Spontaneous coronary artery dissection in association with cabergoline therapy.

Spontaneous coronary artery dissection (SCAD) is a rare but increasingly recognised cause of acute coronary syndrome. While numerous risk factors are associated with SCAD, one potential cause is coronary artery vasospasm. The use of cabergoline-an ergot derivative and dopamine agonist that may induce vasospasm-has been associated with SCAD in one other case report worldwide. Here, we describe SCAD in a 37-year-old woman on long-term cabergoline therapy with no other cardiac risk factors. Cabergoline-induced SCAD should be considered in patients presenting with an acute coronary syndrome who are treated with this medication.

Outcome of Patients with Renal Cell Carcinoma and Multiple Glandular Metastases Treated with Targeted Agents.

PURPOSE: Pancreatic metastases (PM) from renal cell carcinoma (RCC) have been associated with long-term survival. The aim of this study was to evaluate the outcome of RCC patients with multiple glandular metastases (MGM) treated with targeted therapies (TTs). METHODS: Sixty-four MGM patients treated between 1993 and 2014 were retrospectively identified from a database of 274 RCC patients with PM from 11 European centers. The survival of MGM patients was compared with that of both patients with PM only and a cohort of 325 RCC patients with non-GM (control group) treated with TTs. Survival was estimated using the Kaplan-Meier method and was statistically compared using the log-rank test. RESULTS: Fifty-six patients (88%) had at least 2 MGM, 7 patients (11%) had 3 MGM and 1 patient had 4 MGM, while non-GM were present in the remaining patients. The median overall survival (OS) was 54.2 months for MGM and 73.4 months for patients with PM only. The median OS in the control group was 22.7 months and statistically inferior to both MGM (p < 0.001) and PM patients (p < 0.001). CONCLUSION: MGM from RCC are associated with a remarkable survival. Despite some limitations, these findings suggest that GM might be considered a predictor of a favorable prognosis.

Efficacy and Long-Term Safety of Everolimus in Pancreatic Neuroendocrine Tumor Associated with Multiple Endocrine Neoplasia Type I: Case Report.

BACKGROUND: Approximately 10% of pancreatic neuroendocrine tumors (NET) are associated with familial syndromes, with the most common type being multiple endocrine neoplasia type 1 (MEN-1). However, the available evidence on how to treat NET comes from studies in sporadic NET. CASE REPORT: Here we report the case of a 51-year-old male patient with a metastatic MEN-1-associated pancreatic NET and hypercalcemia related to primary hyperparathyroidism and tumor-secreted parathyroid-related protein. The patient was treated with everolimus, and showed complete resolution of hypercalcemia and tumor control for 3 years when he presented with pulmonary cryptococcosis and disease progression. CONCLUSION: This case report describes the activity of everolimus in a patient with MEN-1-associated pancreatic NET, its efficacy in treating malignant hypercalcemia associated with NET and the risk of opportunistic infections with prolonged use of this agent.

Pasireotide Therapy of Multiple Endocrine Neoplasia Type 1-Associated Neuroendocrine Tumors in Female Mice Deleted for an Men1 Allele Improves Survival and Reduces Tumor Progression.

Pasireotide, a somatostatin analog, is reported to have anti-proliferative effects in neuroendocrine tumors (NETs). We therefore assessed the efficacy of pasireotide for treating pancreatic and pituitary NETs that develop in a mouse model of multiple endocrine neoplasia type 1 (MEN1). Men1(+/-) mice were treated from age 12 mo with 40 mg/kg pasireotide long-acting release formulation, or PBS, intramuscularly monthly for 9 mo. The Men1(+/-) mice had magnetic resonance imaging at 12 and 21 mo, and from 20 mo oral 5-bromo-2-deoxyuridine for 1 mo, to assess tumor development and proliferation, respectively. NETs were collected at age 21 mo, and proliferation and apoptosis assessed by immunohistochemistry and TUNEL assays, respectively. Pasireotide-treated Men1(+/-) mice had increased survival (pasireotide, 80.9% vs PBS, 65.2%; P < .05), with fewer mice developing pancreatic NETs (pasireotide, 86.9% vs PBS, 96.9%; P < .05) and smaller increases in pituitary NET volumes (pre-treated vs post-treated, 0.803 ± 0.058 mm(3) vs 2.872 ± 0.728 mm(3) [pasireotide] compared with 0.844 ± 0.066 mm(3) vs 8.847 ±1.948 mm(3) [PBS]; P < .01). In addition, pasireotide-treated mice had fewer pancreatic NETs compared with PBS-treated mice (2.36 ± 0.25 vs 3.72 ± 0.32, respectively; P < .001), with decreased proliferation in pancreatic NETs (pasireotide, 0.35 ± 0.03% vs PBS, 0.78 ± 0.08%; P < .0001) and pituitary NETs (pasireotide, 0.73 ±0.07% vs PBS, 1.81 ± 0.15%; P < .0001), but increased apoptosis in pancreatic NETs (pasireotide, 0.42 ± 0.05% vs PBS, 0.19 ± 0.03%; P < .001) and pituitary NETs (pasireotide, 14.75 ± 1.58% vs PBS, 2.35 ± 0.44%; P < .001). Thus, pasireotide increased survival and inhibited pancreatic and pituitary NET growth, thereby indicating its potential as an anti-proliferative and pro-apoptotic therapy.

Development of mitotane lipid nanocarriers and enantiomers: two-in-one solution to efficiently treat adreno-cortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with a poor prognosis. Treatment options for advanced ACC are limited. Indeed, radical tumor resection can lead to local or metastatic recurrence, and mitotane (Lysodren(®)), the only recognized adrenolytic drug, offers modest response rates, notably due to some of its physico-chemical and pharmacological properties (i.e. hydrophobicity, low bioavailability). Meantime, high cumulative doses of Lysodren(®) usually cause systemic toxicities. To reduce adverse health effects, the search of safe and efficient mitotane nano-formulations as well as the full characterization and testing of its enantiomers can represent valuable therapeutic options. Interestingly, recent investigations showed that solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) could considerably improve the efficacy of mitotane (i.e. enhanced solubility and bioavailability, progressive release of the loaded drug into blood and targeted tissues) as well as its safety (i.e. lower toxicity, higher biocompatibility). These two nano-carriers for mitotane delivery and targeting are of particular interest over other polymeric particles (i.e. low-cost, efficient and simple scaling to an industrial production level following green methods). Besides, emerging studies suggested that the S-(-)- mitotane is more potent than the R-(+)-mitotane for ACC treatment. Therefore, the production of pure and active S-(-)-mitotane might offer synergic or additive benefits for ACC patients when combined to solid lipid-based nanocarriers. In this review, we first provide an updated overview of the ACC disease before emphasizing on the promising mitotane drug nano-systems, as well as on the separation, purification and production of single mitotane enantiomer using state-of-art chromatographic-based methods.

Duodenal adenocarcinoma with neuroendocrine features in a patient with acromegaly and thyroid papillary adenocarcinoma: a unique combination of endocrine neoplasia.

A 67-year-old woman with familial clustering of thyroid papillary adenocarcinoma was diagnosed with acromegaly due to pituitary macroadenoma. She had multiple skin vegetations, but had no parathyroid and pancreas diseases. Before transsphenoidal surgery, she was further diagnosed as having a duodenal tumor and multiple hypervascular liver nodules. Biopsy specimens from the duodenal tumor and liver nodules were diagnosed histologically as moderately differentiated adenocarcinoma. Immunohistochemically, the tumor cells were positive for chromogranin, synaptophysin and somatostatin receptor 2a, suggestive for neuroendocrine features. After surgery, the patient was not in biochemical remission, and octreotide treatment was initiated. The duodenal cancer was treated with chemotherapy (neoadjuvant cisplatin and S-1). After 24 months, the patient's insulin-like growth factor I level had been normalized, and her liver tumors had not progressed macroscopically. This is a rare case of acromegaly associated with multiple endocrine tumors, not being categorized as conventional multiple endocrine neoplasia. Octreotide treatment might have had beneficial effects on our patient's duodenal adenocarcinoma and liver metastases, both directly via SSTR2a and indirectly via GH suppression, thereby contributing to their slow progression.

The familial Mediterranean fever gene as a modifier of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome.

OBJECTIVE: Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) syndrome is a sporadic disease, characterized by periodic attacks of inflammation. Mutations in the MEFV, the gene associated with familial Mediterranean fever (FMF), may lead to subclinical inflammation in asymptomatic carriers and modify the phenotype of some inflammatory diseases. We aimed at investigating the effect of MEFV gene mutations on disease phenotype in PFAPA. PATIENTS AND METHODS: The cohort of this ongoing prospective study consisted of 124 children with PFAPA syndrome, followed in a single referral center, who were tested for MEFV mutations. Demographic data, clinical characteristics, and disease course of 65 PFAPA patients with and 59 without MEFV mutations (M+ and M-, respectively) were compared. RESULTS: PFAPA attacks in carriers of MEFV mutations were shorter compared with patients without mutations (3.8 ± 1.7 versus 4.8 ± 1.9 days, P < 0.01). The difference was more pronounced in those carrying the M694V mutation. In M+ patients, the rates of patients with regularity of their attacks (49.2%) and oral aphthae (24.6%) were lower, compared with M- patients (74.5% and 43.9%, respectively, P < 0.05 for each of the 2 comparisons). M+ patients needed a lower corticosteroid (beclomethasone) dose to abort the attacks (0.16 ± 0.07mg/kg versus 0.19 ± 0.08, P = 0.028). No differences were observed in all other clinical and laboratory parameters, over a follow-up period of 4.3 years. CONCLUSION: In PFAPA, MEFV is a modifier gene associated with an attenuated disease severity.

8-Cl-adenosine inhibits proliferation and causes apoptosis in B-lymphocytes via protein kinase A-dependent and independent effects: implications for treatment of Carney complex-associated tumors.

CONTEXT: Carney complex, a multiple neoplasia syndrome, characterized primarily by spotty skin pigmentation and a variety of endocrine and other tumors, is caused by mutations in PRKAR1A, the gene that codes for the RIalpha subunit of protein kinase A (PKA). PKA controls cell proliferation in many cell types. The cAMP analogue 8-Cl-adenosine (8-Cl-ADO) is thought to inhibit cancer cell proliferation. OBJECTIVE: The objective of the study was to study the antiproliferative effects of 8-Cl-ADO on growth and proliferation in B-lymphocytes of Carney complex patients that have PKA defects and to determine whether 8-CL-ADO could be used as a therapeutic agent in the treatment of Carney complex-associated tumors. DESIGN: We used a multiparametric approach (i.e. growth and proliferation assays, PKA, and PKA subunit assays, cAMP and (3)H-cAMP binding assays, and apoptosis assays) to understand the growth and proliferative effects of 8-Cl-ADO on human B-lymphocytes. RESULTS: 8-Cl-ADO inhibited proliferation, mainly through its intracellular transport and metabolism, which induced apoptosis. PKA activity, cAMP levels, and (3)H-cAMP binding were increased or decreased, respectively, by 8-Cl-ADO, whereas PKA subunit levels were differentially affected. 8-Cl-ADO also inhibited proliferation induced by G protein-coupled receptors for isoproterenol and adenosine, as well as proliferation induced by tyrosine kinase receptors. CONCLUSIONS: 8-Cl-ADO in addition to unambiguously inhibiting proliferation and inducing apoptosis in a PKA-independent manner also has PKA-dependent effects that are unmasked by a mutant PRKAR1A. Thus, 8-Cl-ADO could serve as a therapeutic agent in patients with Carney complex-related tumors.

Protective effects of Peganum harmala extracts on thiourea-induced diseases in adult male rat.

Cancers and hepatoprotective prevention using traditional medicines have attracted increasing interest. The aim of our study was to characterize the putative protective effects of ethanol and chloroform extracts of Peganum harmala on thiourea-induced diseases in adult male rat. We seek to determine the effects of these plant extracts on body weight, thyroid and endocrine cancer parameters. In addition the putative hepatoprotective effect was checked by the determination of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and the bilirubin level in the blood. Our data show that ethanol and chloroform extracts of Peganum harmala protected the animal against the carcinogenic effects induced by thiourea since neuron-specific enolase (NSE) and thyroglobulin (TG) levels were back to the normal range. In addition, the observed-hepatocytotoxicity after thiourea treatment was greatly reduced (AST and ALT activities were respectively 270 IU/l and 60 IU/l and in the same order of magnitude as in the untreated rats) as well as the bilirubin levels (6 micromol/l) especially for animals receiving the choroform preparation. Therefore we may suggest that extracts of Peganum harmala are efficient to reduce the toxicity induced by thiourea in male rat as far as the above parameters are concerned.

Evaluation of IGF-I levels during long-term somatostatin analogs treatment in patients with gastroenteropancreatic endocrine tumors.

Previous experiments reported desensitization to SS action in rat anterior pituitary cells and cell lines. The aim of the study was to verify whether the lack of desensitization to SS analogs (SSa) observed in acromegalic patients was also present in subjects with normal hypothalamic-pituitary function. The effect of chronic treatment with octreotide long-acting release (o-LAR, 10-30 mg/28 days) on IGF-I levels was then evaluated in 23 patients with gastroenteropancreatic (GEP) endocrine tumors (8 gastrinomas, 6 carcinoids, and 9 functioning pancreatic tumors). Serum IGF-I, clinical symptoms, plasma chromogranin-A (CgA) and markers of hepatic synthesis were evaluated before and after a short-term period in all the patients (median 4.5 months), after a medium-term period in 12 (median 18 months) and after a long-term follow-up period in 9 of them (median 48 months). Mean IGF-I levels decreased from 17.3+/-7.0 to 12.8+/-6.2 nmol/l in the short-term (p<0.005) being reduced from baseline concentrations in 87% and under the normal range for age in 35% of patients. Afterwards, they always remained stable both in the medium- and long-term periods, still being low in 3/12 and 2/9 patients, respectively. No alterations in biochemical markers of liver function were found either before or during therapy. No correlation between IGF-I levels, CgA concentrations and/or clinical definitive outcome was observed. In conclusion, the study demonstrated that: a) similarly to that observed in acromegalic patients, chronic o-LAR treatment did not induce desensitization of pituitary SS receptors (SSR) in humans with intact hypothalamic-pituitary axis, and b) in patients with GEP endocrine tumors, GH/IGF-I inhibition did not contribute to SSa efficacy.

A six month mitotane course induced sustained correction of hypercortisolism in a young woman with PPNAD and Carney complex.

A low-dose mitotane (MT) regimen was evaluated as a pharmacological approach for correcting the severe hypercortisolism in a young woman affected by Carney complex (CNC) and primary pigmented nodular adrenocortical disease (PPNAD). In the first 12 week period, the MT daily dose was progressively increased from 0.5 to 4.0 g/day. This dosage was maintained for an additional 16 weeks (cumulative dose 602 g, plasma MT maximum level 12 microg/ml), and then stopped because of sustained signs of hypoadrenalism requiring prednisone replacement. Complete regression of seborrhea, acne, and plethora was observed after 8 weeks of treatment (cumulative dose 95 g). Regular menses returned after 13 weeks (cumulative dose 197 g, plasma MT 8 microg/ml). Profound decrease of both serum cortisol (from 615 to 220 nmol/l) and urinary free cortisol (UFC) values (from 1498 to 477 nmol/day) was noted after 16 weeks of treatment (cumulative dose 314 g, plasma MT 8 microg/ml). MT treatment was associated with mild gastric discomfort and reversible increase of cholesterol plasma levels. Low serum cortisol and UFC were still observed 41 weeks after MT was discontinued (plasma MT 0.2 microg/ml). Our report demonstrates that low dose MT treatment may be a safe and effective modality for a sustained correction of hypercortisolism by PPNAD in subjects with CNC waiting for surgery.

Case report: patient with multiple paragangliomas treated with long acting somatostatin analogue.

Paragangliomas of the head and neck are uncommon neoplasms. They are usually benign, but tend to be locally invasive. Although surgical resection remains the definitive treatment, important issues about management arise when such lesions are inoperable. Beneficial effects of octreotide treatment have already been reported in a malign paraganglioma case. Here we report a 24 year old female with familial, bilateral, multiple paraganglioma in the head and neck region, who firstly presented with pulsatile tinnitus and hearing loss in her left ear. After embolization was performed, she underwent operation twice because of the gross tumor mass. No significant change in tumor size was determined after the operations, however there were no distant metastases. Although she experienced hypertension attacks, no hormonal overproduction was found in repeated measurements. As the tumor was unresectable, new alternative therapies were sought. Octreotide scintigraphy was positive in the tumoral tissue, so we began to treat her with somatostatin analogue octreotide. After a 16 month follow up period, an improvement of the performance status, the near normalisation of attacks and stabilization of tumor growth were achieved. However, in the last three visits, she began to experience symptoms more frequently and it had been necessary to increase the octreotide dose. She is now well and being followed up. In conclusion, the beneficial effects of octreotide treatment could be quantified by clinical, tumor and scintigraphic criteria. These data suggest that octreotide can be useful in the treatment of inoperable paragangliomas.

[Intraoperative diagnosis of a multilocal pheochromocytoma]. / Intraoperative Diagnose eines multilokulären Phäochromozytoms.

Pheochromocytomas are functionally active, catecholamine-secreting tumours of chromaffin tissue. The mainstay of pharmacological therapy is preoperative treatment with oral phenoxybenzamine. This drug irreversibly alkylates alpha-1-adrenergic receptors on vascular smooth muscle and renders them nonfunctional, thereby causing vasodilatation. The duration of action of a single dose is approximately 24 h. Therefore, postoperative hypotension is a hazard of therapy with phenoxybenzamine if adequate plasma volume repletion is not provided. Prazosin, a short-acting, competitive alpha-1 blocker, has been used preoperatively, but has been criticized for its failure to adequately prevent perioperative hypertensive episodes. We report the case of a 73-year-old woman who was admitted for elective pheochromocytoma resection. Preoperative therapy with phenoxybenzamine was impossible because of the patient's refusal to take the drug. Preoperative antihypertensive preparation was therefore performed with prazosin 30 mg/24 h and metoprolol 100 mg/24 h. During the surgical preparation of the tumor, sodium nitroprusside was started at an average infusion rate of 4.1 micrograms/kg/min. After resection of the primary tumor, when the sodium nitroprusside infusion was stopped the patient exhibited an increase in systolic blood pressure (BP) up to 210 mg Hg. This hypertensive crisis was managed with sodium nitroprusside, nitroglycerin, and esmolol. A multilocular pheochromocytoma was diagnosed. Further stimuli due to tumour palpation resulted in repeated increases in BP. In this manner, two additional areas of tumour could be diagnosed by BP peaks after reduction of the sodium nitroprusside infusion. After complete resection of a total of three tumours, no further hypertensive crises occurred. The patient's postoperative course was uneventful. We conclude that in this patient presenting with an unsuspected multilocular pheochromocytoma, the lack of permanent alpha-blockade was probably helpful in allowing complete resection of all the tumours.

Gastric endocrine cell evolution in patients with Zollinger-Ellison syndrome. Influence of gastrinoma growth and long-term omeprazole treatment.

Evolution of gastrinoma tumoral mass, fasting serum gastrin concentrations, and gastric endocrine cells has been analyzed in 21 patients with the Zollinger-Ellison syndrome committed to long-term omeprazole treatment (up to 7.75 years, median 37 months). Gastrinoma growth was seen in eight patients. Significant increase in serum gastrin was only observed in the group of patients with gastrinoma growth. Fundic argyrophil cell densities were correlated with serum gastrin (r' = 0.68, P = 0.002). Argyrophil and antral gastrin cell densities significantly increased during the survey, but increases were greater in the group with gastrinoma growth (respectively, +136% and +131%) than in the other group (respectively, +34% and +43%). Progression in the degree of argyrophil cell hyperplasia, noted qualitatively, was observed in 11 patients. Fundic carcinoids developed in three of these 11 patients, all three having multiple endocrine neoplasia type 1 (MEN 1). Positive linear individual correlations (r > or = 0.85) between argyrophil cell densities and corresponding durations of omeprazole treatment were found in nine of the 10 patients studied at least three times and who had a clear-cut increase in those cell densities. Thus, increase in serum gastrin and fundic argyrophil cell densities appeared closely associated with gastrinoma growth; however, duration of drug-induced hypochlorhydria may also affect cell proliferation.

[Use of octreotide in the treatment of digestive endocrine tumors. A French multicenter study]. / Utilisation de l'octréotide dans les tumeurs endocrines digestives. Etude française multicentrique.

Morbidity and mortality in endocrine gastro-enteropancreatic (GEP) tumours are mainly related to the clinical consequences of tumoral peptide hypersecretion. Surgical resection at an early stage is the only curative treatment. However, most tumours are detected only when the hypersecretory state reflects the presence of metastases; surgery and chemotherapy then give only palliative results counterbalanced by serious side-effects. Somatostatin inhibits most endocrine secretions of the GEP tract and thus can alleviate invalidating symptoms. Its use is limited by its short half-life (2 min), the necessity of i.v. infusion and the possibility of a rebound phenomenon. Octreotide, a synthetic somatostatin analogue with a long duration of action, is administered subcutaneously and allows ambulatory treatment. In our series of 78 patients we observed about 80 percent of excellent or good clinical results, enabling the patients to resume normal life. Only minor and transient side-effects were noted. The overall tolerance of the drug was considered excellent or good. Prolonged administration of octreotide is a safe and effective symptomatic treatment in patients without any restriction of anti-tumoral procedures. Furthermore, it prevents the severe carcinoid crises that occur during surgery or embolization in patients with carcinoid syndromes.