Manuel Luque-Ramírez

The Exon 3-Deleted Growth Hormone Receptor Is Associated with Better Response to Pegvisomant Therapy in Acromegaly

CONTEXT The deletion of exon 3 in the GH receptor (GHR) has been associated with a different biochemical picture and response to therapy in acromegaly. OBJECTIVE The aim of the study was to determine whether or not the GHR genotype influences the efficacy of pegvisomant treatment. DESIGN AND SETTING A cross-sectional study was conducted in six Spanish university hospitals. PATIENTS Forty-four acromegalic patients with active disease and resistance to somatostatin analogs participated in the study. RESULTS The prevalence of the full-length GHR and the exon 3-deleted GHR homozygous and heterozygous genotypes was 41, 2, and 57%, respectively. There were no differences in IGF-I or GH pre-pegvisomant levels related to GHR genotype. The exon 3-deleted patients required approximately 20% lower doses of pegvisomant per kilogram of weight (28 +/- 11 compared to 22 +/- 7 mg per kg of weight; P = 0.033) to normalize IGF-I. A stepwise multivariate linear regression analysis (R(2) = 0.27; P = 0.003) identified male gender (beta = -0.79; P = 0.03) and d3-GHR genotype (beta = -0.64; P = 0.007) as the only significant predictors of the dose of pegvisomant per kilogram of weight. In addition, d3-GHR carriers required fewer months for IGF-I normalization (P < 0.01). A stepwise multivariate linear regression analysis (R(2) = 0.40; P = 0.001) revealed that the only significant predictor of the time to IGF-I normalization was the dose of pegvisomant per kilogram of weight (beta = 0.451; P = 0.001). CONCLUSIONS The exon 3 deletion in the GHR predicts an improved response to pegvisomant therapy in acromegaly.

Somatotroph Tumor Progression during Pegvisomant Therapy: A Clinical and Molecular Study

CONTEXT There is concern that pegvisomant could be associated with a higher risk of tumor growth. The rate and possible determinants of this tumor growth are unknown. OBJECTIVE The objective of the study was to investigate the clinical, immunohistological, and molecular factors conditioning tumor growth in patients taking pegvisomant. DESIGN AND SETTING This was a cross-sectional study performed from 2004 to 2010 in four university hospitals in Spain. PATIENTS Seventy-five acromegalic patients with active disease resistant to somatostatin analogs treated with pegvisomant were followed up for a mean of 29 ± 20 months. MAIN OUTCOME MEASURES Magnetic resonance images before initiation of pegvisomant, at 6 months, and then yearly were examined in all patients. Immunohistological and molecular studies were performed in tumors that grew. RESULTS A significant increase in tumor size was observed in five patients (6.7%). Absence of previous irradiation (P = 0.014) and shorter duration of prepegvisomant somatostatin analog therapy (P < 0.001) were associated with an increased risk of tumor growth. A stepwise multivariate linear regression analysis (R(2) = 0.334, P < 0.001) identified the duration of somatostatin analog therapy prior to pegvisomant (beta = -4.509, P = 0.014) as the only significant predictor of tumor growth. In those tumors that grew, GH expression and insulin receptor expression were higher (P = 0.033 in both cases) than in the control group. CONCLUSIONS No previous radiotherapy, shorter duration of prepegvisomant somatostatin analog therapy, and higher tumor expression of GH and insulin receptor could be risk factors for tumor growth during pegvisomant therapy.

Pegvisomant-induced liver injury is related to the UGT1A1*28 polymorphism of Gilbert's syndrome.

CONTEXT Pegvisomant (PEG) therapy has been associated with drug-induced liver dysfunction in acromegalic patients. The mechanism of its toxicity remains unknown. OBJECTIVE The primary objective was to determine whether or not the UGT1A1*28 polymorphism associated with Gilberts syndrome influences the development of liver dysfunction during PEG treatment. DESIGN AND SETTING A cross-sectional study was conducted in four Spanish university hospitals. PATIENTS Thirty-six acromegalic patients with active disease, resistant to somatostatin analogs, participated. RESULTS The prevalence of the UGT1A1*28 homozygous and heterozygous genotypes in acromegalic patients was 14 and 44%, respectively. Ten patients (28%) developed liver function test (LFT) abnormalities. There was a tendency for more frequent liver function abnormalities in males (70% males vs. 30% females, P = 0.058). Carriers of the UGT1A1*28 polymorphism had a higher incidence of LFT abnormalities than the UGT1A1 wild type (43% carriers vs. 7% wild type, P = 0.024). This difference persisted when adjusted in an all-factors multiple regression analysis [coefficient of determination (R(2)) = 0.463; P = 0.008] for age, gender, alcohol consumption, and UGT1A1*28 polymorphism. A stepwise multivariate likelihood binary logistic regression analysis (R(2) = 0.40; P = 0.003) identified male gender (beta = 7.21; P = 0.033) and UGT1A1*28 polymorphism (beta = 14.1; P = 0.028) as the only significant predictors for the development of LFT abnormalities. CONCLUSIONS The UGT1A1*28 genotype and male gender predict an increased incidence of LFT abnormalities during PEG therapy in acromegaly.

99MTc-Sestamibi as sole technique in selection of primary hyperparathyroidism patients for unilateral neck exploration

BACKGROUND Unilateral neck exploration (UNE) is becoming the procedure of choice for treatment of primary hyperparathyroidism (PHPT). The aim of this study was to evaluate the role of (99m)Tc-sestamibi (MIBI) parathyroid scintigraphy as the sole technique in selecting patients for UNE. METHOD We selected 136 consecutive PHPT patients who had only 1 solitary uptake at a MIBI were for UNE. The technique was a single dual-phase using MIBI and a subtraction technique with (99m)Tc-pertechnetate. Imaging data were correlated with surgical results. RESULTS In 3 cases, the sestamibi scan was falsely positive, 1 had a contralateral location relative to the uptake, and 2 had multiglandular hyperplasia. Overall, the positive predictive value (PPV) of MIBI for detecting a solitary parathyroid adenoma in patients with 1 solitary uptake was 97.8. Sixteen patients (12%) had evidence of multinodular goiter. Overall, the PPV of MIBI was 98.4% (2 false positive among 120 cases) in patients with no multinodular thyroid disease (MNG) and 93.7% (1 false negative among 16 cases) in patients with MNG. The mean duration of the surgical procedure was 34.17 minutes. Mean hospitalization was 0.6 days. Conversion to bilateral neck exploration was performed in 5 patients. After a period of follow-up of 40 months (range, 6-72 months), the cure rate was 98%. CONCLUSION Patients with PHPT and unequivocally positive preoperative (99m)Tc-sestamibi can safely be managed with UNE without additional localizing techniques.

Cost of Clinical Management of Acromegaly in Spain

AbstractIntroduction and Background: The cost of the therapeutic management of acromegaly depends on the selection of resources used, surgery and/or pharmacological treatment, by the specialist responsible for treatment, related to the characteristics of the patient and tumour. The objective of this work is to evaluate these costs for an illness that is rare but that is associated with a high morbidity in the context of routine clinical practice. Methods: This was an epidemiological, prospective, naturalistic, multicentre study in Spain, in which 38 endocrinologists participated. Adult patients with acromegaly and a pituitary microadenoma or macroadenoma were included in the study. Patients were assigned, according to first-line treatment, to the following two groups: surgery first-line group (surgery in the 6 months before inclusion or during the follow-up period) and pharmaceutical first-line group (treatment with somatostatin analogues [SAs] for at least 6 months and with or without surgery after starting treatment with SAs). Data were collected during routine visits made during a follow-up period of 2 years. All resources were estimated at 2009 prices (€) and adjusted according to the Spanish consumer price index in 2010. Results: Seventy-four patients were included, the majority of them with macroadenoma (70%). Eighty-eight percent of patients were treated surgically (76% as a first-line treatment), while 12% of patients received only SAs. Treatment with SAs was used at some point in the study by 85% of patients. The mean annual total cost of acromegaly is h9668 per patient (€9223 for the surgery group and €11 054 for the pharmaceutical group). Seventy-one percent of the direct cost of the disease corresponds to treatment with SAs. The cost of a patient treated only with surgery is €2501 on an annual basis, versus €9745 for a patient receiving only pharmacological treatment. In cases where a combination of both types of treatment is required, the annual total cost ranges from €10 866 to €12364. Conclusion: The annual direct cost per patients of acromegaly in Spain is €9668. Even though surgery is the preferred option for treatment for a great number of patients, SAs must be added to the treatment regimen of the majority of such patients. The costs associated with this treatment are greater than the cost of treatment with SAs alone.

Cost of management of invasive growth hormone-secreting macroadenoma

Background: At the time of diagnosis, macroadenomas represent 60–80% of GH secreting adenomas, of which 25–30% are invasive macroadenomas. These aggressive tumors have the worst surgical success rates in terms of cure, and often need several therapeutic approaches in order to control disease status. Acromegalic patients are subject to increased mortality and important health resource consumption related to their associated co-morbidities, in addition to the costs that are related to diagnosis itself and initial treatment of the disease. Objective: Assessment of the cost of initial management and outcome of acromegalic patients with invasive pituitary adenomas. Study design: Retrospective and observational study of review of records. Setting: Two tertiary hospitals. Patients: 11 consecutive patients between 18 and 80 yr old diagnosed with acromegaly due to an invasive pituitary macroadenoma. Intervention: Collection of data of biochemical and radiological tests, specialist visits, hospitalisation, surgery, pharmacological and radiotherapy treatment at diagnosis and over 4 yr of follow-up after initial treatment. Costs were evaluated using the data of the Centre for Health Economics and Social Policy Studies and the Official College of Pharmacists of Spain. Main outcome measure: Global and patient/yr follow-up costs of illness. Results: The mean costs for acromegaly for the period of follow-up ranged from 7,072 to 9,874 €/patient/yr, for biochemically non-controlled (no.=6) and controlled patients (no.=5) respectively. The most important cost in the perioperative period was for admission in the intensive care unit. After surgery, SS analogues were the principal contributors to the economic burden. Conclusion: In this paper we have for the first time presented a pharmacoeconomic study of GH secreting invasive macroadenoma. The poor prognosis of our cohort of patients and the higher rate of controlled patients and normal IGF-I levels warrant the employment of multiple therapeutic options. The cost associated with this treatment in this complex disease of low prevalence is not excessive and can be supported by healthcare services.

Estudio OASIS: manejo terapéutico de la acromegalia en un escenario de práctica clínica habitual. Evaluación de la eficacia de las diversas estrategias de tratamiento aplicadas

BACKGROUND AND OBJECTIVES The reported efficacy of treatments for acromegaly varies depending on reference centers and national registries. The aim of this study was to describe clinical management of this disease and to assess the efficacy of treatments used in standard clinical practice. MATERIAL AND METHODS An epidemiological, observational, longitudinal, multicenter study was performed in adult patients with newly diagnosed acromegaly (n = 74) seen by 38 Spanish endocrinologists who collected during routine clinic visits data on disease treatment and control during 2 years of follow-up. RESULTS Pituitary surgery and treatment with somatostatin analogs were the first choice therapies in 76% and 24% of patients respectively, with no differences related to tumor size. Surgery achieved disease control in 27% of operated patients. After surgery failure, the preferred therapeutic option were somatostatin analogs, which normalized insulin-like growth factor-1(IGF-I) in 52% of patients and achieved disease control criteria in more than 40% of patients. At the end of follow-up, normal IGF-I levels were found in 63% and 53% of patients with microadenomas and macroadenomas respectively. Only 19% of patients with macroadenoma met disease control criteria without requiring drug treatment, which was required by 85% of them at some time during follow-up. CONCLUSIONS Surgery is the preferred initial treatment for patients with acromegaly, regardless of tumor size. Treatment efficacy in actual clinical practice is far from the success rates reported by reference centers.

Fibrosis quística, bocio e hipertiroidismo

El aumento de tamano de la glandula tiroidea por deposito de material amiloide, conocido como bocio amiloide, es una rara entidad clinica. En la mayoria de los casos publicados, los pacientes presentan una funcion tiroidea normal; menos frecuente es la presencia de hipofuncion tiroidea, y aun mas infrecuente la asociacion con hiperfuncion tiroidea. Comunicamos un caso de bocio amiloide e hipertiroidismo primario, secundario a amiloidosis sistemica, en un paciente con fibrosis quistica, sin sintomas compresivos y clinica de hiperfuncion tiroidea. A continuacion, realizamos una breve revision de este proceso y su tratamiento.

Nonfunctional Metastatic Parathyroid Carcinoma in the Setting of Multiple Endocrine Neoplasia Type 2A Syndrome.

Parathyroid carcinoma is a very rare malignancy. It has been associated with hyperparathyroidism-jaw tumour syndrome, familial isolated primary hyperparathyroidism, and multiple endocrine neoplasia type 1 (MEN-1) and 2A (MEN-2A) syndromes. We report a 54-year-old man with a MEN-2A which presents with a nonfunctional metastatic parathyroid carcinoma and a pheochromocytoma in the absence of medullary thyroid carcinoma. Only a few cases of parathyroid carcinoma have been reported in the literature associated with this syndrome.

Nell’acromegalia la delezione dell’esone 3 del recettore del GH si associa a una migliore risposta alla terapia con pegvisomant

RiassuntoNei pazienti acromegalici la delezione genomica dell’esone 3 a livello del recettore del GH (GHR) è stata associata a un differente quadro biochimico e a una differente risposta alla terapia. Lo scopo di questo studio è stato quello di valutare se i diversi genotipi del GHR influenzino l’efficacia della terapia con pegvisomant. Sono stati studiati 44 pazienti acromegalici con malattia attiva e resistenti alla terapia con analoghi della somatostatina.RisultatiLa prevalenza dei pazienti con mancata delezione dell’esone 3 del GHR (fl-GHR) e quelli con genotipo omozigote o eterozigote per tale delezione (d3-GHR) era rispettivamente del 41, 2 e 57%. Non sono state osservate differenze nei livelli di GH e IGF-1 prima della terapia con pegvisomant in relazione alle varianti polimorfiche del GHR. I pazienti con delezione dell’esone 3 richiedevano una dose di pegvisomant di circa il 20% più bassa e minor tempo per normalizzare i livelli di IGF-1. L’analisi di regressione lineare multipla ha individuato come unici predittori significativi della dose di pegvisomant il sesso maschile e la delezione dell’esone 3 del GHR e come unico predittore del tempo di normalizzazione dell’IGF-1 la dose di pegvisomant utilizzata.In conclusione, la delezione dell’esone 3 del recettore del GH sembra predire una migliore risposta alla terapia con pegvisomant nei pazienti acromegalici.