Management of acromegaly in Latin America: expert panel recommendations

Although there are international guidelines orienting physicians on how to manage patients with acromegaly, such guidelines should be adapted for use in distinct regions of the world. A panel of neuroendocrinologists convened in Mexico City in August of 2007 to discuss specific considerations in Latin America. Of major discussion was the laboratory evaluation of acromegaly, which requires the use of appropriate tests and the adoption of local institutional standards. As a general rule to ensure diagnosis, the patient’s GH level during an oral glucose tolerance test and IGF-1 level should be evaluated. Furthermore, to guide treatment decisions, both GH and IGF-1 assessments are required. The treatment of patients with acromegaly in Latin America is influenced by local issues of cost, availability and expertise of pituitary neurosurgeons, which should dictate therapeutic choices. Such treatment has undergone profound changes because of the introduction of effective medical interventions that may be used after surgical debulking or as first-line medical therapy in selected cases. Surgical resection remains the mainstay of therapy for small pituitary adenomas (microadenomas), potentially resectable macroadenomas and invasive adenomas causing visual defects. Radiotherapy may be indicated in selected cases when no disease control is achieved despite optimal surgical debulking and medical therapy, when there is no access to somatostatin analogues, or when local issues of cost preclude other therapies. Since not all the diagnostic tools and treatment options are available in all Latin American countries, physicians need to adapt their clinical management decisions to the available local resources and therapeutic options

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course

Aplicación de Biodentine en Endodoncia Regenerativa

Universidad de Buenos Aires. Facultad de Odontología. Cátedra de Odontología Integral Niños. Buenos Aires, Argentina.Universidad de Buenos Aires. Facultad de Odontología. Cátedra de Odontología Integral Niños. Buenos Aires, Argentina.Universidad de Buenos Aires. Facultad de Odontología. Cátedra de Odontología Integral Niños. Buenos Aires, Argentina

Effect of D-Leucine-6-Luteinizing Hormone-Releasing Hormone Ethylamide in Patients with Hypogonadotropic Hypogonadism with Anosmia

Four men with hypogonadotropic hypogonadism and anosmia were tested with acute intravenous injections of luteinizing hormone-releasing hormone (LH-RH) and D-leucine-6-LH-RH-ethylamide (D-Leu-6-LH-RH-EA) with a 1-week interval. Each patient was then treated with this drug for 60 days and tested again after this period with an intravenous injection of D-Leu-6-LH-RH-EA. The administration of LH-RH resulted in a significant increase in the LH level in only one patient and in follicle-stimulating hormone (FSH) and testosterone increases in none. The analog D-Leu-6-LH-RH-EA resulted in significant increases in LH levels in two patients, in FSH levels in three, and in testosterone levels in one. Results obtained after treatment were closely similar to those observed before treatment. Clinical improvement in terms of increased libido, erection, pubic hair growth, and testicular size was observed. D-Leu-6-LH-RH-EA could be useful in the treatment of patients with hypogonadotropic hypogonadism, a possibility deserving further studies

My health smartphone intervention decreases daily fat sources among Latina breast cancer survivors

Breast cancer is the most common cancer among Latina women, and Latina women are at higher risk for breast cancer mortality than white women. Lifestyle factors, such as consuming a nutritious diet and engaging in regular physical activity, promote health and are protective against heart disease, type 2 diabetes, and breast cancer recurrence. Previous studies have developed and tested interventions for Latina breast cancer survivors to improve diet and increase physical activity, however, no studies to date have developed a smartphone delivered intervention. The purpose of the current study was to compare two Smartphone delivered interventions, My Health, which focused on diet and physical activity, and My Guide, which focused on psychosocial functioning, on dietary and physical activity outcomes, post-intervention, and at a 2-week follow-up assessment. Overall, participants receiving the My Health intervention reported a greater reduction in daily fat sources than the My Guide group over time. However, daily sources of fat did not differ between conditions. Walking, measured by estimated weekly metabolic equivalents, increased across time points in both groups. These preliminary findings suggest that eHealth interventions aimed at improving lifestyle factors may favorably impact nutritional intake and physical activity. Future research should utilize more comprehensive and objective measures of diet and physical activity, and incorporate more behavioral lifestyle components into the intervention in larger samples with a longer follow-up period

Pheochromocytomas and pituitary adenomas in three patients with MAX exon deletions

Copy number variations (CNV), an important genetic mechanism in inherited tumor genetics, can affect large genetic regions or can be limited to smaller regions within genes, such deletions of single exons. Such exon deletions can be challenging to identify and sequencing can be normal in these cases. Multiplex ligation dependent probe amplification (MLPA) can identify CNV of individual exons. Mutations in the MAX gene are associated with a risk of sporadic and hereditary pheochromocytoma. As mutations in other pheochromocytoma related genes can also cause pituitary tumors (3P-Association), we studied whether MAX exon deletions were involved in the etiology of patients with an unexplained association of multiple endocrine neoplasia including pituitary adenoma and pheochromocytoma. Using MLPA we identified three patients with pheochromocytoma and pituitary adenomas who had normal MAX sequencing but presented germline heterozygous MAX exon deletions. The three patients had either acromegaly (n=2) or prolactinoma (n=1) in association with bilateral or recurrent pheochromocytoma. Two had germline heterozygous deletions of single exons of MAX, the other had a germline heterozygous deletion of MAX exons 1-3. MAX immunohistochemical staining was lost in the pheochromocytomas of all three patients and genetic analysis confirmed loss of heterozygosity in tumor DNA. A MAX exon deletion was also transmitted from one patient to a currently asymptomatic offspring. Screening studies of pheochromocytoma patients should take into account the potential for co-existing pituitary tumors. MLPA or other techniques to identify discrete MAX exon deletions should be considered in individuals with pheochromocytoma that are negative following comprehensive sequencing

Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial

Background Many patients with acromegaly do not achieve biochemical control despite receiving high doses of the first-generation somatostatin analogues octreotide or lanreotide. In the PAOLA trial, we aimed to assess the efficacy and safety of two different doses of the somatostatin analogue pasireotide long-acting release compared with active control (octreotide or lanreotide) in patients with inadequately controlled acromegaly.Methods In a multicentre, randomised, phase 3 trial, we enrolled eligible patients aged 18 years or older with acromegaly who were inadequately controlled (5-point, 2 h mean growth hormone concentration > 2.5 mu g/L and insulin-like growth factor 1 [IGF-1] concentration >1.3 times the upper normal limit) and had received 30 mg octreotide long-acting repeatable or 120 mg lanreotide (Somatuline Autogel; Ipsen, UK) as monotherapy for 6 months or longer. We randomly assigned patients in a 1:1:1 ratio with an interactive voice-web response system to receive 40 mg pasireotide long-acting release once every 28 days for 24 weeks, 60 mg pasireotide long-acting release once every 28 days for 24 weeks, or continued treatment with octreotide or lanreotide (active control). Patients were stratified according to previous treatment (octreotide or lanreotide) and growth hormone concentrations at screening (2.5-10 mu g/L and > 10 mu g/L). Patients and study investigators were not masked to study drug assignment but were masked to pasireotide dose allocation. The primary endpoint was number of patients achieving biochemical control, defined as mean growth hormone concentration less than 2.5 mu g/L and normalised IGF-1 concentration. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01137682.Findings Between Dec 17, 2010, and Aug 6, 2012, 198 patients were enrolled and randomly assigned to pasireotide 40 mg (n=65), pasireotide 60 mg (n=65), or active control (n=68) groups. At 24 weeks, ten (15%) patients in the pasireotide 40 mg group and 13 (20%) patients in the pasireotide 60 mg group achieved biochemical control, compared with no patients in the active control group (absolute difference from control group 15.4%, 95% CI 7.6-26.5, p=0.0006 for pasireotide 40 mg group, 20.0%, 11.1-31.8, p<0.0001 for pasireotide 60 mg group). The most common adverse events were hyperglycaemia (21 [33%] for treatment with 40 mg pasireotide, 19 [31%] with 60 mg pasireotide, and nine [14%] with active control), diabetes (13 [21%], 16 [26%], and five [8%]), and diarrhoea (ten [16%], 12 [19%], and three [5%]); most were grade 1 or 2 in severity. Serious adverse events were reported in six (10%) patients in the pasireotide 40 mg group, two (3%) in the pasireotide 60 mg group, and three (5%) in the active control group.Interpretation Pasireotide provides superior efficacy compared with continued treatment with octreotide or lanreotide, and could become the new standard pituitary-directed treatment in patients with acromegaly who are inadequately controlled using first-generation somatostatin analogues.Funding Novartis Pharma AG. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation

Clinical characteristics and therapeutic responses in patients with Germ-line AIP mutations and pituitary adenomas : An international collaborative study

Context: AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively. Objective: The objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas. Design: This study was an international, multicenter, retrospective case collection/database analysis. Setting: The study was conducted at 36 tertiary referral endocrine and clinical genetics departments. Patients: Patients included 96 patients with germline AIPmut and pituitary adenomas and 232 matched AIPmut-negative acromegaly controls. Results: The AIPmut population was predominantly young and male (63.5%); first symptoms occurred as children/adolescents in 50%. At diagnosis, most tumors were macroadenomas (93.3%); extension and invasion was common. Somatotropinomas comprised 78.1% of the cohort; there were also prolactinomas (n = 13), nonsecreting adenomas (n = 7), and a TSH-secreting adenoma. AIPmut somatotropinomas were larger (P = 0.00026), with higher GH levels (P = 0.00068), more frequent extension (P = 0.018) and prolactin cosecretion (P = 0.00023), and occurred 2 decades before controls (P < 0.000001). Gigantism was more common in the AIPmut group (P < 0.000001). AIPmut somatotropinoma patients underwent more surgical interventions (P = 0.00069) and had lower decreases in GH (P = 0.00037) and IGF-I (P = 0.028) and less tumor shrinkage with somatostatin analogs (P < 0.00001) vs. controls. AIPmut prolactinomas occurred generally in young males and frequently required surgery or radiotherapy. Conclusions: AIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility