RESUMEN
PURPOSE: Dynamic testing represents the mainstay in the differential diagnosis of ACTH-dependent Cushing's syndrome. However, in case of undetectable or detectable lesion < 6 mm on MRI, bilateral inferior petrosal sinus sampling (BIPSS) is suggested by current guidelines. Aim of this study was to analyze the performance of CRH, desmopressin and high-dose dexamethasone suppression test (HDDST) in the differential diagnosis of ACTH-dependent Cushing's syndrome as well as the impact of invasive and noninvasive tests on surgical outcome in patients affected by Cushing's disease (CD). METHODS: Retrospective analysis on 148 patients with CD and 26 patients with ectopic ACTH syndrome. RESULTS: Among CD patients, negative MRI/lesion < 6 mm was detected in 97 patients (Group A); 29 had a 6-10 mm lesion (Group B) and 22 a macroadenoma (Group C). A positive response to CRH test, HDSST and desmopressin test was recorded in 89.4%, 91·4% and 70.1% of cases, respectively. Concordant positive response to both CRH/HDDST and CRH/desmopressin tests showed a positive predictive value of 100% for the diagnosis of CD. Among Group A patients with concordant CRH test and HDDST, no difference in surgical outcome was found between patients who performed BIPSS and those who did not (66.6% vs 70.4%, p = 0.78). CONCLUSIONS: CRH, desmopressin test and HDDST have high accuracy in the differential diagnosis of ACTH-dependent CS. In patients with microadenoma < 6 mm or non-visible lesion, a concordant positive response to noninvasive tests seems sufficient to diagnose CD, irrespective of MRI finding. In these patients, BIPSS should be reserved to discordant tests.
Asunto(s)
Hormona Adrenocorticotrópica/sangre , Síndrome de Cushing/diagnóstico , Imagen por Resonancia Magnética/métodos , Muestreo de Seno Petroso/métodos , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Pruebas de Función Hipofisaria/métodos , Neoplasias Hipofisarias , Adulto , Síndrome de Cushing/epidemiología , Diagnóstico Diferencial , Técnicas de Diagnóstico Endocrino , Femenino , Humanos , Hipofisectomía/métodos , Hipofisectomía/estadística & datos numéricos , Italia/epidemiología , Masculino , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/sangre , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/diagnóstico , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/epidemiología , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/cirugía , Neoplasias Hipofisarias/diagnóstico por imagen , Neoplasias Hipofisarias/patología , Neoplasias Hipofisarias/cirugía , Estudios RetrospectivosRESUMEN
OBJECTIVE: Patients with Cushing's syndrome (CS) are at high risk of venous thromboembolism related to a hypercoagulability due to procoagulant imbalance. However, whether these alterations are reversible after disease remission is still unclear. The endogenous thrombin potential (ETP) measured with and without the addition of thrombomodulin provides a global representation of coagulation and previous data confirmed hypercoagulable profile in patients with active hypercortisolism. Aim of this study was to assess the short- and long-term modification of ETP in patients with CS after disease remission. DESIGN AND METHODS: Nineteen patients with CS for whom surgical remission was achieved, were prospectively evaluated for clinical characteristics, cortisol secretion profile and ETP at different time points: (i) before surgical intervention; (ii) after 6 months and (iii) 5 years from the time of persistent remission. Nineteen healthy subjects matched for age and gender were also evaluated as control group. RESULTS: Before surgery, patients showed higher ETP-ratio (with/without thrombomodulin) than controls (0.62 ± 0.09-vs-0.56 ± 0.09, p = 0.034). No significant correlation between ETP-ratio and cortisol secretion was found. 6 months after remission, ETP-ratio was still significantly increased compared to controls (0.64 ± 0.09-vs-0.56 ± 0.09, p = 0.01), but was similar to baseline (0.64 ± 0.09-vs-0.62 ± 0.09, p = 0.87). At 5 years, ETP-ratio showed a significant decrease (0.55 ± 0.14-vs-0.62 ± 0.09, p = 0.02) and was comparable to controls (0.55 ± 0.14-vs-0.56 ± 0.09, p = 0.7). CONCLUSIONS: Plasma hypercoagulability detected in patients with active hypercortisolism persists at short-term evaluation and seems to be completely reversible after long-term remission of disease. These data, as part of a whole evaluation of thrombotic risk, can contribute to make appropriate therapeutic choice in these patients.
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Pruebas de Coagulación Sanguínea/métodos , Síndrome de Cushing , Hidrocortisona/sangre , Trombina/análisis , Trombofilia , Tromboembolia Venosa , Adrenalectomía/métodos , Adulto , Coagulación Sanguínea , Síndrome de Cushing/sangre , Síndrome de Cushing/complicaciones , Síndrome de Cushing/cirugía , Femenino , Humanos , Hipofisectomía/métodos , Masculino , Periodo Posoperatorio , Inducción de Remisión , Medición de Riesgo/métodos , Trombofilia/sangre , Trombofilia/etiología , Tiempo , Tromboembolia Venosa/sangre , Tromboembolia Venosa/etiología , Tromboembolia Venosa/prevención & controlRESUMEN
PURPOSE: A long-lasting remission of acromegaly after somatostatin analogues (SAs) withdrawal has been described in some series. Our aim was to update the disease evolution after SAs withdrawal in a cohort of acromegalic patients. METHODS: We retrospectively evaluated 21 acromegalic patients previously included in a multicentre study (Ronchi et al. 2008), updating data at the last follow-up. We added further 8 patients selected for SAs withdrawal between 2008-2018. Pituitary irradiation represented an exclusion criterion. The withdrawal was suggested after at least 9 months of clinical and hormonal disease control. Clinical and biochemical data prior and after SAs withdrawal were analysed. RESULTS: In the whole cohort (29 patients) mean age was 50 ± 14.9 years and 72.4% were females. In 69% pituitary surgery was previously performed. Overall, the median time of treatment before SAs withdrawal was 53 months (IQR = 24-84). At the last follow up in 2019, 23/29 patients (79.3%) had a disease relapse after a median time of 6 months (interquartile range or IQR = 3-12) from the drug suspension, while 6/29 (20.7%) were still on remission after 120 months (IQR = 66-150). IGF-1 levels were significantly lower before withdrawal in patients with persistent remission compared to relapsing ones (IGF-1 SDS: -1.5 ± 0.6 vs -0.11 ± 1, p = 0.01). We did not observe any other difference between patients with and without relapse, including SAs formulation, dosage and treatment duration. CONCLUSION: A successful withdrawal of SAs is possible in a subset of well-controlled acromegalic patients and it challenges the concept that medical therapy is a lifelong requirement.
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Acromegalia , Factor I del Crecimiento Similar a la Insulina/análisis , Prevención Secundaria , Somatostatina , Privación de Tratamiento/estadística & datos numéricos , Acromegalia/sangre , Acromegalia/diagnóstico , Acromegalia/tratamiento farmacológico , Duración de la Terapia , Femenino , Hormonas/farmacología , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Inducción de Remisión/métodos , Prevención Secundaria/métodos , Prevención Secundaria/estadística & datos numéricos , Somatostatina/análogos & derivados , Somatostatina/farmacología , Tiempo , Resultado del TratamientoAsunto(s)
Biomarcadores/metabolismo , Diabetes Insípida/diagnóstico , Glicopéptidos/metabolismo , Procedimientos Neuroquirúrgicos/efectos adversos , Enfermedades de la Hipófisis/cirugía , Complicaciones Posoperatorias/diagnóstico , Diabetes Insípida/etiología , Diabetes Insípida/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades de la Hipófisis/patología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/metabolismo , Pronóstico , Estudios ProspectivosRESUMEN
Adrenocortical carcinomas (ACCs) overexpress insulin-like growth factor 2 (IGF2), that drives a proliferative autocrine loop by binding to IGF1R and IR, but IGF1R/IR-targeted therapies failed in ACC patients. The cytoskeleton actin-binding protein filamin A (FLNA) impairs IR signalling in melanoma cells. Aims of this study were to test FLNA involvement in regulating IGF1R and IR responsiveness to both IGF2 and inhibitors in ACC. In ACC cells H295R and SW13 and primary cultures (1ACC, 4 adenomas) we found that IGF1R and IR interacted with FLNA, and FLNA silencing increased IGF1R and reduced IR expression, with a downstream effect of increased cell proliferation and ERK phosphorylation. In addition, FLNA knockdown potentiated antiproliferative effects of IGF1R/IR inhibitor Linsitinib and IGF1R inhibitor NVP-ADW742 in H295R. Finally, Western blot showed lower FLNA expression in ACCs (n = 10) than in ACAs (n = 10) and an inverse correlation of FLNA/IGF1R ratio with ERK phosphorylation in ACCs only. In conclusion, we demonstrated that low FLNA levels enhance both IGF2 proliferative effects and IGF1R/IR inhibitors efficacy in ACC cells, suggesting FLNA as a new factor influencing tumor clinical behavior and the response to the therapy with IGF1R/IR-targeted drugs.
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Neoplasias de la Corteza Suprarrenal/patología , Carcinoma Corticosuprarrenal/patología , Biomarcadores de Tumor/metabolismo , Filaminas/metabolismo , Factor II del Crecimiento Similar a la Insulina/metabolismo , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor de Insulina/antagonistas & inhibidores , Citoesqueleto de Actina/metabolismo , Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Neoplasias de la Corteza Suprarrenal/metabolismo , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Carcinoma Corticosuprarrenal/metabolismo , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Filaminas/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Imidazoles/farmacología , Factor II del Crecimiento Similar a la Insulina/genética , Mitógenos/farmacología , Pirazinas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Transducción de Señal , Células Tumorales CultivadasAsunto(s)
COVID-19/diagnóstico , COVID-19/epidemiología , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/diagnóstico , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/epidemiología , Centros de Atención Terciaria/tendencias , Adulto , Anciano , COVID-19/terapia , Estudios de Cohortes , Femenino , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/terapiaRESUMEN
BACKGROUND: First-line therapy of Cushing disease (CD) is transsphenoidal surgery (TSS) aimed to obtain a complete removal of the pituitary adenoma and remission of disease. PURPOSE: To analyse the surgical outcome of patients with CD who underwent TSS in our Centre. METHODS: Retrospective analysis on patients with CD who underwent TSS between 1990 and 2016. RESULTS: We analysed 102 TSS that included: 84 first TSS and 18 second and third TSS. The overall remission rate after surgery was 76.5%, with a significant higher percentage of remitted patients after the first TSS compared to the subsequent TSS (82% vs 50%, p = 0.014). The remission after the first TSS was significantly higher when performed by a dedicated surgical team (DST) (89.8% vs 71% p = 0.04) and when the immunohistochemical examination confirmed the adrenocorticotropic adenoma (87% vs 55%, p = 0.04). Neuroradiological findings influenced the surgical outcome in a non-significant manner. Post-TSS complications were reported in 32 patients, with no significant variation when TSS was performed by DST. In case of reintervention, remission of disease was obtained in 72.7% of microadenoma, while no remitted patients were observed in case of macroadenomas. The DST did not significantly improve the outcome. CONCLUSION: Cushing disease is characterized by a broad spectrum of neuroradiological presentation. Despite the availability of a DST make the TSS a safe and effective first-line treatment among all these patients, a precise pre-treatment evaluation is needed in order to define the aim of neurosurgery and to schedule the management of recurrent disease.
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Adenoma/cirugía , Procedimientos Neuroquirúrgicos/métodos , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/cirugía , Neoplasias Hipofisarias/cirugía , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
The role of progenitor/stem cells in pituitary tumorigenesis, resistance to pharmacological treatments and tumor recurrence is still unclear. This study investigated the presence of progenitor/stem cells in non-functioning pituitary tumors (NFPTs) and tested the efficacy of dopamine receptor type 2 (DRD2) and somatostatin receptor type 2 (SSTR2) agonists to inhibit in vitro proliferation. They found that 70% of 46 NFPTs formed spheres co-expressing stem cell markers, transcription factors (DAX1, SF1, ERG1) and gonadotropins. Analysis of tumor behavior showed that spheres formation was associated with tumor invasiveness (OR = 3,96; IC: 1.05-14.88, p = 0.036). The in vitro reduction of cell proliferation by DRD2 and SSTR2 agonists (31 ± 17% and 35 ± 13% inhibition, respectively, p < 0.01 vs. basal) occurring in about a half of NFPTs cells was conserved in the corresponding spheres. Accordingly, these drugs increased cyclin-dependent kinase inhibitor p27 and decreased cyclin D3 expression in spheres. In conclusion, they provided further evidence for the existence of cells with a progenitor/stem cells-like phenotype in the majority of NFPTs, particularly in those with invasive behavior, and demonstrated that the antiproliferative effects of dopaminergic and somatostatinergic drugs were maintained in progenitor/stem-like cells.
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Carcinogénesis/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Hipofisarias/tratamiento farmacológico , Receptores de Dopamina D2/genética , Receptores de Somatostatina/genética , Adulto , Carcinogénesis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ciclina D3/biosíntesis , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/biosíntesis , Receptor Nuclear Huérfano DAX-1/biosíntesis , Dopaminérgicos/administración & dosificación , Resistencia a Antineoplásicos/genética , Canal de Potasio ERG1/biosíntesis , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Gonadotropinas/biosíntesis , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Células Madre Neoplásicas/efectos de los fármacos , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/patología , Factores de Empalme de ARN/biosíntesis , Receptores de Dopamina D2/agonistas , Receptores de Somatostatina/agonistas , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/patologíaRESUMEN
Diabetes mellitus (DM), a worldwide high prevalence disease, is associated with a large variety of rheumatic manifestations. For most of these affections, pathophysiologic correlations are not well established. Some of them, such as diabetic cheiroarthropathy, neuropathic arthritis, diabetic amyotrophy, diabetic muscle infraction, are considered intrinsic complications of DM. For others, like diffuse idiopathic skeletal hyperostosis or reflex sympathetic dystrophy, DM is considered a predisposing condition. In most cases, these affections cause pain and disability, affecting the quality of life of diabetic patients, but once correctly diagnosed, they often respond to the treatment, that generally requires a multidisciplinary team. This article reviews some epidemiological, clinical, diagnostic and therapeutic aspects of these conditions.
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Complicaciones de la Diabetes/complicaciones , Enfermedades Reumáticas/complicaciones , Neuropatías Diabéticas/complicaciones , Humanos , Artropatías/complicacionesRESUMEN
BACKGROUND: Left ventricular pseudoaneurysm (LVPA) is a rare entity characterized by a tendency to spontaneous rupture due to its morphology, a lack of myocardial fibers and fibrous tissue delineating the cavity. An early diagnosis is essential in order to guide appropriate therapy. PURPOSE: To determine the diagnostic accuracy of different imaging techniques, treatment results, and prognosis of patients (pts) with LVPA. METHODS: We evaluated the incidence of LVPA during a five-year period. The initial clinical presentation, the etiology of LVPA, time between symptom onset and diagnosis, and use of various non-invasive techniques were studied. Mean follow-up was 15 months. RESULTS: Of 19113 pts admitted to our Institute in a five-year period, LVPA was diagnosed in 11 pts (0.05%) (mean age 51 +/- 3.9 years, 8 men). The diagnosis of LVPA was confirmed by surgery in 4 pts, and by pathology in 2 pts. LVPA was an incidental finding in one asymptomatic pt, it was diagnosed in 6 pts presenting with an acute myocardial infarction (AMI) and in 4 pts presenting with LV failure. The main etiology was coronary artery disease (CAD) (9 pts), with the remaining 2 cases being post-traumatic (thoracic stab wound, surgery). LVPA location was postero-inferior in 6 patients, infero-lateral in 3 patients, and anterior in 2 patients. ECG, X-ray and TTE were performed in all cases. 6 pts had a radionuclide angiography (RNA), 3 pts had a computed tomography (CT) scan and 2 pts had a magnetic resonance imaging (MRI) study. Two-dimensional transthoracic echocardiography (TTE) provided information regarding LVPA dimensions and LV-LVPA flow. Four pts were operated (one died). Of the seven non-operated pts., 5 died. CONCLUSIONS: The clinical presentation was variable and non-specific. The most frequent cause of LVPA was MI and the most frequent location was inferior. Echocardiography offered the most reliable information when compared to ventriculography. Because clinical examination, ECG, X-ray data are non-specific for the diagnosis of LVPA, an adequate TTE study performed with a high clinical index of suspicion (especially in pts with inferior MI or thoracic trauma) could facilitate the early diagnosis of LVPA and could be relevant to outcome.
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Aneurisma Falso/diagnóstico , Aneurisma Falso/etiología , Cardiopatías/complicaciones , Cardiopatías/diagnóstico , Aneurisma Falso/cirugía , Diagnóstico Diferencial , Ecocardiografía , Electrocardiografía , Femenino , Estudios de Seguimiento , Aneurisma Cardíaco/diagnóstico , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Infarto del Miocardio/complicaciones , Pronóstico , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Disfunción Ventricular Izquierda/etiologíaRESUMEN
Young albino rats were repeatedly stimulated by a pulverized suspension of living pneumococci and others by intramuscular injection of killed microbes emulsified in complete Freund adjuvant. The bronchus associated lymphoid nodules increase in size and number; the proximal nodules contain one more follicle with germinal centers formed of pyroninophilic lymphoblasts and plasma cells at the periphery. The follicular organization and the pyronine - plasma cells differentiation point out the ability of these nodules to elaborate a local immune response to antigenic stimulation.