Association between Intracellular Calcium Signaling and Tumor Recurrence in Human Non-Functioning Pituitary Adenomas.

Clinically non-functioning pituitary adenomas (CNFPAs) are the second most frequent sellar tumor among studies on community-dwelling adults. They are characterized by the absence of hormonal hypersecretion syndrome, and patients present with compressive symptoms, such as a headache and visual field defects. Immunohistochemically, most CNFPAs are of gonadotrope differentiation, with only a few of them being truly null cell adenomas. Although these tumors express receptors for one or more hypothalamic releasing hormones, to what extent this has an impact on the biological and clinical behavior of these neoplasms remains to be defined. In this research, we evaluated the basal and hypothalamic secretagogue-stimulated intracellular calcium mobilization in 13 CNFPAs, trying to correlate this response to the phenotypic features of the patients. Our results indicate that the recurrence of a CNFPA correlates positively with cellular responsiveness, as measured by spontaneous intracellular calcium activity and the ability to respond to multiple hypothalamic secretagogues. We conclude that this finding may be a useful tool for predicting the clinicopathologic behavior of CNFPAs, by testing the variation of cellular responsiveness to hypothalamic secretagogues.

Surgical outcomes in patients with acromegaly: Microscopic vs. endoscopic transsphenoidal surgery.

Transsphenoidal resection of growth hormone-secreting pituitary neuroendocrine tumors remains the first-line treatment for acromegaly. This can be performed through microsurgery or endoscopic surgery. For the past decades, endoscopic surgery has become the preferred technique in an increasing number of centers worldwide. However, whether it offers superior clinical outcomes has yet to be determined. In this paper, we performed a narrative review of the literature comparing both techniques in the treatment of acromegaly. We critically assessed available comparative studies from an objective perspective to determine their suitability for defining superiority of either technique. Available evidence displays substantial methodological variations and reports conflicting findings. Although endoscopic surgery provides a wider exposure and enhanced visibility of the surgical field, this does not consistently translate into better clinical outcomes, as most tumors are equally accessible through both techniques. Postoperative outcomes such as remission and complication rates are similar between both techniques. The management of acromegaly should be performed by experienced pituitary neurosurgeons, regardless of the approach. The involvement of a multidisciplinary team in a dedicated pituitary center is critical to ensure optimal outcomes.

Current and Future Perspectives of Microscopic and Endoscopic Transsphenoidal Surgery for Pituitary Adenomas: A Narrative Review.

Transsphenoidal resection remains the standard treatment for most pituitary adenomas. However, the ideal surgical approach to safely access these lesions, either microsurgical or endoscopic, continues to be debated. Since the introduction of endoscopic transsphenoidal surgery, centers around the world have increasingly adopted this technique, experiencing a shift away from the conventional microsurgical approach. Large series reporting the efficacy and safety of endoscopic surgery have fueled a growing interest in comparing clinical outcomes between both approaches. Still, proving superiority of either surgical approach remains an elusive task due to the inherent drawbacks of surgical observational studies, as we are still faced with a growing body of evidence reporting conflicting results. Thus, a comprehensive discussion regarding the reach and limitations of both techniques becomes necessary. In this narrative review, we perform a critical appraisal of the literature and provide an expert opinion on the state-of-the-art in transsphenoidal surgery for pituitary adenomas. The advantages and limitations of each approach are assessed and compared from a technical standpoint, and their reported outcomes evaluated in the framework of this transition phase. Available evidence should be interpreted in light of individual patient characteristics and within the context of each medical center, taking into consideration the known impact that surgical expertise and multidisciplinary management hold on clinical outcomes.

Anatomical Basis of the Zygomatic-Transmandibular Approach: Operative Video.

Tumor growth in infratemporal fossa (ITF) and parapharyngeal space (PPS) is generally slow and generates very few clinical manifestations, so it is not uncommon for tumors to reach large dimensions at the time of diagnosis, making necessary to perform ample approaches. In zygomatic-transmandibular approach (ZTMA), the access of the ITF and PPS is obtained by a combination of a pterional craniotomy plus a zygomatic-mandibular osteotomy. Tumor excision is achieved by its initial dissection from all of the neurovascular structures of the middle fossa by the neurosurgical team and the final resection by the head and neck team from below. In the first part of this video, we present a brief anatomical-surgical description of the ITF and PPS and in the second part, we show case of a trigeminal schwannoma that could be successfully removed through a ZTMA. Using this approach, an ample and safe exposure of the ITF and PPS is achieved, without affecting the chewing or facial nerve function and with excellent cosmetic results, so it can be considered as a reliable surgical option, particularly in cases of giant tumors that affect these regions ( Figs. 1 and 2 ). The link to the video can be found at: https://youtu.be/oxVFhzT8HsQ .

The Genomic Landscape of Corticotroph Tumors: From Silent Adenomas to ACTH-Secreting Carcinomas.

Corticotroph cells give rise to aggressive and rare pituitary neoplasms comprising ACTH-producing adenomas resulting in Cushing disease (CD), clinically silent ACTH adenomas (SCA), Crooke cell adenomas (CCA) and ACTH-producing carcinomas (CA). The molecular pathogenesis of these tumors is still poorly understood. To better understand the genomic landscape of all the lesions of the corticotroph lineage, we sequenced the whole exome of three SCA, one CCA, four ACTH-secreting PA causing CD, one corticotrophinoma occurring in a CD patient who developed Nelson syndrome after adrenalectomy and one patient with an ACTH-producing CA. The ACTH-producing CA was the lesion with the highest number of single nucleotide variants (SNV) in genes such as USP8, TP53, AURKA, EGFR, HSD3B1 and CDKN1A. The USP8 variant was found only in the ACTH-CA and in the corticotrophinoma occurring in a patient with Nelson syndrome. In CCA, SNV in TP53, EGFR, HSD3B1 and CDKN1A SNV were present. HSD3B1 and CDKN1A SNVs were present in all three SCA, whereas in two of these tumors SNV in TP53, AURKA and EGFR were found. None of the analyzed tumors showed SNV in USP48, BRAF, BRG1 or CABLES1. The amplification of 17q12 was found in all tumors, except for the ACTH-producing carcinoma. The four clinically functioning ACTH adenomas and the ACTH-CA shared the amplification of 10q11.22 and showed more copy-number variation (CNV) gains and single-nucleotide variations than the nonfunctioning tumors.

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.

"Qué hay de nuevo""Osseous Remodeling Technique of the Sella Turcica: A New Surgical Option for Primary Empty Sella Syndrome" / "What's new ""Osseous Remodeling Technique of the Sella Turcica: A New Surgical Option for Primary Empty Sella Syndrome"

La silla turca vacía (STV) o como se la denominó más recientemente, aracnoidocele selar, es una entidad clínico-radiológica con una prevalencia que, si bien no se conoce con exactitud, se estima que es entre el 2 al 20%1. Dos tipos de STV han sido descriptas según su etiología: primaria y secundaria. En la primaria, no existe antecedente de cirugía hipofisaria previa y se cree que se produce debido a un diafragma selar deficiente. Por otro lado, cuando se genera luego de la exéresis de un tumor hipofisario se denomina secundaria. Por lo general, la STV primaria es diagnosticada como un hallazgo incidental en resonancia magnética, en donde se evidencia una herniación aracnoidea y de líquido cefalorraquídeo (LCR) a través del diafragma selar, comprimiendo la glándula hipofisiaria contra el piso de la silla turca. Algunos pacientes pueden manifestar síntomas clínicos (síndrome de silla turca vacía), entre ellos, cefalea, alteraciones endocrinológicas, fístula de LCR y alteraciones visuales. La cirugía está indicada en estas dos últimas manifestaciones

Petroclival Meningiomas: A Simple System That Could Help in Selecting the Approach.

BACKGROUND: Petroclival meningiomas (PCM) represent a neurosurgical challenge due to their strategic location close to the brainstem. OBJECTIVE: To assess the applicability of a retrosigmoid approach (RSA) by analyzing the degree of displacement of the middle cerebellar peduncle (MCP) elicited by PCM. METHODS: Patients with PCM were prospectively included and divided into those whose imaging studies showed that the posterior end of the MCP was displaced by the tumor and were eligible for and underwent RSA (group A) and those who were not eligible for RSA and who underwent surgery via a posterior transpetrosal approach (group B). We compared tumor behavior, clinical characteristic of patients and surgical results. RESULTS: Twenty patients with PCM were enrolled and allocated to group A (n = 15) or group B (n = 5). The clinical manifestations were more severe in group B; tumors in this group were larger and gross total removal was achieved in only 1 patient (20%). In comparison, in 12 cases on group A, tumors could be totally removed (80%) and all of these patients could recover their quality of life after surgery. CONCLUSION: To our knowledge, this study is the first to consider displacement of the MCP when establishing a suitable surgical approach for PCM. Our results suggest that the RSA becomes increasingly suitable when peduncle displacement is greater. By using this method, it was also possible to identify two types of tumors: petroclivals (group A) and clivopetrosals (group B), that show some specific clinical and surgical differences.

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.

Evaluación semicuantitativa de gliomas cerebrales en adultos: un enfoque de las características neuropatológicas.

INTRODUCTION: Gliomas are neoplasms with high recurrence and mortality. Due to the difficulty to apply the World Health Organization (2016) classification, developing countries continue to use histological evaluation to diagnose and classify these neoplasms. OBJECTIVE: To develop a semi-quantitative scale to numerically grade gliomas morphological characteristics. METHOD: A cohort of patients with gliomas was assessed and followed for 36 months. Tumor tissue sections were analyzed and graded, including aspects such as cell line, cellularity, nuclear pleomorphism, mitosis, endothelial hyperplasia, hypoxic changes, apoptotic bodies, necrosis, hemorrhage and proliferation index. RESULTS: 58 cases were analyzed. Low-grade gliomas median score was 12 points (9 and 13.5 for percentiles 25 and 75, respectively), whereas for high-grade gliomas it was 17 points (16 and 20.5 for percentiles 25 and 75, respectively) (p < 0.0001). Thirty-six-month survival of patients with low (13/17) and high grade gliomas (6/41) was also significantly different (p < 0.0001). CONCLUSIONS: The semi-quantitative morphological scale allows an objective evaluation of gliomas, with an adequate correlation between the score, tumor grade and survival time.

INTRODUCCIÓN: Los gliomas son neoplasias con alta recurrencia y mortalidad. Por la dificultad para aplicar la clasificación de la Organización Mundial de la Salud (2016), los países en desarrollo siguen utilizando la evaluación histológica para diagnosticarlos y clasificarlos. OBJETIVO: Desarrollar una escala semicuantitativa para calificar numéricamente las características morfológicas de los gliomas. MÉTODO: Cohorte de pacientes con gliomas evaluada y seguida durante 36 meses. Se analizaron y calificaron cortes del tejido tumoral, incluyendo aspectos como estirpe celular, celularidad, pleomorfismo nuclear, mitosis, hiperplasia endotelial, cambios hipóxicos, cuerpos apoptóticos, necrosis, hemorragia e índice de proliferación. RESULTADOS: Se analizaron 58 casos. La mediana de la calificación de los gliomas de bajo grado fue de 12 puntos (percentiles 25 y 75 de 9 y 13.5, respectivamente) y la de los gliomas de alto grado fue de 17 puntos (percentiles 25 y 75 de 16 y 20.5, ­respectivamente) (p < 0.0001). La supervivencia a 36 meses de los pacientes con gliomas de bajo (13/17) y alto grado (6/41) también fue significativamente diferente (p < 0.0001). CONCLUSIONES: La escala morfológica semicuantitativa permite una evaluación objetiva de los gliomas, con una adecuada correlación entre la calificación, el grado del tumor y el tiempo de supervivencia.

Semi-quantitative evaluation of brain gliomas in adults: A focus on neuropathological characteristics

Introduction: Gliomas are neoplasms with high recurrence and mortality. Due to the difficulty to apply the World Health Organization (2016) classification, developing countries continue to use histological evaluation to diagnose and classify these neoplasms. Objective: To develop a semi-quantitative scale to numerically grade gliomas by its morphological characteristics. Method: A cohort of patients with gliomas was assessed and followed for 36 months. Tumor tissue sections were analyzed and graded, including aspects such as cell line, cellularity, nuclear pleomorphism, mitosis, endothelial hyperplasia, hypoxic changes, apoptotic bodies, necrosis, hemorrhage and proliferation index. Results: 58 cases were analyzed. Low-grade gliomas median score was 12 points (9 and 13.5 for percentiles 25 and 75, respectively), whereas for high-grade gliomas it was 17 points (16 and 20.5 for percentiles 25 and 75, respectively) (p < 0.0001). Thirty-six-month survival of patients with low (13/17) and high grade gliomas (6/41) was also significantly different (p < 0.0001). Conclusions: The semi-quantitative morphological scale allows an objective evaluation of gliomas, with an adequate correlation between the score, tumor grade and survival time.

Osseous Remodeling Technique of the Sella Turcica: A New Surgical Option for Primary Empty Sella Syndrome.

BACKGROUND: Empty sella is an anatomic finding that is usually asymptomatic. However, when patients with empty sella finding present with visual deficits, surgical treatment may be necessary. The main goal of surgery is to elevate sellar content through a transsphenoidal approach. The aim of this study was to demonstrate a new technique for precise reconstruction of the sellar floor using a heterologous bone block to restore the anatomic elements of the sella turcica. METHODS: Three patients with primary empty sella who presented with visual field defects were prospectively included. Surgery was performed through a microsurgical transsphenoidal approach and involved elevating the sellar content by using a tricortical heterologous bone graft, the dimensions of which were obtained considering the exact dimensions of each patient's sella turcica. The graft was premodeled outside the surgical bed and carefully introduced into the sella turcica to achieve the required elevation (chiasmapexy). RESULTS: Vision of all 3 patients improved, and the improvement persisted throughout the follow-up period. 2 patients, this improvement was noted immediately after surgery, and in the third patient, this change in vision occurred 1 week later. Long-term imaging studies showed the persistence of the bone graft in the sella turcica and the exact elevation of the sellar content at the end of the follow-up period. There were no complications in the present series. CONCLUSIONS: The technique presented here is simple and reproducible and allows an almost exact and persistent elevation of the sellar content.

Surgical-pharmacological interactions in the treatment of acromegaly.

INTRODUCTION: Acromegaly requires a multimodal treatment approach that includes surgery by an expert pituitary neurosurgeon, pharmacological treatment with one or more of the available drugs and radiation therapy. These treatment alternatives are not mutually exclusive but rather complement each other when properly indicated in the individual patient. In this review, we summarize and analyze the available data concerning the choice of the surgical approach (microscopy vs. endoscopy) and the interactions between medical treatment with somatostatin analogs and pituitary surgery. AREAS COVERED: Technical aspects, complications and outcome of transsphenoidal surgery (TSS); Advantages and disadvantages of the microscopic and endoscopic approaches; Safety and efficacy of somatostatin analogs (SSA); Primary pharmacological therapy versus primary TSS; Benefits of the preoperative treatment with SSA; and the effect of surgical tumor debulking in the therapeutic response to SSA. EXPERT COMMENTARY: Continuing efforts at improving surgical techniques and at generating more efficacious pharmacological therapies for acromegaly are likely to improve the outcome of these patients. However, an integral approach of the patient aimed not only at achieving biochemical criteria of cure but also at treating the individual comorbidities is mandatory to improve the quality of life of these patients and to reduce their mortality rate.

Semi-quantitative evaluation of brain gliomas in adults: A focus on neuropathological characteristics.

INTRODUCTION: Gliomas are neoplasms with high recurrence and mortality. Due to the difficulty to apply the World Health Organization (2016) classification, developing countries continue to use histological evaluation to diagnose and classify these neoplasms. OBJECTIVE: To develop a semi-quantitative scale to numerically grade gliomas by its morphological characteristics. METHOD: A cohort of patients with gliomas was assessed and followed for 36 months. Tumor tissue sections were analyzed and graded, including aspects such as cell line, cellularity, nuclear pleomorphism, mitosis, endothelial hyperplasia, hypoxic changes, apoptotic bodies, necrosis, hemorrhage and proliferation index. RESULTS: 58 cases were analyzed. Low-grade gliomas median score was 12 points (9 and 13.5 for percentiles 25 and 75, respectively), whereas for high-grade gliomas it was 17 points (16 and 20.5 for percentiles 25 and 75, respectively) (p < 0.0001). Thirty-six-month survival of patients with low (13/17) and high grade gliomas (6/41) was also significantly different (p < 0.0001). CONCLUSIONS: The semi-quantitative morphological scale allows an objective evaluation of gliomas, with an adequate correlation between the score, tumor grade and survival time.

Neurosurgical Residency Training in Latin America: Current Status, Challenges, and Future Opportunities.

BACKGROUND: This analysis provides an overview of neurosurgery residency programs in Latin America; it evaluates strengths, weaknesses, and limitations within the Latin American Federation for Societies in Neurosurgery countries. Considering the shared cultural background between these neighboring countries and globalization of neurosurgical education, similarities in training characteristics and equal opportunities are expected. However, program differences are inevitable and should be investigated to promote collaboration and homogenization of training. METHODS: A 39-item survey was distributed to 970 neurosurgeons and residents in Latin America to assess aspects including working conditions, teaching, research, training, educational opportunities, and socioeconomics. RESULTS: In total, 276 neurosurgeons (28%) from 16 countries completed the survey. The average participant's age was 37 ± 7 years, and the average duration of residency programs was 5 ± 1 years. Trainees participated in around 5-10 cases during the typical 80-100 work hour week. Only 5% of survey respondents had a day off after a night shift, and 60% worked at least 3 night shifts per week. Only 34% had a mentorship program, Morbidity and mortality conferences were reported by 57% and research activities were compulsory in 45%. Satisfaction with evaluation methods was reported in 29%, although 96% reported satisfaction with their training programs overall. CONCLUSIONS: This study is the first of its kind to review neurosurgical training in Latin America's. Suggested areas of improvement include regulation of working hours, implementation of mentorship programs and standardized examinations, protected research time, increased support for conferences, and more opportunities for exchange rotations that will potentially bolster collaboration between programs.

Clinical characteristics and treatment outcome of 485 patients with nonfunctioning pituitary macroadenomas.

Background. Nonfunctioning pituitary adenomas (NFPAs) are the most common benign lesions of the pituitary gland. Objective. To describe our experience with the management of NFPA. Study Design and Methods. Retrospective evaluation of NFPA patients managed between 2008 and 2013. We analyzed data regarding clinical presentation, imaging diagnosis, hormonal status, surgical, radiotherapeutic, and pharmacological treatment, and outcome. Results. 485 patients (54% men, mean age 53 ± 14 years) were followed for a median of 6.5 years. Visual field abnormalities and headaches were the presenting complaints in 87% and 66%, respectively. The diagnosis of NFPA was made incidentally in 6.2%, and 8% presented with clinical evidence of apoplexy. All patients harbored macroadenomas, with a median volume of 10306 mm(3); 57.9% had supra- or parasellar invasion and 19.6% had tumors larger than 4 cm. Central hypothyroidism, hypogonadism, and hypocortisolism were present in 47.2%, 35.9%, and 27.4%, respectively. Surgical resection was performed at least once in 85.7%. Tumor persistence was documented in 27% and was related to the size and invasiveness of the lesion. In selected cases, radiotherapy proved to be effective in controlling or preventing tumor growth. Conclusions. The diagnosis and treatment of NFPA are complex and require a multidisciplinary approach.