RESUMEN
Emerging evidence suggests the composition of the tumour microenvironment (TME) correlates with clinical outcome and that each tumour type has a unique TME including a variable population of inflammatory cells. We performed immunohistochemistry on 65 phaeochromocytoma and paraganglioma (PPGL) tumour samples with 20 normal adrenal medulla samples for comparison. The immune cells assessed were macrophages, lymphocytes and neutrophils, and we compared the proportion of infiltration of these immune cells with clinical and histopathological factors. There was a higher proportion of immune cells in tumour tissue compared to non-neoplastic adrenal medulla tissue, with a predominance of macrophages. There was a higher proportion of M2:M1 macrophages and T-helper lymphocytes in aggressive tumours compared to indolent ones. For SDHB-associated tumours, there was a higher proportion of M2 macrophage infiltration, with higher M2:M1 in aggressive SDHB PPGLs compared to indolent tumours. These data demonstrate that immune cells do infiltrate the TME of PPGLs, confirming that PPGLs are immunologically active tumours. Differences in the TME of PPGLs were observed between aggressive and indolent tumours. These differences could potentially be exploited as an aid in predicting tumour behaviour.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales , Paraganglioma , Feocromocitoma , Neoplasias de las Glándulas Suprarrenales/patología , Humanos , Inmunohistoquímica , Paraganglioma/patología , Feocromocitoma/patología , Microambiente TumoralRESUMEN
BACKGROUND: In approximately half of cases of primary aldosteronism (PA), the cause is a surgically-resectable unilateral aldosterone-producing adrenal adenoma. However, long-term data on surgical outcomes are sparse. AIM: We report on clinical outcomes post-adrenalectomy in a cohort of patients with PA who underwent surgery. DESIGN: Retrospective review of patients treated for PA in a single UK tertiary centre. METHODS: Of 120 consecutive patients investigated for PA, 52 (30 male, median age 54, range 30-74) underwent unilateral complete adrenalectomy. Blood pressure, number of antihypertensive medications, and serum potassium were recorded before adrenalectomy, and after a median follow-up period of 50 months (range 7-115). Recumbent renin and aldosterone were measured, in the absence of interfering antihypertensive medication, ≥3months after surgery, to determine if PA had been biochemically cured. RESULTS: Overall, blood pressure improved from a median (range) 160/95 mmHg (120/80-250/150) pre-operatively to 130/80 mmHg (110/70-160/93), P < 0.0001. 24/52 patients (46.2%) had cured hypertension, with a normal blood pressure post-operatively on no medication. 26/52 (50%) had improved hypertension. 2/52 patients (3.8%) showed no improvement in blood pressure post-operatively. Median (range) serum potassium level increased from 3.2 (2.3-4.7) mmol/l pre-operatively to 4.4 mmol/l (3.3-5.3) post-operatively, P < 0.0001). Median (range) number of antihypertensive medications used fell from 3 (0-6) pre- to 1 post-operatively (range 0-4), P < 0.0001. CONCLUSIONS: Unilateral adrenalectomy provides excellent long-term improvements in blood pressure control, polypharmacy and hypokalaemia in patients with lateralizing PA. These data may help inform discussions with patients contemplating surgery.
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Adrenalectomía/métodos , Hiperaldosteronismo/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Aldosterona/sangre , Antihipertensivos/administración & dosificación , Presión Sanguínea/fisiología , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Hiperaldosteronismo/sangre , Hiperaldosteronismo/complicaciones , Hiperaldosteronismo/fisiopatología , Hipertensión/etiología , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Polifarmacia , Potasio/sangre , Renina/sangre , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
SDHB mutations are linked to the familial paraganglioma syndrome type 4 (PGL4), which is associated with predominantly extra-adrenal disease and has high metastatic rates. Despite the lower penetrance rates in carriers of SDHB mutations compared to mutations in other paraganglioma susceptibility genes, the aggressive behavior of SDHB-linked disease warrants intensive surveillance to identify and resect tumors early. Patients with similar SDHB genotypes in whom the PGL syndrome manifests often exhibit very heterogeneous phenotypes. Tumors can arise in various locations, and management can be considerably different, depending on tumor site and pathology. We present a case series of five SDHB mutation carriers over four generations from the same family to illustrate the complexities in management.
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Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/genética , Paraganglioma Extraadrenal/diagnóstico , Paraganglioma Extraadrenal/genética , Succinato Deshidrogenasa/genética , 3-Yodobencilguanidina , Adulto , Cromogranina A/orina , Detección Precoz del Cáncer , Exones , Pruebas Genéticas , Genotipo , Heterocigoto , Humanos , Laparotomía , Masculino , Mutación , Síndromes Neoplásicos Hereditarios/radioterapia , Síndromes Neoplásicos Hereditarios/orina , Norepinefrina/orina , Paraganglioma Extraadrenal/radioterapia , Paraganglioma Extraadrenal/orina , Linaje , Penetrancia , Fenotipo , Cintigrafía , Radiocirugia , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: (131)I-meta-iodobenzylguanidine ((131)I-MIBG) has been in therapeutic use since 1980s. Newer treatment modalities are emerging for neuroendocrine tumours (NETs) and chromaffin cell tumours (CCTs), but many of these do not yet have adequate long-term follow-up to determine their longer term efficacy and sequelae. METHODS: Fifty-eight patients with metastatic NETs and CCTs who had received (131)I-MIBG therapy between 2000 and 2011 were analysed. Survival and any long-term haematological or renal sequelae were investigated. RESULTS: In the NET group, the overall median survival and median survival following the diagnosis of metastatic disease was 124 months. The median survival following the commencement of (131)I-MIBG was 66 months. For the CCT group, median survival had not been reached. The 5-year survival from diagnosis and following the diagnosis of metastatic disease was 67% and 67.5% for NETs and CCTs, respectively. The 5-year survival following the commencement of (131)I-MIBG therapy was 68%. Thirty-two patients had long-term haematological sequelae: 5 of these 32 patients developed haematological malignancies. Two patients developed a mild deterioration in renal function. CONCLUSION: Long follow up of (131)I-MIBG therapy reveals a noteable rate of bone marrow toxicities and malignancy and long term review of all patients receiving radionuclide therapies is recommended.
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3-Yodobencilguanidina/uso terapéutico , Neoplasias de las Glándulas Suprarrenales/radioterapia , Células Cromafines/patología , Células Cromafines/efectos de la radiación , Radioisótopos de Yodo/uso terapéutico , Tumores Neuroendocrinos/radioterapia , Radiofármacos/uso terapéutico , 3-Yodobencilguanidina/efectos adversos , Neoplasias de las Glándulas Suprarrenales/patología , Adulto , Estudios de Cohortes , Femenino , Humanos , Radioisótopos de Yodo/efectos adversos , Masculino , Persona de Mediana Edad , Radiofármacos/efectos adversos , Estudios RetrospectivosRESUMEN
BACKGROUND: It has been debated that the epidemic of melanoma is largely due to overdiagnosis, since increases in incidence were mainly among thin melanomas and mortality rates remained stable. Our objective was to examine this controversy in The Netherlands. PATIENTS AND METHODS: Information on newly diagnosed melanoma patients was obtained from The Netherlands Cancer Registry. European Standardized Rates and estimated annual percentage change were calculated for the period 1989-2008. Cohort-based, period-based and multivariate survival analyses were carried out. RESULTS: The incidence rate of melanoma increased with 4.1% (95% confidence interval 3.6-4.5) annually. Incidence rates of both thin melanomas (≤ 1 mm) and thick melanomas (> 4 mm) increased since 1989. Mortality rates increased mainly in older patients (> 65 years). Ten-year relative survival of males improved significantly from 70% in 1989-1993 to 77% in 2004-2008 (P < 0.001) and for females the 10-year relative survival increased from 85% to 88% (P < 0.01). Recently diagnosed patients had a better prognosis even after adjusting for all known prognostic factors. CONCLUSION: Since incidence of melanomas among all Breslow thickness categories increased as well as the mortality rates, the melanoma epidemic in The Netherlands seems to be real and not only due to overdiagnosis.
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Melanoma/epidemiología , Sistema de Registros , Neoplasias Cutáneas/epidemiología , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Incidencia , Lactante , Masculino , Melanoma/mortalidad , Melanoma/patología , Persona de Mediana Edad , Países Bajos/epidemiología , Pronóstico , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Análisis de Supervivencia , Adulto JovenRESUMEN
The aim of the study was to evaluate the effects of steroid administration under standardised conditions in a range of patients both normal and with adrenal pathologies and to review the impact on plasma catecholamines and metanephrines. Corticosteroid administration has been linked to the development of hypertensive crises in patients with phaeochromocytoma, however a mechanism for this is not fully understood. We aimed to add useful information about the effect of steroids on levels of these hormones under usual circumstances. A prospective, observational cohort study of 50 patients undergoing the low-dose dexamethasone suppression test (LDDST) was undertaken. Additional blood samples were taken at the start and end of the standard LDDST. Biochemical analysis was carried out for plasma catecholamines and plasma free metanephrines. Demographic and hormonal data were acquired from review of the notes or measured at baseline. No significant changes in plasma catecholamines or metanephrines were seen at the end of the LDDST compared to baseline. This was also true of subgroup analysis, divided by age, gender, or type of underlying pathology. Our results suggest that hypertensive reaction responses, rare as they are, are unlikely to be related to normal adrenal physiology. Thus LDDST is likely to be safe under most circumstances, however caution should be exercised in patients with adrenal masses with imaging characteristics compatible with phaeochromocytoma. It may be prudent to defer glucocorticoid administration until functioning phaeochromocytoma has been excluded biochemically.
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Catecolaminas/sangre , Glucocorticoides/administración & dosificación , Metanefrina/sangre , Feocromocitoma/tratamiento farmacológico , Adulto , Estudios de Cohortes , Femenino , Glucocorticoides/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Feocromocitoma/sangre , Estudios ProspectivosRESUMEN
Background. Management of multiple-endocrine neoplasia type 1- (MEN1-) associated hyperparathyroidism is associated with high recurrence rates and high surgical morbidity due to multiple neck explorations. Cinacalcet, a calcimimetic agent licensed for the treatment of secondary hyperparathyroidism and parathyroid carcinoma, may provide a medical alternative for the management of these complex patients. Methods. A prospective audit was performed of eight patients; three males and five females, aged 20-38 at diagnosis. Two patients commenced cinacalcet as primary treatment and six had previous surgery. Six patients had complications of hyperparathyroidism: renal calculi, renal dysfunction, and reduced bone mineral density. All were commenced on cinacalcet 30 mg bd for MEN1 associated hyperparathyroidism; doses were subsequently reduced to 30 mg od in four patients. Results. Significant reductions were observed in serum calcium and PTH measurements. Serum calcium reduced by a median of 0.35 mmol/L (P = .012 Wilcoxon Signed Rank). Serum PTH levels decreased by a median of 5.05 pmol/L (P = .012). There was no change in urine calcium. Duration ranged from 10-35 months with maintenance of control. Cinacalcet was well tolerated by six patients; one experienced nausea and one experienced diarrhoea. Conclusion. Cinacalcet is an effective and well-tolerated medical treatment for the management of complex primary hyperparathyroidism.
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Hormona de Crecimiento Humana/efectos adversos , Recurrencia Local de Neoplasia/etiología , Neoplasias de Células Germinales y Embrionarias/patología , Adolescente , Adulto , Bases de Datos Factuales , Femenino , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Estudios Longitudinales , Masculino , Recurrencia Local de Neoplasia/patología , Factores de RiesgoRESUMEN
OBJECTIVE: It is suggested that patients with acromegaly have an increased risk of colorectal cancer and pre-malignant adenomatous polyps. However, the optimum frequency with which colonoscopic screening should be offered remains unclear. DESIGN: To determine the optimum frequency for repeated colonoscopic surveillance of acromegalic patients. METHODS: We retrospectively reviewed the case records of all patients with acromegaly seen in our centre since 1992: 254 patients had at least one surveillance colonoscopy, 156 patients had a second surveillance colonoscopy, 60 patients had a third surveillance colonoscopy and 15 patients had a fourth surveillance colonoscopy. RESULTS: The presence of hyperplastic or adenomatous polyps was assessed in all patients, while one cancer was detected at the second surveillance. At the third surveillance, mean (+/-s.d.) serum IGF1 levels (ng/ml) in patients with hyperplastic polyps were significantly higher than those with normal colons (P<0.05). The presence of an adenoma rather than a normal colon at the first colonoscopy was associated with a significantly increased risk of adenoma at the second (odds ratio (OR) 4.4, 95% confidence interval (CI) 1.9-10.4) and at the third (OR 8.8, 95% CI 2.9-26.5) screens. Conversely, a normal colon at the first surveillance gave a high chance of normal findings at the second (78%) or third surveillance (78%), and a normal colon at the second colonoscopy was associated with normality at the third colonoscopy (81%). CONCLUSIONS: Repeated colonoscopic screening of patients with acromegaly demonstrated a high prevalence of new adenomatous and hyperplastic colonic polyps, dependent on both the occurrence of previous polyps and elevated IGF1 levels.
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Acromegalia/diagnóstico , Neoplasias del Colon/etiología , Colonoscopía , Acromegalia/complicaciones , Pólipos Adenomatosos/etiología , Anciano , Colon/patología , Hormona de Crecimiento Humana/sangre , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Persona de Mediana Edad , RadioinmunoensayoRESUMEN
BACKGROUND: Fibrosis is a hallmark of neuroendocrine tumours (NETs) arising in the jejunum and ileum and may manifest in the mesentery and elsewhere. It is clinically important and once-established, there are few effective therapies. AIM: To examine the frequency, radiological manifestations and clinical significance of intra-abdominal fibrosis in a patient cohort using modern cross-sectional imaging. Current prevalence is compared to historical series and correlation with cardiac fibrosis evaluated. DESIGN: Cross-sectional, retrospective survey of a cohort of patients with mid-gut NETs from a single centre. METHODS: Review of clinical features, biochemistry and imaging of patients with sporadic mid-gut NET and available imaging between 2002 and 2008. RESULTS: Thirty-one patients were included: 26 (83.9%) had liver metastases and 11 (35.4%) had small-bowel wall thickening; 17 patients (55%) had mesenteric involvement, with a mass, which contained coarse calcification in seven patients and fine calcification in a further two. There was soft-tissue stranding in 13 patients (plus in a further patient with no mass) and 'indrawing' of tissues in 11 patients. Two patients had a 'misty' mesentery and two had early retroperitoneal fibrosis. Mesenteric involvement was unrelated to gender and urinary 5HIAA excretion. CONCLUSION: Intra-abdominal fibrosis can be detected radiologically in around half of patients with mid-gut NET using contemporary cross-sectional imaging. Although not statistically significant, small-bowel obstruction was seen more frequently in the group with fibrosis. There was no relationship with cardiac fibrosis. Prospective studies are needed to evaluate predictors of fibrosis onset and clinical course and determine optimal methods of prevention and treatment.
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Tumor Carcinoide/patología , Neoplasias Intestinales/patología , Intestino Delgado/patología , Adulto , Anciano , Anciano de 80 o más Años , Tumor Carcinoide/diagnóstico por imagen , Tumor Carcinoide/epidemiología , Femenino , Fibrosis/diagnóstico por imagen , Humanos , Neoplasias Intestinales/diagnóstico por imagen , Neoplasias Intestinales/epidemiología , Obstrucción Intestinal/patología , Masculino , Persona de Mediana Edad , Prevalencia , Radiografía , Estudios RetrospectivosRESUMEN
OBJECTIVE: Heterogeneity in growth hormone (GH) responsiveness in adult hypopituitary patients receiving recombinant human GH (rhGH) is poorly understood; doses vary up to fourfold between individuals. Deletion of exon 3 in the GH receptor (d3-GHR) has been linked to enhanced rhGH responsiveness in children. We investigated the role of the d3-GHR polymorphism in determining adult rhGH responsiveness. METHODS: One hundred and ninety-four patients treated with an identical rhGH dosing protocol in a single centre were genotyped for the d3-GHR, and the results correlated with changes in serum IGF-I and clinical parameters of GH responsiveness after 6 and 12 months of GH replacement therapy. RESULTS: Allele frequencies for homozygous full length (fl/fl), heterozygous d3 (fl/d3) and homozygous d3 (d3/d3) were 52%, 38.7% and 9.3%, respectively, and were in Hardy-Weinberg equilibrium. Baseline IGF-I and DeltaIGF-I at 6 months were comparable between groups. DeltaIGF-I at 12 months was significantly greater in the d3/d3 group (P = 0.028). No difference was detected between fl/d3 and fl/fl groups. Regression analyses of DeltaIGF-I at 12 months and DeltaIGF-I/rhGH dose confirmed a significant relationship of d3/d3 genotype on rhGH response. There was no difference between groups in maintenance rhGH dose between genotypes. CONCLUSION: Homozygosity for d3-GHR confers a marginal increase in GH responsiveness at 12 months but without a detectable change in maintenance rhGH dose required. Both d3 alleles are required to achieve this response; given that only 10% of the population are d3 homozygotes, the d3GHR does not explain the marked heterogeneity of GH responsiveness in hypopituitary adults.
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Hormona de Crecimiento Humana/uso terapéutico , Hipopituitarismo/tratamiento farmacológico , Hipopituitarismo/genética , Receptores de Somatotropina/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores Farmacológicos/análisis , Exones/genética , Femenino , Eliminación de Gen , Heterogeneidad Genética , Genotipo , Terapia de Reemplazo de Hormonas , Hormona de Crecimiento Humana/deficiencia , Humanos , Individualidad , Masculino , Persona de Mediana Edad , Isoformas de Proteínas/genética , Resultado del Tratamiento , Adulto JovenAsunto(s)
Insuficiencia Suprarrenal/tratamiento farmacológico , Terapia de Reemplazo de Hormonas/efectos adversos , Hidrocortisona/uso terapéutico , Insuficiencia Suprarrenal/epidemiología , Adrenalectomía , Adulto , Anciano , Femenino , Humanos , Hidrocortisona/sangre , Londres/epidemiología , Masculino , Auditoría Médica , Persona de Mediana Edad , MorbilidadRESUMEN
BACKGROUND: Published data suggest that growth hormone replacement (GHR) may be given safely to patients with hypopituitarism consequent upon a pituitary/peripituitary tumour. However, a preponderance of patients treated with external pituitary irradiation were included. OBJECTIVE: To assess the safety of GHR in nonirradiated pituitary/peripituitary tumour. DESIGN: Prospective audit. SETTING: Tertiary university referral centre. PATIENTS: We imaged prospectively the pituitary glands of 48 patients (18 males; mean age 51.6 years range 21-77) who had adult onset growth hormone deficiency (AO-GHD) after appropriate treatment for a pituitary/peripituitary tumour but who did not receive external pituitary irradiation. INTERVENTION: All patients were treated with a dose titration regimen of GH to maintain serum IGF-1 between the median and upper end of the age-related reference range. Pituitary surveillance imaging was performed prior to the commencement of GHR, at 6-12 months and then yearly. For patients with secretory tumours, biochemical markers (cortisol and prolactin) were used as evidence of tumour recurrence. RESULTS: 48 patients with median follow up since commencement of GHR was 38 months (range 9-104). Three patients were judged to have an apparent increase in tumour volume and/or marker, although only one was thought to be possibly GH related--a patient with a cystic chromophobe adenoma who demonstrated a marginal increase in residual tumour volume 4 years after commencement of GHR. CONCLUSION: These data add to the growing body of evidence for the safety of GHR in hypopituitary patients consequent upon pituitary/peripituitary mass lesions and represents the first reported series in a heterogeneous group of nonirradiated patients.
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Hormona de Crecimiento Humana/efectos adversos , Hormona de Crecimiento Humana/uso terapéutico , Hipopituitarismo/tratamiento farmacológico , Neoplasias Hipofisarias/tratamiento farmacológico , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Hormona de Crecimiento Humana/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
CONTEXT: Inherited GH insensitivity (GHI) is usually caused by mutations in the GH receptor (GHR). Patients present with short stature associated with high GH and low IGF-I levels and may have midfacial hypoplasia (typical Laron syndrome facial features). We previously described four mildly affected GHI patients with an intronic mutation in the GHR gene (A(-1)-->G(-1) substitution in intron 6), resulting in the activation of a pseudoexon (6Psi) and inclusion of 36 amino acids. OBJECTIVE: The study aimed to analyze the clinical and genetic characteristics of additional GHI patients with the pseudoexon (6Psi) mutation. DESIGN/PATIENTS: Auxological, biochemical, genetic, and haplotype data from seven patients with severe short stature and biochemical evidence of GHI were assessed. MAIN OUTCOME MEASURES: We assessed genotype-phenotype relationship. RESULTS: One patient belongs to the same extended family, previously reported. She has normal facial features, and her IGF-I levels are in the low-normal range for age. The six unrelated patients, four of whom have typical Laron syndrome facial features, have heights ranging from -3.3 to -6.0 sd and IGF-I levels that vary from normal to undetectable. We hypothesize that the marked difference in biochemical and clinical phenotypes might be caused by variations in the splicing efficiency of the pseudoexon. CONCLUSIONS: Activation of the pseudoexon in the GHR gene can lead to a variety of GHI phenotypes. Therefore, screening for the presence of this mutation should be performed in all GHI patients without mutations in the coding exons.
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Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Trastornos del Crecimiento/genética , Hormona de Crecimiento Humana/metabolismo , Seudogenes/fisiología , Adolescente , Adulto , Estatura/genética , Niño , Análisis Mutacional de ADN , Exones/genética , Femenino , Trastornos del Crecimiento/metabolismo , Haplotipos , Humanos , Intrones/genética , Masculino , Linaje , Fenotipo , Empalme del ARN , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND/OBJECTIVE: Pegvisomant is a pegylated analogue of human GH and functions as a potent GH receptor antagonist. This novel mode of action gives it the potential to achieve biochemical control in patients with acromegaly whose disease activity cannot be satisfactorily controlled by conventional therapy. We have documented the clinical details of seven patients with residual active acromegaly after surgery and/or radiation therapy successfully treated with pegvisomant. PATIENTS/METHODS: Seven patients (four male, mean age 47 years, range 34-67 years) who participated in two separate clinical trials of pegvisomant have completed 2 years (four patients) or 1 year (three patients) of treatment. All had active acromegaly (mean serum GH level >5 mU/l; serum IGF-I elevated for age) that could not be controlled with standard medical therapy (dopamine agonist and/or a somatostatin analogue) following appropriate primary treatment with surgery and/or radiotherapy. RESULTS: On a median dose of 20 mg/day (range 15-40) pegvisomant, serum IGF-I fell from a mean of 920+/-351 ng/ml (s.d.) to 258+/-91 ng/ml and was normalised in all seven patients. These changes were associated with improvements in soft tissue enlargement and general well being. Treatment was well tolerated and no change in pituitary tumour size was evident on MRI scans performed every 6 months. CONCLUSIONS: Treatment with pegvisomant is safe and efficacy is maintained after 2 years. Serum IGF-I may be normalised in patients who are refractory to conventional therapy.
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Acromegalia/tratamiento farmacológico , Hormona de Crecimiento Humana/análogos & derivados , Hormona de Crecimiento Humana/uso terapéutico , Receptores de Somatotropina/antagonistas & inhibidores , Adulto , Anciano , Femenino , Hormona de Crecimiento Humana/efectos adversos , Humanos , Factor I del Crecimiento Similar a la Insulina/análisis , Masculino , Persona de Mediana Edad , Retratamiento , Resultado del TratamientoRESUMEN
The mammalian nucleus has considerable control over nascent transcripts. The basic mechanisms of post-transcriptional processing are well understood and recently some of the principles underlying the regulation of nuclear processing events have been elucidated. Here we review the recent progress in identification of signalling pathways that modulate the action of key RNA-binding proteins which regulate splicing, and the mechanisms of action of the C-terminal domain of RNA polymerase II that co-ordinate transcription with nuclear mRNA processing events.
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Núcleo Celular/genética , Núcleo Celular/metabolismo , Regulación de la Expresión Génica , Procesamiento Postranscripcional del ARN , Empalme Alternativo , Animales , Humanos , Modelos Biológicos , ARN Polimerasa II/química , ARN Polimerasa II/metabolismo , Precursores del ARN/genética , Precursores del ARN/metabolismo , Empalme del ARN , Proteínas de Unión al ARN/metabolismo , Transducción de Señal , Transcripción GenéticaRESUMEN
Inherited growth-hormone insensitivity (GHI) is a heterogeneous disorder that is often caused by mutations in the coding exons or flanking intronic sequences of the growth-hormone receptor gene (GHR). Here we describe a novel point mutation, in four children with GHI, that leads to activation of an intronic pseudoexon resulting in inclusion of an additional 108 nt between exons 6 and 7 in the majority of GHR transcripts. This mutation lies within the pseudoexon (A(-1)-->G(-1) at the 5' pseudoexon splice site) and, under in vitro splicing conditions, results in inclusion of the mutant pseudoexon, whereas the wild-type pseudoexon is skipped. The presence of the pseudoexon results in inclusion of an additional 36-amino acid sequence in a region of the receptor known to be involved in homo-dimerization, which is essential for signal transduction.