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© 2017 Elsevier Ltd. Background: Cushing's disease is a rare debilitating endocrine disorder for which few prospective interventional studies have been done. We report results of the first phase 3 trial assessing long-acting intramuscular pasireotide in patients with Cushing's disease. Methods: In this phase 3 clinical trial we recruited patients aged 18 years or older with persistent, recurrent, or de-novo (non-surgical candidates) Cushing's disease who had a mean urinary free cortisol (mUFC) concentration (from three 24 h samples) of 1·5-5·0 times the upper limit of normal (ULN), a normal or greater than normal morning plasma adrenocorticotropic hormone concentration, and a pituitary source of Cushing's syndrome, from 57 sites across 19 countries. Exclusion criteria included previous pasireotide treatment, mitotane therapy within 6 months, and pituitary irradiation within 10 years. We randomly allocated patients 1:1 (block size of four) using an interactive-response-technology system to intramuscular pasireotide 10 mg or 30 mg every 4 weeks for 12 months (in the core phase). We stratified randomisation by screening mUFC concentration (1·5 to < 2·0 × ULN and 2·0-5·0 × ULN). The dose could be uptitrated (from 10 mg to 30 mg or from 30 mg to 40 mg) at month 4 if the mUFC concentration was greater than 1·5 × ULN, and at month 7, month 9, or month 12 if the mUFC concentration was greater than 1·0 × ULN. Investigators, patients, site personnel, and those assessing outcomes were masked to dose group allocation. The primary endpoint was the proportion of patients in each group with an mUFC concentration of less than or equal to the ULN at month 7. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01374906. Findings: Between Dec 28, 2011, and Dec 9, 2014, we randomly allocated 150 patients to receive pasireotide 10 mg (74 [49%] patients) or 30 mg (76 [51%] patients). The primary efficacy endpoint was met by 31 (41·9% [95% CI 30·5-53·9]) of 74 patients in the 10 mg group and 31 (40·8% [29·7-52·7] ) of 76 in the 30 mg group. The most common adverse events were hyperglycaemia (36 [49%] in the 10 mg group and 36 [47%] in the 30 mg group), diarrhoea (26 [35%] and 33 [43%] ), cholelithiasis (15 [20%] and 34 [45%] ), diabetes mellitus (14 [19%] and 18 [24%] ), and nausea (15 [20%] and 16 [21%] ). Serious adverse events suspected to be study drug related were reported in eight (11%) patients in the 10 mg group and four (5%) in the 30 mg group. Two (3%) patients in the 30 mg group died during the study (pulmonary artery thrombosis and cardiorespiratory failure); neither death was judged to be related to the study drug. Interpretation: Long-acting pasireotide normalised mUFC concentration in about 40% of patients with Cushing's disease at month 7 and had a similar safety profile to that of twice-daily subcutaneous pasireotide. Long-acting pasireotide is an efficacious treatment option for some patients with Cushing's disease who have persistent or recurrent disease after initial surgery or are not surgical candidates, and provides a convenient monthly administration schedule. Funding: Novartis Pharma AG.

En los pacientes quemados, existen diferentes factores como la edad, sexo y días de estancia hospitalaria entre otros, que influyen en el desarrollo de infección intrahospitalaria (IIH). Debido a la mayor frecuencia de este tipo de infecciones en los pacientes quemados, pretendemos identificar qué factores influyen en la presentación y predicción de la infección intrahospitalaria en el sitio de la quemadura (IISQ). El presente estudio es una cohorte retrospectiva, sobre 298 registros de expedientes clínicos de pacientes ingresados en la Unidad Nacional de Quemados del Hospital San Juan de Dios (UNQ-HSJD) en Costa Rica, continuando otra investigación del mismo grupo de autores publicada anteriormente en Cirugía Plástica Iberolatinoamericana. A cada factor de riesgo estudiado se le calcularon los odds ratio crudos en un análisis univariado definiendo como variables de exposición principal la superficie corporal total quemada (SCTQ) y la profundidad de la quemadura (PQ). Observamos con este cálculo que el tipo de accidente no presentaba asociación con la IISQ. Después, realizamos un modelo multivariado logístico, no condicional, en el que se introdujeron los siguientes factores de riesgo: SCTQ, PQ, edad, número de segmentos corporales quemados (NSCQ), días de estancia hospitalaria previos a la infección intrahospitalaria en el sitio de la quemadura (DEHP-IISQ) y el agente causal de la quemadura. Consideramos variables confusora y modificadora de efecto al NSCQ y DEHP-IISQ. Determinamos que las principales variables predictoras para la IISQ fueron SCTQ (OR=3.02; 1.20-7.84), PQ (OR=11.44; 4.90-26.71), NCSQ (OR=2.80; 1.13-6.95), y DEHP-IISQ (9 a 14 días: OR=2.43; 0.52- 11.29, >19 días: OR=31.89; 2.17-467.68). Pese a que no mostró significancia estadística, también se introdujo la edad en el modelo, debido a la tendencia a aumentar el riesgo conforme ésta aumentaba ( >64 años: OR= 3.15; 0.61-16.29). Concluimos que los pacientes quemados presentan características endógenas y exógenas para el desarrollo de las IISQ y que el conocer cómo se comportan esas características puede ayudar a disminuir la incidencia de IISQ y a promover medidas para su control y prevención, en la atención de los pacientes en la UNQ-HSJD. In burn victims, different factors such as age, gender and days of hospitalization among others, are influential in the development of inner-hospital infections (IHI). Due to a higher incidence of IHI in burn victims, it is pretended to identify which factors influence the presence and prediction of inner-hospital infections in the burned area (IHIBA). This study is a retrospective cohort that recruited 298 registries of medical reports from patients admitted into the National Burn Victims Unit at San Juan de Dios Hospital (NBVU-HSJD), Costa Rica, and following a previous report in this journal. The odds ratio (OR) were calculated for each risk factor in a univariated analysis, and defined as principal exposition variables were the total burn surface (TBS) and the depth of the burn (DB). It was deduced from this calculation that the type of accident did not show any association with IHIBA. Subsequently, a multivariate logistic not conditioned study was carried out, in which, the following risk factors were introduced: TBS, DB, age, number of burnt body segments (NBBS), days of hospital stay previous to the IHIBA (DHSP-IHIBA) and the burn's causing agent. Confusing and modifying variables of effect were also considered, respectively, for the NBBS and the DHSP-IHIBA. It was concluded that the main predicting variables for the IHIBA were TBS (OR=3.02; 1.20-7.84), DB (OR=11.44; 4.90-26.71), NBBS (OR= 2.80; 1.13-6.95), and DHS- IHIBA (9 to 14 days: OR=2.43; 0.52-11.29, > 19 days: OR=31.89; 2.17-467.68). Even though it didn't show statistical relevance, the age was introduced in the model, due to the fact that the risk factor increased with time (>64 years old: OR= 3.15; 0.61-16 29). It was concluded that burn victims present endogenous and exogenous characteristics for the development of the IHIBA and by getting to know those characteristics, we can help to lessen the incidence of IHIBA, promoting measures for its control and prevention in the treatment of the patients at the NBVU-HSJD.

La infección intrahospitalaria es una de las principales causas de morbilidad y mortalidad en los pacientes quemados. El presente estudio caracteriza a los ingresados por quemadura(s) y la presencia de esta clase de infección en la Unidad Nacional de Quemados del Hospital San Juan de Dios, en Costa Rica, entre los años 2003 y 2005. Realizamos un análisis descriptivo de la infección intrahospitalaria en el sitio de la quemadura según las características de los pacientes y de la quemadura así como el total de días de estancia hospitalaria, utilizando para ello un diseño de estudio tipo cohorte retrospectiva. La incidencia acumulada de la infección intrahospitalaria en el sitio de la quemadura fue de 19.0%. Los meses posteriores al ingreso a clases presentaron un mayor número de hospitalizaciones por quemaduras. La edad, la superficie corporal total quemada, el número de segmentos corporales quemados, la profundidad de la quemadura y los días de estancia hospitalaria presentaron diferencias significativas entre los individuos infectados y no infectados. El tipo de accidente que produjo la quemadura y el sexo no presentaron diferencias significativas entre ambos grupos de pacientes. La electricidad fue el agente causal más frecuente en los pacientes con infección, mientras que el agua caliente lo fue en los pacientes sin infección. Concluimos que las características fisiopatológicas de las quemaduras favorecen infección en los pacientes quemados; asimismo, existen factores que pueden y deben ser tomados en cuenta para controlar y prevenir la infección y sus efectos. Intrahospitalary infection in burned patients is one of the most important causes of morbidity and mortality. This study characterizes the admitted burn victims and the presence of inner-hospital infection at the National Burn Victims Unit , San Juan de Dios Hospital, Costa Rica, between 2003 and 2005. We made a descriptive analyze of intrahospital infection in the burned area according characteristics of the patients and their burn(s), as well as the total number of days of hospital stay, using a prospective cohort. The accumulated incidence for intra hospital infection in the burned area was 19.0%. In the months following the beginning of the school year, the number of burn victims admitted in the hospital increased. Age, total burnt surface, the number of burnt body segments, the depth of the burn and the days of hospital stay varied significantly between infected and not infected individuals. The cause of the burn and the victim's gender did not reveal any relevant differences between the groups of patients. For patients that developed intrahospital infection in the burned area, electricity was the most frequent causing agent, as was hot water for patients without intra hospital infection in the burned area. As a conclusion, physiopathologic characteristics of the burns favor the occurrence of the intra hospital infection in the burned area; furthermore, there are factors than can and must be taken into account to control and prevent intrahospital infection in the burned area and its effects.

BACKGROUND: Cushing's disease is a rare debilitating endocrine disorder for which few prospective interventional studies have been done. We report results of the first phase 3 trial assessing long-acting intramuscular pasireotide in patients with Cushing's disease. METHODS: In this phase 3 clinical trial we recruited patients aged 18 years or older with persistent, recurrent, or de-novo (non-surgical candidates) Cushing's disease who had a mean urinary free cortisol (mUFC) concentration (from three 24 h samples) of 1·5-5·0 times the upper limit of normal (ULN), a normal or greater than normal morning plasma adrenocorticotropic hormone concentration, and a pituitary source of Cushing's syndrome, from 57 sites across 19 countries. Exclusion criteria included previous pasireotide treatment, mitotane therapy within 6 months, and pituitary irradiation within 10 years. We randomly allocated patients 1:1 (block size of four) using an interactive-response-technology system to intramuscular pasireotide 10 mg or 30 mgevery 4 weeks for 12 months (in the core phase). We stratified randomisation by screening mUFC concentration (1·5 to