Desnutrición relacionada con la enfermedad crónica y fragilidad. Implicaciones en la evaluación integral de nuestros pacientes crónicos complejos y pluripatológicos

A 73-year-old patient with chronic diseases and malnutrition secondary to short bowel syndrome. She is admitted for dehydration, hydroelectrolytic alterations and acute renal failure secondary to ileostomy diarrhea. We remember during the evaluation of the case, the relevance of a comprehensive assessment of the patient during hospital- ization that included nutritional status and frailty, because of its implications.  Paciente de 73 años con enfermedades crónicas y desnutrición secundaria a intestino corto. Ingresó por deshidratación, alteraciones hidroelectrolíticas y fracaso renal agudo secundario a diarrea por ileostomía. Recordamos durante la exposición del caso la importancia de una valoración integral del paciente durante la hospitalización, que tenga presente, por sus implicaciones, la situación nutricional y la fragilidad.

A Silent Corticotroph Pituitary Carcinoma: Lessons From an Exceptional Case Report

Nowadays, neither imaging nor pathology evaluation can accurately predict the aggressiveness or treatment resistance of pituitary tumors at diagnosis. However, histological examination can provide useful information that might alert clinicians about the nature of pituitary tumors. Here, we describe our experience with a silent corticothoph tumor with unusual pathology, aggressive local invasion and metastatic dissemination during follow-up. We present a 61-year-old man with third cranial nerve palsy at presentation due to invasive pituitary tumor. Subtotal surgical approach was performed with a diagnosis of silent corticotroph tumor but with unusual histological features (nuclear atypia, frequent multinucleation and mitotic figures, and Ki-67 labeling index up to 70%). After a rapid regrowth, a second surgical intervention achieved successful debulking. Temozolomide treatment followed by stereotactic fractionated radiotherapy associated with temozolomide successfully managed the primary tumor. However, sacral metastasis showed up 6 months after radiotherapy treatment. Due to aggressive distant behavior, a carboplatine-etoposide scheme was decided but the patient died of urinary sepsis 31 months after the first symptoms. Our case report shows how the presentation of a pituitary tumor with aggressive features should raise a suspicion of malignancy and the need of follow up by multidisciplinary team with experience in its management. Metastases may occur even if the primary tumor is well controlled.This work was supported by grants from the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación co-funded with Fondos FEDER (PI16/00175 to AS-M and DC) and the Sistema Andaluz de Salud (A-0003-2016 and A-0006-2017 to AS-M, C-0015-2014 and RC-0006-2018 to DC)

Sex Hormone Receptor Expression in Craniopharyngiomas and Association with Tumor Aggressiveness Characteristics

Craniopharyngiomas (CPs) are rare tumors of the sellar and suprasellar regions of embryonic origin. The primary treatment for CPs is surgery but it is often unsuccessful. Although CPs are considered benign tumors, they display a relatively high recurrence rate that might compromise quality of life. Previous studies have reported that CPs express sex hormone receptors, including estrogen and progesterone receptors. Here, we systematically analyzed estrogen receptor α (ERα) and progesterone receptor (PR) expression by immunohistochemistry in a well-characterized series of patients with CP (n = 41) and analyzed their potential association with tumor aggressiveness features. A substantial proportion of CPs displayed a marked expression of PR. However, most CPs expressed low levels of ERα. No major association between PR and ERα expression and clinical aggressiveness features was observed in CPs. Additionally, in our series, β-catenin accumulation was not related to tumor recurrence. View Full-TextThis work was supported by grants from the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación co-funded with Fondos FEDER (PI16/00175 to A.S-M. and D.A.C.) and the Sistema Andaluz de Salud (A-0006-2017 and A-0055-2018 to A.S-M, RC-0006-2018 to D.A.C.)

Molecular analysis of prolactinoma formation in Pten-deficient mice.

Pituitary tumors are abnormal masses developed in the pituitary gland. Although they are generally benign, between 40-50% of pituitary adenomas cannot be removed by surgery alone due to local invasion. Moreover, they are associated with hormonal dysregulation. Prolactinoma is the most common type (50-60%), followed by somatotropic cell adenoma (10-15%), corticotropic cell adenoma (5-10%) and finally thyrotropinoma (less than 1%) (Cano González et al., 2015).Previous descriptive studies have suggested a possible role for the PI3K/AKT/mTOR signaling pathway in the formation of pituitary adenomas. In this study, we used genetic mouse models to assess the oncogenic capacity of this signaling pathway in the pituitary. For this purpose, conditional knockout mice have been generated in which the Pten gene is inactivated specially in the pituitary, indirectly causing the AKT overexpression. To accomplish this, a HesX1-Cre mouse line, whose expression is controlled by a pituitary-specific promoter and which is present in very early stages of embryonic development (Rizzoti, 2015) were crossed with mouse lines in which the Pten gene is floxed by two LoxP sequences.We have analyzed the pituitary in Pten-deficient mice at three different ages: 12, 6 and 1 month of age, comparing genotype and sex. At young ages, Pten-deficient mice show pituitary hyperplasia. After 12 months of age, Pten-deficient mice develop pituitary tumors. However, this is only observed in mutant female mice, whereas male mice simply display pituitary hyperplasia. Data from immunohistochesmistry, immunofluorescence, and blood hormones show that Pten-deficient mice developed prolactinomas. These tumors show high rates of cell proliferation as well as alterations in the expression levels of several cell cycle inhibitors

Splicing Machinery is Dysregulated in Pituitary Neuroendocrine Tumors and is Associated with Aggressiveness Features

Pituitary neuroendocrine tumors (PitNETs) constitute approximately 15% of all brain tumors, and most have a sporadic origin. Recent studies suggest that altered alternative splicing and, consequently, appearance of aberrant splicing variants, is a common feature of most tumor pathologies. Moreover, spliceosome is considered an attractive therapeutic target in tumor pathologies, and the inhibition of SF3B1 (e.g., using pladienolide-B) has been shown to exert antitumor effects. Therefore, we aimed to analyze the expression levels of selected splicing-machinery components in 261 PitNETs (somatotropinomas/non-functioning PitNETS/corticotropinomas/prolactinomas) and evaluated the direct effects of pladienolide-B in cell proliferation/viability/hormone secretion in human PitNETs cell cultures and pituitary cell lines (AtT-20/GH3). Results revealed a severe dysregulation of splicing-machinery components in all the PitNET subtypes compared to normal pituitaries and a unique fingerprint of splicing-machinery components that accurately discriminate between normal and tumor tissue in each PitNET subtype. Moreover, expression of specific components was associated with key clinical parameters. Interestingly, certain components were commonly dysregulated throughout all PitNET subtypes. Finally, pladienolide-B reduced cell proliferation/viability/hormone secretion in PitNET cell cultures and cell lines. Altogether, our data demonstrate a drastic dysregulation of the splicing-machinery in PitNETs that might be associated to their tumorigenesis, paving the way to explore the use of specific splicing-machinery components as novel diagnostic/prognostic and therapeutic targets in PitNETs

Craniopharyngioma in the elderly: a multicenter and nationwide study in Spain

[Abstract] Background: Craniopharyngioma (CP) is a rare tumor in the elderly whose clinical features and prognosis are not well known in this population. Aim: To evaluate the clinicopathological features and therapeutic outcomes of CP diagnosed in the elderly. Patients and Methods: This was a retrospective, multicenter, national study of CP patients diagnosed over the age of 65 years and surgically treated. Results: From a total of 384 adult CP patients, we selected 53 (13.8%) patients (27 women [50.9%], mean age 72.3 ± 5.1 years [range 65–83 years]) diagnosed after the age of 65 years. The most common clinical symptoms were visual field defects (71.2%) followed by headache (45.3%). The maximum tumor diameter was 2.9 ± 1.1 cm. In most patients, the tumor was suprasellar (96.2%) and mixed (solid-cystic) (58.5%). The surgical approach most commonly used was transcranial surgery (52.8%), and more than half of the patients (54.7%) underwent subtotal resection (STR). Adamantinomatous CP and papillary CP were present in 51 and 45.1%, respectively, with mixed forms in the remaining. Surgery was accompanied by an improvement in visual field defects and in headaches; however, pituitary hormonal hypofunction increased, mainly at the expense of an increase in the prevalence of diabetes insipidus (DI) (from 3.9 to 69.2%). Near-total resection (NTR) was associated with a higher prevalence of DI compared with subtotal resection (87.5 vs. 53.6%, p = 0.008). Patients were followed for 46.7 ± 40.8 months. The mortality rate was 39.6% with a median survival time of 88 (95% CI: 57–118) months. DI at last visit was associated with a lower survival. Conclusion: CP diagnosed in the elderly shows a similar distribution by sex and histologic forms than that diagnosed at younger ages. At presentation, visual field alterations and headaches are the main clinical symptoms which improve substantially with surgery. However, surgery, mainly NTR, is accompanied by worsening of pituitary function, especially DI, which seems to be a predictor of mortality in this population

Nuestra experiencia en prolactinomas mayores de 60 mm

[EN] Introduction: Giant prolactinomas (tumor size larger than 40 mm) are a rare entity of benign nature. Prolactinomas larger than 60 mm are usually underrepresented in published studies and their clinical presentation, outcomes and management might be different from smaller giant prolactinomas. Patients and methods: We retrospective collected data from patients with prolactinomas larger than 60 mm in maximum diameter and prolactin (PRL) serum levels higher than 21,200 μIU/mL in our series of prolactinomas (283). Data were collected from January 2012 to December 2017. We included three patients with prolactinomas larger than 60 mm. Results: At diagnosis, two patients presented neurological symptoms and one nasal protrusion. All patients received medical treatment with dopamine agonists. No surgical procedure was performed. Median prolactin levels at diagnosis was 108,180 [52,594–514,984] μIU/mL. Medical treatment achieved a marked reduction (>99%) in prolactin levels in all cases. Tumor size reduction (higher than 33%) was observed in all cases. In one patient cerebrospinal fluid (CSF) leak was observed after tumor shrinkage. Conclusions: Dopamine agonists appear to be an effective and safe first-line treatment in prolactinomas larger than 60 mm even in life-threatening situations. More studies with a higher number of patients are necessary to obtain enough data to make major recommendations.[ES] Introducción: Los prolactinomas gigantes (de tamaño superior a 40 mm) son una entidad rara de naturaleza benigna. Los prolactinomas mayores de 60 mm suelen estar infrarrepresentados en los estudios publicados, y su presentación clínica, resultados y tratamiento podrían ser diferentes de los de prolactinomas gigantes más pequeños. Pacientes y métodos: Recogimos retrospectivamente datos de pacientes con prolactinomas de más de 60 mm de diámetro máximo y con concentraciones séricas de prolactina (PRL) superiores a 21.200 μIU/ml de nuestra serie de prolactinomas (283). Los datos se recogieron entre enero de 2012 y diciembre de 2017. Se incluyeron 3 pacientes con prolactinomas mayores de 60 mm. Resultados: En el momento del diagnóstico, 2 pacientes presentaban síntomas neurológicos, y uno protrusión nasal. Todos los pacientes recibieron tratamiento médico con agonistas dopaminérgicos. No se realizó ninguna intervención quirúrgica. La mediana de las concentraciones de PRL al diagnóstico fue de 108.180 (52.594-514.984) μIU/ml. El tratamiento médico logró una reducción notable (> 99%) de los valores de prolactina en todos los casos. En todos los casos se observó una reducción del tamaño del tumor (superior al 33%). En un paciente se observó una fuga de líquido cefalorraquídeo (LCR) tras la reducción del tumor. Conclusión: Los agonistas dopaminérgicos parecen ser un tratamiento de primera línea eficaz y seguro en los prolactinomas mayores de 60 mm incluso en situaciones peligrosas para la vida. Se necesitan más estudios con un mayor número de pacientes para obtener datos suficientes para hacer recomendaciones importantes

A silent corticotroph pituitary carcinoma: lessons from an exceptional case

Nowadays, neither imaging nor pathology evaluation can accurately predict the aggressiveness or treatment resistance of pituitary tumors at diagnosis. However, histological examination can provide useful information that might alert clinicians about the nature of pituitary tumors. Here, we describe our experience with a silent corticothoph tumor with unusual pathology, aggressive local invasion and metastatic dissemination during follow-up. We present a 61-year-old man with third cranial nerve palsy at presentation due to invasive pituitary tumor. Subtotal surgical approach was performed with a diagnosis of silent corticotroph tumor but with unusual histological features (nuclear atypia, frequent multinucleation and mitotic figures, and Ki-67 labeling index up to 70%). After a rapid regrowth, a second surgical intervention achieved successful debulking. Temozolomide treatment followed by stereotactic fractionated radiotherapy associated with temozolomide successfully managed the primary tumor. However, sacral metástasis showed up 6 months after radiotherapy treatment. Due to aggressive distant behavior, a carboplatine-etoposide scheme was decided but the patient died of urinary sepsis 31 months after the first symptoms. Our case report shows how the presentation of a pituitary tumor with aggressive features should raise a suspicion of malignancy and theneed of follow up by multidisciplinary team with experience in its management. Metastases may occur even if the primary tumor is well controlled

Postoperative water and electrolyte disturbances after extended endoscopic endonasal transsphenoidal surgery.

Water and electrolyte disturbances are common after pituitary surgery and can generally be classified into transient hypotonic polyuria and transient or permanent diabetes insipidus (DI). The prevalence varies in the literature between 31-51% for transient hypotonic polyuria, 5.1-25.2% for transient DI, and 1-8.8% for permanent DI. The aim of this study was to identify the prevalence of water and electrolyte disturbances with polyuria and the preoperative and postoperative predictive factors in patients undergoing surgery with an extended endoscopic endonasal approach. This retrospective observational descriptive study included 203 patients with a diagnosis of pituitary adenoma who underwent their first transsphenoidal surgery via the extended endoscopic endonasal approach between April 2013 and February 2020. The diagnosis of water and electrolyte disturbances was based on the criterion for polyuria (>4 ml/kg/h). Postoperative polyuria was defined as those cases diagnosed during the immediate postsurgical period that resolved prior to discharge. Transient DI included all cases with a duration of less than 6 months but still present at hospital discharge, and permanent DI included cases lasting more than 6 months. The overall prevalence of water and electrolyte disorders was 30.5% (62), and the prevalence of postoperative polyuria was 23.6% (48). The median number of desmopressin doses administered to patients with postoperative polyuria was one dose (interquartile range [IQR] 1-2), and thus the median duration of treatment was 0 days. The median initiation of desmopressin was the second day after surgery (IQR 1-2). The overall prevalence of DI was 6.89%. Among the patients with transient DI, the duration was less than 3 months in three patients (1.47%), and between 3 and 6 months in two (0.98%). Nine patients had permanent DI (4.43%). (4.43%). The prevalence of electrolyte disturbances in our study was high, although similar to that found in the literature. Most of the cases were transient hypotonic polyuria that resolved within one day. The prevalence of transient DI in our cohort was lower than that described in the literature, while permanent DI was similar

Cardiometabolic and Nutritional Morbidities of a Large, Adult, PKU Cohort from Andalusia

The establishment of national neonatal screening systems has resulted in improved quality of life and life expectancy in patients with phenylketonuria (PKU). This has led to the development of multidisciplinary treatment units for adult patients with PKU. We present a retrospective descriptive study of a cohort of 90 adult patients (>16 years) with PKU under active follow-up in two reference centers in Andalusia. We analyzed disease severity, treatment type, demographic variables, cardiovascular risk factors, vitamin and hormone profiles, and bone metabolism. The median (interquartile range)age was 29 (23–38) years, 47 (52.2%) were women and 43 (47.8%) were men. Eighty (88.9%) had classical PKU, five (5.6%) moderate PKU, and five (5.6%) mild PKU. Diagnosis was by neonatal screening in 62 (68.9%) of the patients. The rest had late diagnosis. Treatment with sapropterin was given to 18 (20%) patients and diet and nutrition therapy to 72 (80%). There was adequate metabolic control according to Phe levels in 43 (47.78%) patients. Body mass index was 26.61 (22.7–31.1) kg/m2. Twenty-six (29.2%) patients had obesity, 7 (7.9%) hypertension, 2 (2.2%) type 2 diabetes, 26 (28.89%) dyslipidemia, 14 (15.6%) elevated total cholesterol, 9 (15.8%) decreased high-density lipoprotein cholesterol and 16 (17.8%) hypertriglyceridemia. Seven (10.3%) patients had osteoporosis and 28 (41.17%) osteopenia. Twenty-six (30.6%) had vitamin D (25OH) deficiency and four (4.5%) vitamin B12 deficiency. Although we observed no differences with most vascular risk factors, we found a high prevalence of obesity in relation to the age of the cohort. A continued evaluation of comorbidities in these patients is therefore needed, despite adequate metabolic control