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Pituitary neuroendocrine tumors (PitNETs) account for approximately 15% of all intracranial neoplasms. Although they usually appear to be benign, some tumors display worse behavior, displaying rapid growth, invasion, refractoriness to treatment, and recurrence. Increasing evidence supports the role of primary cilia (PC) in regulating cancer development. Here, we showed that PC are significantly increased in PitNETs and are associated with increased tumor invasion and recurrence. Serial electron micrographs of PITNETs demonstrated different ciliation phenotypes (dot-like versus normal-like cilia) that represented PC at different stages of ciliogenesis. Molecular findings demonstrated that 123 ciliary-associated genes (eg, doublecortin domain containing protein 2, Sintaxin-3, and centriolar coiled-coil protein 110) were dysregulated in PitNETs, representing the upregulation of markers at different stages of intracellular ciliogenesis. Our results demonstrate, for the first time, that ciliogenesis is increased in PitNETs, suggesting that this process might be used as a potential target for therapy in the future.
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Biomarcadores Tumorais , Cílios , Tumores Neuroendócrinos , Neoplasias Hipofisárias , Humanos , Cílios/patologia , Cílios/ultraestrutura , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/genética , Feminino , Masculino , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/genética , Pessoa de Meia-Idade , Adulto , Idoso , Recidiva Local de Neoplasia/patologia , Invasividade Neoplásica , Imuno-HistoquímicaRESUMO
AIM: To investigate the impact of pituitary surgery on glucose metabolism and to identify predictors of remission of diabetes after pituitary surgery in patients with acromegaly. METHODS: A national multicenter retrospective study of patients with acromegaly undergoing transsphenoidal surgery for the first time at 33 tertiary Spanish hospitals (ACRO-SPAIN study) was performed. Surgical remission of acromegaly was evaluated according to the 2000 and 2010 criteria. RESULTS: A total of 604 acromegaly patients were included in the study with a total median follow up of 91 months (interquartile range [IQR] 45-163). At the acromegaly diagnosis, 23.8% of the patients had diabetes mellitus (DM) with a median glycated hemoglobin (HbA1c) of 6.9% (IQR 6.4-7.9) [51.9 mmol/mol (IQR 46.4-62.8)]. In the multivariate analysis, older age (odds ratio [OR] 1.02, 95% CI 1.00-1.05), dyslipidemia (OR 5.25, 95% CI 2.81 to 9.79), arthropathy (OR 1.39, 95% CI 2.82 to 9.79), and higher IGF-I levels (OR 1.30, 95% CI 1.05 to 1.60) were associated with a greater prevalence of DM. At the last follow-up visit after surgery, 21.1% of the DM patients (56.7% of them with surgical remission of acromegaly) experienced diabetes remission. The cure rate of DM was more common in older patients (hazard ratio [HR] 1.77, 95% CI 1.31 to 2.43), when surgical cure was achieved (HR 2.10, 95% CI 1.01 to 4.37) and when anterior pituitary function was not affected after surgery (HR 3.38, 95% CI 1.17 to 9.75). CONCLUSION: Glucose metabolism improved in patients with acromegaly after surgery and 21% of the diabetic patients experienced diabetes remission; being more frequent in patients of older age, and those who experienced surgical cure and those with preserved anterior pituitary function after surgery.
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INTRODUCTION: It is estimated that 30-40% of patients with apparently sporadic pheochromocytomas (PHEOs) have an inherited predisposition syndrome. The aim of our study was to develop a predictive model of hereditary PHEO based on the clinical, hormonal, and radiological features present at the diagnosis of patients with PHEOs. METHODS: A retrospective multicenter cohort study of patients with PHEOs with available genetic study from 18 tertiary hospitals. Clinical, biochemical, and radiological features were used to build a multivariate logistic regression model. The estimation of all possible equations was used to select the model with the best diagnostic accuracy (lower Akaike index). RESULTS: A total of 245 patients were included: 169 (69.0%) patients with sporadic PHEOs and 76 (31%) with hereditary PHEOs. The parsimonious predictive model with the highest diagnostic accuracy for the prediction of hereditary PHEO combined the variables age, non-cardiovascular disease, urinary norepinephrine levels, and tumor size. The area under the ROC curve of this model was 0.800 (0.705-0.887). Based on the predictive model, the probability of hereditary PHEO in patients older than 60 years with cardiovascular disease, high levels of urinary norepinephrine and unilateral PHEOs >60 mm was <2%. And if the age was above 80 years, lower than 1%. The probability of sporadic PHEO linearly increased with age (MH Test for linear Trend: χ2 (1) = 30.05; p < 0.001). CONCLUSION: In certain populations such as old patients with cardiovascular disease, with high levels of urinary norepinephrine and large tumors in which the probability of hereditary PHEO is very low, genetic testing could be avoided in the absence of specific suspicion.
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Neoplasias das Glândulas Suprarrenais , Feocromocitoma , Humanos , Idoso de 80 Anos ou mais , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Feocromocitoma/patologia , Estudos de Coortes , Testes Genéticos , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , NorepinefrinaRESUMO
PURPOSE: To compare the clinical, hormonal, and radiological presentation and surgical outcomes of patients with macroadenomas presenting with pituitary apoplexy and patients not presenting pituitary apoplexy. METHODS: Multicentre retrospective study of patients presenting with macroadenomas and pituitary apoplexy in three Spanish tertiary hospitals between 2008 and 2022. We selected as control group (non-pituitary apoplexy), patients with pituitary macroadenomas without apoplexy who underwent pituitary surgery between 2008 and 2020. RESULTS: A total of 60 patients with apoplexy and 185 without apoplexy were enrolled. Patients with pituitary apoplexy were more frequently men (70% vs. 48.1%, p = 0.003), had higher prevalence of hypertension (43.3% vs. 26.0%, p = 0.011) and of obesity (23.3% vs. 9.7%, P = 0.007), were under treatment with anticoagulants more commonly (11.7% vs. 4.3%, P = 0.039) and had larger (27.5 ± 11.03 vs. 23.6 ± 12.55 mm, p = 0.035) and invasive pituitary macroadenomas more frequently (85.7% vs. 44.3%, P < 0.001) than those without apoplexy. Surgical remission was more frequent in patients with pituitary apoplexy than those without apoplexy (OR 4.55, P < 0.001), but they developed new pituitary deficits (OR 13.29, P < 0.001) and permanent diabetes insipidus (OR 3.40, P = 0.022) more commonly. However, visual improvement (OR 6.52, p < 0.001) and complete pituitary function recovery (OR 2.37, P < 0.001) was more common in patients without apoplexy. CONCLUSION: Surgical resection is more common in patients presenting with pituitary apoplexy than those without apoplexy; however, visual improvement and complete recovery of pituitary function is more common in patients without apoplexy. The risk of new pituitary deficits and permanent diabetes insipidus is higher in patients with apoplexy than in those without it.
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Adenoma , Diabetes Insípido , Apoplexia Hipofisária , Neoplasias Hipofisárias , Masculino , Humanos , Estudos Retrospectivos , Adenoma/diagnóstico por imagem , Adenoma/cirurgia , Apoplexia Hipofisária/cirurgia , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/cirurgia , Resultado do TratamentoRESUMO
OBJECTIVE: Acromegaly is associated with increased vertebral fracture (VFs) risk not correlated to bone mineral density (BMD). Trabecular bone score (TBS), related to bone microarchitecture, provides information on bone strength. This cross-sectional study considered the usefulness of TBS and BMD to assess bone status in long-term controlled acromegalic patients. DESIGN, PATIENTS, MEASUREMENTS: 26 acromegaly patients (14 female and 12 males) were included in the study. A further 117 subjects were recruited as controls (58 females and 57 males). BMD was measured using dual-energy X-ray absorptiometry (DXA), TBS was obtained applying Medimaps software 2.0. Biochemical parameters were determined by standardized techniques. RESULTS: 73% of patients with acromegaly exhibited normal lumbar spine (LS) BMD. TBS was normal in 38% of acromegalic patients and partially degraded or degraded in 31% of patients, respectively. No differences were found in LS BMD between acromegalic patients and controls. TBS values were significantly lower in patients with acromegaly (1.27 ± 0.13 vs. 1.35 ± 0.17, p = .01). Postsurgical remission was associated with higher TBS values (1.35 ± 0.10 vs. 1.23 ± 0.13, p = .02) and pituitary radiotherapy treatment with lower TBS values (1.18 ± 0.12 vs. 1.31 ± 0.12, p = .004). On multivariate analysis, age, BMI and LS BMD were predictors of TBS changes in patients with acromegaly (p < .05). CONCLUSIONS: Patients with long-term controlled acromegaly can exhibit deterioration of bone microstructure measured with TBS, despite BMD measurement not showing bone loss. Our study suggests that TBS is useful for monitoring the bone status changes in acromegalic patients.
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Acromegalia , Fraturas por Osteoporose , Absorciometria de Fóton , Acromegalia/complicações , Densidade Óssea , Osso Esponjoso/diagnóstico por imagem , Estudos Transversais , Feminino , Humanos , Vértebras Lombares/diagnóstico por imagem , MasculinoRESUMO
BACKGROUNDS: The incidence of germline mutations in the newly discovered cryptic exon (E1') of VHL gene in patients with von Hippel-Lindau (VHL) disease and in patients with paraganglioma or pheochromocytoma (PPGL) is not currently known. METHODS: We studied a large international multicentre cohort of 1167 patients with a previous negative genetic testing. Germline DNA from 75 patients with a single tumour of the VHL spectrum ('Single VHL tumour' cohort), 70 patients with multiple tumours of the VHL spectrum ('Multiple VHL tumours' cohort), 76 patients with a VHL disease as described in the literature ('VHL-like' cohort) and 946 patients with a PPGL were screened for E1' genetic variants. RESULTS: Six different genetic variants in E1' were detected in 12 patients. Two were classified as pathogenic, 3 as variants of unknown significance and 1 as benign. The rs139622356 was found in seven unrelated patients but described in only 16 patients out of the 31 390 of the Genome Aggregation Database (p<0.0001) suggesting that this variant might be either a recurrent mutation or a modifier mutation conferring a risk for the development of tumours and cancers of the VHL spectrum. CONCLUSIONS: VHL E1' cryptic exon mutations contribute to 1.32% (1/76) of 'VHL-like' cohort and to 0.11% (1/946) of PPGL cohort and should be screened in patients with clinical suspicion of VHL, and added to panels for Next Generation Sequencing (NGS) diagnostic testing of hereditary PPGL. Our data highlight the importance of studying variants identified in deep intronic sequences, which would have been missed by examining only coding sequences of genes/exomes. These variants will likely be more frequently detected and studied with the upcoming implementation of whole-genome sequencing into clinical practice.
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Predisposição Genética para Doença , Paraganglioma/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Doença de von Hippel-Lindau/genética , Adulto , Idoso , Éxons/genética , Feminino , Testes Genéticos , Mutação em Linhagem Germinativa/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Paraganglioma/epidemiologia , Paraganglioma/patologia , Linhagem , Adulto Jovem , Doença de von Hippel-Lindau/epidemiologia , Doença de von Hippel-Lindau/patologiaRESUMO
BACKGROUND: Utilization of stereotactic radiosurgery (SRS) for brain metastases (BM) has become the technique of choice as opposed to whole brain radiation therapy (WBRT). The aim of this work is to evaluate the feasibility and potential benefits in terms of normal tissue (NT) and dose escalation of volumetric modulated arc therapy (VMAT) in SRS metastasis treatment. A VMAT optimization procedure has therefore been developed for internal dose scaling which minimizes planner dependence. MATERIALS AND METHODS: Five patient-plans incorporating treatment with frame-based SRS with dynamic conformal arc technique (DA) were re-planned for VMAT. The lesions selected were between 4-6 cm3. The same geometry used in the DA plans was maintained for the VMAT cases. A VMAT planning procedure was performed attempting to scale the dose in inner auxiliary volumes, and to explore the potential for dose scaling with this technique. Comparison of dose-volume histogram (DVH) parameters were obtained. RESULTS: VMAT allows a superior NT sparing plus conformity and dose scaling using the auxiliary volumes. The VMAT results were significantly superior in NT sparing, improving both the V10 and V12 values in all cases, with a 2-3 cm3 saving. In addition, VMAT improves the dose coverage D95 by about 0.5 Gy. The objective of dose escalation was achieved with VMAT with an increment of the Dmean and the Dmedian of about 2 Gy. CONCLUSIONS: This work shows a benefit of VMAT in SRS treatment with significant NT sparing. A VMAT optimization procedure, based on auxiliary inner volumes, has been developed, enabling internal dose escalation.
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Investigations over half a century have indicated that mechanical forces induce neurite growth, with neurites elongating at a rate of 0.1-0.3 µm h-1 pN-1 when mechanical force exceeds a threshold, with this being identified as 400-1000 pN for neurites of PC12 cells. In this article, we demonstrate that neurite elongation of PC12 cells proceeds at the same previously identified rate on application of mechanical tension of â¼1 pN, which is significantly lower than the force generated in vivo by axons and growth cones. This observation raises the possibility that mechanical tension may act as an endogenous signal used by neurons for promoting neurite elongation.
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Fenômenos Mecânicos , Neuritos/metabolismo , Animais , Fenômenos Biomecânicos , Compostos Férricos/química , Compostos Férricos/metabolismo , Nanopartículas/química , Células PC12 , RatosRESUMO
PURPOSE: MDH2 (malate dehydrogenase 2) has recently been proposed as a novel potential pheochromocytoma/paraganglioma (PPGL) susceptibility gene, but its role in the disease has not been addressed. This study aimed to determine the prevalence of MDH2 pathogenic variants among PPGL patients and determine the associated phenotype. METHODS: Eight hundred thirty patients with PPGLs, negative for the main PPGL driver genes, were included in the study. Interpretation of variants of unknown significance (VUS) was performed using an algorithm based on 20 computational predictions, by implementing cell-based enzymatic and immunofluorescence assays, and/or by using a molecular dynamics simulation approach. RESULTS: Five variants with potential involvement in pathogenicity were identified: three missense (p.Arg104Gly, p.Val160Met and p.Ala256Thr), one in-frame deletion (p.Lys314del), and a splice-site variant (c.429+1G>T). All were germline and those with available biochemical data, corresponded to noradrenergic PPGL. CONCLUSION: This study suggests that MDH2 pathogenic variants may play a role in PPGL susceptibility and that they might be responsible for less than 1% of PPGLs in patients without pathogenic variants in other major PPGL driver genes, a prevalence similar to the one recently described for other PPGL genes. However, more epidemiological data are needed to recommend MDH2 testing in patients negative for other major PPGL genes.
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Neoplasias das Glândulas Suprarrenais/genética , Malato Desidrogenase/genética , Paraganglioma/genética , Feocromocitoma/genética , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Paraganglioma/patologia , Feocromocitoma/patologia , Isoformas de ProteínasRESUMO
AIM: The present retrospective study was to compare toxicity and survival outcomes in a group of low-risk PCa patients treated with either the preoperative planning technique (145â¯Gy) or the real-time IoP technique (160â¯Gy). BACKGROUND: The two most common permanent seed implantation techniques are preoperative planning (PP) with 145â¯Gy and real-time intraoperative planning (IoP) with 160â¯Gy. Although IoP has largely replaced PP at many centres in recent years, few studies have directly compared these two techniques. MATERIALS AND METHODS: Retrospective study of 408 patients with low-risk PCa treated with permanent seed implant brachytherapy at our institution between October 2003 and December 2014. Of these, 187 patients were treated with PP at a dose of 145â¯Gy while 221 received real-time IoP with 160â¯Gy. RESULTS: At a median follow up of 90 months, 5- and 8-year rates of biochemical relapse-free survival (BRFS) were 94.8% and 86% with the IoP technique versus 90.8% and 83.9%, respectively, with PP. The maximum dose to the urethra was <217â¯Gy with both techniques. Despite the higher dose, IoP did not cause any significant increase in toxicity (pâ¯=â¯0.11). CONCLUSIONS: The present study shows that real-time intraoperative brachytherapy at a dose of 160â¯Gy yield better biochemical control than preoperative planning at 145â¯Gy. In addition, urinary toxicity did not increase, despite the dose escalation, probably because the dose constraints to the urethra were met despite the increased dose escalation. These findings support the use of real-time IoP.
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This study aimed to clinically evaluate the efficacy of two different home whitening protocols and to determine which is more effective: applying the whitening gel every 48 hours or every 72 hours for 6 weeks. The differences in terms of tooth sensitivity are also analyzed. A sample of 72 patients was randomly divided into 3 groups of 24 (N=24). Group A: 16% carbamide peroxide applied every 48h for 6 weeks. Group B: 16% carbamide peroxide applied every 72h for 6 weeks. Group C (control group): a placebo gel without peroxide (glycerin gel) was applied every 48h for 6 weeks. To compare the groups, color measurements were made using a spectrophotometer and ANOVA test and Bonferroni test was used. The confidence level was set at 95% (p ≤ 0.05) and no statistically significant differences between applying 16% carbamide peroxide every 48h or every 72h for 6 weeks (p> 0.05) were found. The study concluded that carbamide peroxide 16% is equally effective applied with both protocols, obtaining the same results.
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PURPOSE: To identify clinical and radiological factors associated with a higher risk of developing a severe pituitary apoplexy (PA). METHODS: Multicenter retrospective study of patients presenting with clinical PA in three Spanish tertiary hospitals of Madrid between 2008 and 2022. We classified PA as severe when presenting with an altered level of consciousness (Glasgow Coma Scale (GCS) < 15) or visual involvement. RESULTS: A total of 71 PA cases were identified, of whom 80.28% (n = 57) were classified as severe PA. The median age was 60 (18 to 85 years old) and 67.6% (n = 48) were male. Most patients had macroadenomas, except for one patient with a microadenoma of 9 mm. Headache was the most common presenting symptom (90.1%) and anticoagulation was the most frequent predisposing risk factor, but it was not associated with a higher risk for severe PA (odds ratio [OR] 1.13 [0.21-5.90]). Severe cases were associated with male gender (OR 5.53 [1.59-19.27]), tumor size >20 mm (OR 17.67 [4.07-76.64]), and Knosp grade ≥2 (OR 9.6 [2.38-38.73]). In the multivariant analysis, the only variables associated with a higher risk for severe PA were tumor size and Knosp grade. Surgery was more common in severe PA than in non-severe (91.2% vs. 64.3%, P = 0.009). CONCLUSION: A tumor size >20 mm and cavernous sinus invasion are risk factors for developing a severe PA. These risk factors can stratify patients at a higher risk of a worse clinical picture, and subsequently, more need of decompressive surgery.
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The aim of this work was to evaluate the inter- and intra-observer variation in contouring vestibular schwannoma (VS) and the organs-at-risk (OAR), and its dosimetric impact in Volumetric Modulated Arc Therapy (VMAT). Three VS typical cases were contoured by four clinicians. The Agreement Volume Index (AVI) appeared to be notably higher in VS than in OARs, such that the dose coverage of VS is fairly robust. In OARs, the largest variation was +1.02Gy in dmax for the brainstem, +0.78Gy in dmean for the cochlea and +1.05Gy in dmax of the trigeminal nerve. Accordingly, it was decided that all VS delineations for stereotactic radiosurgery (SRS), and all frame-based SRS contouring in general, should always be reviewed by a second physician. In addition, the retrospective presentation of VS cases at daily peer review meetings has also been adopted to ensure that the consensus is constantly updated, as well as for training purposes.
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PURPOSE: To identify presurgical and surgical risk factors for intraoperative hypertensive crisis in patients with pheochromocytomas and sympathetic paragangliomas (PGLs) (PPGLs). METHODS: Retrospective multicenter cohort study of patients with PPGLs from 18 tertiary hospitals. Intraoperative hypertensive crisis was defined as systolic blood pressure (SBP) greater than 200âmmHg lasting more than 1âmin and postoperative hypertensive crisis as SBP greater than 180âmmHg or diastolic blood pressure (DBP) greater than 110âmmHg. RESULTS: A total of 296 surgeries were included. Alpha presurgical blockade was employed in 93.2% of the cases and beta-adrenergic in 53.4%. Hypertensive crisis occurred in 20.3% ( n â=â60) of the surgeries: intraoperative crisis in 56 and postoperative crisis in 6 cases (2 cases had both types of crises). We identified as risk factors of intraoperative hypertensive crisis, absence of presurgical glucocorticoid therapy (odds ratio [OR] 3.48; 95% confidence interval [CI] 1.19-10.12) higher presurgical SBP (OR 1.22 per each 10âmmHg, 95% CI 1.03-1.45), a larger tumor size (OR 1.09 per each 10âmm, 95% CI 1.00-1.19) and absence of oral sodium repletion (OR 2.59, 95% CI 1.25-5.35). Patients with hypertensive crisis had a higher rate of intraoperative bleeding ( P â<â0.001), of intraoperative hemodynamic instability ( P â<â0.001) and of intraoperative hypotensive episodes ( P â<â0.001) than those without hypertensive crisis. CONCLUSION: Intraoperative hypertensive crisis occurs in up to 20% of the PPGL resections. Patients not pretreated with glucocorticoid therapy before surgery, with larger tumors and higher presurgical SBP and who do not receive oral sodium repletion have a higher risk for developing hypertensive crisis during and after PPGL surgery.
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Neoplasias das Glândulas Suprarrenais , Hipertensão , Crise Hipertensiva , Paraganglioma , Feocromocitoma , Humanos , Feocromocitoma/complicações , Feocromocitoma/cirurgia , Feocromocitoma/patologia , Hipertensão/epidemiologia , Estudos de Coortes , Glucocorticoides , Pressão Sanguínea/fisiologia , Paraganglioma/complicações , Paraganglioma/cirurgia , Fatores de Risco , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/cirurgia , Neoplasias das Glândulas Suprarrenais/patologia , Sódio , Estudos RetrospectivosRESUMO
Medical treatment of acromegaly is currently performed through a trial-error approach using first generation somatostatin receptor ligands (fgSRLs) as first-line drugs, with an effectiveness of about 50%, and subsequent drugs are indicated through clinical judgment. Some biomarkers can predict fgSRLs response. Here we report the results of the ACROFAST study, a clinical trial in which a protocol based on predictive biomarkers of fgSRLs was evaluated. METHODS AND SUBJECTS: prospective trial (21 university hospitals) comparing the effectiveness and time-to control of two treatment protocols during 12 months: A) A personalized protocol in which first option were fgSRLs as monotherapy or in combination with pegvisomant or, pegvisomant as monotherapy depending on the short Acute Octreotide Test (sAOT) results, tumor T2 Magnetic Resonance (MRI) signal or immunostaining for E-cadherin and, B) A control group with treatment always started by fgSRLs and the other drugs included after demonstrating inadequate control. RESULTS: Eighty-five patients participated; 45 in the personalized and 40 in the control group. More patients in the personalized protocol achieved hormonal control compared to those in the control group (78% vs 53%, p < 0.05). Survival analysis revealed a hazard ratio for achieving hormonal control adjusted by age and sex of 2.53 (CI 1.30-4.80). Patients from personalized arm were controlled in a shorter period of time (p = 0.01). CONCLUSION: Personalized medicine is feasible using a relatively simple protocol and allows a higher number of patients achieving control in a shorter period of time.
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INTRODUCTION: Primary aldosteronism (PA) is associated with several cardiometabolic comorbidities. Specific treatment by mineralocorticoid receptor antagonists (MRA) or adrenalectomy has been reported to reduce the cardiometabolic risk. However, the cardiovascular benefit could depend on plasma renin levels in patients on MRA. AIM: To compare the development of cardiovascular, renal and metabolic complications between medically treated patients with PA and those who underwent adrenalectomy, taking the renin status during MRA treatment into account. METHODS: A multicenter retrospective study (SPAIN-ALDO Register) of patients with PA treated at 35 Spanish tertiary hospitals. Patients on MRA were divided into two groups based on renin suppression (n = 90) or non-suppression (n = 70). Both groups were also compared to unilateral PA patients (n = 275) who achieved biochemical cure with adrenalectomy. RESULTS: Adrenalectomized patients were younger, had higher plasma aldosterone concentration, and lower potassium levels than MRA group. Patients on MRA had similar baseline characteristics when stratified into treatment groups with suppressed and unsuppressed renin. 97 (55.1%) of 176 patients without comorbidities at diagnosis, developed at least one comorbidity during follow-up (median 12 months vs. 12.5 months' follow-up after starting MRA and surgery, respectively). Surgery group had a lower risk of developing new cardiovascular events (HR 0.40 [95% CI 0.18-0.90]) than MRA group. Surgical treatment improved glycemic and blood pressure control, increased serum potassium levels, and required fewer antihypertensive drugs than medical treatment. However, there were no differences in the cardiometabolic profile or the incidence of new comorbidities between the groups with suppressed and unsuppressed renin levels (HR 0.95 [95% CI 0.52-1.73]). CONCLUSION: Cardiovascular, renal, and metabolic events were comparable in MRA patients with unsuppressed and suppressed renin. Effective surgical treatment of PA was associated with a decreased incidence of new cardiovascular events when compared to MRA therapy.
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Doenças Cardiovasculares , Hiperaldosteronismo , Hipertensão , Humanos , Adrenalectomia , Aldosterona , Biomarcadores , Doenças Cardiovasculares/tratamento farmacológico , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/tratamento farmacológico , Hiperaldosteronismo/epidemiologia , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Potássio/metabolismo , Sistema de Registros , Renina/metabolismo , Estudos Retrospectivos , Espanha/epidemiologiaRESUMO
OBJECTIVE: The aim of this study is to compare the response to first-line medical treatment in treatment-naive acromegaly patients with pure growth hormone (GH)-secreting pituitary adenoma (GH-PA) and those with GH and prolactin cosecreting PA (GH&PRL-PA). DESIGN: This is a retrospective multicentric study of acromegaly patients followed from 2003 to 2023 in 33 tertiary Spanish hospitals with at least 6 months of first-line medical treatment. METHODS: Baseline characteristics, first-line medical treatment strategies, and outcomes were analyzed. We employed a multiple logistic regression full model to estimate the impact of some baseline characteristics on disease control after each treatment modality. RESULTS: Of the 144 patients included, 72.9% had a GH-PA, and 27.1% had a GH&PRL-PA. Patients with GH&PRL-PA were younger (43.9 ± 15.0 vs 51.9 ± 12.7 years, P < .01) and harboring more frequently macroadenomas (89.7% vs 72.1%, P = .03). First-generation somatostatin receptor ligand (fgSRL) as monotherapy was given to 106 (73.6%) and a combination treatment with fgSRL and cabergoline in the remaining 38 (26.4%). Patients with GH&PRL-PA received more frequently a combination therapy (56.4% vs 15.2%, P < .01). After 6 months of treatment, in the group of patients under fgSRL as monotherapy, those patients with GH&PRL-PA had worse control compared to GH-PAs (29.4% vs 55.1%, P = .04). However, these differences in the rate of disease control between both groups disappeared when both received combination treatment with fgSRL and cabergoline. CONCLUSION: In GH&PRL-PA, the biochemical control achieved with fgSRL as monotherapy is substantially worse than in patients harboring GH-PA, supporting the inclusion of cabergoline as first-line medical treatment in combination with fgSRLs in these subgroups of patients.
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Acromegalia , Cabergolina , Prolactina , Humanos , Acromegalia/tratamento farmacológico , Acromegalia/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto , Cabergolina/uso terapêutico , Resultado do Tratamento , Prolactina/sangue , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/sangue , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Hormônio do Crescimento Humano , Adenoma/tratamento farmacológico , Adenoma/sangue , Adenoma/metabolismo , Adenoma/complicações , Idoso , Quimioterapia Combinada , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/sangue , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/complicações , Espanha/epidemiologiaRESUMO
Purpose: To compare the clinical and hormonal characteristics of patients with familial hyperaldosteronism (FH) and sporadic primary aldosteronism (PA). Methods: A systematic review of the literature was performed for the identification of FH patients. The SPAIN-ALDO registry cohort of patients with no suspicion of FH was chosen as the comparator group (sporadic group). Results: A total of 360 FH (246 FH type I, 73 type II, 29 type III, and 12 type IV) cases and 830 sporadic PA patients were included. Patients with FH-I were younger than sporadic cases, and women were more commonly affected (P = 0.003). In addition, the plasma aldosterone concentration (PAC) was lower, plasma renin activity (PRA) higher, and hypokalemia (P < 0.001) less frequent than in sporadic cases. Except for a younger age (P < 0.001) and higher diastolic blood pressure (P = 0.006), the clinical and hormonal profiles of FH-II and sporadic cases were similar. FH-III had a distinct phenotype, with higher PAC and higher frequency of hypokalemia (P < 0.001), and presented 45 years before sporadic cases. Nevertheless, the clinical and hormonal phenotypes of FH-IV and sporadic cases were similar, with the former being younger and having lower serum potassium levels. Conclusion: In addition to being younger and having a family history of PA, FH-I and III share other typical characteristics. In this regard, FH-I is characterized by a low prevalence of hypokalemia and FH-III by a severe aldosterone excess causing hypokalemia in more than 85% of patients. The clinical and hormonal phenotype of type II and IV is similar to the sporadic cases.
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Hiperaldosteronismo , Hipopotassemia , Feminino , Humanos , Aldosterona , Hiperaldosteronismo/complicações , Hiperaldosteronismo/genética , Hiperaldosteronismo/epidemiologia , Hipopotassemia/etiologia , PotássioRESUMO
PURPOSE: To evaluate differences in clinical presentation and in surgical outcomes between growth hormone-secreting pituitary adenomas (GH-PAs) and GH and prolactin co-secreting pituitary adenomas (GH&PRL-PAs). METHODS: Multicenter retrospective study of 604 patients with acromegaly submitted to pituitary surgery. Patients were classified into two groups according to serum PRL levels at diagnosis and immunohistochemistry (IHC) for PRL: a) GH&PRL-PAs when PRL levels were above the upper limit of normal and IHC for GH and PRL was positive or PRL levels were >100ng/and PRL IHC was not available (n=130) and b) GH-PAs who did not meet the previously mentioned criteria (n=474). RESULTS: GH&PRL-PAs represented 21.5% (n=130) of patients with acromegaly. The mean age at diagnosis was lower in GH&PRL-PAs than in GH-PAs (P<0.001). GH&PRL-PAs were more frequently macroadenomas (90.6% vs. 77.4%, P=0.001) and tended to be more invasive (33.6% vs. 24.7%, P=0.057) than GH-PAs. Furthermore, they had presurgical hypopituitarism more frequently (OR 2.8, 95% CI 1.83-4.38). IGF-1 upper limit of normality (ULN) levels at diagnosis were lower in patients with GH&PRL-PAs (median 2.4 [IQR 1.73-3.29] vs. 2.7 [IQR 1.91-3.67], P=0.023). There were no differences in the immediate (41.1% vs 43.3%, P=0.659) or long-term post-surgical acromegaly biochemical cure rate (53.5% vs. 53.1%, P=0.936) between groups. However, there was a higher incidence of permanent arginine-vasopressin deficiency (AVP-D) (7.3% vs. 2.4%, P=0.011) in GH&PRL-PAs patients. CONCLUSIONS: GH&PRL-PAs are responsible for 20% of acromegaly cases. These tumors are more invasive, larger and cause hypopituitarism more frequently than GH-PAs and are diagnosed at an earlier age. The biochemical cure rate is similar between both groups, but patients with GH&PRL-PAs tend to develop permanent postsurgical AVP-D more frequently.
RESUMO
The objective of the study was to evaluate the efficacy of second-line therapies in patients with acromegaly caused by a growth hormone (GH) and prolactin (PRL) co-secreting pituitary neuroendocrine tumor (GH&PRL-Pit-NET) compared to their efficacy in patients with acromegaly caused by a GH-secreting pituitary neuroendocrine tumor (GH-Pit-NET). This is a multicenter retrospective study of patients with acromegaly on treatment with pasireotide and/or pegvisomant. Patients were classified in two groups: GH&PRL-Pit-NETs when evidence of hyperprolactinemia and immunohistochemistry (IHC) for GH and PRL was positive or if PRL were >200 ng/dL regardless of the PRL-IHC and GH-Pit-NETs when the previously mentioned criteria were not met. A total of 28 cases with GH&PRL-Pit-NETs and 122 with GH-Pit-NETs met the inclusion criteria. GH&PRL-Pit-NETs presented at a younger age, caused hypopituitarism, and were invasive more frequently than GH-Pit-NETs. There were 124 patients treated with pegvisomant and 49 with pasireotide at any time. The efficacy of pegvisomant for IGF-1 normalization was of 81.5% and of pasireotide of 71.4%. No differences in IGF-1 control with pasireotide and with pegvisomant were observed between GH&PRL-Pit-NETs and GH-Pit-NETs. All GH&PRL-Pit-NET cases treated with pasireotide (n = 6) and 82.6% (n = 19/23) of the cases treated with pegvisomant normalized PRL levels. No differences in the rate of IGF-1 control between pegvisomant and pasireotide were detected in patients with GH&PRL-Pit-NETs (84.9% vs 66.7%, P = 0.178). We conclude that despite the more aggressive behavior of GH&PRL-Pit-NETs than GH-Pit-NETs, no differences in the rate of IGF-1 control with pegvisomant and pasireotide were observed between both groups, and both drugs have shown to be effective treatments to control IGF-1 and PRL hypersecretion in these tumors.