Extra-adrenal and metastatic pheochromocytoma: The role of 131 I meta-iodobenzylguanidine ( 131 I MIBG) in localization and management

From June, 1980, to August, 1983, 131 I MIBG scintiscans were performed in 353 patients with suspected pheochromocytomas. Extra-adrenal pheochromocytomas were identified in 15 of 18 patients who at operation were proven to have such tumors and normal adrenal glands. Conventional localization studies, often repeated, had failed to localize these tumors in nearly all cases. Nine of the extraadrenal pheochromocytomas were found within the middle mediastinum. This group of unique tumors required further specialized localization studies with augmented computed tomography (CT) scans for specific anatomical delineation. These complementary studies allowed for precise planning of surgical excision of the tumors, which required cardiopulmonary bypass in some patients. Extraadrenal pheochromocytomas were identified in a family with no other endocrinopathies. The tumors in 3 patients from 3 different generations all were perirenal and involved the vena cava. 131 I MIBG scintiscans detected metastatic lesions in 40 patients with malignant pheochromocytomas. Metastases were not readily demonstrated in 4 patients. The diagnosis of malignant and metastatic pheochromocytoma was first made by the scintiscan findings in 5 patients. 131 I MIBG scans were not false-positive in any cases and were falsenegative in 10.5% of 95 patients proven to have pheochromocytomas by biochemical evidence or operation. Ten patients have been treated for malignant pheochromocytomas with therapeutic doses of 131 I MIBG. Five patients have had objective responses with diminution in size of metastases or primary malignant tumor and a decrease in the secretion of catecholamines. This agent has been found to be of great value in detecting pheochromocytomas that often have defied all other means of localization. 131 I MIBG concentrates in most malignant pheochromocytomas, and preliminary results suggest that it will be very useful in the treatment of this disease. De juin 1980 à août 1983, 353 malades suspects d'être porteurs de phéochromocytomes ont été soumis à la scintigraphie à l'iode marqué: I 131 métaiodobenzylguanidine (I 131 MIBG). Des phéochromocytomes extra-surrénaliens ont été découverts chez 15 des 18 sujets suspects d'être porteurs de telles lésions extra-surrénaliennes, ce qui fut constaté lors de l'intervention qui démontra que les surrénales étaient normales. Les autres méthodes conventionnelles n'avaient pas permis de localiser ces tumeurs dans la majorité des cas. Neuf des phéochromocytomes extra-surrénaliens furent découverts dans la partie moyenne du médiastin. Ce groupe de tumeurs implique la mise en oeuvre de techniques particulières en plus du scanner pour localiser la tumeur. Ces explorations complémentaires permettent de planifier l'intervention chirurgicale qui peut nécessiter l'emploi d'une circulation extra-corporelle. Des phéochromocytomes extra-surrénaliens ont été découverts dans une famille qui ne présentait pas d'autres endocrinopathies. Les tumeurs chez 3 malades appartenant à 3 générations différentes siégeaient hors de la surrénale et intéressaient la veine cave. La scintigraphie à l'I 131 marqué a permis de découvrir des métastases chez 40 malades porteurs d'un phéochromocytome malin, mais fut en défaut dans 4 cas. Le diagnostic de phéochromocytome malin avec métastase fut porté initialement chez 5 malades. La scintigraphie ne se solda par aucun faux positif mais 10,5% de faux négatifs furent constatés chez 95 malades où la présence d'un phéochromocytome fut prouvée par les données biologiques ou opératoires. Dix malades atteints de phéochromocytomes malins ont été traités par l'I 131 marqué. Cinq d'entre eux accusèrent une diminution de volume de la tumeur et des métastases et une diminution de la sécrétion des catécholamines. L'iode marqué: I 131 méta-iodobenzylguanidine permet de déceler les phéochromocytomes qui échappent aux autres explorations. Le fait qu'il s'accumule électivement au niveau de la tumeur permet de penser qu'il pourra jouer un rôle actif dans le traitement de l'affection. El diagnóstico de feocromocitoma con frecuencia es más simple que establecer la localización anatómica del tumor, lo cual es difícil, especialmente cuando el feocromocitoma es maligno, extraadrenal o bilateral. Aproximadamente el 10% de los feocromocitomas se origina en tejido cromafino ubicado en algún lugar entre la base del cráneo y la vejiga. La tomografía computadorizada de tercera generación es extremadamente precisa en la localización de lesiones intra-adrenales, pero no es muy util en la identificación de feocromocitomas extra-adrenaleso metastásicos. Hasta muy recientemente no existía modalidad alguna capaz de proveer documentación anatómica y funcional del tumor con anterioridad a la intervención quirúrgica. La síntesis de la I 131 metayodo-benzilguanidina (I 131 MIBG) ha hecho posible obtener imágenes scintigráficas de feocromocitomas y de tejido cromafino hiperplásico.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41315/1/268_2005_Article_BF01654948.pd

Salt Restriction Leads to Activation of Adult Renal Mesenchymal Stromal Cell-Like Cells via Prostaglandin E2 and E-Prostanoid Receptor 4

Despite the importance of juxtaglomerular (JG) cell recruitment in the pathophysiology of cardiovascular diseases, the mechanisms that underlie renin production under conditions of chronic stimulation remain elusive. We have previously shown that CD44+ mesenchymal-like cells (CD44+ cells) exist in the adult kidney. Under chronic sodium deprivation these cells are recruited to the JG area and differentiate to new renin-expressing cells. Given the proximity of macula densa (MD) to the JG area and the importance of MD released prostanoids in renin synthesis and release, we hypothesized that chronic sodium deprivation induces MD release of prostanoids; stimulating renal CD44+ cell activation and differentiation. CD44+ cells were isolated from adult kidneys and co-cultured with the MD cell line, MMDD1, in normal or low sodium medium. Low sodium stimulated PGE2 production by MMDD1 and induced migration of CD44+ cells. These effects were inhibited by addition of a Cox-2 inhibitor (NS398) or an EP4 receptor antagonist (AH23848) to MMDD1 or CD44+ cells respectively. Addition of PGE2 to CD44+ cells increased cell migration and induced renin expression. In vivo activation of renal CD44+ cells during JG recruitment was attenuated in wild type mice subjected to salt restriction in the presence of Cox-2 inhibitor Rofecoxib. Similar results were observed in EP4 receptor knockout mice subjected to salt restriction. These results show that the PGE2/ EP4 pathway plays a key role in the activation of renal CD44+ MSC-like cells during conditions of JG recruitment; highlighting the importance of this pathway as a key regulatory mechanism of JG recruitment

Successful and unsuccessful approaches to imaging carcinoids: Comparison of a radiolabelled tryptophan hydroxylase inhibitor with a tracer of biogenic amine uptake and storage, and a somatostatin analogue

A mouse mastocytoma model was used to determine the biodistribution and tumour uptake of four radiopharmaceuticals developed to target the serotonin synthetic pathway in carcinoid tumours. Three of the compounds were competitive inhibitors of the rate-limiting enzyme of serotonin synthesis, tryptophan hydroxylase. Radiolabelled iodo- dl -phenylalanine (iodine-131 PIPA) was found to have the highest uptake and tumourto-liver ratio. Four patients with known carcinoid tumours were then injected with 0.5 mCi 131 I-PIPA and imaged at 1, 4, 24 and 48 h post-injection. The radiopharmaceutical, however, failed to localize in the known tumour sites. This result was in contrast to the authors' experience of 131 I- and 123 I-MIBG imaging of carcinoid tumours. Seven patients with known metastatic carcinoid tumours, two patients with symptoms of recurrence following tumour resection, one patient with completely resected disease, and two patients with a flushing syndrome of uncertain aetiology were studied with 131 I-MIBG. Three of the seven patients with known metastatic disease had positive 131 I-MIBG scans. Both patients with clinical evidence of recurrent disease had negative scans, as did the patient who was considered to have had complete resection of her primary tumour. The two patients with idiopathic flushing syndrome also had negative scans. Among seven patients imaged with 123 I-MIBG there were four true-negative scans and one falsenegative, the latter in a patient with biochemical and CT evidence of recurrence. In a seventh patient with distant metastases there was variable uptake in some of the lesions. Four patients were studied with indium-111 penetetreodide. Two patients with metastatic carcinoid disease had positive scans, although hepatic metastases were not seen in one. Another two with idiopathic flushing syndrome had normal studies. The literature suggests that up 50% of carcinoid tumour cases are detected with 131 I-MIBG, compared to a sensitivity of 87% reported with somatostatin receptor imaging using 111 In-pentetreotide. The experience with 123 I-MIBG is much less extensive. The mechanisms of carcinoid tumour localization for each of the three classes of radiotracers are discussed and contrasted to their varying sensitivities. The relative success of 131 I-MIBG and 111 In-pentetreotide relative to 131 I-PIPA may be related to the fact that 131 I-MIBG is actively taken up and stored by the enterochromaffin cells of the tumours and 111 In-pentetreotide binds to cell surface receptors, whereas 131 I-PIPA binds to tryptophan hydroxylase, which may be present in quantities too small to permit tumours to be imaged.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46840/1/259_2005_Article_BF01731835.pd

Localization and function of the renal calcium-sensing receptor

The ability to monitor changes in the ionic composition of the extracellular environment is a crucial feature that has evolved in all living organisms. The cloning and characterization of the extracellular calcium-sensing receptor (CaSR) from the mammalian parathyroid gland in the early 1990s provided the first description of a cellular, ion-sensing mechanism. This finding demonstrated how cells can detect small, physiological variations in free ionized calcium (Ca 2+) in the extracellular fluid and subsequently evoke an appropriate biological response by altering the secretion of parathyroid hormone (PTH) that acts on PTH receptors expressed in target tissues, including the kidney, intestine, and bone. Aberrant Ca 2+ sensing by the parathyroid glands, as a result of altered CaSR expression or function, is associated with impaired divalent cation homeostasis. CaSR activators that mimic the effects of Ca 2+ (calcimimetics) have been designed to treat hyperparathyroidism, and CaSR antagonists (calcilytics) are in development for the treatment of hypercalciuric disorders. The kidney expresses a CaSR that might directly contribute to the regulation of many aspects of renal function in a PTH-independent manner. This Review discusses the roles of the renal CaSR and the potential impact of pharmacological modulation of the CaSR on renal function

2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer

Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Association's (ATA's) guidelines for the management of these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer

El neoplatonismo de Schelling

The author reflects on some perspective of the early, medium and last thought of Schelling, to show how a glance to its objective and historical entailment with the neoplatonic thought can clarify the structure of its philosophy. In the philosophy of Schelling (a figure of the philosophy who has determined “modernity”) the permanent importance of the neoplatonism is revealed

El neoplatonismo de Schelling

The author reflects on some perspective of the early, medium and last thought of Schelling, to show how a glance to its objective and historical entailment with the neoplatonic thought can clarify the structure of its philosophy. In the philosophy of Schelling (a figure of the philosophy who has determined “modernity”) the permanent importance of the neoplatonism is revealed