin concentrations (in g/L) (mean difference MD 2.75, 95% CI 0.71 to 4.80; 8 studies, 2831 participants; very low-certainty evidence). No trials reported data on adverse effects in children (including constipation, nausea, vomiting, heartburn or diarrhoea), except for risk of infection or inflammation at the individual level. The intervention probably makes little or no difference to the risk of Infection or inflammation at individual level as measured by C-reactive protein (CRP) (mean difference (MD) 0.04, 95% CI -0.02 to 0.11; 2 studies, 558 participants; moderate-certainty evidence). Iron-fortified wheat flour with other micronutrients added versus unfortified wheat flour (nil micronutrients added) It is unclear whether wheat flour fortified with iron, in combination with other micronutrients decreases anaemia (RR 0.77, 95% CI 0.41 to 1.46; 2 studies, 317 participants; very low-certainty evidence). The intervention probably reduces the risk of iron deficiency (RR 0.73, 95% CI 0.54 to 0.99; 3 studies, 382 participants; moderate-certainty evidence) and it is unclear whether it increases average haemoglobin concentrations (MD 2.53, 95% CI -0.39 to 5.45; 4 studies, 532 participants; very low-certainty evidence). No trials reported data on adverse effects in children. Nine out of 10 trials reported sources of funding, with most having multiple sources. Funding source does not appear to have distorted the results in any of the assessed trials. AUTHORS' CONCLUSIONS: Fortification of wheat flour with iron (in comparison to unfortified flour, or where both groups received the same other micronutrients) may reduce anaemia in the general population above two years of age, but its effects on other outcomes are uncertain. Iron-fortified wheat flour in combination with other micronutrients, in comparison with unfortified flour, probably reduces iron deficiency, but its effects on other outcomes are uncertain. None of the included trials reported data on adverse side effects except for risk of infection or inflammation at the individual level. The effects of this intervention on other health outcomes are unclear. Future studies at low risk of bias should aim to measure all important outcomes, and to further investigate which variants of fortification, including the role of other micronutrients as well as types of iron fortification, are more effective, and for whom.

Role of Tris-CaEDTA as an adjuvant with nebulised tobramycin in cystic fibrosis patients with Pseudomonas aeruginosa lung infections: A randomised controlled trial.

BACKGROUND: We tested if disrupting iron utilisation by P. aeruginosa by adding the Tris-buffered chelating agent CaEDTA to nebulised tobramycin would enhance bacterial clearance and improve lung function in CF patients. METHODS: In this double-blind, randomised controlled trial, 26 episodes (25 patients) with P. aeruginosa infection admitted to two CF centres for treatment of an acute pulmonary exacerbation were randomly assigned to receive either 75 mg CaEDTA in Tris-buffered saline or placebo (Tris-buffered saline) nebulised in combination with 250 mg tobramycin twice daily for six weeks followed with four week safety follow-up. Primary endpoints were safety, tolerability, and bacterial density of P. aeruginosa. A secondary endpoint was lung function. RESULTS: The study drug was well tolerated with adverse events comparable in both groups. The mean (SD) reduction in sputum P. aeruginosa count (log10 CFU/g) in the CaEDTA vs placebo group was 2·05 (2·57) vs 0·82 (2·71) at two weeks relative to admission (p = 0·39). The mean improvement in ppFEV1 was 16 vs 5 (p = 0·16); 11 vs 2 (p = 0·28); and 6 vs 2 percentage points (p = 0·47) at two, six, and ten weeks in CaEDTA and placebo groups, respectively. CONCLUSIONS: In this pilot study in CF patients, an increase in the reduction of sputum density of P. aeruginosa and an increase in ppFEV1 was observed in the group of patients who received Tris-CaEDTA added to inhaled tobramycin compared to the group who received inhaled tobramycin alone, although these differences were not statistically significant. The treatment was also shown to be safe.

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.

Manganese-Enhanced MRI in Patients with Multiple Sclerosis.

BACKGROUND AND PURPOSE: Cellular uptake of the manganese ion, when administered as a contrast agent for MR imaging, can noninvasively highlight cellular activity and disease processes in both animals and humans. The purpose of this study was to explore the enhancement profile of manganese in patients with multiple sclerosis. MATERIALS AND METHODS: Mangafodipir is a manganese chelate that was clinically approved for MR imaging of liver lesions. We present a case series of 6 adults with multiple sclerosis who were scanned at baseline with gadolinium, then injected with mangafodipir, and followed at variable time points thereafter. RESULTS: Fourteen new lesions formed during or shortly before the study, of which 10 demonstrated manganese enhancement of varying intensity, timing, and spatial pattern. One gadolinium-enhancing extra-axial mass, presumably a meningioma, also demonstrated enhancement with manganese. Most interesting, manganese enhancement was detected in lesions that formed in the days after mangafodipir injection, and this enhancement persisted for several weeks, consistent with contrast coming from intracellular uptake of manganese. Some lesions demonstrated a diffuse pattern of manganese enhancement in an area larger than that of both gadolinium enhancement and T2-FLAIR signal abnormality. CONCLUSIONS: This work demonstrates the first use of a manganese-based contrast agent to enhance MS lesions on MR imaging. Multiple sclerosis lesions were enhanced with a temporal and spatial profile distinct from that of gadolinium. Further experiments are necessary to uncover the mechanism of manganese contrast enhancement as well as cell-specific uptake.

Wheat flour fortification with iron for reducing anaemia and improving iron status in populations.

BACKGROUND: Anaemia is a condition where the number of red blood cells (and consequently their oxygen-carrying capacity) is insufficient to meet the body's physiologic needs. Fortification of wheat flour is deemed a useful strategy to reduce anaemia in populations. OBJECTIVES: To determine the benefits and harms of wheat flour fortification with iron alone or with other vitamins and minerals on anaemia, iron status and health-related outcomes in populations over two years of age. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, and other databases up to 4 September 2019. SELECTION CRITERIA: We included cluster- or individually randomised controlled trials (RCT) carried out among the general population from any country aged two years and above. The interventions were fortification of wheat flour with iron alone or in combination with other micronutrients. Trials comparing any type of food item prepared from flour fortified with iron of any variety of wheat were included. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results and assessed the eligibility of studies for inclusion, extracted data from included studies and assessed risk of bias. We followed Cochrane methods in this review. MAIN RESULTS: Our search identified 3048 records, after removing duplicates. We included nine trials, involving 3166 participants, carried out in Bangladesh, Brazil, India, Kuwait, Phillipines, Sri Lanka and South Africa. The duration of interventions varied from 3 to 24 months. One study was carried out among adult women and one trial among both children and nonpregnant women. Most of the included trials were assessed as low or unclear risk of bias for key elements of selection, performance or reporting bias. Three trials used 41 mg to 60 mg iron/kg flour, two trials used less than 40 mg iron/kg and three trials used more than 60 mg iron/kg flour. One trial employed various iron levels based on type of iron used: 80 mg/kg for electrolytic and reduced iron and 40 mg/kg for ferrous fumarate. All included studies contributed data for the meta-analyses. Seven studies compared wheat flour fortified with iron alone versus unfortified wheat flour, three studies compared wheat flour fortified with iron in combination with other micronutrients versus unfortified wheat flour and two studies compared wheat flour fortified with iron in combination with other micronutrients versus fortified wheat flour with the same micronutrients (but not iron). No studies included a 'no intervention' comparison arm. None of the included trials reported any other adverse side effects (including constipation, nausea, vomiting, heartburn or diarrhoea). Wheat flour fortified with iron alone versus unfortified wheat flour (no micronutrients added) Wheat flour fortification with iron alone may have little or no effect on anaemia (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.61 to 1.07; 5 studies; 2200 participants; low-certainty evidence). It probably makes little or no difference on iron deficiency (RR 0.43, 95% CI 0.17 to 1.07; 3 studies; 633 participants; moderate-certainty evidence) and we are uncertain about whether wheat flour fortified with iron increases haemoglobin concentrations by an average 3.30 (g/L) (95% CI 0.86 to 5.74; 7 studies; 2355 participants; very low-certainty evidence). No trials reported data on adverse effects in children, except for risk of infection or inflammation at the individual level. The intervention probably makes little or no difference to risk of Infection or inflammation at individual level as measured by C-reactive protein (CRP) (moderate-certainty evidence). Wheat flour fortified with iron in combination with other micronutrients versus unfortified wheat flour (no micronutrients added) Wheat flour fortified with iron, in combination with other micronutrients, may or may not decrease anaemia (RR 0.95, 95% CI 0.69 to 1.31; 2 studies; 322 participants; low-certainty evidence). It makes little or no difference to average risk of iron deficiency (RR 0.74, 95% CI 0.54 to 1.00; 3 studies; 387 participants; moderate-certainty evidence) and may or may not increase average haemoglobin concentrations (mean difference (MD) 3.29, 95% CI -0.78 to 7.36; 3 studies; 384 participants; low-certainty evidence). No trials reported data on adverse effects in children. Wheat flour fortified with iron in combination with other micronutrients versus fortified wheat flour with same micronutrients (but not iron) Given the very low certainty of the evidence, the review authors are uncertain about the effects of wheat flour fortified with iron in combination with other micronutrients versus fortified wheat flour with same micronutrients (but not iron) in reducing anaemia (RR 0.24, 95% CI 0.08 to 0.71; 1 study; 127 participants; very low-certainty evidence) and in reducing iron deficiency (RR 0.42, 95% CI 0.18 to 0.97; 1 study; 127 participants; very low-certainty evidence). The intervention may make little or no difference to the average haemoglobin concentration (MD 0.81, 95% CI -1.28 to 2.89; 2 studies; 488 participants; low-certainty evidence). No trials reported data on the adverse effects in children. Eight out of nine trials reported source of funding with most having multiple sources. Funding source does not appear to have distorted the results in any of the assessed trials. AUTHORS' CONCLUSIONS: Eating food items containing wheat flour fortified with iron alone may have little or no effect on anaemia and probably makes little or no difference in iron deficiency. We are uncertain on whether the intervention with wheat flour fortified with iron increases haemoglobin concentrations improve blood haemoglobin concentrations. Consuming food items prepared from wheat flour fortified with iron, in combination with other micronutrients, has little or no effect on anaemia, makes little or no difference to iron deficiency and may or may not improve haemoglobin concentrations. In comparison to fortified flour with micronutrients but no iron, wheat flour fortified with iron with other micronutrients, the effects on anaemia and iron deficiency are uncertain as certainty of the evidence has been assessed as very low. The intervention may make little or no difference to the average haemoglobin concentrations in the population. None of the included trials reported any other adverse side effects. The effects of this intervention on other health outcomes are unclear.

Use of scanning electron microscopy in the cochlea of guinea pigs / Microscopia eletrônica de varredura em cócleas de cobaias

Abstract Introduction: The use of electron microscopy in the study of the inner ear has allowed us to observe minute details of the hair cells, especially in ototoxicity studies; however, the preparation of this material is a difficult and delicate task. In an attempt to simplify the handling of these materials, two agents, toluidine blue and ethylenediamine tetra-acetic acid were tested, in addition to the elimination of osmium tetroxide during the preparation of albino guinea pig cochleae. We also tested the applicability of these methodologies in an ototoxicity protocol. Objective: To verify the quality of the images obtained with and without the use of ethylenediamine tetra-acetic acid, toluidine blue and osmium tetroxide in the preparation of cochleae of albino guinea pigs for the scanning electron microscopy. Methods: Three groups of cochleae were used. In Group 1, 10 cochleae were prepared with the usual methodology, dissecting the optical capsule without decalcification and using osmium tetroxide as a post-fixative agent. In Group 2, we prepared 10 cochleae decalcified with ethylenediamine tetra-acetic acid, injecting toluidine blue in the endolymphatic space to facilitate the identification of the organ of Corti. In Group 3, we used 4 cochleae of guinea pigs that received 3 doses of cisplatin (7.5 mg/kg, D1-D5-D6), two prepared according to the methodology used in Group 1 and two with that used in Group 2. Scanning electron microscopy images were obtained from the organ of Corti region of the basal turn of each cochlea. Results: The organ of Corti was more easily identified with the use of toluidine blue. The dissection of the cochlea was more accurate in the decalcified cochleae. The quality of the images and the preservation of the organ of Corti obtained with the two methodologies were similar. Conclusion: The proposed modifications resulted in images of similar quality as those observed using the traditional methodology.

Resumo Introdução: O emprego da microscopia eletrônica no estudo da orelha interna permitiu observar detalhes minuciosos das células ciliadas especialmente em estudos de ototoxicidade. Entretanto, o preparo desse material é trabalhoso e delicado. Para simplificar a manipulação desses materiais, testou-se o uso de dois agentes, azul de toluidina e ácido etilenodiamino tetra-acético, além da retirada do tetróxido de ósmio na preparação de cócleas de cobaias albinas. Testamos também a aplicabilidade dessas metodologias em um protocolo de ototoxicidade. Objetivo: Verificar a qualidade das imagens obtidas com e sem o uso de ácido etilenodiamino tetra-acético, azul de toluidina e tetróxido de ósmio na preparação de cócleas de cobaias albinas para a microscopia eletrônica de varredura. Método: Foram utilizados três grupos de cócleas. No Grupo 1 preparou-se 10 cócleas com a metodologia usual, dissecando a cápsula ótica sem descalcificac¸ão e utilizando tetróxido de ósmio como pós-fixador. No Grupo 2 preparamos 10 cócleas descalcificadas com ácido etilenodiamino tetra-acético, injetando azul de toluidina no espac¸o endolinfático para facilitar a identificação do órgão de Corti. No Grupo 3 utilizamos 4 cócleas de cobaias que receberam 3 doses de cisplatina (7,5 mg/kg, D1-D5-D6), duas preparadas com a metodologia do Grupo 1 e duas com a do Grupo 2. Foram obtidas imagens da microscopia eletrônica de varredura da região do órgão de Corti do giro basal de cada cóclea. Resultados: O órgão de Corti foi mais facilmente identificado com o azul de touidina. A dissecção da cóclea foi mais precisa nas cócleas descalcificadas A qualidade das imagens e a preservac¸ão do órgão de Corti obtidas com as duas metodologias foi similar. Conclusão: As modificações propostas resultaram em imagens de qualidade similar as observadas com o uso da metodologia tradicional.

Reversible redox-responsive 1H/19F MRI molecular probes.

Herein we report a pair of redox-responsive manganese complexes Mn(iii)/(ii)-N,N'-bis(2-hydroxy-4-trifluoromethylbenzyl)ethylenediamine-N,N'-diacetate (HTFBED, L1), which are water soluble and biologically interconvertible, as reversible redox-responsive probes in 1H/19F MRI for detecting and imaging biological redox species, offering a means to access valuable redox information associated with various diseases.

EDTA-Modified 17ß-Estradiol-Laden Upconversion Nanocomposite for Bone-Targeted Hormone Replacement Therapy for Osteoporosis.

Hormone therapy (HT) is one of the most effective treatments for osteoporosis. However, the nonselective accumulation of hormone in organs such as breast, heart and uterus other than bones causes serious side effects, which impedes the application of HT. Hence, it is critically important to develop a HT strategy with reduced non-specific enrichment of hormone drugs in non-target tissues and enhanced bone-targeting ability. Methods: Herein, a 17ß-estradiol (E2)-laden mesoporous silica-coated upconversion nanoparticle with a surface modification of ethylenediaminetetraacetic acid (EDTA) (NaLuF4:Yb,Tm@NaLuF4@mSiO2-EDTA-E2, E2-csUCNP@MSN-EDTA) is developed for bone-targeted osteoporosis hormone therapy. EDTA was attached onto the surface of E2 upconversion nanocomposite to enhance its affinity and efficiency targeting bone tissue and cells to optimize hormone replacement therapy for osteoporosis. We characterized the size, cytotoxicity, loading and release efficiency, in situ and ex vivo imaging. Further, in vitro and in vivo osteogenic ability was tested using preosteoblast and ovariectomy mouse model of osteoporosis. Results: The upconversion core of E2-csUCNP@MSN-EDTA nanoparticle serves as an excellent imaging agent for tracking the loaded hormone drug in vivo. The mesoporous silica layer has a high loading efficiency for E2 and provides a relatively long-lasting drug release within 50 h. EDTA anchored on the silica layer endows the nanocomposite with a bone targeting property. The nanocomposite effectively reverses estrogen deficiency-induced osteoporosis and reduces the damage of hormone to the uterus. The bone mineral density in the nanocomposite treatment group is nearly twice that of the ovariectomized (OVX) group. Compared with the E2 group, the uterine weight and luminal epithelial height were significantly lower in the nanocomposite treatment group. Conclusion: This work demonstrated that E2-csUCNP@MSN-EDTA alleviates the side effect of hormone therapy while maintaining its therapeutic efficacy, which has great potential for developing the next generation of methods for osteoporosis treatment.

68Ga-PSMA-HBED-CC PET/CT imaging for adenoid cystic carcinoma and salivary duct carcinoma: a phase 2 imaging study.

Rationale: Treatment options for recurrent and/or metastatic (R/M) adenoid cystic carcinoma (ACC) and salivary duct carcinoma (SDC), major subtypes of salivary gland cancer, are limited. Both tumors often show overexpression of prostate-specific membrane antigen (PSMA). In prostate cancer, PSMA-ligands labeled with 68Ga or 177Lu are used for imaging and therapy, respectively. Primary aim of this study in R/M ACC and SDC patients was to systematically investigate 68Ga-PSMA-uptake by PET/CT imaging to determine if PSMA radionuclide therapy could be a treatment option. Methods: In a prospective phase II study, PET/CT imaging was performed 1 h post injection of 68Ga-PSMA-HBED-CC in 15 ACC patients and 10 SDC patients. Maximum standardized uptake values (SUV) were determined in tumor lesions. Immunohistochemical PSMA expression was scored in primary tumors and metastatic tissue. Standard imaging (MRI or CT) was performed for comparison. Results: In ACC patients, SUVmax ranged from 1.1 to 30.2 with a tumor/liver-ratio >1 in 13 out of 14 evaluable patients (93%). In SDC patients, SUVmax ranged from 0.3 to 25.9 with a tumor/liver-ratio >1 in 4 out of 10 patients (40%). We found a large intra-patient inter-metastatic variation in uptake of 68Ga-PSMA, and immunohistochemistry did not predict ligand uptake in ACC and SDC. Finally, PSMA-PET detected additional bone metastases compared to CT in 2 ACC patients with unexplained pain. Conclusion: In 93% of ACC patients and 40% of SDC patients we detected relevant PSMA-ligand uptake, which warrants to study PSMA radionuclide therapy in these patients. Additionally, our data provide arguments for patient selection and treatment timing. Finally, PSMA-PET imaging has added diagnostic value compared to CT in selected patients.

Compatibility of [99mTc]Tc-EDDA/HYNIC-TOC and [68Ga] Ga-DOTA-TOC in a syringe for intravenous administration.

OBJECTIVE: Drug quality in medical devices is not evaluated during the marketing authorization of radiopharmaceuticals. Therefore, the extemporaneous change of packaging made for preparation of patient unit doses in a syringe is the responsibility of radiopharmacists. The present study aimed to determine the impact of packaging and storage in a polypropylene syringe on the quality of hydrophilic drugs [Tc]Tc-EDDA/HYNIC-TOC (Tektrotyd) and [Ga]Ga-DOTA-TOC (Somakit-TOC). METHODS: Appearance, pH, radiochemical purity, sterility, and endotoxin tests were performed according the current European Pharmacopoeia. Subvisible and visible particles tests of the European Pharmacopoeia were adapted due to limited preparation volume (<25 ml). Sorption tests were performed according to the literature. RESULTS: After 2 h storage in a syringe, drug sorption of Tektrotyd and Somakit-TOC was of less than 2.5% and similar to other Tc-radiopharmaceuticals (range: from 1.1 ± 0.5% to 4.2 ± 0.6%). For Tektrotyd, this sorption phenomenon was positively influenced by the drug concentration and a short contact with the medical device (4.8 ± 0.2% up to 5 s vs. 2.3 ± 0.2%, n = 4; P < 0.001). For Somakit-TOC, the duration of contact with syringe had no impact (1.6 ± 0.2% up to 5 s vs. 1.7 ± 0.6%; P = 1.000). No drug radiolysis or alteration of microbiological aspects were observed. No impurity from a 3-piece-syringe was observed according to drug aspect, pH, and subvisible and visible particles, which remained within specification of the current European Pharmacopoeia. CONCLUSION: This study found that drug sorption to packaging was compatible with clinical use and absence of drug alteration of Tektrotyd and Somakit-TOC after repackaging in a syringe in polypropylene and prolonged storage during 2 h.

Therapeutic use of tetrasodium ethylenediaminetetraacetic acid solution for treatment of subcutaneous ureteral bypass device mineralization in cats.

BACKGROUND: Subcutaneous ureteral bypass (SUB) device placement is an increasingly popular treatment option for decompression of ureteral obstruction in cats. Mineralization occlusion of the device occurs in a minority of cases but is the most common complication. OBJECTIVE: To evaluate a 2% tetrasodium ethylenediaminetetraacetic acid (tEDTA) solution for treatment of mineralization occlusion in cats with SUBs. ANIMALS: Six client-owned cats (8 obstructed devices). METHODS: Case series. Each cat was found to have device occlusion based on a combination of ultrasound examination, SUB irrigation, and failure to identify another cause of device obstruction. Each SUB was drained, irrigated using sterile saline, and infused with 1-2 mL of 2% tEDTA solution. Success was defined as normalization of flow during subsequent ultrasound visualization while irrigating. The volume and frequency of tEDTA instillations, time to achieve device patency, follow-up biochemical and ultrasound findings, and future reobstruction events were recorded. RESULTS: Resolution of mineralization was documented in all 8 SUBs. Reobstruction events occurred in 2 cats, all of which resolved after additional tEDTA infusions, but 1 cat ultimately required device exchange at 356 days from the first tEDTA infusion. In 1 cat, a single infusion was prematurely discontinued because of persistent pelvic dilatation after 1.25 mL of tEDTA had been instilled. No complications were observed. CONCLUSIONS AND CLINICAL IMPORTANCE: Tetrasodium EDTA infusions can be safely considered as a treatment option for mineralized SUB devices in cats. This solution was easily infused, well tolerated, and avoided the need for SUB device exchange in the majority of cats in which it was used.

18F-fluciclovine PET-CT and 68Ga-PSMA-11 PET-CT in patients with early biochemical recurrence after prostatectomy: a prospective, single-centre, single-arm, comparative imaging trial.

BACKGROUND: National Comprehensive Cancer Network guidelines consider 18F-fluciclovine PET-CT for prostate cancer biochemical recurrence localisation after radical prostatectomy, whereas European Association of Urology guidelines recommend prostate-specific membrane antigen (PSMA) PET-CT. To the best of our knowledge, no prospective head-to-head comparison between these tests has been done so far. The aim of this study was to compare prospectively paired 18F-fluciclovine and PSMA PET-CT scans for localising biochemical recurrence of prostate cancer after radical prostatectomy in patients with low prostate-specific antigen (PSA) concentrations (<2·0 ng/mL). METHODS: This was a prospective, single-centre, open-label, single-arm comparative study done at University of California Los Angeles (Los Angeles, CA, USA). Patients older than 18 years of age with prostate cancer biochemical recurrence after radical prostatectomy and PSA levels ranging from 0·2 to 2·0 ng/mL without any prior salvage therapy and with a Karnofsky performance status of at least 50 were eligible. Patients underwent 18F-fluciclovine (reference test) and PSMA (index test) PET-CT scans within 15 days. Detection rate of biochemical recurrence at the patient level and by anatomical region was the primary endpoint. A statistical power analysis demonstrated that a sample size of 50 patients was needed to show a 22% difference in detection rates in favour of PSMA (test for superiority). Each PET scan was interpreted by three independent masked readers and a consensus majority interpretation was generated (two vs one) to determine positive findings. This study is registered with ClinicalTrials.gov, number NCT02940262, and is complete. FINDINGS: Between Feb 26, 2018, and Sept 20, 2018, 143 patients were screened for eligibility, of whom 50 patients were enrolled into the study. Median follow-up was 8 months (IQR 7-9). The primary endpoint was met; detection rates were significantly lower with 18F-fluciclovine PET-CT (13 [26%; 95% CI 15-40] of 50) than with PSMA PET-CT (28 [56%; 41-70] of 50), with an odds ratio (OR) of 4·8 (95% CI 1·6-19·2; p=0·0026) at the patient level; in the subanalysis of the pelvic nodes region (four [8%; 2-19] with 18F-fluciclovine vs 15 [30%; 18-45] with PSMA PET-CT; OR 12·0 [1·8-513·0], p=0·0034); and in the subanalysis of any extrapelvic lesions (none [0%; 0-6] vs eight [16%; 7-29]; OR non-estimable [95% CI non-estimable], p=0·0078). INTERPRETATION: With higher detection rates, PSMA should be the PET tracer of choice when PET-CT imaging is considered for subsequent treatment management decisions in patients with prostate cancer and biochemical recurrence after radical prostatectomy and low PSA concentrations (≤2·0 ng/mL). Further research is needed to investigate whether higher detection rates translate into improved oncological outcomes. FUNDING: None.

Postoperative Quality of Life Following Conventional Endodontic Intracanal Irrigation Compared with Laser-Activated Irrigation: A Randomized Clinical Study.

Objective: The aim of this randomized clinical study was to evaluate the effect of laser-activated irrigation using a photon-induced photoacoustic streaming (PIPS) technique on postoperative pain following completion of root canal obturation. Methods: Fifty-six patients were enrolled in this randomized clinical trial. Fifty-six healthy premolars or molars with asymptomatic irreversible pulpitis, symptomatic irreversible pulpitis, or symptomatic pulpal necrosis, with or without apical periodontitis, were mechanically prepared for endodontic treatment and divided into two groups. Patients were randomly allocated to treatment groups. In the positive control group G1, the final irrigation with 2 cc of 5.25% sodium hypochlorite (NaOCl) was achieved using a 27G needle, introduced into the canal to a distance of 5 mm from the predetermined working length. In the experimental group G2, the root canals were irrigated with 17% ethyldiamine tetric acid (EDTA) and 5.25% NaOCl following the PIPS protocol, using an Er:YAG 2940 nm laser (LightWalker ATS®; Fotona, Slovenia) with a 600 µm diameter tip and operating parameters of 20 mJ per pulse, 15 Hz frequency, 0.3 W average power, and a 50-µs pulse duration. Postoperatively, the patients were advised to take a minor analgesic (ibuprofen 400 mg) in the event of pain perception. Postoperative pain levels were assessed after 24, 48, and 72 h and 7 days through the use of a Visual Analogue Scale questionnaire, completed by each patient. Data were analyzed using Kolmogorov-Smirnov, Fisher Exact, Chi square, Mann-Whitney test, and Friedman's test. The level of significance was set at α = 0.05. Results: There was no significant difference between the laser-irradiated group and the control group (p < 0.5). Laser activation of irrigating solutions did not increase postoperative pain. Conclusions: The outcome of this investigation indicated that PIPS was as effective as conventional irrigation in relation to postoperative pain, making this activation technique interesting to use for supplementary root canal disinfection.

Assessing intestinal permeability in Crohn's disease patients using orally administered 52Cr-EDTA.

BACKGROUND: Intestinal permeability can be assessed by monitoring renal excretion of orally administered radioactively 51Cr-labeled ethylenediaminetetraacetic acid (51Cr-EDTA). Although considered safe, patient participation in using radio-labeled tracers is low. Here, we used orally administered 52Cr-EDTA as non-radioactive alternative to assess intestinal permeability in CD and analyzed the association with disease activity, disease location and gut microbial dysbiosis. MATERIALS AND METHODS: 60 CD patients with low (n = 25) and increased (n = 35) fecal calprotectin levels (cut-off: 100 µg/g feces) ingested 20 mL 52Cr-EDTA (20 mmol/L) solution whereafter 24-h urine was collected. Urinary 52Cr-EDTA concentrations were quantified using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Fecal Enterobacteriaceae and Faecalibacterium prausnitzii were quantified using FISH. Correlations between urinary 52Cr-EDTA excretion and other parameters were established using nonparametric Spearman's correlation coefficients (ρ). RESULTS: CD patients with increased fecal calprotectin levels (> 100 µg/g) demonstrated an elevated urinary 52Cr-EDTA/creatinine ratio (772 vs. 636 µmol/mol, P = 0.132). Patients with primarily colonic disease showed the highest 52Cr-EDTA excretion. Importantly, a positive correlation was observed for the urinary 52Cr-EDTA/creatinine ratio and fecal calprotectin levels (ρ = 0.325, P < 0.05). Finally, urinary 52Cr-EDTA/creatinine ratio negatively correlated with the relative abundance of Faecalibacterium prausnitzii (ρ = -0.221, P = 0.092), while positively correlating with Enterobacteriaceae (ρ = 0.202, P = 0.126). CONCLUSIONS: Orally administered and renal excreted 52Cr-EDTA may be used to assess intestinal permeability in CD and correlates with fecal calprotectin levels and bacterial species relevant to CD. This test may improve non-invasive detection of disease exacerbations and help monitor disease activity.

Randomised open label exploratory, safety and tolerability study with calmangafodipir in patients treated with the 12-h regimen of N-acetylcysteine for paracetamol overdose-the PP100-01 for Overdose of Paracetamol (POP) trial: study protocol for a randomised controlled trial.

BACKGROUND: Paracetamol (acetaminophen) overdose (POD) is the commonest cause of acute liver failure in Europe and North America. Current treatment involves the use of the antidote N-acetylcysteine (NAC) in patients deemed at risk of liver damage. This regimen was introduced in the 1970s and has remained largely unchanged even though the initial NAC infusion is frequently associated with adverse reactions, in particular nausea, vomiting, and anaphylactoid reactions. NAC has reduced efficacy for preventing liver injury in those patients who present later after overdose. We designed a randomised study investigating the safety and tolerability of a superoxide dismutase (SOD) mimetic, calmangafodipir (PP100-01), co-treatment with a 12-h NAC regimen compared with NAC treatment alone in patients with POD. METHODS/DESIGN: We have designed an open-label, randomised, exploratory, rising dose design, NAC-controlled, phase 1 safety and tolerability study in patients treated with NAC for POD. A total of 24 patients will be assigned into one of three dosing cohorts of eight patients (n = 6 for PP100-01 and NAC; n = 2 for NAC alone). The doses of PP100-01 are 2, 5, and 10 µmol/kg. The primary outcome is the safety and tolerability of PP100-01 when co-administered with a 12-h NAC regimen compared with NAC treatment alone. Furthermore, the study will explore if PP100-01 has potential efficacy for the treatment of paracetamol-induced liver injury by measurement of conventional clinical and exploratory biomarkers. DISCUSSION: The aim of the study is to test the safety and tolerability of a SOD mimetic, PP100-01, in combination with a 12-h NAC regimen in patients presenting within 24 h of POD. This study will provide valuable data regarding the incidence of adverse events caused by the 12-h NAC plus PP100-01 regimen and may provide evidence of PP100-01 efficacy in the treatment of paracetamol-induced liver injury. TRIAL REGISTRATION: EudraCT, 2017-000246-21; ClinicalTrials.gov, NCT03177395 . Registered on 6 June 2017.

68Ga-PSMA-11 PET/CT: the rising star of nuclear medicine in prostate cancer imaging?

Ever since the introduction of 68Ga-prostate-specific membrane antigen 11 positron-emission tomography/computed tomography (68Ga-PSMA-11 PET/CT) a few years ago, it has rapidly achieved great success in the field of prostate cancer imaging. A large number of studies have been published to date, indicating a high potential of 68Ga-PSMA-11 PET/CT in the work-up of prostate cancer patients, including primary diagnosis, staging and biochemical recurrence. The aim of this review is to present the most important data on this novel, highly promising imaging technique, and to formulate recommendations for possible applications of 68Ga-PSMA-11 PET/CT in clinical routine.

Can Local Ablative Radiotherapy Revert Castration-resistant Prostate Cancer to an Earlier Stage of Disease?

In prostate cancer, disease progression after primary treatment and subsequent androgen deprivation therapy is common. Intensification of systemic treatment is the standard of care. Recently, 68Ga prostate-specific membrane antigen positron emission tomography (PSMA-PET) imaging was introduced to identify oligometastatic prostate cancer patients. In this retrospective, exploratory study, we report on the efficacy of PSMA-PET-guided local ablative radiotherapy (aRT) in 15 oligometastatic castration-resistant prostate cancer (CRPC) patients, selected from our prospective institutional database and treated between 2013 and 2016. After multidisciplinary discussion, aRT was delivered with two different schedules. Androgen deprivation therapy remained unchanged. Prostate-specific antigen (PSA) response and time to PSA progression were analysed. For comparison, individual time to PSA progression without aRT was estimated by individual PSA doubling time (PSADT). PSA response was observed in 11 patients (73%). Mean time to PSA progression or last follow-up was 17.9mo, as opposed to 2.9mo estimated from the PSADT without aRT (p<0.001). A relevant subset of CRPC patients had a PSA response with aRT to PET-positive lead metastases. A prospective trial is in preparation. PATIENT SUMMARY: In selected patients with prostate-specific antigen (PSA) increase during androgen deprivation, metastases were detected with prostate-specific membrane antigen positron emission tomography imaging. Fifteen patients with three or fewer metastases were treated with high-dose radiotherapy. Subsequently, PSA values dropped in 11 patients and in six patients no PSA progression was detected for >12mo.

Dual 0.02% chlorhexidine digluconate - 0.1% disodium EDTA loaded thermosensitive ocular gel for Acanthamoeba keratitis treatment.

Poor bioavailability and low residence time limit the efficiency of conventional biguanide-based eye drops against Acanthamoeba keratitis. The aim of this work was to formulate an original anti-amoebic thermoreversible ocular gel combining biguanide and metalloproteases inhibitor - chelating agent. Chlorhexidine digluconate (CHX)-ethylenediaminetetraacetic acid disodium salt (Na2EDTA) were compounded in poloxamer 407 saline solution. 0.02% CHX - 0.1% Na2EDTA loaded thermosensitive ocular gel exhibited appropriate pH (5.73 ±â€¯0.06), iso-osmolality (314 ±â€¯5 mOsm/kg), viscosity (ranged between 15 and 25 mPa.s) and thermal gelation (26.5 °C and 33 °C) properties. Bioadhesion of gel was successfully tested onto isolated bovine eyes as well as the assessment of CHX penetration into the cornea. Intracorneal CHX concentration was found greater than trophozoite minimum amoebicidal concentration and minimal cysticidal concentration after 15-min and 2-h ocular exposure, respectively, while any CHX permeation through the cornea was detected (<51 ng/cm2/h). Improvement of CHX ocular bioavailability was attributed to probable solubilization of tear film lipid layer by poloxamer. In vitro efficiency of CHX-Na2EDTA ocular gel was confirmed from the drastic reduction of trophozoite and cyst survival (to 25% and 2%, respectively), confirming the potential of the multicomponent pharmaceutical material strategy for the treatment of Acanthamoeba keratitis.