Development and validation of a LC-MS/MS method for in vivo quantification of meta-iodobenzylguanidine (mIBG).

meta-iodobenzylguanidine (mIBG) is a radiopharmaceutical used for the diagnosis and treatment of neuroendocrine cancers. Previous quantification of mIBG in biodistribution and pharmacokinetic studies mainly relied on the use of radiolabeled mIBG, which involves the handling of highly radioactive materials. The goal of this study was to develop a nonradioactive analytical method for quantifying mIBG in mouse plasma and tissue homogenates using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Samples were prepared for analysis using a protein precipitation method. Mass spectrometry analysis was performed using 4-hydroxyphenformin as the internal standard, and the mass-to-charge transitions were 276.1 → 217.0 for mIBG and 222.1 → 121.0 for 4-hydroxyphenformin. The quantification limit of mIBG was 0.98 ng/mL, and the method was linear up to 500 ng/mL. The accuracy, inter-day and intra-day precision were 96-112%, 5.5-14.4%, and 3.7-14.1%, respectively, suggesting that the method was accurate and precise in quantifying mIBG at multiple concentrations in mouse plasma and liver homogenates. The extraction recovery was 96-106% and the matrix effect was 95-110%, indicating that the method was reproducible in quantifying mIBG with minimal impact from the biological matrices. In summary, we have developed and validated a fast, high-throughput quantification method of non-radiolabeled mIBG using LC-MS/MS. This method is reproducible, accurate, and precise, and can be used to quantify mIBG in plasma and tissue matrices to determine the pharmacokinetics and biodistribution of mIBG in preclinical animal models.

Prevalence and Clinical Correlations of Somatostatin Receptor-2 (SSTR2) Expression in Neuroblastoma.

Alternative radiolabeled, targeted agents are being investigated for children with relapsed neuroblastoma (NB) who do not respond to I-metaiodobenzylguanidine (MIBG) therapy. (DOTA-Tyr)-octreotate targets somatostatin receptors (SSTRs), particularly SSTR2, which are expressed on NB cells. We investigated SSTR2 expression in NB tumors (36 high-risk [HR]; 33 non-HR patients) and correlated SSTR2 levels with clinical features, norepinephrine transporter (NET) expression, and MIBG avidity. SSTR2 and NET immunohistochemistry scores (0 to 3) were calculated on biopsies using digital image analysis based on staining intensity and distribution. Clinical data were correlated with SSTR2 expression. Median SSTR2 score for 69 patients was 1.31 (0.26 to 2.55). Non-HR NB was associated with a higher SSTR2 score (P=0.032). The SSTR2 expression did not correlate with age, International Neuroblastoma Staging System (INSS) stage, MYCN amplification and histology. Higher SSTR2 scores were observed in MIBG-avid versus MIBG-nonavid NB. SSTR2 score was not significantly associated with NET score (r=-0.062, P=0.62). Twenty-six patients who relapsed or progressed had a median SSTR2 score of 1.33 (0.26 to 2.55). Patients with NB including relapsed or progressive disease showed SSTR2 expression at diagnosis, suggesting they could be candidates for radiolabeled-DOTA-conjugated peptide imaging or therapy.

Use of ESI-MS for semi-quantitative estimation of inactive precursor in no-carrier-added 131I- meta-Iodobenzylguanidine radiopharmaceutical preparation.

No-carrier-added (nca)-131I-meta-Iodobenzylguadine (mIBG) is a clinical agent used for the therapy of Neuroendocrine tumors. It is prepared by reaction of radioiodine with precursors that are chemically different from mIBG. The precursor in few cases is structurally similar and may co-elute along during purification step. Presence of these precursors in final radiolabeled formulation may affect the clinical behaviour of the radiopharmaceutical. The present paper describes the use of Electron-spray ionization-Mass Spectrometry (ESI-MS) where up to nano-molar concentrations of these precursors could be estimated with high precision in the final radiolabeled formulation.

Hibernoma retroperitoneal bilateral identificado por I-MIBG SPECT/TC en un paciente con feocromocitoma unilateral / Bilateral retroperitoneal hibernoma identified by I-MIBG SPECT/CT in a patient with single pheochromocytoma

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Transcatheter Aortic Valve Implantation Improves Cardiac Sympathetic Nerve Activity on 123I-Metaiodobenzylguanidine Myocardial Scintigraphy in Severe Aortic Valve Stenosis.

BACKGROUND: There is a consensus that overactivation of the cardiac sympathetic nervous system (CSN) proportionately increases the severity of heart failure and is accompanied by worse prognosis. Because it is unknown whether patients with aortic valve stenosis (AS) have similar CSN activation, we investigated the effect of transcatheter aortic valve implantation (TAVI).Methods and Results:We enrolled 31 consecutive patients with AS treated by TAVI. 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy was performed at baseline and at 2 weeks after TAVI. At baseline, the early heart-mediastinum ratio (H/M) was within normal limits (3.0±0.5), but the delayed H/M was low (2.6±0.6) and the washout rate (WR) was high (34±13%). WR negatively correlated with aortic valve area (r=-0.389, P<0.01) and cardiac output (r=-0.595, P<0.01) and positively correlated with norepinephrine (r=0.519, P<0.01) and log NT-proBNP level (r=0.613, P<0.01). After TAVI, there were significant decreases in the norepinephrine level (366±179 ng/mL vs. 276±125 ng/mL, P<0.01) and WR (34±13 vs. 26±11%, P<0.01). CONCLUSIONS: The WR of MIBG was a useful marker of CSN activity and severity of AS. Immediate improvement of CSN activity after TAVI implied that AS hemodynamics per se enhanced CSN.

Incidental finding of 131I uptake in mesenteric cystic lymphangioma on post-therapy 131I SPECT/CT imaging / Hallazgo fortuito de captación de 131I en un linfangioma quístico mesentérico en el SPECT/TC con 131I posterapia

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Acúmulo de 131INa en quistes renales sin relación con enfermedad metastásica en un paciente con carcinoma diferenciado de tiroides / Accumulation of 131INa activity in renal cysts unrelated to metastatic disease in a patient with differentiated thyroid cancer

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A case of (123)I-MIBG scintigram-negative functioning pheochromocytoma: immunohistochemical and molecular analysis with review of literature.

A 70-year-old Japanese woman was referred to our hospital due to hyperhidrosis and rapid weight loss of 10 kg in a month. A lump measuring 26 mm in diameter was detected in the left adrenal gland by computed tomography. Biochemical tests showed high levels of serum and urinary norepinephrine and epinephrine. However, a (123)I-MIBG scintigram failed to detect any accumulation in the left adrenal tumor. A left adrenalectomy was performed post clinical diagnosis of (123)I-MIBG negative pheochromocytoma. Microscopically, the tumor exhibited pheochromocytoma compatible features. Immunohistochemical analysis revealed low expression of VMAT1 in the tumor compared to the normal, surrounding tissue. To test for a possible genetic alteration of the monoamine transporter genes, we performed whole-exome sequencing of the VMAT1, VMAT2, and NET genes in the tumor. No significant base sequence substitution or deletion/insertion was found in any transporter. This suggests that MIBG negativity is caused by a change that is independent of the base sequence abnormalities, such as an epigenetic change. Furthermore, a retrospective literature review of (123)I-MIBG negative-scintigraphy cases indicates that a negative finding in the (123)I-MIBG scintigram is frequently associated with metastatic pheochromocytomas or SDHB mutations. However, a SDHB/D gene mutation has not been identified in the reported case. Although the patient needs careful monitoring following the surgery, to date she has been disease free for 12 months. This study could not find clear reasons for negative conversion, however, investigations of the negative conversion mechanism might reveal significant insights towards the improvement of patient survival.

Quality control of iodine-131-labeled metaiodobenzylguanidine.

AIM/OBJECTIVES/BACKGROUND: Iodine-131-m-iodobenzylguanidine ([(131)I]mIBG) is used worldwide for the diagnosis and therapy of neuroendocrine tumors, particularly adrenal medullae tumors. After the synthesis and preparation of a radioiodinated MIBG drug formulation, quality control testing to determine its radiochemical purity (RCP) should be performed. European Pharmacopoeia 8.0 requires that the quality control include a test for RCP for the determination of [(131)I]mIBG. Previously reported procedures using reversed-phase conditions require long retention times. Our system enables the separation of [(131)I]mIBG within a few minutes. The aim of this work was to carry out RCP testing for [(131)I]mIBG without any type of sample pretreatment. METHODS: RCP testing for ([(131)I]mIBG has been carried out using high-performance liquid chromatography and thin-layer chromatography methods. RESULTS: A simple and rapid reversed-phase isocratic system enables the HPLC investigation of RCP testing for [(131)I]mIBG used for therapy within a few minutes. CONCLUSIONS: From the point of view of radiation protection, this method is safer, especially for therapeutic amounts of [(131)I]mIBG.

Extenso patrón hipermetabólico por activación de la grasa parda en un paciente diagnosticado de paraganglioma para-vesical secretor de catecolaminas explorado mediante 18F-FDG PET/TC / Extensive hypermetabolic pattern of brown adipose tissue activation on 18F-FDG PET/CT in a patient diagnosed of catecholamine-secreting para-vesical paraganglioma

El uso generalizado de la exploración 18F-FDG PET-TC en pacientes de cáncer ha permitido demostrar la existencia de grasa parda metabólicamente activa, también llamada tejido adiposo pardo (TAP), en sujetos humanos adultos, y conocer su distribución anatómica in vivo. Como determinantes fisiológicos de la captación de 18F-FDG por el TAP se han identificado el sexo, la edad, la temperatura y el índice de masa corporal. Hemos observado una extensa activación del TAP, incluyendo la región mesentérica, en un paciente con un paranganglioma paravesical secretor de catecolaminas. La activación extensa del TAP podría ser secundaria a la estimulación adrenérgica por un exceso de la concentración de noradrenalina circulante (AU)

The widespread use of 18F-FDG PET-CT scanning in oncological patients has allowed to demonstrate the existence of metabolically active brown fat, also called brown adipose tissue (BAT), in adult humans, and specifying its anatomical distribution in vivo. As physiological determinants to BAT 18F-FDG uptake has been identified gender, age, temperature, and body mass index. We have observed extensive activation of the BAT, including the mesenteric region, in a patient with a catecholamine-secreting para-vesical paranganglioma. The extensive BAT activation could be secondary to adrenergic stimulation due to excess of circulating norepinephrine concentration (AU)

Mathematical methods to determine quantitative parameters of myocardial 123I-MIBG studies: a review of the literature.

(123)I-meta-iodobenzyl-guanidine ((123)I-MIBG) scintigraphy is used to visualize and quantify the sympathetic nerve activity. Although it has been used since 1980 to identify myocardial innervation, it is not yet regarded a routine sympathetic imaging agent in this respect. The lack of large multicentre studies and the presence of variations in the protocols that are used for planar MIBG acquisition confines the comparability of study results and application of normal values. Therefore, the aim of this study was to assess the variations in mathematical methods that are currently used to quantify the heart-to-mediastinum ratio and washout rate (WOR). In addition, normal values were evaluated in concordance with these methods. A systematic literature search yielded 169 unique manuscripts, of which 30 contained a complete description of the acquisition protocol for planar MIBG acquisition, image analysis and quantification of the parameters. The results indicate not only large variations in mathematical methods, but also in various aspects of the protocols that are used during acquisition. In many manuscripts method-specific normal values were used; however, these values were generally generated from small, single-centre studies. This study stresses the need to produce guidelines to achieve a standardized method for MIBG acquisition, image analysis and methods to quantify parameters.

Multimodality palliative treatment of (111)In-pentetreotide negative/(123)I-MIBG positive metastatic carcinoid - a case report.

Patients with carcinoid tumours frequently present with metastatic disease. There are only a few therapeutic options for these patients, and the main goal of palliative treatment is to reduce symptoms and thus to improve quality of life. Current therapy includes surgical resection, hepatic artery embolisation, chemotherapy and somatostatin analogue treatment; however, all these options have limitations. It seems probable that therapeutic modalities based on radiopharmaceuticals may provide better therapy, not only in relation to symptom reduction but may also improve patient survival. In this case report we present a 46-year-old woman with a symptomatic carcinoid, who at the time of diagnosis had liver and abdominal lymph node metastases, the primary tumour being located in the terminal ileum. (111)In-pentetreotide scanning was negative, whereas (123)I-MIBG scanning showed high avidity in the tumour tissue. After right hemicolectomy, two courses of (131)I-MIBG treatment were given (12.95 GBq and 12 GBq, respectively). After the second dose of (131)I-MIBG temporary pancytopenia was present. Octreotide therapy was given empirically only for a short time and was stopped because of drug intolerance. The patient underwent tricuspid and pulmonary valve replacement because of her carcinoid heart disease, followed by two courses of embolisation of liver metastases. While (131)I-MIBG therapy reduced the patient's symptoms of flushing and diarrhoea, there has not yet been any effect on tumour response or 5-HIAA production. This case illustrates the multimodality and multidisciplinary approach to such patients.

Smoking is associated with insulin resistance and cardiovascular autonomic dysfunction in type 2 diabetic patients.

BACKGROUND: Smoking and cardiovascular autonomic dysfunction are associated with high mortality in type 2 diabetic patients. This study tested the hypothesis that smoking is associated with insulin resistance/hyperinsulinaemia and cardiovascular autonomic dysfunction in type 2 diabetic patients who are not treated with insulin. MATERIALS AND METHODS: The study patients were 22 current smokers with type 2 diabetes mellitus (age: 57 +/- 5 years, mean +/- SD) and 30 age-matched never-smoked patients with type 2 diabetes mellitus (control group, 57 +/- 8 years). The quality of blood glucose was assessed by fasting plasma glucose (FPG), fasting immunoreactive insulin (F-IRI), homeostasis model assessment (HOMA) index and haemoglobin A1c (HbA1c). The severity of smoking status was expressed by the Brinkman index, which is calculated as number of cigarettes per day multiplied by years of smoking. Cardiovascular autonomic function was assessed by baroreflex sensitivity (BRS), heart-rate variability, plasma norepinephrine concentration and cardiac (123)I-metaiodobenzylguanidine (MIBG) scintigraphic findings. RESULTS: Baroreflex sensitivity was lower in the current smokers group than in the never-smoked group (P < 0.05). Early and delayed (123)I-MIBG myocardial uptake values were lower (P < 0.05, and P < 0.01, respectively) and the percentage washout-rate of (123)I-MIBG was higher (P < 0.0001) in the current smokers group than in the never-smoked group. Fasting immunoreactive insulin (F-IRI) concentration (P < 0.0001) and the homeostasis model assessment (HOMA) index (P < 0.0001) were higher in the current smokers group than the never-smoked group. Multiple logistic regression analysis revealed that smoking was independently predicted by F-IRI and the percentage washout-rate of (123)I-MIBG. CONCLUSIONS: The results of the study suggested that smoking was associated with cardiovascular autonomic dysfunction and hyperinsulinaemia and that F-IRI and the percentage washout-rate of (123)I-MIBG were independent predictors of smoking in these Japanese patients with type 2 diabetes mellitus.

Increased urinary dopamine excretion in association with bilateral carotid body tumours-- clinical, biochemical and genetic findings.

This report describes a rare case of a patient with increased urinary dopamine excretion in association with bilateral carotid body tumours. Excretion of adrenaline, noradrenaline, metadrenaline, normetadrenaline and 4-hydroxy-3-methoxymandelic acid (HMMA) were within the reference ranges, and an (123)I-meta-iodobenzylguanidine (MIBG) scan showed uptake in the neck masses, with no other abnormal uptake anywhere else in the body. The patient is being managed conservatively as the tumours are not amenable to resection on account of their size and vascularity. There are only four previous case reports of dopamine-secreting tumours of the carotid body described in the literature, all of whom were women. The tumours were unilateral in three cases and bilateral in the fourth case. Familial cases of carotid body tumours have a higher prevalence of bilateral tumours than non-familial cases. Recent reports in the literature have suggested that a significant number of patients with extra-adrenal catecholamine-secreting paragangliomas have a genetic mutation in one of the identified susceptibility genes for catecholamine-secreting tumours, despite having no other affected family members, and a mutation has been found in the succinate dehydrogenase gene for this patient.

Effect of collimator choice on quantitative assessment of cardiac iodine 123 MIBG uptake.

BACKGROUND: Quantitative accuracy in iodine 123 studies may be impaired by septal penetration. We evaluated the effect of collimator choice on estimation of the heart-to-mediastinum (H/M) ratio in cardiac I-123 metaiodobenzylguanidine (MIBG) imaging. METHODS AND RESULTS: A low-energy high-resolution (LEHR) collimator, special LEHR (SLEHR) collimator, and medium-energy (ME) collimator were used. In experiments in which a phantom of simple geometry was used, the use of the LEHR collimator provided the lowest contrast accuracy, suggesting the effect of septal penetration. Thoracic phantom studies demonstrated contamination of heart and mediastinum counts by lung and liver activities, which was greatest with the LEHR collimator and least with the ME collimator. In 8 patients anterior chest views were acquired successively with the three collimators after I-123 MIBG injection. H/M ratios were significantly higher with the SLEHR collimator than with the LEHR collimator and were still higher with the ME collimator. The difference in H/M ratios between the LEHR and ME collimators showed a high positive correlation with the lung-to-mediastinum ratio. CONCLUSIONS: Collimator choice substantially influences estimation of the H/M ratios in cardiac I-123 MIBG imaging. The use of an ME collimator provides high quantitative accuracy and may enhance reliability in the evaluation of cardiac sympathetic nerve function.

The treatment of malignant pheochromocytoma with iodine-131 metaiodobenzylguanidine (131I-MIBG): a comprehensive review of 116 reported patients.

Iodine-131 metaiodobenzylguanidine (131I-MIBG), a radiopharmaceutical agent used for scintigraphic localization of pheochromocytomas, has been employed to treat malignant pheochromocytomas since 1983 in a few specialized centers around the world. We review our clinical experience together with the published experience of 23 other centers in 10 countries, regarding the use of 1311-MIBG for treating patients with malignant adrenal pheochromocytomas or extra-adrenal paragangliomas. There were a total of 116 evaluable patients: 3 were from our current report and another 113 were reported in the literature from 1983 to 1996. A majority of the patients were selected for treatment based upon positive tracer uptake studies. The cumulative dose of 131I-MIBG administered ranged from 96 to 2,322 mCi (3.6 to 85.9 GBq), with a mean (+/-SD) of 490+/-350 mCi (18.1+/-13.0 GBq). The subjects received a mean single therapy dose of 158 mCi (5.8 GBq) and the number of doses administered ranged from 1 to 11, with a mean of 3.3+/-2.2 doses. Initial symptomatic improvement was achieved in 76% of patients, tumor responses in 30%, and hormonal responses in 45%. Five patients had complete tumor and hormonal responses, ranging from 16 to 58 months, which were sustained at the time of reporting. Patients with metastases to soft tissue had more favorable responses to treatment than those with metastases to bone. No difference was noted in the age between the responders and non-responders. Adverse effects, recorded in 41% of the treated patients, were generally mild except for one fatality from bone marrow aplasia. Among 89 patients with follow-up data, 45% of the responders had relapsed with recurrent or progressive disease after a mean interval of 29.3+/-31.1 months (median 19 months). Of patients with an initial response to 1311-MIBG, death was reported in 33% after a mean of 23.2+/-8.1 months (median 22 months) following treatment. Of non-responders, death was reported in 45% after a mean of 14.3+/-8.3 months (median 13 months). In conclusion, this review suggests that 131I-MIBG therapy may be a useful palliative adjunct in selected patients with malignant pheochromocytoma or paraganglioma. Although controlled studies are lacking, our review raises the hope that this therapeutic modality may prolong survival with an occasional sustained complete remission or possible cure.