RESUMO

Somatic alpha thalassemia/mental retardation syndrome X-linked (ATRX) pathogenic variants have been shown to predict a malignant phenotype in neuroendocrine tumors. They were recently identified in aggressive pituitary tumors and carcinomas, mainly of corticotrophic origin. To our knowledge, these tumors are rare in a general cohort of pituitary tumors, with no cases described in null cell tumors. These variants can lead to loss of protein expression as revealed by immunohistochemistry. We describe a case of an aggressive null cell pituitary tumor with loss of ATRX expression. The patient underwent two transsphenoidal surgeries and radiotherapy and exhibited tumor growth despite conventional therapy. Analysis of the tumor samples revealed loss of ATRX expression in both surgical specimens, suggesting that ATRX may be a useful biomarker for the early identification of aggressive pituitary tumors.

RESUMO

Pituitary apoplexy (PA) is a clinical syndrome resulting from a hemorrhagic infarction of the pituitary gland. It is characterized by the sudden onset of visual disturbances, nausea, vomiting, headache and occasionally, signs of meningeal irritation and an altered mental status. The exact pathogenesis of PA remains to be elucidated, although tumor overgrowth of its blood supply remains the most popular theory. Main risk factors for the development of PA include systemic, iatrogenic, and external factors as well as the presence of an underlying pituitary tumor. The diagnostic approach of PA includes both neuroimaging and evaluation of pituitary secretory function. PA is a potentially life-threatening condition which should be managed with hemodynamic stabilization, correction of electrolyte abnormalities and replacement of hormonal deficiencies. PA treatment should be individualized based on the severity of the clinical picture which may vary widely. Treatment options include conservative management with periodic follow-up or neurosurgical intervention, which should be decided by a multidisciplinary team. We conducted a systematic review of the literature to unveil the frequency of PA predisposing factors, clinical and biochemical presentations, management strategies and outcomes.

Assuntos

RESUMO

CONTEXT: The tumor microenvironment (TME) includes diverse cellular components such as mesenchymal stem cells (MSCs) and immune cells, among others. MSC have been isolated from different tumors and they favor tumor cell growth; however, their role in pituitary tumors (PTs) remains unknown. OBJECTIVE: Herein we report the presence of MSCs in 2 adrenocorticotropin (ACTH)-secreting PTs causing Cushing disease (MCU), 2 nonfunctioning adenomas of gonadotrope differentiation (MNF), and 2 nontumoral pituitary glands (MS). METHODS: We have analyzed the transcriptomic profiles by RNA sequencing and compared MSCs in terms of their immunosuppressive effects against lymphoid T-cell and macrophage populations by means of cocultures and flow cytometry. RESULTS: Our transcriptomic analysis revealed molecular differences between MSCs derived from nontumoral pituitaries and MSCs derived from PTs. Two distinct subpopulations of MSC emerged: one displaying immunosuppressive properties and the other with increased proproliferative capabilities, regardless of their origin. MSCs derived from ACTH- and nonfunctioning PTs, but not those derived from nontumoral glands, significantly inhibited the proliferation of activated T cells, favored the generation of regulatory T cells, and promoted M2 macrophage polarization. Such immunosuppressive effects were correlated with an upregulation of programmed death ligand 1 and intracellular expression of macrophage colony-stimulating factor (M-CSF) and interleukin-10. Importantly, MSC derived from ACTH-PTs showed a higher immunosuppressive potential than MSC isolated from nonfunctioning tumors. CONCLUSION: This study demonstrates the presence of at least 2 MSC subpopulations in the pituitary gland and suggests that immunosuppressive effects of MSCs may have important implications in PT growth.

Assuntos

RESUMO

Hyperprolactinemia is a frequent cause of menstrual irregularity, galactorrhea, hypogonadism, and infertility. The most common etiologies of hyperprolactinemia can be classified as physiological, pharmacological, and pathological. Among pathological conditions, it is essential to distinguish prolactinomas from other tumors and pituitary lesions presenting with hyperprolactinemia due to pituitary stalk disconnection. Proper investigation considering clinical data, laboratory tests, and, if necessary, imaging evaluation, is important to identify the correctcause of hyperprolactinemia and manage the patient properly. This position statement by the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) and Brazilian Societyof Endocrinology and Metabolism (SBEM) addresses the recommendations for measurement of serum prolactin levels and the investigations of symptomatic and asymptomatic hyperprolactinemia and medication-induced hyperprolactinemia in women.

Assuntos

RESUMO

ABSTRACT Hyperprolactinemia is a frequent cause of menstrual irregularity, galactorrhea, hypogonadism, and infertility. The most common etiologies of hyperprolactinemia can be classified as physiological, pharmacological, and pathological. Among pathological conditions, it is essential to distinguish prolactinomas from other tumors and pituitary lesions presenting with hyperprolactinemia due to pituitary stalk disconnection. Proper investigation considering clinical data, laboratory tests, and, if necessary, imaging evaluation, is important to identify the correct cause of hyperprolactinemia and manage the patient properly. This position statement by the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) and Brazilian Society of Endocrinology and Metabolism (SBEM) addresses the recommendations for measurement of serum prolactin levels and the investigations of symptomatic and asymptomatic hyperprolactinemia and medication-induced hyperprolactinemia in women.

RESUMO

Cushing's disease (CD) is a life-threatening condition with a challenging diagnostic process and scarce treatment options. CD is caused by usually benign adrenocorticotrophic hormone (ACTH)-secreting pituitary neuroendocrine tumors (PitNETs), known as corticotropinomas. These tumors are predominantly of sporadic origin, and usually derive from the monoclonal expansion of a mutated cell. Somatic activating variants located within a hotspot of the USP8 gene are present in 11-62% of corticotropinomas, making USP8 the most frequent genetic driver of corticotroph neoplasia. In contrast, other somatic defects such as those affecting the glucocorticoid receptor gene (NR3C1), the BRAF oncogene, the deubiquitinase-encoding gene USP48, and TP53 are infrequent. Moreover, patients with familial tumor syndromes, such as multiple endocrine neoplasia, familial isolated pituitary adenoma, and DICER1 rarely develop corticotropinomas. One of the main molecular alterations in USP8-driven tumors is an overactivation of the epidermal growth factor receptor (EGFR) signaling pathway, which induces ACTH production. Hotspot USP8 variants lead to persistent EGFR overexpression, thereby perpetuating the hyper-synthesis of ACTH. More importantly, they condition a characteristic transcriptomic signature that might be useful for the clinical prognosis of patients with CD. Nevertheless, the clinical phenotype associated with USP8 variants is less well defined. Hereby we discuss the current knowledge on the molecular pathogenesis and clinical picture associated with USP8 hotspot variants. We focus on the potential significance of the USP8 mutational status for the design of tailored clinical strategies in CD.

Assuntos

RESUMO

Introducción: desde el punto de vista anatómico, los adenomas hipofisarios (AH) se observan en el 10% de la población. Son en su mayoría pequeños y no funcionantes. La mayoría de los incidentalomas descubiertos en estudios de imágenes con alta resolución pedidos en situaciones clínicas frecuentes, como el traumatismo craneoencefálico, el accidente cerebrovascular y las demencias, corresponden a AH indolentes. Nos preguntamos cuál es la relevancia clínica de los adenomas hipofisarios. Desarrollo: los AH clínicamente relevantes son tumores en su mayoría benignos que conllevan, en diferentes proporciones, aumento en la morbilidad y/o mortalidad de los pacientes por mecanismos relacionados con la hipersecreción hormonal, la insuficiencia hormonal y/o los efectos de masa ocupante. La prevalencia de los AH clínicamente relevantes es mayor de la que se suponía hace 20 años. Afecta aproximadamente a 1/1000 habitantes. Los más prevalentes son los prolactinomas y los adenomas no funcionantes. La acromegalia, la enfermedad de Cushing y los tumores agresivos se traducen en pacientes complejos con mayor morbimortalidad. El diagnóstico temprano y el tratamiento multimodal proveen una razonable mejoría de la sobrevida. El estudio epidemiológico de los AH clínicamente relevantes es importante para la estimación del impacto en los sistemas de salud. Conclusiones: los estudios por imágenes de mejor resolución continuarán señalando incidentalomas hipofisarios. Una evaluación cuidadosa de los pacientes podrá identificar aquellos AH clínicamente relevantes. (AU)

Introduction: from the anatomical point of view, pituitary adenomas (HA) are observed in 10% of the population. They are mostly small and non-functioning. Most incidentalomas discovered in high-resolution imaging studies ordered in frequent clinical situations, such as head trauma, stroke and dementia, correspond to indolent HA. We wonder what is the clinical relevance of pituitary adenomas. Development: clinically relevant HAs are mostly benign tumors that lead, in different degrees, to an increased morbidity and/or mortality in patients by mechanisms related to hormone hypersecretion, hormone insufficiency and/or occupying mass effects. The prevalence of clinically relevant HA is higher from what was assumed 20 years ago. It affects approximately 1/1000 of the population. The most prevalent are prolactinomas and non-functioning adenomas. Acromegaly, Cushing's disease and aggressive tumors make for complex patients with increased morbidity and mortality. Early diagnosis and multimodal treatment provide a reasonable improvement in survival. Epidemiological study of clinically relevant HAs is important for estimating the impact on health systems. Conclusions: Higher-resolution imaging studies will continue to highlight pituitary incidentalomas. Careful evaluation of patients will identify clinically relevant HAs. (AU)

Assuntos

RESUMO

Background: Pituicytoma (PTs) is a rare tumor of the sella and suprasellar region, derived from the pituicytes of the neurohypophysis, having distinct histological characteristics of glial neoplasms. We reported, the clinical data, neuroimaging studies, surgical approaches and pathology in five patients with PTs and also, we reviewed the literature. Methods: Retrospective chart from five consecutive patients with PTs treated at one University Hospital from 2016 to 2021 were reviewed. In addition, we conducted a search in PubMed/Medline databases using the term "Pituicytoma". Data regarding age, gender, pathological findings, and treatment modality applied were extracted. Results: All patients were female, aged 29-63, complaining of headaches, visual loss and field defects, dizziness and normal or abnormal levels of circulating pituitary hormones. Magnetic Resonance Imaging (MRI) showed in all patients a sellar and suprasellar mass, which was removed through an endoscopic transsphenoidal approach. Our third patient had a subtotal resection followed by close observation. Histopathology showed a glial non-infiltrative tumors with spindle cells, and a final diagnosis of pituicytoma was made. After surgery, visual field defects in all patients were normalized, and in two patients normal levels of plasma hormones were restored. After a mean of three years follow-up, the patients were managed post-operatively through close clinical observation and serial MRI. None of the patients had recurrence of the disease. Conclusion: PTs is a rare glial tumor of the sellar and suprasellar region that arises from neurohypophyseal pituicytes. Disease control may be achieved by total excision.

RESUMO

INTRODUCTION: Macroautophagy is a lysosome-mediated degradation process that controls the quality of cytoplasmic components and organelles, with its regulation depending on autophagy-related proteins (Atg) and with Beclin1/Atg6 and microtubule-associated protein light chain 3 (LC3/Atg8) being key players in the mammalian autophagy. As reports on this mechanism in the field of pituitary neuropathology and neuroendocrinology are scarce, our study analyzed the ultrastructural signs of macroautophagy and the expression of Beclin1 and LC3 proteins in human functioning PitNETs and in experimental pituitary tumors. METHODS: A group of humans functioning PitNETs and an experimental lactotroph model in rats of the F344 strain stimulated with estradiol benzoate (BE) were used. Ultrastructural and molecular evidence of the macroautophagic process was evaluated using different techniques. RESULTS: In functioning PitNETs cohort, 60% exhibited evidence of macroautophagy, with a significant difference found for Beclin1 and LC3 between macro- and micro-PitNETs (p < 0.05). In the experimental model, the expression of both Beclin1 and LC3 proteins was immunopositive in normal and tumoral glands when analyzed by immunofluorescence, Western blot, and immunohistochemistry. In the experimental model, protein expression was associated with increased glandular size and weight. CONCLUSIONS: Our study revealed evidence of macroautophagy at the pituitary level and the important role of Beclin1 and LC3 in the progression of functioning PitNETs, implying that this mechanism participate in regulating pituitary cell growth.

Assuntos

Assuntos

RESUMO

Over 20 years ago, Hanahan and Weinberg published a seminal review that addressed the biological processes that underly malignant transformation. This classical review, along with two revisions published in 2011 and 2022, has remain a classic of the oncology literature. Since many of the addressed biological processes may apply to non-malignant tumorigenesis, we evaluated to what extent these hallmarks pertain to the development of pituitary adenomas.Some of the biological processes analyzed in this review include genome instability generated by somatic USP8 and GNAS mutations in Cushing's diseases and acromegaly respectively; non-mutational epigenetic reprograming through changes in methylation; induction of angiogenesis through alterations of VEGF gene expression; promotion of proliferative signals mediated by EGFR; evasion of growth suppression by disrupting cyclin dependent kinase inhibitors; avoidance of immune destruction; and the promotion of inflammation mediated by alteration of gene expression of immune check points. We also elaborate further on the existence of oncogene induced senescence in pituitary tumors. We conclude that a better understanding of these processes can help us dilucidated why pituitary tumors are so resistant to malignant transformation and can potentially contribute to the development of novel anticancer treatments.

Assuntos

RESUMO

Abstract: Cushing's disease (CD) is the most common cause of endogenous hypercortisolemia. The clinical management of this condition is complex and entails multiple therapeutic strategies, treatment of chronic comorbidities, and lifelong surveillance for recurrences and complications. The identification of robust, practical, and reliable markers of disease behavior and prognosis could potentially allow for a tailored and cost-efficient management of each patient, as well as for a reduction of the medical procedure-associated stress. For this purpose, multiple clinical, biochemical, imaging, histopathological, molecular, and genetic features have been evaluated over the years. Only a handful of them, however, have been sufficiently validated for their application in the routine care of patients with CD. This review summarizes the current status of the established and potential biomarkers of CD, bases for their use, proposed and/or established utility, as well as advantages and barriers for their implementation in the clinic. (Rev Invest Clin. 2022;74(5):244-57).

Assuntos

RESUMO

ABSTRACT Cushing's disease (CD) is the most common cause of endogenous hypercortisolemia. The clinical management of this condition is complex and entails multiple therapeutic strategies, treatment of chronic comorbidities, and lifelong surveillance for recurrences and complications. The identification of robust, practical, and reliable markers of disease behavior and prognosis could potentially allow for a tailored and cost-efficient management of each patient, as well as for a reduction of the medical procedure-associated stress. For this purpose, multiple clinical, biochemical, imaging, histopathological, molecular, and genetic features have been evaluated over the years. Only a handful of them, however, have been sufficiently validated for their application in the routine care of patients with CD. This review summarizes the current status of the established and potential biomarkers of CD, bases for their use, proposed and/or established utility, as well as advantages and barriers for their implementation in the clinic.

RESUMO

Abstract Stereotactic radiosurgery with gamma knife (GKS) is a treatment option for persistent or recurrent pituitary adenoma. The aim of our study was to report Argentine experience in GKS, assessing the efficacy and safety in our patients with pituitary adenomas. We performed a retrospective analysis of patients with pituitary adenomas treated with GKS between 2002 and 2017 in a single institution. Patient characteristics, biochemical remission rate (for functioning tumors), tumor control rate and adverse effects with GKS were inves tigated. The study cohort comprised 99 patients with a mean follow-up of 63 months: 51 somatotropinomas, 28 non-functioning adenomas, 15 corticotropinomas, 2 prolactinomas and 3 mixed pituitary tumors. The mean radiation dose was 30.6Gy for corticotropinomas, 29.3Gy for somatotropinomas and 19.6Gy for non-secreting adenomas. Global tumor control rate was 94.2%. Biochemical remission rate was 55.9%, being higher in acromegaly than in Cushing's disease (OR4.7, 95%Ci 2.1-10.4, p<0.0001). The mean time to remission was 29.5 months (range: 6-156). Hypopituitarism occurred in 26% of patients and those with Cushing's disease were more prone to develop new hormone deficiency after GKS (OR 2.93, 95%Ci 1.2-7.2, p = 0.019). This study shows argentine experience with the use of GKS in patients with pituitary adenomas, with similar results to those reported by centers with large radiosurgical experience. We achieved biochemical remission in more than 50% of patients and global tumor control in most of them. Hypopituitarism was the most frequent adverse effect, while others were infrequent.

Resumen La radiocirugía gamma-knife (GKS) constituye una alternativa de tratamiento en adenomas hipofisarios persis tentes o recurrentes. El objetivo de nuestro trabajo fue comunicar la experiencia argentina con GKS, evaluando eficacia y seguridad en nuestros pacientes con adenomas hipofisarios. Realizamos un análisis retrospectivo de pacientes con adenomas hipofisarios tratados con GKS entre 2002 y 2017. Se investigaron: características basales, tasa de remisión bioquímica, tasa de control tumoral y efectos adversos del GKS. Estudiamos 99 pa cientes adultos con un seguimiento medio de 63 meses: 51 somatotropinomas, 28 adenomas no funcionantes, 15 corticotropinomas, 2 prolactinomas y 3 tumores mixtos. La do sis media de radiación fue 30.6 Gy para cortico tropinomas, 29.3 Gy para somatotropinomas y 19.6 Gy para adenomas no secretores. La tasa global de control tumoral fue 94.2%. La tasa de remisión bioquímica fue 55.9%, si endo mayor en acromegalia que en enfermedad de Cushing (OR4.7, 95% Ci 2.1-10.4, p < 0.0001). El tiempo medio hasta la remisión fue 29.5 meses (rango: 6-156). Se produjo hipopituitarismo en el 26% de los pacientes. Aquellos con enfermedad de Cushing fueron más propensos a desarrollar nuevas deficiencias hormonales después del GKS (OR2.93, 95% Ci 1.2-7.2, p = 0.019). Este trabajo muestra la experiencia argentina con GKS en pacientes con adenomas hipofisarios, con resultados similares a los reportados por centros con amplia experiencia radioquirúrgica. Logramos remisión bioquímica en más del 50% de los pacientes y control tumoral global en la mayoría de ellos. El hipopituitarismo fue el efecto adverso más frecuente, mientras que otros fueron infrecuentes.

RESUMO

Stereotactic radiosurgery with gamma knife (GKS) is a treatment option for persistent or recurrent pituitary adenoma. The aim of our study was to report Argentine experience in GKS, assessing the efficacy and safety in our patients with pituitary adenomas. We performed a retrospective analysis of patients with pituitary adenomas treated with GKS between 2002 and 2017 in a single institution. Patient characteristics, biochemical remission rate (for functioning tumors), tumor control rate and adverse effects with GKS were investigated. The study cohort comprised 99 patients with a mean follow-up of 63 months: 51 somatotropinomas, 28 non-functioning adenomas, 15 corticotropinomas, 2 prolactinomas and 3 mixed pituitary tumors. The mean radiation dose was 30.6Gy for corticotropinomas, 29.3Gy for somatotropinomas and 19.6Gy for non-secreting adenomas. Global tumor control rate was 94.2%. Biochemical remission rate was 55.9%, being higher in acromegaly than in Cushing's disease (OR4.7, 95%Ci 2.1-10.4, p <0.0001). The mean time to remission was 29.5 months (range: 6-156). Hypopituitarism occurred in 26% of patients and those with Cushing's disease were more prone to develop new hormone deficiency after GKS (OR 2.93, 95%Ci 1.2-7.2, p = 0.019). This study shows argentine experience with the use of GKS in patients with pituitary adenomas, with similar results to those reported by centers with large radiosurgical experience. We achieved biochemical remission in more than 50% of patients and global tumor control in most of them. Hypopituitarism was the most frequent adverse effect, while others were infrequent.

La radiocirugía gamma-knife (GKS) constituye una alternativa de tratamiento en adenomas hipofisarios persistentes o recurrentes. El objetivo de nuestro trabajo fue comunicar la experiencia argentina con GKS, evaluando eficacia y seguridad en nuestros pacientes con adenomas hipofisarios. Realizamos un análisis retrospectivo de pacientes con adenomas hipofisarios tratados con GKS entre 2002 y 2017. Se investigaron: características basales, tasa de remisión bioquímica, tasa de control tumoral y efectos adversos del GKS. Estudiamos 99 pacientes adultos con un seguimiento medio de 63 meses: 51 somatotropinomas, 28 adenomas no funcionantes, 15 corticotropinomas, 2 prolactinomas y 3 tumores mixtos. La do sis media de radiación fue 30.6 Gy para cortico-tropinomas, 29.3 Gy para somatotropinomas y 19.6 Gy para adenomas no secretores. La tasa global de control tumoral fue 94.2%. La tasa de remisión bioquímica fue 55.9%, si endo mayor en acromegalia que en enfermedad de Cushing (OR4.7, 95% Ci 2.1-10.4, p < 0.0001). El tiempo medio hasta la remisión fue 29.5 meses (rango: 6-156). Se produjo hipopituitarismo en el 26% de los pacientes. Aquellos con enfermedad de Cushing fueron más propensos a desarrollar nuevas deficiencias hormonales después del GKS (OR2.93, 95% Ci 1.2-7.2, p = 0.019). Este trabajo muestra la experiencia argentina con GKS en pacientes con adenomas hipofisarios, con resultados similares a los reportados por centros con amplia experiencia radioquirúrgica. Logramos remisión bioquímica en más del 50% de los pacientes y control tumoral global en la mayoría de ellos. El hipopituitarismo fue el efecto adverso más frecuente, mientras que otros fueron infrecuentes.

Assuntos

RESUMO

Bone diseases are commonly found in the fossil record, especially in mammals of the Pleistocene megafauna, which exhibit signs of overload in the articulations. However, pathologies that affect soft tissues are not usually reported, even due to the nature of fossilization that rarely preserves such materials. In paleoneurological research using CT scan and three-dimensional reconstructions of Pleistocene sloths, an anomaly is discovered in the space that houses the pituitary gland, the sella turcica. The tomographic analysis of a Valgipes bucklandi skull revealed a great enlargement at the sella turcica, at the medial region in the body of the basisphenoid bone. The images delimit an enlarged dorsal-ventral projection, measuring approximately 15 mm height, at the tridimensional reconstructed endocranium. Taphonomic processes, such as the action of necrophagous agents, were discarded due to the shape and conditions of the structure, which also showed signs of bone remodeling. Thus, it is possible to affirm that a paleopathological process altered the size of the pituitary gland of the specimen MCT 3993-M, being probably a pituitary tumor.

Assuntos

RESUMO

To investigate the putative stem cell/tumor stem cell (SC/TSC) niche contribution to hyperplasic/adenomatous pituitary lesions, we analyzed variation in the pituitary stem cell population during the development of experimental pituitary tumors. Pituitary tumors were induced in female F344 rats with estradiol benzoate for 5, 10, 20 and 30 days. Cells positive for GFRa2, Sox2, Sox9, Nestin, CD133 and CD44 were identified in the marginal zone and in the adenoparenchyma in both control and 30D groups, with predominant adenoparenchyma localization of GRFa2 and SOX9 found in tumoral pituitaries. GFRa2, Nestin, CD133 and CD44 were upregulated at the initial stages of tumor growth, whereas Sox9 significantly decreased at 5D, with Sox2 remaining invariable during the hyperplasic/adenomatous development. In addition, isolated pituispheres from normal and tumoral pituitary glands enriched in SC/TSC were characterized. Pituispheres from the 30D glands were positive for the above-mentioned markers and showed a significant increase in the proliferation. In conclusion, our data revealed pituitary SC pool fluctuations during hyperplastic/adenomatous development, with differential localization of the SC/TSC niche in this process. These findings may help to provide a better understanding of these cell populations, which is crucial for achieving advancements in the field of pituitary tumor biology.

Assuntos

RESUMO

Corticotroph tumors (CTs) are pituitary neoplasms arising from the Tpit lineage, which may or not express adrenocorticotrophic hormone (ACTH). Functioning CTs cause Cushing's disease (CD), which has high morbidity and mortality due to hypercortisolemia. "Non-functioning" or silent CTs (SCT) and the Crooke's cell subtypes do not cause CD and may be asymptomatic until manifested by compressive symptoms and are more frequently found as macroadenoma. Both tend toward more aggressive behavior, recurrence, and a higher rate of malignant transformation to pituitary carcinoma. Tumorigenesis involves genetic, epigenetic, and post-transcriptional disruption of cell-cycle regulators, which increase cell proliferation, POMC overexpression, ACTH transcription, and/or hypersecretion. Furthermore, functioning CTs develop resistance to glucocorticoid-mediated negative feedback on ACTH secretion, through increased expression of testicular orphan nuclear receptor 4 (TR4), heat-shock protein 90 (HSP90), and loss-of-function mutation of CDK5 and ABL enzyme substrate 1 (CABLES1) gene. Overt autonomous hypercortisolemia is difficult to control, and multiple diagnostic studies and therapeutic modalities are commonly required. Cell-cycle regulation depends mainly on p27, cyclin E, cyclin-dependent kinases (CDKs), and the retinoblastoma protein (Rb)/E2F1 transcription factor complex. Gain-of-function mutations of ubiquitin-specific protease (USP) 8, USP48, and BRAF genes may subsequently cause overexpression of epithelial growth factor receptor (EGFR), and enhance POMC transcription, cell proliferation, and tumor growth. Epigenetic changes through micro RNAs and decreased DNA deacetylation by histone deacetylase type 2 (HDAC2), may also affect tumor growth. All the former mechanisms may become interesting therapeutic targets for CTs, aside from temozolomide, currently used for aggressive tumors. Potential therapeutic agents are EGFR inhibitors such as gefitinib and lapatinib, the purine analog R-roscovitine by dissociation of CDK2/Cyclin E complex, the HSP90 inhibitor silibinin (novobiocin), to reduce resistance to glucocorticoid-mediated negative feedback, and BRAF inhibitors vemurafenib and dabrafenib in BRAF V600E positive tumors. This review summarizes the molecular mechanisms related to CTs tumorigenesis, their diagnostic approach, and provides an update of the potential novel therapies, from the lab bench to the clinical translation.

Assuntos

RESUMO

PURPOSE: Non-functioning pituitary adenomas (NFPA) are benign tumors, however, some are agressive. We aimed to assess if human telomerase reverse transcriptase (hTERT) is present in NFPA and if it can be used as a marker of aggressiveness and proliferation. METHODS: Consecutive patients operated for NFPA whose fresh frozen tumors were available were included. We analyzed tumor's aggressiveness (based on radiological progression) and proliferation (based on Ki-67), as well as hTERT mRNA by quantitative real-time polymerase chain reaction (RT-qPCR). RESULTS: We included 109 samples from 86 patients followed for a median period of 60 months (5-120 months). Aggressive tumors were present in 66% cases and proliferative tumors in 47.7%. Seven (6.4%) samples expressed hTERT: 3 (42.8%) had aggressive and proliferative tumors, 2 (28.6%) only exhibited aggressiveness and the remaining 2 (28.6%) only proliferation. From the aggressive and proliferative tumors, 14% and 16%, respectively, expressed hTERT. From the non-aggressive and non-proliferative tumors, 9% and 6%, respectively, expressed hTERT. CONCLUSION: hTERT expression is present in a minority of NFPA and does not seem to be related to aggressiveness or proliferation in NFPA.

Assuntos

RESUMO

The 2020 pandemic caused by the novel coronavirus, COVID-19, had its headquarters in China. It causes Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and presents a broad spectrum of clinical manifestations, ranging from entirely asymptomatic through severe acute respiratory failure and death. Presuming a significant quantity of ventilator-dependent patients, several institutions strategically delayed elective surgeries. Particularly procedures performed involving the nasal mucosa, such as a transsphenoidal approach of the pituitary gland, considering the tremendous level of viral shedding. Nevertheless, critical cases demand expeditious resolution. Those situations are severe pituitary apoplexy, declining consciousness level, or risk of acute visual loss. This case presents a successful urgent perioperative management of a 47 year-old male COVID-19 positive patient who presented to the Emergency Department with a left frontal headache that culminated with diplopia, left eye ptosis, and left visual acuity loss after 5 days. Transsphenoidal hypophysectomy was uneventfully performed, and the patient was discharged from the hospital on postoperative day four. It additionally describes in detail the University of Mississippi Medical Center airway management algorithm for patients infected with the novel coronavirus who need emergent surgical attention.

A pandemia de 2020, causada pelo novo coronavírus, COVID-19, teve seu epicentro na China. Causa Síndrome Respiratória Aguda Grave pelo Coronavírus 2 (SARS-CoV-2) e apresenta um amplo espectro de manifestações clínicas, que vão desde nenhum sintoma a insuficiência respiratória aguda grave e óbito. Com a expectativa de um número significativo de pacientes dependentes de ventilador, várias instituições estrategicamente adiaram cirurgias eletivas. Esse é o caso principalmente de procedimentos envolvendo a mucosa nasal, como a via transesfenoidal para a hipófise, devido ao nível imenso de disseminação de material viral. Não obstante, casos críticos requerem resolução acelerada. Essas situações são grave apoplexia hipofisária, diminuição do nível de consciência ou risco de perda visual aguda. O presente caso relata o manejo perioperatório bem sucedido de urgência de paciente do sexo masculino de 47 anos de idade com COVID-19 que chegou ao Pronto Socorro com cefaléia frontal à esquerda que culminou com diplopia, ptose do olho esquerdo e perda de acuidade visual à esquerda após 5 dias. A hipofisectomia transesfenoidal ocorreu sem intercorrências e o paciente recebeu alta do hospital no quarto dia do pós-operatório. Adicionalmente, descrevemos em detalhe o algoritmo de manejo de via aérea da University of Mississippi Medical Center para pacientes infectados pelo novo coronavírus e que necessitam de atenção cirúrgica de emergência.