Alpelisib-Induced Diabetes Mellitus: Case Report, Pharmacodynamics and Management Considerations.

Introduction: Alpelisib is an orally selective PI3K alpha inhibitor recently available for the treatment of advanced breast cancer. PI3K pathway is an intracellular signaling pathway that plays an important role in regulating glucose metabolism. Hyperglycemia is the most common adverse event associated. Methods: We describe the case of a severe hyperglycemia associated with alpelisib treatment in a patient with metastatic breast cancer and previously near-normal glycemia. We analyze the clinical presentation, PI3K inhibitor pharmacodynamic aspects, its influence in glycemic control and the required treatment approach. Results: An important impairment of glycemic control was observed after initiation of alpelisib. In addition to insulin sensitizers drugs, intensive insulin regimen was necessary. Flash glucose monitoring (FGM) information has been helpful in understanding the pharmacodynamic aspects of alpelisib and insulin titration. Development of hyperglycemia is fast, already observed 24 hours after initiation of therapy. FGM shows severe and persistent hyperglycemia during most of the day, with a significant downward effect in the 4 hours after each daily intake, which evidences the strong but transitory effect of the drug enzyme blockade. C-peptide level is remarkable in accordance with drug pharmacodynamics, consistent with a significant insulin resistance. Conclusions: Glucose monitoring should always be performed in patients treated with alpelisib, especially in patients with diabetes and prediabetes. It is crucial to anticipate in these patients. Any delay can lead to a worsening in metabolic control resulting in the discontinuation or reduction of alpelisib, which would lead to a decrease in its effectiveness, and consequently would deny patients an effective treatment with an impact on survival.

A practical approach to normocalcemic primary hyperparathyroidism.

Normocalcemic primary hyperparathyroidism is an entity on which several issues about its clinical management remains unclear. This is reflected in the main current guidelines, where there are no evidence-based specific recommendations. Through an exhaustive review of current literature, a clinical management algorithm for these patients is proposed. We consider the diagnosis criteria, the differential diagnosis, the clinical manifestations, and the treatment indications. When indicated, we also review the preoperative locations techniques and the surgical approach. Finally, when surgical treatment is not indicated, the patient is not a candidate to surgery or refuse surgical management, we review the medical treatment options and the follow-up schemes.

ACROSTART: A retrospective study of the time to achieve hormonal control with lanreotide Autogel treatment in Spanish patients with acromegaly / ACROSTART: Estudio retrospectivo del período de tiempo para lograr el control hormonal con lanreótida Autogel en pacientes con acromegalia en la práctica clínica española

Objectives: The ACROSTART study was intended to determine the time to achieve normalization of GH and IGF-I levels in responding patients with acromegaly administered different dosage regimens of lanreotide Autogel (Somatuline(R) Autogel(R)). Methods: From March 2013 to October 2013, clinical data from 57 patients from 17 Spanish hospitals with active acromegaly treated with lanreotide for ≥4 months who achieved hormonal control (GH levels <2.5ng/ml and/or normalized IGF-I levels in ≥2 measurements) were analyzed. The primary objective was to determine the time from start of lanreotide treatment to hormonal normalization. Results: Median patient age was 64 years, 21 patients were male, 39 patients had undergone surgery, and 14 patients had received radiotherapy. Median hormonal values at start of lanreotide treatment were: GH, 2.6ng/ml; IGF-I, 1.6×ULN. The most common starting dose of lanreotide was 120mg (29 patients). The main initial regimens were 60mg/4 weeks (n=13), 90mg/4 weeks (n=6), 120mg/4 weeks (n=13), 120mg/6 weeks (n=6), and 120mg/8 weeks (n=9). An initial treatment regimen with a long interval (≥6 weeks) was administered in 25 patients. Mean duration of lanreotide treatment was 68 months (7-205). Median time to achieve hormonal control was 4.9 months. Injections were managed without healthcare assistance in 13 patients. Median number of visits to endocrinologists until hormonal control was achieved was 3. Fifty-one patients were "satisfied"/"very satisfied" with treatment and 49 patients did not miss any dose. Conclusions: Real-life treatment with lanreotide Autogel resulted in early hormonal control in responding patients, with high treatment adherence and satisfaction despite disparity in starting doses and dosing intervals

Objetivos: El objetivo del estudio ACROSTART era determinar el período de tiempo para lograr la normalización hormonal (GH e IGF-I) en pacientes con acromegalia respondedores al tratamiento considerando los regímenes de lanreótida Autogel (Somatuline(R) Autogel(R)) utilizados en la práctica clínica. Métodos: Desde marzo de 2013 hasta octubre de 2013, en 17 hospitales españoles se analizaron los datos clínicos de 57 pacientes con acromegalia activa tratados con lanreótida durante ≥4 meses que lograron control hormonal (niveles de GH <2,5ng/ml y/o IGF-I normalizado en ≥2 evaluaciones). El objetivo principal fue determinar el período de tiempo desde el inicio del tratamiento con lanreótida hasta la normalización hormonal. Resultados: La mediana de edad de los pacientes fue 64 años, 21 pacientes eran hombres, 39 pacientes habían recibido cirugía, 14 pacientes habían recibido radioterapia. Los valores hormonales medianos al inicio del tratamiento con lanreótida fueron GH: 2,6ng/ml, IGF-I: 1,6×LSN. La dosis inicial más frecuente de lanreótida fue de 120mg (29 pacientes). Los principales regímenes iniciales fueron 60mg/4 semanas (n=13), 90mg/4 semanas (n=6), 120mg/4 semanas (n=13), 120mg/6 semanas (n=6), 120mg/8 semanas (n=9). Se administró un régimen de intervalo prolongado (≥6 semanas) en 25 pacientes. La duración media del tratamiento con lanreótida fue de 68 meses (7-205). El tiempo medio hasta lograr el control hormonal fue de 4,9 meses. Las inyecciones se manejaron sin asistencia médica en 13 pacientes. La mediana del número de visitas al endocrinólogo hasta el control hormonal fue 3. Cincuenta y un pacientes estaban "satisfechos"/"muy satisfechos" con el tratamiento y 49 pacientes no olvidaron ninguna dosis. Conclusiones: El tratamiento en la vida real con lanreótida Autogel condujo a un control hormonal temprano en pacientes que respondieron, con una alta adherencia al tratamiento y satisfacción con el tratamiento, a pesar de la disparidad de las dosis iniciales y los intervalos de dosificación

ACROSTART: A retrospective study of the time to achieve hormonal control with lanreotide Autogel treatment in Spanish patients with acromegaly.

OBJECTIVES: The ACROSTART study was intended to determine the time to achieve normalization of GH and IGF-I levels in responding patients with acromegaly administered different dosage regimens of lanreotide Autogel (Somatuline® Autogel®). METHODS: From March 2013 to October 2013, clinical data from 57 patients from 17 Spanish hospitals with active acromegaly treated with lanreotide for ≥4 months who achieved hormonal control (GH levels <2.5ng/ml and/or normalized IGF-I levels in ≥2 measurements) were analyzed. The primary objective was to determine the time from start of lanreotide treatment to hormonal normalization. RESULTS: Median patient age was 64 years, 21 patients were male, 39 patients had undergone surgery, and 14 patients had received radiotherapy. Median hormonal values at start of lanreotide treatment were: GH, 2.6ng/ml; IGF-I, 1.6×ULN. The most common starting dose of lanreotide was 120mg (29 patients). The main initial regimens were 60mg/4 weeks (n=13), 90mg/4 weeks (n=6), 120mg/4 weeks (n=13), 120mg/6 weeks (n=6), and 120mg/8 weeks (n=9). An initial treatment regimen with a long interval (≥6 weeks) was administered in 25 patients. Mean duration of lanreotide treatment was 68 months (7-205). Median time to achieve hormonal control was 4.9 months. Injections were managed without healthcare assistance in 13 patients. Median number of visits to endocrinologists until hormonal control was achieved was 3. Fifty-one patients were "satisfied"/"very satisfied" with treatment and 49 patients did not miss any dose. CONCLUSIONS: Real-life treatment with lanreotide Autogel resulted in early hormonal control in responding patients, with high treatment adherence and satisfaction despite disparity in starting doses and dosing intervals.

Two types of ectopic Cushing syndrome or a continuum? Review.

BACKGROUND: Two types of ectopic Cushing syndrome (ECS) are described: ECS associated with aggressive neoplasms, and ECS with indolent and occult tumors, however, there is a lack of studies that thoroughly review their characteristics. METHODS: A systematic review was carried out on PUBMED of all the papers about the ECS, in order to better define the types of this subcategory of Cushing's syndrome, highlighting the differential aspects between these subgroups. RESULTS: It was found that in 50% of cases the prototypic "aggressive" ECS is caused by small cell lung carcinomas (SCLC). In these cases, the clinical presentation may be atypical, predominating the signs and symptoms derived from the protein catabolism. Cortisol and ACTH levels are extremely high, the clinical presentation is abrupt (< 3-6 months) and the tumor is usually advanced, being impossible a curative treatment. On the other hand, "indolent" ECS is mainly represented by carcinoid tumors (CT). In these cases the clinical presentation overlaps enormously with that of Cushing's disease (CD). Cortisol and ACTH levels are slightly elevated, the clinical presentation is progressive (> 6 months) and the prognosis is usually good, and a curative treatment is possible in about 75% of the cases. CONCLUSION: Although there is no absolute differentiation between the two extremes of ECS, a classification could be established in two groups, guided by its clinical and biochemical characteristics, and mainly by the type and stage of the ACTH-secreting tumor. However, a small percentage of tumors do not fit in this simple grouping, and may present both phenotypes or an intermediate one.

[Low-dose cinacalcet reduces serum calcium in patients with primary hyperparathyroidism not eligible for surgery]. / Dosis bajas de cinacalcet reducen el calcio sérico en pacientes con hiperparatiroidismo primario no subsidiario de tratamiento quirúrgico.

We present our experience with low-dose cinacalcet to normalize serum calcium in patients with primary hyperparathyroidism (PHPT) not eligible for surgery. We analyzed the impact of this drug on various parameters of calcium-phosphorus metabolism and its tolerability profile. We recruited 17 patients diagnosed with PHPT who had hypercalcemia and also met one or more of the following inclusion criteria: elevated risk for parathyroidectomy, persistent/recurrent PHPT after previous parathyroid surgery or refusal to undergo surgery. The starting dose of cinacalcet was 30 or 60 mg/day, which was adjusted depending on the degree of calcemia reduction and tolerance to the drug. We observed a reduction in serum calcium that was already evident in the first post-treatment test. Appropriate dose adjustment was performed when required and normal serum calcium levels were achieved in most patients, remaining stable during follow-up. Parathyroid hormone was reduced but not normalized in most patients. Calciuria decreased while serum phosphate and alkaline phosphatase levels increased. Cinacalcet tolerance was generally good at the doses used. The most common adverse effects were weakness, dizziness and asthenia, leading to treatment withdrawal in only one patient. We conclude that low-dose cinacalcet reduces serum calcium efficiently, normalizes calcium levels in most patients with PHPT not eligible for surgical treatment and has a good tolerability profile.

Dosis bajas de cinacalcet reducen el calcio sérico en pacientes con hiperparatiroidismo primario no subsidiario de tratamiento quirúrgico / Low-dose cinacalcet reduces serum calcium in patients with primary hyperparathyroidism not eligible for surgery

Presentamos nuestra experiencia con cinacalcet a dosis bajas, en pacientes con hiperparatiroidismo primario (HPTP) no subsidiario de tratamiento quirúrgico con el objetivo principal de normalizar la calcemia. Analizamos el impacto del fármaco sobre diversos parámetros del metabolismo calcio-fósforo y su perfil de tolerancia. Reclutamos un total de 17 pacientes diagnosticados de HPTP que presentaban hipercalcemia y que reunían además alguno de los siguientes criterios de inclusión: riesgo elevado para paratiroidectomía, HPTP persistente/recurrente tras cirugía paratiroidea previa o rechazo del paciente a la intervención quirúrgica. La dosis inicial de cinacalcet fue de 30 o 60mg/día, la cual se ajustó en función del grado de reducción de la calcemia y la tolerancia al fármaco. Observamos una reducción del calcio sérico que ya resultaba evidente en el primer control postratamiento. Tras el ajuste pertinente de dosis cuando fue preciso, se consiguió normalizar la calcemia en una mayoría de los pacientes, la cual se mantuvo estable a lo largo del seguimiento. La PTH se redujo, aunque no se normalizó en la mayor parte de los pacientes. La calciuria descendió mientras que la fosforemia y la fosfatasa alcalina sérica aumentaron. La tolerancia a cinacalcet fue buena en general a las dosis utilizadas. Los efectos secundarios más frecuentes fueron debilidad, mareos y astenia, y solamente en un paciente motivaron la suspensión del tratamiento. Concluimos que cinacalcet a dosis bajas reduce la calcemia de forma eficaz y consigue una normalización de la misma en una mayoría de pacientes con HPTP no subsidiarios de tratamiento quirúrgico con un buen perfil de tolerancia al fármaco (AU)

We present our experience with low-dose cinacalcet to normalize serum calcium in patients with primary hyperparathyroidism (PHPT) not eligible for surgery. We analyzed the impact of this drug on various parameters of calcium-phosphorus metabolism and its tolerability profile We recruited 17 patients diagnosed with PHPT who had hypercalcemia and also met one or more of the following inclusion criteria: elevated risk for parathyroidectomy, persistent/recurrent PHPT after previous parathyroid surgery or refusal to undergo surgery. The starting dose of cinacalcet was 30 or 60mg/day, which was adjusted depending on the degree of calcemia reduction and tolerance to the drug.We observed a reduction in serum calcium that was already evident in the first post-treatment test. Appropriate dose adjustment was performed when required and normal serum calcium levels were achieved in most patients, remaining stable during follow-up. Parathyroid hormone was reduced but not normalized in most patients. Calciuria decreased while serum phosphate and alkaline phosphatase levels increased. Cinacalcet tolerance was generally good at the doses used. The most common adverse effects were weakness, dizziness and asthenia, leading to treatment withdrawal in only one patient. We conclude that low-dose cinacalcet reduces serum calcium efficiently, normalizes calcium levels in most patients with PHPT not eligible for surgical treatment and has a good tolerability profile (AU)

Control metabólico en pacientes diabéticos tipo 2 con triple terapia farmacológica / Glycemic control in type 2 diabetes patients with three drug treatment

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Carcinoma adrenal: una causa poco frecuente de hipopotasemia grave / Adrenal carcinoma: an unfrequent cause of severe hypokalemia

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