RESUMO
BACKGROUND: L-[methyl-11C]-methionine-positron emission tomography (Met-PET) is a potentially important imaging adjunct in the diagnostic workup of pituitary adenomas, including somatotroph tumors. Met-PET can identify residual or occult disease and make definitive therapies accessible to a subgroup of patients who would otherwise require lifelong medical therapy. However, existing data on its use are still limited to small case series. Here, we report the largest single-center experience (n = 61) in acromegaly. METHODS: A total of 189 cases of acromegaly were referred to our national Met-PET service in the last 12 years. For this analysis, we have reviewed outcomes in those 61 patients managed exclusively by our multidisciplinary team (single center, single surgeon). Referral indications were as follows: indeterminate magnetic resonance imaging (MRI; n = 38, 62.3%), occult residual (n = 14, 23.0%), (radio-)surgical planning (n = 6, 9.8%), and occult de novo tumor (n = 3, 4.9%). RESULTS: A total of 33/61 patients (54.1%) underwent PET-guided surgery. Twenty-four of 33 patients (72.7%) achieved complete biochemical remission following (re-)surgery. Insulin-like growth factor 1 levels were reduced to <2 × upper limit of normal (ULN) in 6 of the remaining 9 cases, 3 of whom achieved levels of <1.1 × ULN compared with mean preoperative levels of 2.4 × ULN (SD 0.8) for n = 9. Only 3 patients developed single new hormonal deficits (gonadotropic/thyrotropic insufficiency). There were no neurovascular complications after surgery. CONCLUSION: In patients with persistent/recurrent acromegaly or occult tumors, Met-PET can facilitate further targeted intervention (surgery/radiosurgery). This led to complete remission in most cases (24/33) or significant improvement with comparatively low risk of complications. L-[methyl-11C]-methionine-positron emission tomography should therefore be considered in all patients who are potential candidates for further surgical intervention but present no clear target on MRI.
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Acromegalia , Adenoma , Humanos , Acromegalia/diagnóstico por imagem , Acromegalia/etiologia , Acromegalia/terapia , Radioisótopos de Carbono , Tomografia por Emissão de Pósitrons/métodos , Adenoma/diagnóstico por imagem , Adenoma/cirurgia , Metionina , Imageamento por Ressonância Magnética/métodos , RacemetioninaRESUMO
OBJECTIVE: The aim of this study was to evaluate the prevalence of venous thromboembolism (VTE) in patients included in the European Registry on Cushing's syndrome (ERCUSYN), compare their clinical characteristics with those who did not develop VTE and identify risk factors for VTE. DESIGN: A retrospective observational cohort study. METHODS: Data extraction from the registry was taken on February, 7, 2022. At the time there were 2174 patients diagnosed with Cushing's syndrome (CS) and 95 VTEs were reported in the database. RESULTS: Of 95 VTE events 70 (74%) were in pituitary-dependent CS patients, 12 (12.5%) in adrenal-dependant CS, 10 (10.5%) in ectopic CS, and 3 (3%) in CS due to other causes. Sex, 24-hour urinary free cortisol (UFC) value at diagnosis, as well as the number of operations remained statistically significant predictors of VTE. Of patients who were treated with at least one surgery, 12 (13%) VTE occurred before and 80 (87%) after the surgery. Nearly half of these VTEs occurred within six months since the operation (36; 45%). Over half of the centers that reported VTE did not routinely anticoagulate CS patients. Anticoagulation schemes varied widely. CONCLUSION: Patients with CS have an elevated risk of developing VTE for an extended period of time. From ERCUSYN cohort patients have higher risk for VTE if they need multiple surgeries to treat CS, are males and have high UFC values at the diagnosis of CS. Since there is no agreement on thromboprohpylaxis, a protocol for VTE prevention that is widely adopted appears to be necessary for patients with CS.
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Síndrome de Cushing , Hipersecreção Hipofisária de ACTH , Trombose , Tromboembolia Venosa , Masculino , Humanos , Feminino , Síndrome de Cushing/complicações , Síndrome de Cushing/epidemiologia , Síndrome de Cushing/cirurgia , Estudos Retrospectivos , Prevalência , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/complicações , Hipersecreção Hipofisária de ACTH/complicações , HidrocortisonaRESUMO
Metastatic involvement of the pituitary gland is a rare but clinically significant phenomenon, that often poses diagnostic and therapeutic challenges. The aim of this study was to provide a comprehensive analysis of the origin of pituitary metastases using data from the German Pituitary Tumor Registry, one of the globally largest collections of pituitary pathology specimens. Here, we report data from a retrospective analysis of patients with metastases to the pituitary registered between 1990 and 2022. Out of 17,896 pituitary cases in the registry during this period, a total of 96 metastases to the pituitary gland were identified, accounting for 0.5% of all pituitary tumors in the registry. The mean age of the patients was 64 years. Breast cancer was identified as the primary tumor in 25% of total cases (n = 24/96) and in 50% of female patients. The second most prevalent primary tumor was lung cancer (18.75%, n = 18/96), followed by renal cell carcinoma (14.58%, n = 14/96). In comparison to current meta-analyses, this cohort shows a higher prevalence of metastases originating from the kidney. Furthermore, in contrast to the existing literature, no case of primary thyroid tumor was identified. Our study highlights the importance of pituitary metastases as a differential diagnosis in patients presenting with pituitary tumors.
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Neoplasias Renais , Doenças da Hipófise , Neoplasias Hipofisárias , Humanos , Feminino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/patologia , Estudos Retrospectivos , Neoplasias Renais/patologia , Hipófise/patologia , Sistema de RegistrosRESUMO
Pegvisomant, the first and currently only clinically available growth hormone receptor antagonist, is an effective therapeutic option for the medical treatment of acromegaly, a rare disorder characterized by excessive growth hormone secretion. With now over 20 years of real world experience, its safety and efficacy is well-established. However, several aspects of its clinical use are still controversially discussed. The high cost of pegvisomant has limited its use in several countries, and recent studies have reported a lower efficacy than the initial clinical trials. A reported increase in tumor volume under therapy varies between studies and has been attributed to either actual growth or re-expansion after cessation of somatostatin receptor ligand therapy. Furthermore, different combinations of pegvisomant and other therapeutic agents aiming at reduction of acromegaly disease activity have been proposed to increase or retain effectiveness while lowering side effects and cost. This review aims to assess current clinical data on the safety and efficacy of pegvisomant while also addressing controversies surrounding its use.
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Acromegalia , Hormônio do Crescimento Humano , Humanos , Acromegalia/tratamento farmacológico , Acromegalia/induzido quimicamente , Acromegalia/patologia , Receptores da Somatotropina/uso terapêutico , Hormônio do Crescimento Humano/efeitos adversos , Antagonistas de Hormônios/efeitos adversos , Fator de Crescimento Insulin-Like IRESUMO
Corticotroph tumor progression after bilateral adrenalectomy/Nelson's syndrome (CTP-BADX/NS) is a severe complication of bilateral adrenalectomy (BADX). The aim of our study was to investigate the prevalence, presentation and outcome of CTP-BADX/NS in patients with Cushing's disease (CD) included in the European Registry on Cushing's Syndrome (ERCUSYN). We examined data on 1045 CD patients and identified 85 (8%) who underwent BADX. Of these, 73 (86%) had follow-up data available. The median duration of follow-up since BADX to the last visit/death was 7 years (IQR 2-9 years). Thirty-three patients (45%) experienced CTP-BADX/NS after 3 years (1.5-6) since BADX. Cumulative progression-free survival was 73% at 3 years, 66% at 5 years and 46% at 10 years. CTP-BADX/NS patients more frequently had a visible tumor at diagnosis of CD than patients without CTP-BADX/NS (P < 0.05). Twenty-seven CTP-BADX/NS patients underwent surgery, 48% radiotherapy and 27% received medical therapy. The median time since diagnosis of CTP-BADX/NS to the last follow-up visit was 2 years (IQR, 1-5). Control of tumor progression was not achieved in 16 of 33 (48%) patients, of whom 8 (50%) died after a mean of 4 years. Maximum adenoma size at diagnosis of CD was associated with further tumor growth in CTP-BADX/NS despite treatment (P = 0.033). Diagnosis of CTP-BADX/NS, older age, greater UFC levels at diagnosis of CD and initial treatment predicted mortality. In conclusion, CTP-BADX/NS was reported in 45% of the ERCUSYN patients who underwent BADX, and control of tumor growth was reached in half of them. Future studies are needed to establish effective strategies for prevention and treatment.
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Síndrome de Nelson , Hipersecreção Hipofisária de ACTH , Humanos , Adrenalectomia/efeitos adversos , Corticotrofos , Síndrome de Nelson/diagnóstico , Síndrome de Nelson/etiologia , Síndrome de Nelson/cirurgiaRESUMO
OBJECTIVE: Craniopharyngiomas (CPs) are benign, dysontogenetic tumors associated with complex endocrinologic and neurologic symptoms and high morbidity. The aim of this study is to elucidate modifiable effectors of health-related quality of life (HrQoL) of adult patients with CP following neurosurgical intervention using standardized instruments as well as descriptive analysis. METHODS: HrQoL (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 and BN20) was evaluated in 20 adult patients with CP. We examined pre- as well as postoperative radiologic, hormonal, and symptom-oriented data in a retrospective analysis. Surgical approach, postoperative complications, and extent of resection were recorded. Additional descriptive analysis was performed on case records of all patients with HrQoL results. RESULTS: Long-term follow-up of HrQoL (mean of 75 months) was lower than the in healthy reference group (CP = 58, reference = 75). The most common postoperative complaints were endocrinologic disturbances (88%). Overall, univariate and multivariate logistic regression analysis revealed no significant predictors of reduced postoperative HrQoL. Descriptive analysis did, however, reveal a cluster of patients among those with the lowest global HrQoL which reported new postoperative anosmia and ageusia. CONCLUSIONS: The global HrQoL of our cohort showed a substantial reduction compared with a healthy reference population. Postoperative hyposmia and ageusia is found in patients with the lowest postoperative HrQoL who otherwise had no new significant endocrinologic or neurologic complications. As these symptoms are not regularly accounted for in the HrQoL instruments used in this study, further analysis is needed to determine the possible significance of this complication in CP surgery, and it may affect the choice of surgical approach as well as the information patients receive before consenting to surgery.
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Neoplasias Encefálicas/psicologia , Craniofaringioma/psicologia , Qualidade de Vida , Adulto , Idoso , Ageusia/etiologia , Ageusia/psicologia , Anosmia/etiologia , Anosmia/psicologia , Neoplasias Encefálicas/cirurgia , Craniofaringioma/cirurgia , Doenças do Sistema Endócrino/etiologia , Doenças do Sistema Endócrino/psicologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/psicologia , Estudos Retrospectivos , Fatores Socioeconômicos , Inquéritos e Questionários , Resultado do Tratamento , Adulto JovemRESUMO
Introduction: Little is known about psychological reasons associated with adherence to growth hormone (GH) replacement therapy (GHRx) in adults. As in other chronic diseases, medication-related beliefs, coping strategies and disease impact on quality of life (QoL) might play an important role. We thus explored these psychological factors in relation to adherence in patients with GH deficiency (GHD) in order to find leverage points for the improvement of adherence. Patients and Methods: Cross-sectional analysis including 107 adult GHD patients on GHRx who completed self-assessment inventories on health-related QoL (Short-Form SF-36), coping style (Freiburg questionnaire on coping with illness, FKV-LIS) and medication beliefs (Beliefs about Medicine questionnaire, BMQ). Results were correlated to general and GH-specific adherence to medication. Results: In the BMQ, 92.5% of the patients (n=99) reported a strong belief in the need for their medication, which correlated significantly with general adherence (rs = 0.325). Active coping was significantly related to general (rs = 0.307) and GH-specific adherence (rs = 0.226). Better mental QoL (rs = 0.210) but worse physical QoL (rs = -0.198; all p < 0.05) were related to higher GH-specific adherence. Older age was associated with a higher degree of active coping, a higher belief in the necessity of medication and worse physical QoL. Conclusion: We provide preliminary data that most GHD patients on GHRx are strongly convinced of their need for medication and that adherence to GHRx is influenced by coping strategies and QoL. Patients with impaired psychological QoL are less able to translate their convictions into good adherence, a phenomenon to be addressed in future research.
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Adaptação Psicológica/fisiologia , Adenoma/complicações , Hormônio do Crescimento Humano/uso terapêutico , Hipopituitarismo/etiologia , Adesão à Medicação , Neoplasias Hipofisárias/complicações , Adulto , Idoso , Estudos Transversais , Feminino , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/deficiência , Humanos , Hipopituitarismo/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Qualidade de VidaRESUMO
Guidelines and consensus statements ensure that physicians managing acromegaly patients have access to current information on evidence-based treatments to optimize outcomes. Given significant novel recent advances in understanding acromegaly natural history and individualized therapies, the Pituitary Society invited acromegaly experts to critically review the current literature in the context of Endocrine Society guidelines and Acromegaly Consensus Group statements. This update focuses on how recent key advances affect treatment decision-making and outcomes, and also highlights the likely role of recently FDA-approved therapies as well as novel combination therapies within the treatment armamentarium.
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Acromegalia/sangue , Animais , Feminino , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Octreotida/uso terapêutico , Neoplasias Hipofisárias/sangue , Receptores de Somatostatina/sangueRESUMO
INTRODUCTION: While reasons for non-adherence in children requiring growth hormone (GH) replacement (GH-Rx) are well researched, few studies have investigated adherence in adult GH deficient patients. Against the background of the adverse medical sequelae of untreated severe GH deficiency (GHD) in adults, we explored adherence to GH-Rx and associated factors in this patient group. METHOD: Cross-sectional analysis including 107 adult patients with severe GHD on GH-Rx, 15 untreated GDH patients and 19 who had discontinued therapy. Patients completed self-developed ad hoc surveys on adherence to medication and GH-Rx, specific beliefs about GH-Rx, side effects and burden of injection, reasons for never receiving or dropping out of therapy, respectively. RESULTS: Adherence to GH-Rx was high (mean 15.8/18 points on the self-developed adherence score) and significantly correlated with general medication adherence. Higher age was significantly associated with better adherence to GH-Rx, while injection side effects, duration of treatment or device used were not. The most frequent reasons for not being on GH-Rx apart from medical reasons included fear of side effects, lack of belief in treatment effects and dislike of injections. In patients not on GH-Rx, the proportion of patients in employment was significantly smaller than in the treatment group, despite similar age and comorbidities. CONCLUSIONS: Adherence to GH-Rx was high for those patients on therapy. Instead of focusing on improving adherence in those adults already on GH-Rx, efforts should be undertaken to ally fear of side effects and provide education on positive treatment effects for those eligible but not receiving therapy.
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Hormônio do Crescimento/uso terapêutico , Terapia de Reposição Hormonal/métodos , Terapia de Reposição Hormonal/psicologia , Hipopituitarismo/tratamento farmacológico , Adolescente , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Motivação , Inquéritos e Questionários , Adulto JovemRESUMO
A homozygous mutation in growth hormone 1 (GH1) was recently identified in an individual with growth failure. This mutation, c.705G>C, causes replacement of cysteine at position 53 of the 191-amino-acid sequence of 22 kDa human GH (hGH) with serine (p.C53S). This hGH molecule (hereafter referred to as GH-C53S) lacks the disulfide bond between p.Cys-53 and p.Cys-165, which is highly conserved among species. It has been reported previously that monomeric GH-C53S has reduced bioactivity compared with WT GH (GH-WT) because of its decreased ability to bind and activate the GH receptor in vitro In this study, we discovered that substitution of p.Cys-53 in hGH significantly increased formation of hGH dimers in pituitary cells. We expressed His-tagged hGH variants in the cytoplasm of genetically modified Rosetta-gami B DE3 Escherichia coli cells, facilitating high-yield production. We observed that the bioactivity of monomeric GH-C53S is 25.2% of that of GH-WT and that dimeric GH-C53S-His has no significant bioactivity in cell proliferation assays. We also found that the expression of GH-C53S in pituitary cells deviates from that of GH-WT. GH-C53S was exclusively stained in the Golgi apparatus, and no secretory granules formed for this variant, impairing its stimulated release. In summary, the unpaired Cys-165 in GH-C53S forms a disulfide bond linking two hGH molecules in pituitary cells. We conclude that the GH-C53S dimer is inactive and responsible for the growth failure in the affected individual.
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Cisteína/genética , Nanismo/patologia , Hormônio do Crescimento Humano/química , Hormônio do Crescimento Humano/genética , Hipófise/patologia , Mutação Puntual , Multimerização Proteica , Cisteína/química , Cisteína/metabolismo , Nanismo/genética , Glicosilação , Células HEK293 , Hormônio do Crescimento Humano/metabolismo , Humanos , Hipófise/metabolismo , Estabilidade ProteicaRESUMO
CONTEXT: Despite growing evidence that temozolomide (TMZ) therapy is effective for the treatment of aggressive pituitary tumors (APTs) or carcinomas (PCs), individual therapy decisions remain challenging. OBJECTIVE: We therefore aimed to report on clinical characteristics leading to initiation of TMZ therapy and to add evidence on TMZ long-term effectiveness. DESIGN AND SUBJECTS: Retrospective survey on TMZ treatment in patients with APTs or PCs. TMZ therapy was initiated in 47 patients (22 females) with APTs (n = 34) or PCs (n = 13). Mean age at diagnosis was 45 ± 15 years. The immunohistochemical subtypes were corticotroph (n = 20), lactotroph (n = 18), and nonfunctioning (n = 9) tumors. TMZ therapy started 8 years after initial diagnosis using a standard regimen (median 6 cycles) for the majority of patients. RESULTS: Long-term radiological response to TMZ after a median follow-up of 32 months with 4 patients still on TMZ therapy was tumor regression for 9 (20%), stable disease for 8 (17%), and tumor progression for 29 patients (63%) (outcome data available for 46 patients). Progression occurred 16 months after initiation of TMZ. Median estimated progression-free survival was 23 months. Disease stabilization and median progression-free survival did not differ between patients with APTs or PCs. Predictors of tumor response were not identified. Overall, TMZ was well tolerated. CONCLUSION: We performed a nationwide survey on TMZ therapy in patients with APTs and PCs. While early response rates to TMZ are promising, long-term outcome is less favorable. Prolonged TMZ administration should be considered. We were not able to confirm previously reported predictors of tumor response to TMZ.
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Adenoma/tratamento farmacológico , Antineoplásicos Alquilantes/uso terapêutico , Carcinoma/tratamento farmacológico , Neoplasias Hipofisárias/tratamento farmacológico , Temozolomida/uso terapêutico , Adulto , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: Patients with Cushing's syndrome (CS) have increased mortality. The aim of this study was to evaluate the causes and time of death in a large cohort of patients with CS and to establish factors associated with increased mortality. METHODS: In this cohort study, we analyzed 1564 patients included in the European Registry on CS (ERCUSYN); 1045 (67%) had pituitary-dependent CS, 385 (25%) adrenal-dependent CS, 89 (5%) had an ectopic source and 45 (3%) other causes. The median (IQR) overall follow-up time in ERCUSYN was 2.7 (1.2-5.5) years. RESULTS: Forty-nine patients had died at the time of the analysis; 23 (47%) with pituitary-dependent CS, 6 (12%) with adrenal-dependent CS, 18 (37%) with ectopic CS and two (4%) with CS due to other causes. Of 42 patients whose cause of death was known, 15 (36%) died due to progression of the underlying disease, 13 (31%) due to infections, 7 (17%) due to cardiovascular or cerebrovascular disease and 2 due to pulmonary embolism. The commonest cause of death in patients with pituitary-dependent CS and adrenal-dependent CS were infectious diseases (n = 8) and progression of the underlying tumor (n = 10) in patients with ectopic CS. Patients who had died were older and more often males, and had more frequently muscle weakness, diabetes mellitus and ectopic CS, compared to survivors. Of 49 deceased patients, 22 (45%) died within 90 days from start of treatment and 5 (10%) before any treatment was given. The commonest cause of deaths in these 27 patients were infections (n = 10; 37%). In a regression analysis, age, ectopic CS and active disease were independently associated with overall death before and within 90 days from the start of treatment. CONCLUSION: Mortality rate was highest in patients with ectopic CS. Infectious diseases were the commonest cause of death soon after diagnosis, emphasizing the need for careful clinical vigilance at that time, especially in patients presenting with concomitant diabetes mellitus.
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Síndrome de Cushing/mortalidade , Doenças das Glândulas Suprarrenais/etiologia , Doenças das Glândulas Suprarrenais/mortalidade , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Estudos de Coortes , Comorbidade , Síndrome de Cushing/complicações , Complicações do Diabetes/mortalidade , Europa (Continente)/epidemiologia , Feminino , França/epidemiologia , Humanos , Infecções/complicações , Infecções/mortalidade , Masculino , Pessoa de Meia-Idade , Doenças da Hipófise/etiologia , Doenças da Hipófise/mortalidade , Sistema de Registros , Fatores Sexuais , Adulto JovemRESUMO
BACKGROUND: Adrenal crisis, the most feared complication of adrenal insufficiency, is a potentially life-threatening state of acute glucocorticoid deficiency. After successful surgery for Cushing's syndrome, many patients develop (transient) adrenal insufficiency. The incidence of adrenal crisis in patients treated for hypercortisolism is unknown. METHODS: Cohort study included consecutive patients with Cushing's syndrome with adrenal insufficiency after surgery from Leiden and Berlin from 2000 to 2015. We summarized the incidence of adrenal crisis, compared patients with and without adrenal crisis regarding potential risk factors for its occurrence and assessed the effect of better education in time on incidence of adrenal crisis. RESULTS: We included 106 patients, of whom 19 patients had a total of 41 adrenal crises. There were 9.0 crises per 100 patient-years at risk (95% confidence interval (CI): 6.7-12.0). All crises occurred while on hydrocortisone replacement. The risk ratio for a recurrent crisis was 2.3 (95% CI: 1.2-4.6). No clear change in incidence of adrenal crisis due to better education in time was observed. There was no difference in recurrence rate between patients with, and without any crisis, but patients with adrenal crisis had more often pituitary deficiencies. CONCLUSIONS: The incidence of adrenal crises after treatment for Cushing's syndrome is substantial, and patients who suffered from an adrenal crisis have higher risk for recurrent crisis. Adrenal crisis tends to present early after remission of Cushing's syndrome, which is probably the period of severest HPA axis suppression, despite in general higher hydrocortisone replacement doses for withdrawal complaints in this period. Additional pituitary hormone deficiencies may be a risk marker for increased risk of adrenal crisis. However, further risk factor analysis is needed to identify risks for a first crisis. Effective education methods to prevent adrenal crises should be identified and implemented, including stress instructions by trained nursing staff before hospital discharge.
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Insuficiência Adrenal/metabolismo , Síndrome de Cushing/metabolismo , Síndrome de Cushing/cirurgia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Complicações Pós-Operatórias/metabolismo , Adolescente , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos de Coortes , Síndrome de Cushing/diagnóstico , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Adulto JovemRESUMO
Objectives ACROSTUDY is an international, non-interventional study of acromegaly patients treated with pegvisomant (PEGV), a growth hormone receptor antagonist and has been conducted since 2004 in 15 countries to study the long-term safety and efficacy of PEGV. This report comprises the second interim analysis of 2090 patients as of May 12, 2016. Methods Descriptive analyses of safety, pituitary imaging and outcomes on PEGV treatment up to 12 years were performed. Results Prior to starting PEGV, 96% of patients had reported surgery, radiation, medical therapy or any combinations of those. At start of PEGV, 89% of patients had IGFI levels above the upper limit of normal (ULN). The percentage of patients with normal IGFI levels increased from 53% at year 1 to 73% at year 10, and the average daily dose of PEGV increased from 12.8 mg (year 1) to 18.9 mg (year 10). A total of 4832 adverse events (AEs) were reported in 1137 patients (54.4%), of which 570 were considered treatment related in 337 patients (16.1%). Serious AEs were reported in 22% of patients, of which 2.3% were considered treatment related. Locally reported MRIs showed most patients (72.2%) had no change in tumor size relative to the prior scan; 16.8% had a decrease, 6.8% an increase and 4.3% both. In patients with normal liver tests at PEGV start, an ALT or AST elevation of >3× ULN at any time point during their follow-up was reported in 3%. Conclusions This second interim analysis confirms that long-term use of PEGV is an effective and safe treatment in patients with acromegaly.
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Acromegalia/diagnóstico , Acromegalia/tratamento farmacológico , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/metabolismo , Internacionalidade , Acromegalia/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Esquema de Medicação , Feminino , Seguimentos , Hormônio do Crescimento Humano/administração & dosagem , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
Objective: Acromegalic patients display a distinct neuropsychological profile and suffer from chronic physical complaints. We aimed to investigate in more detail these aspects in acromegalic patients, dependent on influencing factors like disease activity, age, sex, chronic medication, surgery, pituitary radiation, pituitary insufficiency and comorbidities. Design: Cross sectional, multicentric. Methods: 129 patients (M/W 65/64, 58.3 ± 12.7 years, 53/76 with active/controlled disease). Acromegalic patients completed the following inventories: NEO-FFI, IIP-D, and the Giessen Complaints List (GBB-24), after written informed consent. Age, sex, IGF-1 concentrations, comorbidities, treatment modalities and pituitary insufficiency were documented. Results: Acromegalic patients or specific patient-subgroups were more agreeable, neurotic, exploitable/permissive, introverted/socially avoidant, non-assertive/insecure, nurturant and less open to experience, cold/denying, domineering, compared to normal values from the healthy population (controls). Multivariable analysis demonstrated that these overall results were due to the specific patient subgroups as patients on chronic medication, with arthrosis and pituitary insufficiency. Disease activity was only associated with the trait nurturant. Higher scores for introversion were associated with arthrosis. Lower domineering was independent of any disease- or treatment related variable or comorbidity. The GBB inventory showed overall higher scores in patients, with higher scores for exhaustion and general complaints being associated with pituitary insufficiency, coronary heart disease and history of malignancy in the multivariable analysis. Joint complaints were independent of any disease- or treatment- related variable. Conclusions: We define new aspects of a distinct neuropsychological profile in patients with acromegaly, which are largely independent of disease activity. Chronic physical complaints are more pronounced in patients than in controls, with exhaustion and general complaints showing no association with disease activity.
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The 11th Acromegaly Consensus Conference in April 2017 was convened to update recommendations on therapeutic outcomes for patients with acromegaly. Consensus guidelines on the medical management of acromegaly were last published in 2014; since then, new pharmacological agents have been developed and new approaches to treatment sequencing have been considered. Thirty-seven experts in the management of patients with acromegaly reviewed the current literature and assessed changes in drug approvals, clinical practice standards and clinical opinion. They considered current treatment outcome goals with a focus on the impact of current and emerging somatostatin receptor ligands, growth hormone receptor antagonists and dopamine agonists on biochemical, clinical, tumour mass and surgical outcomes. The participants discussed factors that would determine pharmacological choices as well as the proposed place of each agent in the guidelines. We present consensus recommendations highlighting how acromegaly management could be optimized in clinical practice.
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Acromegalia/diagnóstico , Acromegalia/tratamento farmacológico , Hormônio do Crescimento Humano/administração & dosagem , Guias de Prática Clínica como Assunto , Somatostatina/análogos & derivados , Somatostatina/administração & dosagem , Consenso , Feminino , Humanos , Masculino , Prognóstico , Medição de Risco , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Purpose: The diagnosis of adult GH deficiency (AGHD) is challenging and often requires confirmation with a GH stimulation test (GHST). The insulin tolerance test (ITT) is considered the reference standard GHST but is labor intensive, can cause severe hypoglycemia, and is contraindicated for certain patients. Macimorelin, an orally active GH secretagogue, could be used to diagnose AGHD by measuring stimulated GH levels after an oral dose. Materials and Methods: The present multicenter, open-label, randomized, two-way crossover trial was designed to validate the efficacy and safety of single-dose oral macimorelin for AGHD diagnosis compared with the ITT. Subjects with high (n = 38), intermediate (n = 37), and low (n = 39) likelihood for AGHD and healthy, matched controls (n = 25) were included in the efficacy analysis. Results: After the first test, 99% of macimorelin tests and 82% of ITTs were evaluable. Using GH cutoff levels of 2.8 ng/mL for macimorelin and 5.1 ng/mL for ITTs, the negative agreement was 95.38% (95% CI, 87% to 99%), the positive agreement was 74.32% (95% CI, 63% to 84%), sensitivity was 87%, and specificity was 96%. On retesting, the reproducibility was 97% for macimorelin (n = 33). In post hoc analyses, a GH cutoff of 5.1 ng/mL for both tests resulted in 94% (95% CI, 85% to 98%) negative agreement, 82% (95% CI, 72% to 90%) positive agreement, 92% sensitivity, and 96% specificity. No serious adverse events were reported for macimorelin. Conclusions: Oral macimorelin is a simple, well-tolerated, reproducible, and safe diagnostic test for AGHD with accuracy comparable to that of the ITT. A GH cutoff of 5.1 ng/mL for the macimorelin test provides an excellent balance between sensitivity and specificity.
Assuntos
Testes Diagnósticos de Rotina/métodos , Hormônio do Crescimento Humano/deficiência , Hipopituitarismo/diagnóstico , Indóis/administração & dosagem , Testes de Função Hipofisária/métodos , Triptofano/análogos & derivados , Administração Oral , Adolescente , Adulto , Idade de Início , Idoso , Estudos Cross-Over , Testes Diagnósticos de Rotina/efeitos adversos , Feminino , Humanos , Hipopituitarismo/sangue , Hipopituitarismo/epidemiologia , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Testes de Função Hipofisária/efeitos adversos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Triptofano/administração & dosagem , Triptofano/efeitos adversos , Adulto JovemRESUMO
OBJECTIVE: Hypercortisolism in Cushing's syndrome (CS) is associated with impaired health-related quality of life (HRQoL), which may persist despite remission. We used the data entered into the European Registry on Cushing's syndrome (ERCUSYN) to evaluate if patients with CS of pituitary origin (PIT-CS) have worse HRQoL, both before and after treatment than patients with adrenal causes (ADR-CS). METHODS: Data from 595 patients (492 women; 83%) who completed the CushingQoL and/or EQ-5D questionnaires at baseline and/or following treatment were analysed. RESULTS: At baseline, HRQoL did not differ between PIT-CS (n = 293) and ADR-CS (n = 120) on both EuroQoL and CushingQoL. Total CushingQoL score in PIT-CS and ADR-CS was 41 ± 18 and 44 ± 20, respectively (P = .7). At long-time follow-up (>1 year after treatment) total CushingQoL score was however lower in PIT-CS than ADR-CS (56 ± 20 vs 62 ± 23; P = .045). In a regression analysis, after adjustment for baseline age, gender, remission status, duration of active CS, glucocorticoid dependency and follow-up time, no association was observed between aetiology and HRQoL. Remission was associated with better total CushingQoL score (P < .001), and older age at diagnosis with worse total score (P = .01). Depression at diagnosis was associated with worse total CushingQoL score at the last follow-up (P < .001). CONCLUSION: PIT-CS patients had poorer HRQoL than ADR-CS at long-term follow-up, despite similar baseline scoring. After adjusting for remission status, no interaetiology differences in HRQoL scoring were found. Age and presence of depression at diagnosis of CS may be potential predictors of worse HRQoL regardless of CS aetiology.
Assuntos
Adenoma/fisiopatologia , Hidrocortisona/metabolismo , Hipersecreção Hipofisária de ACTH/metabolismo , Hipersecreção Hipofisária de ACTH/fisiopatologia , Adenoma/tratamento farmacológico , Adenoma/metabolismo , Adulto , Feminino , Glucocorticoides/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Estudos Prospectivos , Qualidade de Vida , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Surgery is the definitive treatment of Cushing's syndrome (CS) but medications may also be used as a first-line therapy. Whether preoperative medical treatment (PMT) affects postoperative outcome remains controversial. OBJECTIVE: (1) Evaluate how frequently PMT is given to CS patients across Europe; (2) examine differences in preoperative characteristics of patients who receive PMT and those who undergo primary surgery and (3) determine if PMT influences postoperative outcome in pituitary-dependent CS (PIT-CS). PATIENTS AND METHODS: 1143 CS patients entered into the ERCUSYN database from 57 centers in 26 countries. Sixty-nine percent had PIT-CS, 25% adrenal-dependent CS (ADR-CS), 5% CS from an ectopic source (ECT-CS) and 1% were classified as having CS from other causes (OTH-CS). RESULTS: Twenty per cent of patients took PMT. ECT-CS and PIT-CS were more likely to receive PMT compared to ADR-CS (P < 0.001). Most commonly used drugs were ketoconazole (62%), metyrapone (16%) and a combination of both (12%). Median (interquartile range) duration of PMT was 109 (98) days. PIT-CS patients treated with PMT had more severe clinical features at diagnosis and poorer quality of life compared to those undergoing primary surgery (SX) (P < 0.05). Within 7 days of surgery, PIT-CS patients treated with PMT were more likely to have normal cortisol (P < 0.01) and a lower remission rate (P < 0.01). Within 6 months of surgery, no differences in morbidity or remission rates were observed between SX and PMT groups. CONCLUSIONS: PMT may confound the interpretation of immediate postoperative outcome. Follow-up is recommended to definitely evaluate surgical results.
Assuntos
Síndrome de Cushing/tratamento farmacológico , Síndrome de Cushing/cirurgia , Glândulas Suprarrenais/fisiopatologia , Adulto , Idoso , Síndrome de Cushing/fisiopatologia , Bases de Dados Factuais , Europa (Continente) , Feminino , Humanos , Cetoconazol/uso terapêutico , Masculino , Metirapona/uso terapêutico , Pessoa de Meia-Idade , Síndromes Endócrinas Paraneoplásicas , Hipófise/fisiopatologia , Cuidados Pós-Operatórios , Período Pós-Operatório , Qualidade de Vida , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate human placental growth hormone (hGH-V) in ectopic pregnancy (EP): detection in maternal blood, correlation with immunohistochemistry and possible role as a marker for the course of EP. DESIGN: Women presenting in the outpatient or emergency department of a tertiary care university hospital with a positive pregnancy test and strong suspicion of EP by ultrasound and/or symptoms were eligible for the study (n=70). Tissue specimens from the surgically treated patients (n=50) were examined by histopathology as well as by a hGH-V specific immohistochemistry set-up. A highly sensitive hGH-V specific immunoassay was used to analyse serum samples collected before treatment, day 1 post surgery samples and serial samples for medical treatment. RESULT(S): In EP patients' sera hGH-V was shown to be measurable for the first time (n=18). HGH-V however could not be detected in all patients' sera. HCG levels were significantly higher in the hGH-V serum positive group (p 0.001). HGH-V was localized to the syncytiotrophoblast in all specimens of EP examined by immunohistochemistry (n=10) regardless of the detection in the patient's blood. CONCLUSION(S): Placental growth hormone (hGH-V) was shown to be present both in ectopic pregnancy patients' sera and tissue. It may serve as a biomarker for monitoring the course and treatment of EP.