Radiotherapy and Mortality in Pituitary Adenomas.

BACKGROUND: Pituitary adenomas (PA), comprising 10-20% of intracranial tumors, are classified as functioning and non-functioning and are further divided by size. Non-functioning tumors cause mechanical symptoms while functioning ones result in hormonal hypersecretion syndromes. Initial treatment involves surgery, with medical treatment for prolactinomas. Radiotherapy (RT) is employed as an adjuvant treatment, with various modalities including conventional, stereotactic radiosurgery (SRS), and fractionated stereotactic RT (FSRT). Although effective, RT is associated with complications and toxicities such as hypopituitarism, optic neuritis, secondary CNS tumors, and neurocognitive deficits. AIM: Describe the information on mortality from radiotherapy as treatment of functioning PA. METHODS: A PubMed search spanning 2000-2017 was conducted for articles on pituitary RT. RESULTS: Conventional RT entails high-energy radiation over multiple sessions, while SRS delivers precise high doses in a single session. FSRT offers enhanced precision using a linear accelerator, delivering multiple doses. Optic structure proximity and tumor volume dictate RT modality. Studies have shown SRS and FSRT's efficacy in tumor and endocrine control, with variable risks and complications. Mortality rates in pituitary adenomas treated with RT have been evaluated, revealing complexities. Acromegaly, associated with increased mortality due to cerebrovascular disease, may result from RT. Irradiation of non-functioning pituitary macroadenomas also elevates cerebrovascular risk, while radiotherapy-induced hypopituitarism is associated with increased cardiovascular mortality. RT-induced damage is attributed to microvascular lesions and arteriolar changes. CONCLUSION: Modern techniques mitigate complications, and although safer, long-term studies are needed. Multidisciplinary evaluation guides the treatment decision, optimizing efficacy and minimizing risk, ultimately improving the patient's quality of life.

Pharmacological Treatment of Non-Functioning Pituitary Adenomas.

Treatment strategies for NFPA include surgery, radiotherapy, medical treatment, or follow-up. The treatment of NFPAs with compressive symptoms is surgical. However, in case of post-surgical tumor remnants, there may be treatment strategies that include observation and radiotherapy. Recently, medical treatment with cabergoline (CAB) has been recommended to contain and/or reduce the size of the tumor remnant. Based on the findings that many NFPAs show a dopamine receptor (DR) and somatostatin receptor (SR) expression, medical therapy with dopamine agonists (DAs) and somatostatin receptor ligands (SSRLs) has been tested as an alternative to prevent recurrence after surgery. The DAs have been the most extensively studied, showing some potential in terms of tumor shrinkage. SSRLs and other emerging medical options are much less studied. We will review and critically evaluate the current data on the medical therapy of NFPAs to elucidate their role in the management of this tumor type. In the case of actively growing remnants (more than 10% growth per year) and high-risk pituitary adenomas, treatment with CAB at a dose of 1.5-3.0 mg is indicated for tumor containment and/or reduction. In relation to combined chemotherapy with CAB, there is little information in the literature to support its use. In our experience, CAB treatment can be used after radiotherapy as an adjuvant treatment.

Pituitary Abscess: A General Retrospective Diagnosis.

We present the case of a 27-year-old female who had a history of recurrent headaches and visual disturbances. Magnetic resonance imaging of the brain showed a lesion that suggested pituitary adenoma, with indications of a recent bleeding or cystic degeneration. Nonhormonal deficiencies were documented, restricted to nontumoral hyperprolactinemia. Transsphenoidal approach surgery was performed and the purulent material was drained, confirming the diagnosis of pituitary abscess. Sinusitis was considered to be the only possible cause of this condition. Empirical treatment to Gram-positive anaerobic cocci was administrated, with a satisfactory response.

Efficiency and Safety of CyberKnife Robotic Radiosurgery in the Multimodal Management of Patients with Acromegaly.

OBJECTIVE: To analyze, in a cohort of acromegalic patients, the results of the efficiency and safety of radiosurgery (CyberKnife), as well as the prognostic factors associated with disease remission. MATERIAL AND METHODS: Observational, retrospective, longitudinal, and analytical study that included acromegalic patients with persistent biochemical activity after initial medical-surgical treatment, who received treatment with CyberKnife radiosurgery. GH and IGF-1 levels at baseline after one year and at the end of follow-up were evaluated. RESULTS: 57 patients were included, with a median follow-up of four years (IQR, 2-7.2 years). The biochemical remission rate was 45.6%, 33.33% achieved biochemical control, and 12.28% attained biochemical cure at the end of follow-up. A progressive and statistically significant decrease was observed in the comparison of the concentrations of IGF-1, IFG-1 x ULN, and baseline GH at one year and at the end of follow-up. Both cavernous sinus invasion and elevated baseline IGF-1 x ULN concentrations were associated with an increased risk of biochemical non-remission. CONCLUSION: Radiosurgery (CyberKnife) is a safe and effective technique in the adjuvant treatment of GH-producing tumors. Elevated levels of IGF x ULN before radiosurgery and invasion of the cavernous sinus by the tumor could be predictors of biochemical non-remission of acromegaly.

[Vitamin D and its positive effect on the PTH/vitamin D/calcium-FGF23/klotho/phosphorus axis in kidney transplant recipients]. / Vitamina D y su efecto positivo sobre el eje PTH/vitamina D/calcio-FGF23/klotho/fósforo en pacientes con trasplante renal.

Introduction: Background: hypovitaminosis D is frequent in kidney transplant recipient (KTR) patients and is associated with deleterious effects both at the bone and extraosseous levels. Treatment with cholecalciferol is effective for the normalization of 25(OH)D, demonstrating a beneficial effect on the calcium-tropic axis in other populations; however, its effect on the PTH/vitamin D/calcium and FGF23/klotho/phosphorus axis in RTR has not been reported. The aim of this study was to evaluate the effect of normalization of serum 25(OH)D concentrations on the PTH/vitamin D/calcium-FGF23/klotho/phosphorus axis in KTR treated with cholecalciferol, as well as the association between the components of this axis. Methods: a prospective study in 23 KTR with hypovitaminosis D, with evolution from 1 to 12 months post-transplantation, an estimated glomerular filtration rate > 60 mL/min/1.73 m2 and a history of primary nephropathy treated with cholecalciferol, in whom the PTH/vitamin D/calcium and FGF23/klotho/phosphorus axis was evaluated during the state of hypovitaminosis D and at normalization of 25(OH)D. Results: at the normalization of 25(OH)D, a reduction in PTH [103 (58.5-123.9) vs 45.6 (30.1-65.1) pg/mL; p = 0.002] and an increase in serum phosphorus [3.1 (2.3-3.5) vs 3.3 (3-3.6) mg/dL; p = 0.01] were evident, with no differences in calcium, klotho and FGF23 concentrations. The time to achieve normalization of 25(OH)D was 12 weeks (RIC, 4-12), with a dose of 5000 IU/day (RIC, 4000-6000). A positive association between klotho and PTH was corroborated (r = 0.54; p = 0.008; linear regression, ß = 0.421; B = 0.004; 95 % CI, 0.003-0.007; p = 0.045). Conclusions: treatment with cholecalciferol is effective for the normalization of 25(OH)D, with a beneficial effect on calcium-phosphotropic metabolism characterized by a reduction in PTH concentration, without significant changes in calcemia or calciuria, as well as an increase in phosphatemia, without modifications in FGF23 or klotho concentrations.

Introducción: Introducción: la hipovitaminosis D es frecuente en los receptores de trasplante renal (RTR) y se asocia con efectos deletéreos tanto a nivel óseo como extraóseo. El tratamiento con colecalciferol es eficaz para la normalización de la 25(OH)D, demostrándose un efecto benéfico sobre el eje calciotrópico; sin embargo, su efecto sobre el eje fosfotrópico no se ha reportado. El objetivo de este estudio fue evaluar el efecto de la normalización de las concentraciones séricas de 25(OH)D sobre el eje PTH/vitamina D/calcio-FGF23/klotho/fósforo en RTR tratados con colecalciferol, así como la asociación entre sus componentes. Métodos: estudio prospectivo en 23 RTR con hipovitaminosis D y antecedente de nefropatía primaria tratados con colecalciferol, en quienes se evaluó el eje PTH/vitamina D/calcio y FGF23/klotho/fósforo durante el estado de hipovitaminosis D y a la normalización de la 25(OH)D. Resultados: a la normalización de la 25(OH)D se evidenció una reducción de la PTH [103 (58,5-123,9) vs. 45,6 (30,1-65,1) pg/mL; p = 0,002] y un aumento del fósforo sérico [3,1 (2,3-3,5) vs. 3,3 (3-3,6) mg/dL; p = 0,01], sin diferencias en las concentraciones de calcio, klotho y FGF23. El tiempo para lograr la normalización de la 25(OH)D fue de 12 semanas (4-12), con una dosis de 5000 UI/día (4000-6000). Se corroboró una asociación positiva entre klotho y PTH (r = 0,54; p = 0,008; regresión lineal, ß = 0,421; IC 95 %: 0,003-0,007; p = 0,045). Conclusiones: el tratamiento con colecalciferol es eficaz para la normalización de la 25(OH)D con un efecto benéfico sobre el metabolismo calcio-fosfotrópico caracterizado por una reducción de la PTH y un incremento de la fosfatemia, sin modificaciones de calcemia, calciuria, FGF23 o klotho.

Hypothalamic-pituitary-gonadal axis disturbance and its association with insulin resistance in kidney transplant recipients / Distúrbio do eixo hipotálamo-hipófise-gonadal e sua associação com resistência à insulina em receptores de transplante renal

Abstract Objective: To evaluate hypothalamic-pi- tuitary-gonadal (HPG) axis alterations at 1 and 12 months after kidney transplan- tation (KT) and their association with in- sulin resistance. Methods: A retrospective clinical study was conducted in a tertiary care center in kidney transplantation recipients (KTRs) aged 18- 50 years with primary kidney disease and stable renal graft function. LH, FSH, E2/T, and HOMA-IR were assessed at 1 and 12 months after KT. Results: Twenty-five KTRs were included; 53% were men, and the mean age was 30.6±7.7 years. BMI was 22.3 (20.4-24.6) kg/m2, and 36% had hypogonadism at 1 month vs 8% at 12 months (p=0.001). Re- mission of hypogonadism was observed in all men, while in women, hypogonadotropic hypogonadism persisted in two KTRs at 12 months. A positive correlation between go- nadotrophins and age at 1 and 12 months was evident. Fifty-six percent of patients had insulin resistance (IR) at 1 month and 36% at 12 months (p=0.256). HOMA-IR showed a negative correlation with E2 (r=- 0.60; p=0.050) and T (r=-0.709; p=0.049) at 1 month, with no correlation at 12 months. HOMA-IR at 12 months after KT correlated positively with BMI (r=0.52; p=0.011) and tacrolimus dose (r=0.53; p=0.016). Conclusion: Successful KT restores the HPG axis in the first year. Hypogonadism had a negative correlation with IR in the early pe- riod after KT, but it was not significant at 12 months.

Resumo Objetivo: Avaliar as alterações do eixo hipotálamo-hipófise-gonadal (HHG) em 1 e 12 meses após transplante renal (TR) e sua associação com a resistência à insulina. Métodos: Foi realizado um estudo clínico retrospectivo em um centro de cuidados terciários em receptores de transplante renal (RTR) com idade entre 18-50 anos com doença renal primária e função do enxerto renal estável. LH, FSH, E2/T e HOMA-IR foram avaliados em 1 e 12 meses após o TR. Resultados: foram incluídos 25 RTR; 53% eram homens e a média de idade foi de 30,6±7,7 anos. O IMC foi de 22,3 (20,4-24,6) kg/m2 e 36% apresentaram hipogonadismo em 1 mês vs 8% aos 12 meses (p=0,001). A remissão do hipogonadismo foi observada em todos os homens, enquanto nas mulheres, o hipogonadismo hipogonadotrófico persistiu em dois RTR aos 12 meses. Ficou evidente uma correlação positiva entre gonadotrofinas e idade em 1 e 12 meses. Cinquenta e seis por cento dos pacientes apresentaram resistência à insulina (RI) em 1 mês e 36% aos 12 meses (p=0,256). O HOMA-IR mostrou uma correlação negativa com E2 (r=-0,60; p=0,050) e T (r=-0,709; p=0,049) em 1 mês, sem correlação em 12 meses. O HOMA-IR aos 12 meses após TR correlacionou-se positivamente com o IMC (r=0,52; p=0,011) e a dose de tacrolimus (r=0,53; p=0,016). Conclusão: O TR bem-sucedido restaura o eixo HHG no primeiro ano. O hipogonadismo apresentou uma correlação negativa com a RI no período inicial após o TR, mas essa correlação não foi significativa aos 12 meses.

Efficacy of cabergoline therapy in patients with non-functioning pituitary adenomas: A single center clinical experience

ABSTRACT Objective: To evaluate the response to cabergoline (CBG) treatment in patients with non-functioning pituitary adenomas (NFPA). Subjects and methods: Retrospective, single tertiary care center study. A total of 44 patients were treated with 3 mg/week of CBG, 32 after surgical treatment (transsphenoidal surgery [TSS] in 27 and TC in 5 patients) and 12 as primary therapy. Mean age was 59.2 ± 12 years and 23 (52.2%) were women. Response to therapy was ascertained by serial magnetic resonance imaging. The median duration of CBG therapy was 30 months (IQR 24-48). Response to CBG therapy was defined as a greater than 20% reduction in tumor size and volume. Results: A significant reduction in tumor size was documented in 29 patients (66%), whereas in 11 patients (25%) the tumor increased in size and in 4 (9%), it remained stable. Significant tumor shrinkage was documented in 4 (33.3%) of 12 patients treated primarily and in 23 (71.8%) of those treated secondarily. The three-year progression-free survival was 0.61. Conclusion: Cabergoline therapy is effective in reducing tumor growth in over two thirds of patients with NFPA, however 16% of patients will escape to this beneficial effect and will require alternative forms of treatment to halt tumor progression.

Efficacy of cabergoline therapy in patients with non-functioning pituitary adenomas: A single center clinical experience.

Introduction: To evaluate the response to cabergoline (CBG) treatment in patients with non-functioning pituitary adenomas (NFPA). Subjects and methods: Retrospective, single tertiary care center study. A total of 44 patients were treated with 3 mg/week of CBG, 32 after surgical treatment (transsphenoidal surgery [TSS] in 27 and TC in 5 patients) and 12 as primary therapy. Mean age was 59.2 ± 12 years and 23 (52.2%) were women. Response to therapy was ascertained by serial magnetic resonance imaging. The median duration of CBG therapy was 30 months (IQR 24-48). Response to CBG therapy was defined as a greater than 20% reduction in tumor size and volume. Results: A significant reduction in tumor size was documented in 29 patients (66%), whereas in 11 patients (25%) the tumor increased in size and in 4 (9%), it remained stable. Significant tumor shrinkage was documented in 4 (33.3%) of 12 patients treated primarily and in 23 (71.8%) of those treated secondarily. The three-year progression-free survival was 0.61. Conclusion: Cabergoline therapy is effective in reducing tumor growth in over two thirds of patients with NFPA, however 16% of patients will escape to this beneficial effect and will require alternative forms of treatment to halt tumor progression.

The kinome, cyclins and cyclin-dependent kinases of pituitary adenomas, a look into the gene expression profile among tumors from different lineages.

BACKGROUND: Pituitary adenomas (PA) are the second most common intracranial tumors and are classified according to hormone they produce, and the transcription factors they express. The majority of PA occur sporadically, and their molecular pathogenesis is incompletely understood. METHODS: Here we performed transcriptome and proteome analysis of tumors derived from POU1F1 (GH-, TSH-, and PRL-tumors, N = 16), NR5A1 (gonadotropes and null cells adenomas, n = 17) and TBX19 (ACTH-tumors, n = 6) lineages as well as from silent ACTH-tumors (n = 3) to determine expression of kinases, cyclins, CDKs and CDK inhibitors. RESULTS: The expression profiles of genes encoding kinases were distinctive for each of the three PA lineage: NR5A1-derived tumors showed upregulation of ETNK2 and PIK3C2G and alterations in MAPK, ErbB and RAS signaling, POU1F1-derived adenomas showed upregulation of PIP5K1B and NEK10 and alterations in phosphatidylinositol, insulin and phospholipase D signaling pathways and TBX19-derived adenomas showed upregulation of MERTK and STK17B and alterations in VEGFA-VEGFR, EGF-EGFR and Insulin signaling pathways. In contrast, the expression of the different genes encoding cyclins, CDK and CDK inhibitors among NR5A1-, POU1F1- and TBX19-adenomas showed only subtle differences. CDK9 and CDK18 were upregulated in NR5A1-adenomas, whereas CDK4 and CDK7 were upregulated in POUF1-adenomas. CONCLUSIONS: The kinome of PA clusters these lesions into three distinct groups according to the transcription factor that drives their terminal differentiation. And these complexes could be harnessed as molecular therapy targets.

Risk factors associated with thyroid nodular disease in acromegalic patients: A case-cohort study in a tertiary center.

INTRODUCTION: Goiter is very common in patients with acromegaly; its development is correlated to the duration of the disease. Thyroid cells express the IGF-1 receptor and the TSH/IGF-1 interaction has been demonstrated to have a synergistic effect in thyroid cell growth. There is a correlation between IGF-1 levels and the thyroid volume of patients with acromegaly. The aim of this study was to evaluate, in a retrospective case-cohort study of patients with acromegaly, the associated risk factors for thyroid nodules disease in this population. METHODS: This was a case-cohort study matched by age, gender, and growth hormone at diagnosis. Cases consisted of acromegalic patients that developed thyroid nodules during the follow up, and controls consisted in acromegalic patients without thyroid nodules. A Cox proportional hazard estimation was carried out for measure the associated risk factors for thyroid nodules disease in acromegalic patients. A nodular thyroid disease-free survival analysis was estimated using the Kaplan-Meier analysis. RESULTS: We recruited 49 cases and 56 controls. In a multivariate Cox proportional hazard analysis age and IGF-1 ≥ 2.2 x ULN were significantly related with the presence of thyroid nodules [HR of 2.21 (95% CI; 1.15-4.25, p = 0.01)]. Nodularity-free survival rates in patients who had an IGF-1 X ULN ≥ 2.2 was found to be lower in comparison to those who had IGF-1 X ULN < 2.2, according to a Kaplan-Meier survival analysis. CONCLUSIONS: Our findings support that exist more probability to develop thyroid nodular disease in patients with acromegaly that present IGF-1 X ULN ≥ 2.2, suggesting a possible direct effect between the time of exposure to the IGF-1 axis hyperactivity and the genesis of thyroid nodules.

Delayed Calcium Normalization after Successful Parathyroidectomy in Primary Hyperparathyroidism.

INTRODUCTION: Parathyroidectomy is the curative treatment option in primary hyperparathyroidism (PHPT). The decrease of parathormone (PTH) by 50% or more from levels prior to surgery after excision predicts successful parathyroidectomy. Serum calcium is expected to return to normal within 24-72 hours after the surgery; however, nearly 10% have transient, persistent postoperative hypercalcemia. We present a case report of delayed calcium normalization after successful parathyroidectomy in a 38-year-old patient with PHPT. METHODS: Parathyroidectomy was performed, with evidence of a decrease in PTH levels of more than 50% in the first 24 hours postoperatively compared to presurgical PTH; however, despite curative parathyroidectomy, a delayed calcium normalization was evidenced, with hypercalcemia persistence up to 120 hours postoperatively. RESULTS: After the first month postoperatively, serum calcium remained normal. In conclusion, approximately 10% of patients with curative parathyroidectomy have transient, persistent postoperative hypercalcemia, which is more likely to occur in patients with higher preoperative serum calcium and PTH levels. CONCLUSION: Persistent hypercalcemia after the first month postoperatively is related with persistent PHPT, highlighting the importance of calcium monitoring after parathyroidectomy to predict short-term, medium-term, and long-term outcomes and prognosis.

Proteomic and Transcriptomic Analysis Identify Spliceosome as a Significant Component of the Molecular Machinery in the Pituitary Tumors Derived from POU1F1- and NR5A1-Cell Lineages.

BACKGROUND: Pituitary adenomas (PA) are the second most common tumor in the central nervous system and have low counts of mutated genes. Splicing occurs in 95% of the coding RNA. There is scarce information about the spliceosome and mRNA-isoforms in PA, and therefore we carried out proteomic and transcriptomic analysis to identify spliceosome components and mRNA isoforms in PA. METHODS: Proteomic profile analysis was carried out by nano-HPLC and mass spectrometry with a quadrupole time-of-flight mass spectrometer. The mRNA isoforms and transcriptomic profiles were carried out by microarray technology. With proteins and mRNA information we carried out Gene Ontology and exon level analysis to identify splicing-related events. RESULTS: Approximately 2000 proteins were identified in pituitary tumors. Spliceosome proteins such as SRSF1, U2AF1 and RBM42 among others were found in PA. These results were validated at mRNA level, which showed up-regulation of spliceosome genes in PA. Spliceosome-related genes segregate and categorize PA tumor subtypes. The PA showed alterations in CDK18 and THY1 mRNA isoforms which could be tumor specific. CONCLUSIONS: Spliceosome components are significant constituents of the PA molecular machinery and could be used as molecular markers and therapeutic targets. Splicing-related genes and mRNA-isoforms profiles characterize tumor subtypes.

Transcriptome and methylome analysis reveals three cellular origins of pituitary tumors.

Pituitary adenomas (PA) are the second most common intracranial tumors. These neoplasms are classified according to the hormone they produce. The majority of PA occur sporadically, and their molecular pathogenesis is incompletely understood. The present transcriptomic and methylomic analysis of PA revealed that they segregate into three molecular clusters according to the transcription factor driving their terminal differentiation. First cluster, driven by NR5A1, consists of clinically non-functioning PA (CNFPA), comprising gonadotrophinomas and null cell; the second cluster consists of clinically evident ACTH adenomas and silent corticotroph adenomas, driven by TBX19; and the third, POU1F1-driven TSH-, PRL- and GH-adenomas, segregated together. Genes such as CACNA2D4, EPHA4 and SLIT1, were upregulated in each of these three clusters, respectively. Pathway enrichment analysis revealed specific alterations of these clusters: calcium signaling pathway in CNFPA; renin-angiotensin system for ACTH-adenomas and fatty acid metabolism for the TSH-, PRL-, GH-cluster. Non-tumoral pituitary scRNAseq data confirmed that this clustering also occurs in normal cytodifferentiation. Deconvolution analysis identify potential mononuclear cell infiltrate in PA consists of dendritic, NK and mast cells. Our results are consistent with a divergent origin of PA, which segregate into three clusters that depend on the specific transcription factors driving late pituitary cytodifferentiation.

Detection of polyps in the small bowel of patients with acromegaly via capsule endoscopy.

BACKGROUND: the prevalence of small bowel (SB) polyps is unknown in acromegaly patients. OBJECTIVE: to evaluate the prevalence of polyps/tumors in SB of acromegaly patients. MATERIAL: this was a prospective and observational study that compared the prevalence of polyps/tumors using capsule endoscopy with a standard protocol in asymptomatic acromegaly patients and non-acromegaly patients, with abdominal pain, diarrhea or anemia. RESULTS: one hundred and eighty-three cases were included (61 acromegaly and 122 non-acromegaly). Polyps were found in six (9.8%) and three (2.5%) patients, respectively (RR: 4 [95% CI, 1.03-15.45; p = 0.038]). There were no differences in the tumors (n = 4, 6.6% vs n = 7, 5.7%). CONCLUSIONS: acromegaly may be associated with more polyps in SB.

The Testosterone Effect on Metabolic and Urologic Outcomes in Patients with Nonfunctioning Pituitary Macroadenomas and Hypogonadotropic Hypogonadism.

OBJECTIVE: To evaluate cardiovascular risk, metabolic profile, low urinary tract symptoms (LUTS), and sexual function in patients with nonfunctional pituitary macroadenoma (NFPMA) and hypogonadotropic hypogonadism with testosterone therapy (TTh). METHODS: A retrospective clinical study at a tertiary care center was performed in 101 men with NFPMA, HH, and TTh; metabolic profile, cardiovascular risk, International Prostate Symptoms Score (IPSS), and International Index of Erectile Function 5 (IIEF-5) scores were evaluated before initiation of TTh and at the last checkup with TTh. RESULTS: Age was 49.3 ± 8.8 years; T before TTh was 195 ng/mL (101-259) vs. 574 (423-774) at the last checkup. The time of TTh administration was 34 months (12-72). An increase in triglyceride levels (200 (153-294) vs. 174 (134-233) mg/dL; p=0.03), dyslipidemia (40% vs. 52%; p=0.03), and MetS (25% vs. 34%; p=0.05) was corroborated. A statistical difference in the Globorisk score and cardiovascular (CV) risk stratification was not found. IIEF-5 score was 15.5 ± 6.5 vs. 17.8 ± 5.3 (p=0.11). An improvement in penetration quality (2.0 ± 1.5 vs. 2.6 ± 1.3; p=0.05), erection after penetration (1.8 ± 1.2 vs. 2.5 ± 1.6; p=0.02), completion of intercourse (1.8 ± 1.2 vs. 2.4 ± 1.3; p=0.03), and satisfaction of sexual intercourse (1.8 ± 1.3 vs. 2.5 ± 1.5; p=0.01) was evidenced. IPSS score was 6 (IQR 2-10) vs. 7 (IQR 4-12); p=0.30. A lower rate of intermittency (14% vs. 3%; p=0.02), urgency (39% vs. 16%; p=0.01), and episodes of nocturia (18% vs. 4%; p=0.02) was found. An increase of hematocrit (44.1 ± 4.4 vs. 47.3 ± 4.4%; p=0.001), hemoglobin (14.9 ± 1.4 vs. 15.9 ± 1.4 g/dL; p=0.001), and prostatic specific antigen (0.59 (0.43-1.19) vs. 0.82 (0.45-1.4) ng/mL; p=0.02) was evidenced during TTh. CONCLUSION: TTh in young men with NFPMA improves LUTS, sexual function, and some metabolic parameters, and it is relatively safe in the prostatic context.

Efficacy and safety of fractionated conformal radiation therapy in acromegaly: a long-term follow-up study.

BACKGROUND AND PURPOSE: Conformal, fractionated radiation therapy (XRT) is variably used as a treatment alternative for active acromegaly patients, usually, after failed pituitary surgery. Our objective was to evaluate the long-term efficacy and safety of XRT using strict criteria of biochemical control. SETTING, DESIGN, PATIENTS, AND METHODS: Retrospective cohort study of 94 patients (73 women, mean age at radiation 53.16 ± 12.9 years) attending a specialized multidisciplinary clinic between 1998 and 2014 with a mean duration of follow-up of 12.9 ± 7.3 years. RESULTS: A basal growth hormone < 1 ng/mL and an IGF-1 < 1.2 × the upper limit of normal was achieved by 41% and 50.8%, respectively, at 5 years of follow-up, and by 44% and 66%, respectively, 10 years after XRT. Median tumor volume decreased significantly from 904 mm3 at baseline to 424 mm3 upon last follow-up (p = 0.01). The prevalence of central hypogonadism, central hypocortisolism, and central hypothyroidism increased from 18%, 35%, and 35% at baseline, to 38%, 53%, and 64%, respectively, after 10 years of follow-up. One patient was diagnosed with a meningioma and another one developed optic neuritis. No cerebrovascular events were recorded, and all patients are currently alive. CONCLUSION: XRT is an effective and reasonably safe means of controlling acromegalic activity. Its main disadvantages are the time required to achieve biochemical control and the development of anterior pituitary hormone deficiencies.

Silent pituitary plurihormonal adenoma: clinical relevance of immunohistochemical analysis / Adenoma hipofisario silente plurihormonal: relevancia clínica de la inmunohistoquímica

Background: Non-functional pituitary adenomas (NFPAs) present low growth rates; however, some are aggressive and invasive. In 2017 the World Health Organization recognized clinically aggressive adenomas as "high-risk pituitary adenomas". These include the sparsely granulated somatotroph adenoma, the Crooke's cell adenoma, the silent corticotroph adenoma and the plurihormonal Pit-1-positive adenoma (subtype 3). Clinical case: 25-year-old woman who presented oligomenorrhea, increased weight, decreased visual acuity and chronic headache. Biochemical and imaging evaluation showed a NFPA. Transsphenoidal surgery was performed with complete resection of lesion, and during short-term follow-up it was observed recurrence, which is why the patient needed two more interventions. The immunohistochemistry reported: ACTH ++ 90%, prolactin ++ 20%, GH ++ 5%, CKAE1-AE3 +++ 90%, Ki-67 10%. The final diagnosis was plurihormonal adenoma, since the immunohistochemical analysis was positive for more than one pituitary hormone and suggested two distinct cell lineages: Pit-1 and Tpit, both recognized as aggressive adenomas. Conclusions: This case report highlights the significance of a comprehensive immunohistochemical study, which includes transcriptional factors to classify cell lineage, in order to predict aggressiveness and provide personalized treatment.

Introducción: los adenomas hipofisarios no funcionantes (AHNF) presentan una baja tasa de crecimiento; sin embargo, algunos son agresivos e invasivos. En 2017 la Organización Mundial de la Salud denominó los adenomas de comportamiento clínico agresivo como "tumores hipofisarios de alto riesgo", incluyendo los adenomas del somatotropo escasamente granulados, los adenomas de células de Crooke, los silentes de corticotropo y los adenomas plurihormonal Pit-1 positivo (subtipo 3). Caso clínico: mujer de 25 años de edad con oligoamenorrea, aumento de peso, disminución del campo visual y cefalea crónica. La evaluación bioquímica y de imagen correspondió a un AHNF. Se realizó cirugía transesfenoidal con resección completa de la lesión y durante el seguimiento a corto plazo se observó recurrencia tumoral, por lo que ameritó dos intervenciones más. La inmunohistoquímica reportó: ACTH ++ 90%, prolactina ++ 20%, GH ++ 5%, CKAE1-AE3 +++ 90%, Ki-67 10%. El diagnóstico definitivo correspondió a un adenoma plurihormonal, debido a que la inmunohistoquímica fue positiva para la expresión de más de una hormona hipofisaria, con sugerencia de contenido celular con dos linajes distintos, tanto de Pit-1 como de Tpit, ambos reportados como adenomas agresivos. Conclusiones: este caso resalta la importancia de una inmunohistoquímica completa que incluya factores de transcripción que permitan clasificar el linaje celular para predecir agresividad y proporcionar un tratamiento individualizado.

Symptomatic Primary Hyperparathyroidism as a Risk Factor for Differentiated Thyroid Cancer.

BACKGROUND: The primary hyperparathyroidism (PHPT) is a common disease for the endocrinologist. The concomitant thyroid disease and differentiated thyroid cancer (DTC) appear to be more frequent in patients with PHPT than in the general population. The aim of this study was to characterize patients with symptomatic PHPT with and without DTC and analyze frequency and risk factors. METHODS: We consecutively studied patients with symptomatic PHPT diagnosed and treated at our center between 2013 and 2015. Patients with subclinical and syndromic forms of PHPT were excluded. Clinical and biochemical characteristics of patients with and without DTC were compared and risk factors were determined. All patients were studied with thyroid ultrasound and thyroid gammagraphy with TC-MIBI. Two expert surgeons performed all the surgical procedures. RESULTS: In 59 patients included, we found 12 cases of PTC (20.3%). The final histopathological report of the PTC was 7 cases of follicular variant, 2 cases of oncocytic variant, 2 cases of classic variant, and 1 case of columnar cells variant of PTC. Patients with thyroid cancer were older than patients without thyroid cancer (62 ± 9.5 versus 52 ± 15.8, p = 0.03). Higher preoperative levels of iPTH were associated with PTC (p=0.03) [OR 5.16 (95% CI: 1.08-24.7)]. CONCLUSION: PTC is frequent in patients with symptomatic PHPT. Thyroid nodules in patients with symptomatic PHPT must be studied before parathyroidectomy. In symptomatic PHPT, higher level concentration of parathormone (PTH) was associated with higher risk of DTC.

Tratamiento multimodal de los adenomas de hipófisis recidivantes clínicamente no funcionales. Reporte de caso y revisión de la literatura / Multimodal treatment of non-functional recidivant hypophyseal adenomas. A case report and literature review

Resumen Antecedentes: Los adenomas hipofisarios no funcionales generalmente tienen un comportamiento benigno y naturaleza no invasiva, sin embargo, pueden mostrar características de agresividad con invasión a tejidos circundantes, alto índice mitótico, un índice de Ki67 > 3%y positividad extensa para la tinción de p53, diferenciándose de los carcinomas hipofisarios por la ausencia de diseminación cerebroespinal o metástasis a distancia. Los adenomas agresivos muestran resistencia al tratamiento guirúrgico, médico y radioterapia, y los agentes guimioterapéuticos como temozolamida son una opción terapéutica prometedora de acuerdo con los reportes de la literatura médica internacional. Caso clínico: Paciente del sexo femenino en la sexta década de la vida con padecimiento caracterizado por síndrome guiasmático progresivo e hipopituitarismo ante la presencia de un macroadenoma hipofisario no funcional, con resistencia a tratamiento neuroguirúrgico inicial, tratamiento médico con un agonista dopaminérgico y análogo de receptor de la somatostatina así como radioterapia convencional fraccionada, y cumple con los criterios de agresividad. Se establece tratamiento guimioterapéutico a base de temozolamida, y durante su vigilancia muestra tanto estabilidad clínica como ausencia de progresión tumoral. Conclusiones: La determinación de agresividad es de crucial importancia para mejorar el tratamiento del paciente y, con ello, ofrecer un mejor pronóstico y efectividad terapéutica. El tratamiento de los adenomas hipofisarios no funcionales con características de agresividad es un reto clínico gue involucra un abordaje multidisciplinario. La resistencia al tratamiento quirúrgico, médico y radioterapéutico han dado lugar a la investigación de opciones terapéuticas con agentes quimioterapéuticos como la temozolamida, con tasas de respuesta prometedoras.

Abstract Background: Non-functional pituitary adenomas generally have a benign and non-invasive nature, however, it may show aggressiveness with invasion of surrounding tissues, high mitotic index, an index of Ki67> 3% and extensive positive staining for the cellular tumor antigen p53, differing from the pituitary carcinomas by the absence of craniospinal dissemination or systemic metastases. Aggressive adenomas show resistance to surgical, medical and radiation therapy, including chemotherapeutic agents such as temozolomide, a promising therapeutic option according to reports in the international literature. Case presentation: This is a woman in her 6th decade of life with a clinical presentation characterized by a progressive chiasm syndrome and hypopituitarism in the presence of non-functional pituitary macroadenoma, with initial resistance of neurosurgical treatment, medical treatment with a dopaminergic agonist plus a somatostatin receptor agonist and conventional fractionated radiotherapy, meeting the criteria of aggressive pituitary adenoma. After the treatment with temozolomide as a chemotherapy regimen, the patient showed clinical stability and absence of tumor progression during her follow-up. Conclusion: Defining aggressiveness is of crucial importance for improving the management of patients by enhancing prognostic predictions and effectiveness of treatment. The treatment of nonfunctioning pituitary adenomas with aggressiveness is a clinical challenge that involves a multidisciplinary approach. Resistance to surgical, medical and radiotherapeutic treatment have resulted in the investigation of therapeutic options with chemotherapeutic agents such as temozolomide, with promising response rates.

Anorexia-cachexia syndrome-like hypothalamic neuroendocrine dysfunction in a patient with a papillary craniopharyngioma.

The craniopharyngiomas are solid cystic suprasellar tumors that can present extension to adjacent structures, conditioning pituitary and hypothalamic dysfunction. Within hypothalamic neuroendocrine dysfunction, we can find obesity, behavioral changes, disturbed circadian rhythm and sleep irregularities, imbalances in the regulation of body temperature, thirst, heart rate and/or blood pressure and alterations in dietary intake (like anorexia). We present a rare case of anorexia-cachexia syndrome like a manifestation of neuroendocrine dysfunction in a patient with a papillary craniopharyngioma. Anorexia-cachexia syndrome is a complex metabolic process associated with underlying illness and characterized by loss of muscle with or without loss of fat mass and can occur in a number of diseases like cancer neoplasm, non-cancer neoplasm, chronic disease or immunodeficiency states like HIV/AIDS. The role of cytokines and anorexigenic and orexigenic peptides are important in the etiology. The anorexia-cachexia syndrome is a clinical entity rarely described in the literature and it leads to important function limitation, comorbidities and worsening prognosis. LEARNING POINTS: Suprasellar lesions can result in pituitary and hypothalamic dysfunction.The hypothalamic neuroendocrine dysfunction is commonly related with obesity, behavioral changes, disturbed circadian rhythm and sleep irregularities, but rarely with anorexia-cachexia.Anorexia-cachexia syndrome is a metabolic process associated with loss of muscle, with or without loss of fat mass, in a patient with neoplasm, chronic disease or immunodeficiency states.Anorexia-cachexia syndrome results in important function limitation, comorbidities that influence negatively on treatment, progressive clinical deterioration and bad prognosis that can lead the patient to death.Anorexia-cachexia syndrome should be suspected in patients with emaciation and hypothalamic lesions.