Personalized medicine in acromegaly: The ACROFAST study.

Medical treatment of acromegaly is currently performed through a trial-error approach using first generation somatostatin receptor ligands (fgSRLs) as first-line drugs, with an effectiveness of about 50%, and subsequent drugs are indicated through clinical judgment. Some biomarkers can predict fgSRLs response. Here we report the results of the ACROFAST study, a clinical trial in which a protocol based on predictive biomarkers of fgSRLs was evaluated. METHODS AND SUBJECTS: prospective trial (21 university hospitals) comparing the effectiveness and time-to control of two treatment protocols during 12 months: A) A personalized protocol in which first option were fgSRLs as monotherapy or in combination with pegvisomant or, pegvisomant as monotherapy depending on the short Acute Octreotide Test (sAOT) results, tumor T2 Magnetic Resonance (MRI) signal or immunostaining for E-cadherin and, B) A control group with treatment always started by fgSRLs and the other drugs included after demonstrating inadequate control. RESULTS: Eighty-five patients participated; 45 in the personalized and 40 in the control group. More patients in the personalized protocol achieved hormonal control compared to those in the control group (78% vs 53%, p < 0.05). Survival analysis revealed a hazard ratio for achieving hormonal control adjusted by age and sex of 2.53 (CI 1.30-4.80). Patients from personalized arm were controlled in a shorter period of time (p = 0.01). CONCLUSION: Personalized medicine is feasible using a relatively simple protocol and allows a higher number of patients achieving control in a shorter period of time.

Clinical Significance of T2-Weighted Sequence Intensity on Magnetic Resonance Imaging in Clinically Non-Functioning Pituitary Adenomas.

BACKGROUND: Little is known about the relationship between signal intensity patterns on T2-weighted magnetic resonance imaging (MRI) in non-functioning pituitary adenomas (NFPAs). OBJECTIVE: In this study, the clinical, hormonal, histological features, and therapeutic responses were evaluated according to the T2 signal intensity in NFPAs. METHODS: This retrospective and multicenter study included a group of 166 NFPA patients (93 men, 56%, mean age 58.5 ±14.8 yr). RESULTS: Approximately half of the tumors (n=84, 50.6%) were hyperintense, while 34.3% (n=57) and 15.1% (n=25) were iso- and hypointense, respectively. The median maximum tumor diameter of the isointense group [16 (13-25) mm] was significantly lower than that of the hyperintense [23 (16.6-29.7) mm] group (p=0.003). Similarly, the tumor volume of the isointense group [1,523 (618-5,226) mm3] was significantly lower than that of the hyperintense [4,012 (2,506-8,320) mm3] group (p=0.002). Chiasmatic compression occurred less frequently in tumors with isointense signal characteristics (38.6%) compared to tumors with hypointense (68%) and hyperintense (65.5%) signal characteristics (p=0.003). Invasive adenomas (p=0.001) and the degree of cavernous sinus invasion (p<0.001) were more frequent in the hyperintense adenoma group compared to the remaining groups. Plurihormonal tumors and silent lactotroph adenomas were more frequent in the isointense tumor group. CONCLUSION: In conclusion, hyperintensity on T2-weighted MRI in NFPAs is associated with larger and more invasive tumors compared to isointense NFPAs.

Revisiting the usefulness of the short acute octreotide test to predict treatment outcomes in acromegaly.

Introduction: We previously described that a short version of the acute octreotide test (sAOT) can predict the response to first-generation somatostatin receptor ligands (SRLs) in patients with acromegaly. We have prospectively reassessed the sAOT in patients from the ACROFAST study using current ultra-sensitive GH assays. We also studied the correlation of sAOT with tumor expression of E-cadherin and somatostatin receptor 2 (SSTR2) . Methods: A total of 47 patients treated with SRLs for 6 months were evaluated with the sAOT at diagnosis and correlated with SRLs' response. Those patients whose IGF1 decreased to <3SDS from normal value were considered responders and those whose IGF1 was ≥3SDS, were considered non-responders. The 2 hours GH value (GH2h) after s.c. administration of 100 mcg of octreotide was used to define predictive cutoffs. E-cadherin and SSTR2 immunostaining in somatotropinoma tissue were investigated in 24/47 and 18/47 patients, respectively. Results: In all, 30 patients were responders and 17 were non-responders. GH2h was 0.68 (0.25-1.98) ng/mL in responders vs 2.35 (1.59-9.37) ng/mL in non-responders (p<0.001). GH2h = 1.4ng/mL showed the highest ability to identify responders (accuracy of 81%, sensitivity of 73.3%, and specificity of 94.1%). GH2h = 4.3ng/mL was the best cutoff for non-response prediction (accuracy of 74%, sensitivity of 35.3%, and specificity of 96.7%). Patients with E-cadherin-positive tumors showed a lower GH2h than those with E-cadherin-negative tumors [0.9 (0.3-2.1) vs 3.3 (1.5-12.1) ng/mL; p<0.01], and patients with positive E-cadherin presented a higher score of SSTR2 (7.5 ± 4.2 vs 3.3 ± 2.1; p=0.01). Conclusion: The sAOT is a good predictor tool for assessing response to SRLs and correlates with tumor E-cadherin and SSTR2 expression. Thus, it can be useful in clinical practice for therapeutic decision-making in patients with acromegaly.

Effect of cabergoline on tumor remnant after surgery in nonfunctioning pituitary adenoma.

BACKGROUND: In recent years, dopamine agonists (DAs) have become an attractive therapeutic option to prevent both tumor growth and post-surgical tumor remnant growth in clinically non-functioning pituitary adenoma (NFPA). AIM: To analyze our experience on the effect of cabergoline (CAB) on tumor remnant after initial surgery in NFPA patients. PATIENTS AND METHODS: A retrospective and multicenter study of NFPA patients with tumor remnant after surgery treated with CAB was performed. RESULTS: From a total of 142 NFPA patients (79 men, 55.2%; mean age 57.2 ± 14.2 year) who underwent surgery, we selected 62/142 (43.7%) patients (32 men, 51.6%; mean age 59.3 ± 13.9 year) with tumor persistence (TP) after surgery. In 22/62 (35.5%) TP patients CAB was used (CAB group), while the rest of the patients (40/62, 64.5%) underwent active surveillance [observation (OBS) group)]. The maximum diameter of the tumor remnant did not change significantly in either the CAB group [11.5 (6.0-16.9) mm vs. 12.0 (7.0-15.0) mm, p = 0.85) or the OBS group [8.5 (6.0-13.7) mm vs. 9.0 (6.2-14.0) mm, p = 0.064) at the end of the follow-up [13 (10.5-17) vs. 77.5 (50.2-107.2) months, CAB vs. OBS group; p < 0.001]. At the end of the treatment period with CAB most of the patients (n = 20/22, 90.9%) showed no progression of the tumor remnant [stable disease, SD (n = 17/22, 77.2%) and partial response, PR (n = 3/22, 13.6%)], while 2/22 patients (9.1%) exhibited progression. Similar response rates were observed in the OBS group [SD (n = 32/40, 80%), PR (n = 2/40, 5%), and progression (n = 6/40, 15%)]. Although no statistically significant differences (p = 0.42) were found in these responses, the percentage of progression was 1.65 times higher in the OBS group compared to the CAB group. On the contrary, the percentage of PR was 2.72 times higher in the CAB group compared to the OBS group, despite a significantly shorter follow-up period in the CAB group. CONCLUSION: Although the present study showed no significant differences in the type of tumor response between the CAB and OBS groups of patients, the percentage of PR was higher and that of progression lower in the CAB group compared to the OBS group. This finding does not rule out a potential therapeutic benefit of CAB in the management of tumor remnant in patients with NFPA undergoing surgery.

Hiperandrogenismo secundario a tumor suprarrenal: causa rara a tener en cuenta / Hyperandrogenism secondary to suprarrenal tumor: rare cause to take into account

Se conoce como hiperandrogenismo al exceso de andrógenos en la mujer. Una causa poco frecuente de hiperandrogenismo consiste en la presencia de tumores de la corteza suprarrenal productores de andrógenos, siendo la mayoría de ellos malignos. Se exponen 2 casos de tumores suprarrenales productores de andrógenos con diagnóstico final de adenomas a pesar de la presencia inicial de distintos datos que orientaban a una naturaleza maligna (AU)

The excess of androgen in women is known as hyperandrogenism. A rare cause of hyperandrogenism consists of the presence of tumors, mostly malignant tumors, in the adrenal cortex that produces androgens. We present two adrenal tumoral cases that produce androgen with adenoma final diagnosis in spite of the initial presence of several data oriented towards a malignant nature (AU)

Analysis of IGF(CA)19 and IGFBP3-202A/C gene polymorphisms in patients with acromegaly: association with clinical presentation and response to treatments.

OBJECTIVE: IGF1 and IGFBP3 gene polymorphisms have been recently described. However, their potential role in the setting of acromegaly and its outcome is unknown. In this study, we analyze these polymorphisms in patients with acromegaly and investigate their association with clinical presentation and response to treatments. DESIGN: A retrospective observational study was conducted in patients with acromegaly to analyze IGF1 and IGFBP3 gene polymorphisms. METHODS: A total of 124 patients with acromegaly (57.3% women, mean age 44.9±13.1 years old) were followed up for a period of 11.4±8.0 years in eight tertiary referral hospitals in Spain. Clinical and analytical data were evaluated at baseline and after treatment. IGF1 and IGFBP3 gene polymorphisms were analyzed using PCR and specific primers. RESULTS: Baseline laboratory test results were GH 19.3 (8.0-39.6) ng/ml, nadir GH 11.8 (4.1-21.5) ng/ml, and index IGF1 2.65±1.25 upper limit of normal. Regarding the IGF1 gene polymorphism, we did not find any association between the number of cyto-adenosine (CA) repeats and patients' baseline characteristics. Nevertheless, a trend for higher nadir GH values was observed in patients with <19 CA repeats. Regarding the IGFBP3 polymorphism, the absence of an A allele at the -202 position was associated with a higher baseline IGF1 and a higher prevalence of cancer and polyps. There were no differences in response to therapies according to the specific genotypes. CONCLUSIONS: Polymorphisms in the IGF1 and IGFBP3 genes may not be invariably determinant of treatment outcome in acromegalic patients, but they may be associated with higher nadir GH levels or baseline IGF1, and determine a higher rate of colorectal polyps and cancer.

[Cardiac abnormalities in osteogenesis imperfecta. Case-control echocardiographic study]. / Alteraciones cardiacas en la osteogénesis imperfecta. Estudio ecocardiográfico de casos y controles.

BACKGROUND AND OBJECTIVES: Osteogenesis imperfecta is a rare disease with abnormal synthesis of type 1 collagen that affects diverse extra-skeletal tissues. Aortic root dilatation and valvular dysfunction have been described. Our purpose was to evaluate the prevalence of cardiac abnormalities in patients with osteogenesis imperfecta in comparison with an age and sex-matched control group of healthy people. PATIENTS AND METHODS: We prospectively studied 26 patients with osteogenesis imperfecta and compared them with 25 healthy people. All patients underwent a transthoracic standard M-mode, 2D and colour Doppler study. RESULTS: We did not find significant differences between both groups in the left ventricular diastolic and systolic function and the incidence of valvulopathies. The dimensions of the aortic root, left atrium and left ventricle when indexed by body surface area were significantly larger in patients with osteogenesis imperfecta compared with the control group, which was probably due to the reduced body surface of these patients. However there was a significant difference in the aortic root/telediastolic diameter of left ventricle ratio independent of the body surface, which was higher in patients with osteogenesis imperfecta. CONCLUSIONS: The incidence of valvular disease in osteogenesis imperfecta is similar to that of the normal population. However aortic root is larger in the former patients and is related to the left ventricular diastolic diameter.

Effect of glycaemic control on the vascular nitric oxide system in patients with type 1 diabetes.

OBJECTIVE: The mechanisms underlying the relationship between the vascular complications of diabetes and the glycaemic control are not well understood. We tested whether glycaemic control influences the functioning of the nitric oxide system in type 1 diabetic patients and the role for oxidative stress. METHODS: The changes in the forearm blood flow after the infusion in the brachial artery of NG-monomethyl-l-arginine, methacholine, methacholine plus superoxide dismutase, and nitroprusside were evaluated using strain gauge plethysmography in 14 healthy subjects and 24 patients with type 1 diabetes (12 with HbA(1c) < 7.5%; 12 with HbA(1c) > or = 7.5%). After adjusting insulin treatment, the vascular studies were repeated in the initially poorly controlled patients (HbA(1c) > or = 7.5%). RESULTS: Compared with healthy people, impaired vascular responses to NG-monomethyl-l-arginine (P = 0.0001), methacholine (P = 0.007) and nitroprusside (P = 0.0015) were found in the patients with type 1 diabetes and a poor glycaemic control (HbA(1c) >/= 7.5%), but not in subjects with good control (HbA(1c) < 7.5%). Superoxide dismutase improved the responses to methacholine only in those patients with poor control (P = 0.0037). After the adjustment of the insulin treatment in poorly-controlled patients, the responses improved and the effect of superoxide dismutase disappeared only in the patients that achieved good control (n = 9), but not in those who remained poorly-controlled (n = 3). CONCLUSIONS: In patients with diabetes type 1, glycaemic control determines the functioning of the NO system by a reversible mechanism involving superoxide anions. This finding provides an explanation of the relationship between glycaemic control and vascular complications in diabetes.

Tratamiento del dolor postoperatorio con analgésicos no narcóticos / Analgesic processing of the postoperating pain with nonnarcotic

Analiza que el dolor postoperatorio debe permitir una buena calidad analgésica, sin aumentar el tiempo de estancia en la sala de recuperación y el riesgo de complicaciones. Así mismo debe presentar mínimos efectos secundarios, un amplio margen de seguridad y una cómoda administración. Uno de los fármacos que ha demostradp un buen nivel de analgesia con pocos efectos adversos es el diclofenaco sódico. Para ello se selecciona un grupo randomizado de 50 pacientes, durante el período de ene.-mar. 1996, todas ellas con dignóstico de miomatosis uterino y sometidas a histerectomía por vía abdominal, sus edades estuvieron comprendidas entre 27 y 50 años (media de 38.5 años), a todas ellas se les realizó anestesia general previa inducción con tiopental y vencuronio, mantenimiento con ethrane, transanestésico estable; se aplicó para la medición del dolor postoperatorio el análogo visual y verbal del dolor...

Opioides para analgesia en pacientes gineco obstétricos / Opioides for analgesia in patients gineco obstetricos

Expone que el uso de narcóticos opiáceos epidurales con el objeto de aliviar el dolor del paciente durante el transoperatorio y postoperatorio, no es nuevo; sin embargo su uso es controversial a causa de los múltiples efectos adversos de los que se les acusa empezando por náusea, vómito, prurito, retención urinaria y lo que es más depresión respiratoria. Pese a algunos trabajos similares al respecto, hemos querido comprobar en nuestro medio, específicamente en nuestro lugar de trabajo la eficacia o no de dicho tratamiento; para ello se realizó un estudio comparativo randomizado durante los meses de ene.-mar. 1996, en un grupo de 95 pacientes dividido aleatoriamente en dos grupos sin epinefrina 1:2000000 320 mg+112.5 mg de Bicarbonato de sodio, la edad promedio del grupo A fue de 31.9 años y con un peso promedio de 63.9 kg., todas sometidas a cesárea por diferentes causas Grupo B; con anestesia epidural continua con igual dosis, pero se sumó 110 ug de fentanyl por catéter epidural, la edad promedio en este grupo fue de 28.7 años, y el peso promedio de 64.4 kg., todas sometidas a cesárea. Para terminar el grado de analgesia se utilizaron varios parámetros a saber: escala de Mc Gill, análogo visual y verbal del dolor...

Distrofia muscular de duchenne. Estudio de corte de pacientes del servicio de rehabilitación del Hospital de niños Baca Ortíz (HBO)

En el presente trabajo se realiza una revisión retrospectiva de la Distrofia Muscular de Duchenne, con pacientes tratados en la consulta externa del servicio de rehabilitación del Hospital de Niños Baca Ortíz, durante un período de 18 años- comprendido entre los años 1975 y 1993- tiempo en el cual se diagnostica a 18 pacientes con esta enfermedad, de un total de 40 nipos con distrofia muscular progresiva, equivalente al 0.9 por ciento de todos los niños tratados, en rehabilitación, en la época señalada. Se analizan varios parámetros como: sexo, lugar de procedencia, motivo de consulta (lo más consultado constituyó la dificultad para deambular -en un 56 por ciento de los pacientes-) La característica clínica (la más frecuente fue el aumento de volumen de gemelos en un 100 por ciento y en igual porcentaje la disminución de la potencia muscular, especialmente de miembros inferiores). El diagnóstico: se basó en el examen clínico ( en el 100 por ciento) y se confirmó en algunos pacientes con valores de CPK, aldolasa, electromiograma biopsia. El tratamiento en un 61 por ciento fue netamente fisiátrico, 39 por ciento acudieron en forma irregular, 32 por ciento en forma regular. En la actualidad, se logró encontrar a 11 por ciento de los pacientes, los mismos que se hallan confinados a silla de ruedas, pero sin mayores complicaciones en su estado general de salud...