Evaluation of standardized uptake value on 131I-6ß-iodomethyl-19-norcholesterol scintigraphy for diagnosis of primary aldosteronism and correspondence with adrenal venous sampling.

PURPOSE: Adrenal venous sampling (AVS) is a reliable method for lateralization of adrenal hormone secretion, which is important for discriminating between aldosterone-producing adenoma and bilateral adrenal hyperplasia, both of which cause primary aldosteronism (PA). The aim of this study was to evaluate the diagnostic accuracy of the maximum and mean standardized uptake values (SUVmax and SUVmean, respectively) of 131I-6ß-iodomethyl-19-norcholesterol (NP-59) single-photon emission computed tomography (SPECT) for PA and its correspondence with AVS. METHODS: Adrenal NP-59 scintigraphy was performed in 14 patients with suspected PA, and AVS was also performed in 7 of them. SUVmax and SUVmean of the adrenal lesions on the dominant side and their ratios to the values on the non-dominant side (SUVRmax and SUVRmean, respectively) were calculated on SPECT images using ordered-subset conjugate gradient minimization (OSCGM) and three-dimensional ordered-subset expectation maximization (3D-OSEM) reconstruction algorithms. RESULTS: SUVmax and SUVmean on NP-59 SPECT images were significantly higher for aldosterone-producing adenoma than for bilateral adrenal hyperplasia or non-functioning adenoma and slightly superior to SUVRmax and SUVRmean (P = 0.0475 and P = 0.0447 vs. P = 0.124 and P = 0.132, respectively, with OSCGM). The respective areas under the receiver-operating characteristic curve for SUV and SUVR were 0.933 and 0.725 with OSCGM and 0.844 and 0.750 with 3D-OSEM, while SUVmax and SUVRmax had exactly the same diagnostic accuracy as SUVmean and SUVRmean. SUV and SUVR were associated with the diagnostic features on AVS and consistent with lateralization by AVS in most patients. CONCLUSION: In this study, SUV on NP-59 SPECT helped in the diagnosis of PA and was consistent with the results of AVS in nearly all cases.

Dolor lumbar persistente tras la administración de [131I]Iodo-6-beta-iodometil-19-norcolesterol: a propósito de un caso / Lower back pain after iodine-131-6-Beta-iodomethyl-19-norcholesterol injection: a case report

El [131I]Iodo-6-Beta-iodometil-19-norcolesterol ([131I]Norcolesterol), radiofármaco indicado en el diagnóstico del estado funcional de tejido cortical suprarrenal, en la detección del tejido funcional en el hiperadrenocorticalismo así como en el aldosteronismo primario. Presentamos el caso de una mujer de 54 años de edad, remitida para la evaluación de una sospecha de aldosteronismo, y que inmediatamente después de la administración intravenosa de [131I]Norcolesterol sufrió una fuerte reacción adversa al medicamento, con mareo, rubor, aumento de la presión arterial, opresión en el pecho, dolor lumbar y sarpullido eritematoso hasta 9 días postinyección. Los síntomas se resolvieron satisfactoriamente tras la administración de antihistamínicos y corticoides. Se sospechó que esta reacción estuviera relacionada con la administración del [131I]Norcolesterol causada por una reacción alérgica de tipo I (AU)

The [131I]Iodine-6-Beta-iodomethyl-19-norcholesterol ([131I]Norcholesterol; NP-59), is indicated in the diagnosis of the functional state of adrenal cortical tissue, in the detection of functional tissue in hyperadrenocorticalism as well as in primary aldosteronism. We present the case of a 54-year-old woman, referred for evaluation of suspected aldosteronism, and who immediately after intravenous administration of [131I]Norcholesterol suffered a strong adverse drug reaction, with dizziness, flushing, increased blood pressure, chest tightness, low back pain and erythematous rash up to 9 days after injection. Symptoms resolved satisfactorily after administration of antihistamines and corticosteroids. This reaction was suspected to be related to the administration of [131I]Norcholesterol caused by a type I allergic reaction.(AU)

Development of Fluorinated NP-59: A Revival of Cholesterol Use Imaging with PET.

Imaging of cholesterol use is possible with the 131I scintiscanning/SPECT agent NP-59. This agent provided a noninvasive measure of adrenal function and steroid synthesis. However, iodine isotopes resulted in poor resolution, manufacturing challenges, and high radiation dosimetry to patients that have limited their use and clinical impact. A 18F analog would address these shortcomings while retaining the ability to image cholesterol use. The goal of this study was to prepare and evaluate a 18F analog of NP-59 to serve as a PET imaging agent for functional imaging of the adrenal glands based on cholesterol use. Previous attempts to prepare such an analog of NP-59 have proven elusive. Preclinical and clinical evaluation could be performed once the new fluorine analog of NP-59 production was established. Methods: The recent development of a new reagent for fluorination along with an improved route to the NP-59 precursor allowed for the preparation of a fluorine analog of NP-59, FNP-59. The radiochemistry for the 18F-radiolabeled 18F-FNP-59 is described, and rodent radiation dosimetry studies and in vivo imaging in New Zealand rabbits was performed. After in vivo toxicity studies, an investigational new drug approval was obtained, and the first-in-humans images with dosimetry using the agent were acquired. Results: In vivo toxicity studies demonstrated that FNP-59 is safe for use at the intended dose. Biodistribution studies with 18F-FNP-59 demonstrated a pharmacokinetic profile similar to that of NP-59 but with decreased radiation exposure. In vivo animal images demonstrated expected uptake in tissues that use cholesterol: gallbladder, liver, and adrenal glands. In this first-in-humans study, subjects had no adverse events and images demonstrated accumulation in target tissues (liver and adrenal glands). Manipulation of uptake was also demonstrated with patients who received cosyntropin, resulting in improved uptake. Conclusion: 18F-FNP-59 provided higher resolution images, with lower radiation dose to the subjects. It has the potential to provide a noninvasive test for patients with adrenocortical diseases.

NP-59 Adrenal Scintigraphy as an Imaging Biomarker to Predict KCNJ5 Mutation in Primary Aldosteronism Patients.

Purpose: Somatic KCNJ5 mutation occurs in half of unilateral primary aldosteronism (PA) and is associated with more severe phenotype. Mutation status can only be identified by tissue sample from adrenalectomy. NP-59 adrenal scintigraphy is a noninvasive functional study for disease activity assessment. This study aimed to evaluate the predictive value of NP-59 adrenal scintigraphy in somatic KCNJ5 mutation among PA patients who received adrenalectomy. Methods: Sixty-two PA patients who had NP-59 adrenal scintigraphy before adrenalectomy with available KCNJ5 mutation status were included. Two semiquantitative parameters, adrenal to liver ratio (ALR) and lesion to contralateral ratio of bilateral adrenal glands (CON) derived from NP-59 adrenal scintigraphy, of mutated and wild-type patients were compared. Cutoff values calculated by receiver-operating characteristic (ROC) analysis were used as a predictor of KCNJ5 mutation. Results: Twenty patients had KCNJ5 mutation and 42 patients were wild type. Patients harboring KCNJ5 mutation had both higher ALR and CON (p = 0.0031 and 0.0833, respectively) than wild-type patients. With ALR and CON cutoff of 2.10 and 1.95, the sensitivity and specificity to predict KCNJ5 mutation were 85%, 57% and 45%, 93%, respectively. Among 20 patients with KCNJ5 mutation, 16 showed G151R point mutation (KCNJ5- G151R) and 4 showed L168R point mutation (KCNJ5-L168R), which former one had significantly lower ALR (p=0.0471). Conclusion: PA patients harboring somatic KCNJ5 mutation had significantly higher NP-59 uptake regarding to ALR and CON than those without mutation. APAs with KCNJ5-L168R point mutation showed significantly higher ALR than those with KCNJ5-G151R point mutation.

Functional imaging of adrenal cortex. / Estudios de imagen funcional de la corteza adrenal.

The rising number of high-resolution imaging scans has increased the adrenal lesions detection, which require a differential diagnosis. Currently, the most commonly used scans are CT and MRI, but these are sometimes not very specific. In these cases, nuclear medicine scans with 131I-norcolesterol, 11C-metomidate and 18F-fludeoxyglucose help to differentiate benign vs. malignant lesions, to lateralize the involvement in hypersecretion disease, as well as to guide the therapeutic strategy in both unilateral and bilateral lesions.

Efficient in vivo editing of OTC-deficient patient-derived primary human hepatocytes.

BACKGROUND & AIMS: Genome editing technology has immense therapeutic potential and is likely to rapidly supplant contemporary gene addition approaches. Key advantages include the capacity to directly repair mutant loci with resultant recovery of physiological gene expression and maintenance of durable therapeutic effects in replicating cells. In this study, we aimed to repair a disease-causing point mutation in the ornithine transcarbamylase (OTC) locus in patient-derived primary human hepatocytes in vivo at therapeutically relevant levels. METHODS: Editing reagents for precise CRISPR/SaCas9-mediated cleavage and homology-directed repair (HDR) of the human OTC locus were first evaluated against an OTC minigene cassette transposed into the mouse liver. The editing efficacy of these reagents was then tested on the native OTC locus in patient-derived primary human hepatocytes xenografted into the FRG (Fah -/- Rag2 -/- Il2rg -/-) mouse liver. A highly human hepatotropic capsid (NP59) was used for adeno-associated virus (AAV)-mediated gene transfer. Editing events were characterised using next-generation sequencing and restoration of OTC expression was evaluated using immunofluorescence. RESULTS: Following AAV-mediated delivery of editing reagents to patient-derived primary human hepatocytes in vivo, OTC locus-specific cleavage was achieved at efficiencies of up to 72%. Importantly, successful editing was observed in up to 29% of OTC alleles at clinically relevant vector doses. No off-target editing events were observed at the top 10 in silico-predicted sites in the genome. CONCLUSIONS: We report efficient single-nucleotide correction of a disease-causing mutation in the OTC locus in patient-derived primary human hepatocytes in vivo at levels that, if recapitulated in the clinic, would provide benefit for even the most therapeutically challenging liver disorders. Key challenges for clinical translation include the cell cycle dependence of classical HDR and mitigation of unintended on- and off-target editing events. LAY SUMMARY: The ability to efficiently and safely correct disease-causing mutations remains the holy grail of gene therapy. Herein, we demonstrate, for the first time, efficient in vivo correction of a patient-specific disease-causing mutation in the OTC gene in primary human hepatocytes, using therapeutically relevant vector doses. We also highlight the challenges that need to be overcome for this technology to be translated into clinical practice.

NP-59 test for preoperative localization of primary hyperaldosteronism.

PURPOSE: Adrenal venous sampling is generally considered the gold standard to identify unilateral hormone production in cases of primary hyperaldosteronism. The aim of this study is to evaluate whether the iodine-131-6-ß-iodomethyl-19-norcholesterol (NP-59) test may represent an alternative in selected cases. METHODS: Patients submitted to laparoscopic adrenalectomy for suspected primary hyperaldosteronism (n = 27) were retrospectively reviewed. When nuclear medicine tests were preoperatively performed, their results were compared with the histopathologic findings and clinical improvement. RESULTS: Nuclear medicine tests were realized in 13 patients. In 11 (84.6%), a planar anterior and posterior NP-59 scintigraphy was performed and a SPECT/TC in two (15.4%). Scintigraphy indicated a preoperative lateralization in 12 out of 13 patients (92.3%). When the value of NP-59 tests was based on pathologic results, it showed a sensitivity of 90.9% and a positive predictive value of 83.3%. When the nuclear medicine test's performance was based on postoperative blood pressure control, both sensitivity and positive predictive value were 91.6%. CONCLUSIONS: Nuclear medicine tests represent a useful tool in the preoperative localisation of primary hyperaldosteronism with a high sensitivity and positive predictive value. In patients with contraindications to adrenal venous sampling like contrast allergies, or when it is inconclusive, scintigraphy can represent a useful and non-invasive alternative.

The Clinical Usefulness of NP-59 Scintigraphy in Adrenal Cortical Diseases / 대한핵의학회잡지

Laparoscopic cholecystectomy can be performed safely in most patients with symptomatic cholelithiasis. Preoperative evaluation should assess the potential problems that affect the performance of laparoscopic cholecystectomy. Hepatobiliary scintigraphy or oral cholecystography can assess the gallbladder function and nonvisualization of gall bladder usually indicates acute or severe chronic cholecystitis. The purpose of this study was to evaluate the role of preoperative hepatobiliary scintigraphy or oral cholecystography in predicting the performance of laparoscopic cholecystectomy. The study group consists of 176 patients who underwent both hepatobiliary scintigraphy with Tc-99m DISIDA and oral cholecystography within one month before laparoscopic cholecystectomy. Nonvisualization of gallbladder was defined as persistent nonvisualization of gall- bladder until 4 hours on hepatobiliary scintigraphy or 12 hours on oral cholecystography. Among 176 patients, gallbladder was not visualized in 38 patients on hepatobiliary scintigraphy and 41 patients on oral cholecystography, Concordance rate between hepatobiliary scintigraphy and oral cholecystography was 89.2%. The conversion rate to open cholocystectomy was significantly higher in patients with nonvisualization of gallbladder than in patients with gallbladder visualization(15.8% vs 2.9% on hepatobiliary scintigraphy, 12.2% vs 3.7% on oral cholecystography: p<0.01 and p<0.05 respectively). The operative complication rate was also significantly higher in patients with nonvisualization of gallbladder (13.2% vs 2.9% on hepatobiliary scintigraphy, 14.6% vs 2.2% on. oral cholecystography : p<0.0l and p<0.001, respectively). Similarly, operation time was significantly prolonged in patients with nonvisualization of gall bladder (88.8+/-41.9min vs 62.5+/-23.6min on hepatobiliary scintigraphy : p<0.001, 89.4+/-41.3 min vs 61.8+/-22.8 min on oral cholecystography : p<0.001). It is concluded that nonvisualization of gallblader on hepato biliary scintigraphy or oral cholecystography is a valuable preoperative clincal risk factor in predicting increased conversion rate to open cholecystectomy, increased operative complication and prolonged operation time.