Treatment Of Pituitary Tumors Research Articles

Autophagy inhibition suppresses hormone production and cell growth in pituitary tumor cells: A potential approach to pituitary tumors

Pituitary tumors (PTs) represent about 10% of all intracranial tumors, and most are benign. However, some PTs exhibit continued growth despite multimodal therapies. Although temozolomide (TMZ), an alkylating chemotherapeutic agent, is a first-line medical treatment for aggressive PTs, some PTs are resistant to TMZ. Existing literature indicated the involvement of autophagy in cell growth in several types of tumors, including PTs, and autophagy inhibitors have anti-tumor effects. In this study, the expression of several autophagy-inducible genes, including Atg3, Beclin1, Map1lc3A, Map1lc3b, Ulk1, Wipi2, and Tfe3 in two PT cell lines, the mouse corticotroph AtT-20 cells and the rat mammosomatotroph GH4 cells were identified. Down regulation of Tfe3, a master switch of basal autophagy, using RNA interference, suppressed cell proliferation in AtT-20 cells, suggesting basal autophagy contributes to the maintenance of cellular functions in PT cells. Expectedly, treatment with bafilomycin A1, an autophagy inhibitor, suppressed cell proliferation, increased the cleavage of PARP1, and reduced ACTH production in AtT-20 cells. Treatment with two additional autophagy inhibitors, chloroquine (CQ) and monensin, demonstrated similar effects on cell proliferation, apoptosis, and ACTH production in AtT-20 cells. Also, treatment with CQ suppressed cell proliferation and growth hormone production in GH4 cells. Moreover, the combination of CQ and TMZ had an additive effect on the inhibition of cell proliferation in AtT-20 and GH4 cells. The additive effect of anti-cancer drugs such as CQ alone or in combination with TMZ may represent a novel therapeutic approach for PTs, in particular tumors with resistance to TMZ.

Clinical study on the selection of endoscopes and microscopes for transsphenoidal surgery of non-aggressive pituitary macroadenoma and microadenoma and the influencing factors of hyposmia after endoscopic transsphenoidal surgery.

Transsphenoidal surgery, including endoscopic and microscopic resection, is the first choice of treatment for pituitary tumors. With the widespread application of neuroendoscopy in recent decades, there has been a trend to replace microscopes. In clinical practice, we have found that in transsphenoidal surgery for non-invasive microadenomas and macroadenomas, microscopy can achieve a higher total resection rate, shorter operation time, lower incidence of postoperative complications, and faster recovery of olfaction. This study aimed to explore the selection of endoscopes and microscopes for non-aggressive transsphenoidal surgery for pituitary adenomas and the factors affecting olfactory recovery. From August 2019 to October 2022, 93 patients with non-aggressive microadenomas and macroadenomas via the transsphenoidal approach were selected from the First Affiliated Hospital of Harbin Medical University and treated with rich experience in pituitary tumor subspecialty microscopy and endoscopic surgery. Different surgical methods were used to divide the patients into microscopic (n = 35) and endoscopic (n = 58) groups. The total tumor removal rate, intraoperative blood loss, operation time and cost, postoperative hospital stay, recovery of visual function, postoperative changes in hormone levels, complication rate, and recovery from complications 3 months after the operation were compared between the two groups. There were no significant differences in the tumor removal rate, postoperative visual acuity, and visual field recovery between the two groups (p > 0.05). There was a significant difference in the recovery rate of olfactory function between the two groups 3 months after the operation (p < 0.05), and there was no significant difference in the incidence of other complications (p > 0.05); Compared with the two groups, the microscope group had shorter operation time, longer postoperative hospital stay, less average operation cost and less blood loss, and the difference was statistically significant (p < 0.05). The position of the nasal septum mucosal flap incision was a risk factor for hyposmia 3 months after the operation. Microsurgery and endoscopic surgery are suitable surgical treatments for nonaggressive microadenomas and macroadenomas. The total tumor removal and postoperative hormone remission rates of the two surgical methods were approximately the same. However, the microsurgery group had a shorter operation time, less intraoperative blood loss, faster olfactory function recovery, and a lower average operation cost. The position of the nasal septal mucosal flap incision was a risk factor for hyposmia at 3 months postoperatively. Hyposmia is less likely to occur when the superior edge of the nasal septal mucosal flap incision is not higher than the lower edge of the ipsilateral superior turbinate.

FRI304 Prolactinomas In A Pituitary Center From Ecuador: Clinical Presentation With High Prevalence Of Giant Adenomas And Delayed Diagnosis

Abstract Disclosure: D.P. Quishpe Lopez: None. G.C. Freire Salazar: None. M.V. Villagomez Estrada: None. R.M. Ruiz Urbaez: None. S.A. Baquero Contreras: None. R.D. Mino Rodriguez: None. J.L. Salazar Vega: None. Background: Prolactinomas are the most common pituitary neuroendocrine tumors (PitNET) and account for about 50% of cases. Most of them respond favorably to pharmacological treatment (cabergoline). Epidemiological data in our country are scarce and more reports are needed. The aim of this study was to analyze the clinical presentation of patients with prolactinomas in a tertiary center. A cross-sectional study was performed (November 2021 - December 2022) analyzing information from clinical records. Results: Seventy-nine patients were included, mean age at diagnosis 29.5 years (SD 12.09, range 11-65) of which the majority were women (63.3%). Due multiple factors the diagnosis was delay with a mean of 45.63 months (range 2-216). As variables related with the clinical manifestations of prolactinomas, overweight/obesity was recorded in 79.6% of the cases. The predominant reasons of attendance in women were galactorrhea 48%, menstrual alteration 22% and headache 20%. In men, in the other hand, were visual alteration 48.3% and headache 31%. The main components of hypopituitarism identified were hypogonadism 46.8% and central hypothyroidism 27.8%. Serum prolactin levels at diagnosis differed between macroprolactinomas and microprolactinomas from 5617 ng/mL (136-47000) to 140.17 ng/mL (68-278) respectively. We identified 27 (34.2%) microadenomas, 39 (49.4%) macroadenomas and 13 (16.5%) giant adenomas. Giant prolactinomas predominated in men (76.9%). There was a linear correlation between tumor size and hyperprolactinemia (Spearman correlation 0.87). Regarding initial treatment: 94.9% received pharmacological treatment. Only 5.1% underwent surgery (100% macroadenomas). Conclusion: Several factors and limitations in the public health system of Ecuador delay the timely diagnosis and treatment of pituitary tumors, affecting the quality of life of these patients. Being a national referral center, we receive a high percentage of macroprolactinomas and giant prolactinomas (65.9%). Within public health, this study is a reference to motivate future research and the development of a national guideline to optimize the management of prolactinomas. Presentation: Friday, June 16, 2023

Endoscopic four-hands technique for pituitary tumours.

Tumours in the pituitary fossa region can be resected by endoscopic transnasal surgery using a four-hands technique. The technique, which is atraumatic, safe and minimally invasive, should be the first-line treatment for pituitary tumours and certain skull-base tumours.

Dopamine agonists for the treatment of pituitary tumours: From ergot extracts to next generation therapies.

Dopamine agonists are a key tool in the therapeutic arsenal of endocrinologists worldwide. They exert their effects by binding to dopamine-2 (D2) receptors expressed by pituitary tumour cells to modulate hormonal secretion and tumour size. They are the established first-line treatment for prolactinomas which express high levels of D2 receptors. Growing data support their use as an adjuvant treatment option for other pituitary tumours including growth hormone, adrenocorticotrophic hormones, thyroid hormone secreting adenomas and nonfunctional pituitary tumours, all of which have been shown to express D2 receptors as well, albeit to varying extents. For those pituitary tumours inadequately treated by dopamine agonist alone, combined agonism of D2 and somatostatin receptors represent a new frontier in clinical development. Here we review the development and role of dopamine agonist for the treatment of prolactinomas, the literature supporting their adjuvant use for the treatment of all other pituitary tumours, and recent progress in the development of the next generation of chimeric compounds that target D2 and other receptor subtypes highly expressed on pituitary tumour cells.

Prognostic Biomarkers in Pituitary Tumours: A Systematic Review.

Pituitary tumours (PTs) are the second most common intracranial tumour. Although the majority show benign behaviour, they may exert aggressive behaviour and can be resistant to treatment. The aim of this review is to report the recently identified biomarkers that might have possible prognostic value. Studies evaluating potentially prognostic biomarkers or a therapeutic target in invasive/recurrent PTs compared with either non-invasive or non-recurrent PTs or normal pituitaries are included in this review. In the 28 included studies, more than 911 PTs were evaluated. A systematic search identified the expression of a number of biomarkers that may be positively correlated with disease recurrence or invasion in PT, grouped according to role: (1) insensitivity to anti-growth signals: minichromosome maintenance protein 7; (2) evasion of the immune system: cyclooxygenase 2, arginase 1, programmed cell death protein 1 (PD-1)/programmed death ligand 2, cluster of differentiation (CD) 80/CD86; (3) sustained angiogenesis: endothelial cell-specific molecule, fibroblast growth factor receptor, matrix metalloproteinase 9, pituitary tumour transforming gene; (4) self-sufficiency in growth signals: epidermal growth factor receptor; and (5) tissue invasion: matrix metalloproteinase 9, fascin protein. Biomarkers with a negative correlation with disease recurrence or invasion include: (1) insensitivity to anti-growth signals: transforming growth factor β1, Smad proteins; (2) sustained angiogenesis: tissue inhibitor of metalloproteinase 1; (3) tissue invasion: Wnt inhibitory factor 1; and (4) miscellaneous: co-expression of glial fibrillary acidic protein and cytokeratin, and oestrogen receptors α36 and α66. PD-1/programmed cell death ligand 1 showed no clear association with invasion or recurrence, while cyclin A, cytotoxic T lymphocyte-associated protein 4, S100 protein, ephrin receptor, galectin-3 , neural cell adhesion molecule, protein tyrosine phosphatase 4A3 and steroidogenic factor 1 had no association with invasion or recurrence of PT. With the aim to develop a more personalized approach to the treatment of PT, and because of the limited number of molecular targets currently studied in the context of recurrent PT and invasion, a better understanding of the most relevant of these biomarkers by well-d esigned interventional studies will lead to a better understanding of the molecular profile of PT. This should also meet the increased need of treatable molecular targets.

The RAPID Consortium: A Platform for Clinical and Translational Pituitary Tumor Research

Abstract Objectives Pituitary tumor treatment is hampered by the relative rarity of the disease, absence of a multicenter collaborative platform, and limited translational–clinical research partnerships. Prior studies offer limited insight into the formation of a multicenter consortium. Design The authors describe the establishment of a multicenter research initiative, Registry of Adenomas of the Pituitary and Related Disorders (RAPID), to encourage quality improvement and research, promote scholarship, and apply innovative solutions in outcomes research. Methods The challenges encountered during the formation of other research registries were reviewed with those lessons applied to the development of RAPID. Setting/Participants RAPID was formed by 11 academic U.S. pituitary centers. Results A Steering Committee, bylaws, data coordination center, and leadership team have been established. Clinical modules with standardized data fields for nonfunctioning adenoma, prolactinoma, acromegaly, Cushing's disease, craniopharyngioma, and Rathke's cleft cyst were created using a Health Insurance Portability and Accountability Act-compliant cloud-based platform. Currently, RAPID has received institutional review board approval at all centers, compiled retrospective data and agreements from most centers, and begun prospective data collection at one site. Existing institutional databases are being mapped to one central repository. Conclusion The RAPID consortium has laid the foundation for a multicenter collaboration to facilitate pituitary tumor and surgical research. We sought to share our experiences so that other groups also contemplating this approach may benefit. Future studies may include outcomes benchmarking, clinically annotated biobank tissue, multicenter outcomes studies, prospective intervention studies, translational research, and health economics studies focused on value-based care questions.

Second brain tumours after pituitary irradiation: lower risk than once thought

Since its first proposal in the treatment of pituitary tumours more than a century ago, indications for cranial radiotherapy have notably evolved. In rare pituitary carcinomas, indication of radiotherapy remains undisputable after surgical treatment in case of remnant tumour or recurrence. Until the availability of effective medical treatment, radiotherapy was the second-line treatment for many secreting pituitary adenomas after surgery. Thanks to the use of cabergoline, which controls prolactin secretion and is able to shrink even giant macroprolactinomas, nowadays, radiotherapy is hardly ever proposed. 1 Chanson P Maiter D Prolactinoma. in: Melmed S The pituitary. 5th ed. Academic Press, London2022: 495-543 Google Scholar In patients with acromegaly, with the availability of somatostatin receptor ligands and growth hormone receptor antagonists, the indication of radiotherapy in patients in whom surgery was unable to achieve cure of the disease, has also clearly decreased over time. 2 Maione L Chanson P National acromegaly registries. Best Pract Res Clin Endocrinol Metab. 2019; 33101264 Crossref PubMed Scopus (37) Google Scholar In patients with non-functioning pituitary adenomas, indications for radiotherapy have also evolved—while it was routinely administered after surgery some decades ago, it is now reserved to patients with a postoperative remnant, with its timing, immediately after, or only in case of remnant regrowth, being a matter of debate. 3 Chanson P Dormoy A Dekkers OM Use of radiotherapy after pituitary surgery for non-functioning pituitary adenomas. Eur J Endocrinol. 2019; 181: 1-13 Crossref PubMed Scopus (15) Google Scholar Indeed, even if the efficacy of radiotherapy is remarkable for achieving local control of pituitary tumours (roughly 90% of cases), 4 Loeffler JS Shih HA Radiation therapy in the management of pituitary adenomas. J Clin Endocrinol Metab. 2011; 96: 1992-2003 Crossref PubMed Scopus (151) Google Scholar the issue of side effects and particularly late toxicities long after radiation exposure has somewhat dampened the enthusiasm for this technique. The main adverse effect of radiotherapy is the occurrence of anterior pituitary hormone deficiency in about 30% of individuals at 5 years and 50% at 10 years after fractionated radiotherapy, respectively. 3 Chanson P Dormoy A Dekkers OM Use of radiotherapy after pituitary surgery for non-functioning pituitary adenomas. Eur J Endocrinol. 2019; 181: 1-13 Crossref PubMed Scopus (15) Google Scholar , 5 Fernandez A Brada M Zabuliene L Karavitaki N Wass JA Radiation-induced hypopituitarism. Endocr Relat Cancer. 2009; 16: 733-772 Crossref PubMed Scopus (68) Google Scholar Whether or not radiotherapy technical refinement (eg, use of fractionated stereotactic radiotherapy or radiosurgery) will decrease this rate remains to be determined. Optic neuropathy, another side effect of radiotherapy, is nowadays quite rare, thanks to the limited radiation dose administered to the optic chiasm, as a result of improvements in radiotherapy techniques. But one of the main concerns with radiotherapy was the potential occurrence of secondary brain tumours, 6 Yamanaka R Abe E Sato T Hayano A Takashima Y Secondary intracranial tumors following radiotherapy for pituitary adenomas: a systematic review. Cancers (Basel). 2017; 9: 103 Crossref Scopus (27) Google Scholar some being devastating (eg, glioblastomas) when radiotherapy had been used in these patients for treating a benign condition. However, in clinical practice, this adverse effect seemed to be much more exceptional than previously reported. Risk of second brain tumour after radiotherapy for pituitary adenoma or craniopharyngioma: a retrospective, multicentre, cohort study of 3679 patients with long-term imaging surveillanceIrradiated adults with pituitary adenoma or craniopharyngioma are at increased risk of second brain tumours, although this risk is considerably lower than previously reported in studies using general population controls with no imaging surveillance. Our data clarify an important clinical question and guide clinicians when counselling patients with pituitary adenoma or craniopharyngioma on the risks and benefits of radiotherapy. Full-Text PDF Open Access

Identification and Verification of SLC27A1, PTBP1 and EIF5A With Significantly Altered Expression in Aggressive Pituitary Adenomas.

BackgroundAggressive pituitary adenoma encircling the internal carotid artery has a poor clinical prognosis because of a high surgical risk and a high recurrence rate. This seriously affects patients’ quality of life and yet there is no effective medical treatment. The European Diagnostic Guidelines have recommended the use of temozolomide (TMZ) for these aggressive pituitary adenomas, but the treatment remission rate has been less than 50%.MethodsIn this study, transcriptome sequencing of pituitary tumour tissues and TMZ-treated pituitary tumour cell lines were employed to explore the significance gene expressions affecting the efficacy of TMZ treatment for pituitary tumours. To clarify the roles of these gene expressions, six adult patients with pituitary adenomas treated in Tiantan Hospital from 2015 to 2020 and a pituitary adenoma cell line (Att20 sensitive to TMZ treatment) were analyzed by mRNA transcriptome sequencing. The differentially expressed genes were assayed by analyzing the sequencing results, and the expression level of these genes was further verified by immunohistochemistry. In addition, Ki67, VEGF, and p53 of the tumour tissues were also verified by immunohistochemistry.ResultsIn tumour tissues, mRNA sequencing showed that PTBP1 and EIF5A were significantly overexpressed in primary pituitary adenomas and SLC27A1 was significantly overexpressed in aggressive pituitary adenomas. Also in the pituitary adenoma cell line (AtT20), SLC27A1 expression levels were suppressed by TMZ treatment. Subsequent immunohistochemistry confirmed the sequencing results.ConclusionHigh expression of SLC27A1 and low expression of EIF5A and PTBP1 may be potential indicators to predict the progression of aggressive pituitary adenomas, and patients with high SLC27A1 subtype may be sensitive to TMZ in clinical treatments.

Octreotide in the treatment of acromegaly – the possibilities of high-dose therapy

Octreotide is a first-generation somatostatin analog that has been used for 40 years for the medical treatment of acromegaly, both after neurosurgical intervention and as first-line treatment. The frequency of biochemical control against the background of extended-acting octreotide varies from 25 to 56% depending on growth hormone and IGF-1 levels at the disease debut, presence of previous surgery, patient gender and age, treatment compliance and the dose of octreotide used. Longterm clinical experience with prolonged-acting octreotide demonstrates that more than half of patients require an increase in dosage to 30 mg or higher. If during treatment with Octreotide in a dose of 30 mg for 3 months there is no normalization of IGF-1 level, but there was a decrease of 50% or more of the initial level, further dose increase to 40 mg is possible, because this increases the effectiveness of treatment without increasing the frequency of side effects. Foreign researchers have shown that high doses of Octreotide (60 mg every 28 days) can improve biochemical control in patients who have not fully responded to therapy with doses of 30–40 mg of extended-acting Octreotide. Further studies are needed to determine the optimal dose of prolonged octreotide in acromegaly therapy, both at the start of treatment and during treatment. Management of patients by a team of specialists involved in the treatment of pituitary tumors will allow faster achievement of biochemical control of acromegaly.

A Retrospective Trail Investigating Temozolomide Neoadjuvant Chemotherapy Combined with Radiotherapy in Low-Grade Pituitary Tumors.

Objective To study and analyze the clinical application of temozolomide (TMZ) combined with radiotherapy in the treatment of low-grade pituitary tumors. Methods A retrospective trail was conducted among 67 patients with low-grade pituitary tumors who were treated in our hospital from March 2018 to June 2020. According to different treatment methods, they were assigned into a combined group (37 cases, temozolomide capsules and radiotherapy) and a control group (30 cases, radiotherapy). The changes of serum prolactin (PRL), insulin-like growth factor-1 (IGF-1), GH levels, thyroid-stimulating hormone (TSH), serum free thyroxine (FT4), and adrenocorticotropic hormone (ACTH) were compared. Results The chi-square test reports a significantly higher total effective rate in the combined group vs. control group (91.89% vs. 70.00%). Significant reductions in serum levels of PRL, IGF-1, and GH were observed in both groups after treatment, whereas the combined group treated with radiotherapy and TMZ resulted in significantly lower levels compared with the control group (p < 0.05). After treatment, TSH decreased, and FT4 and ACTH increased in both groups, and the treatment with radiotherapy and TMZ in the combined group led to a significantly greater amplitude of variation (p < 0.05). Conclusion The combination of temozolomide and radiotherapy might be a promising technique for the treatment of pituitary tumors, thereby meriting promotion.

Clinical Effect of Neuroendoscopic Placed Nose Transsphenoid Sinus Approach in the Treatment of Pituitary Tumor

Clinical Effect of Neuroendoscopic Placed Nose Transsphenoid Sinus Approach in the Treatment of Pituitary Tumor

Pituitary Surgery

Surgery, more specifically transsphenoidal approach, remains the primary treatment chosen for the majority of pituitary tumors (except for prolactinomas where medical treatment is indicated) allowing for pathologic analysis and complete or partial tumor removal. Transcranial approaches, employing craniotomies, are still needed in some patients with giant pituitary adenomas and in many of those harboring craniopharyngiomas. However, the surgical treatment of pituitary tumors is challenging because of their complex anatomical location and their heterogenous histology. Due to the proximity of critical structures, a successful surgical procedure may often not be achievable due to the high risks related to the procedure itself. Therefore, the treatment of pituitary tumors in 2020 commonly requires a multimodal approach, including surgery, radiosurgery, radiation therapy, and medical therapy. Recently, efforts have been made to develop intraoperative imaging, by increasing the diffusion of radiosurgery. Furthermore, the development of Pituitary Tumor Centers of Excellence (PTCOE) is becoming crucial to provide the optimal treatment for a single patient. There is in fact sufficient evidence that the best and optimal outcome in terms of tumor resection and correction of hormonal over secretion as well as the lowest rate of complications are obtained in centers of excellence with sufficiently experienced, specialized surgeons and a high patient load. Technological developments will probably even gain increasing importance in the future.

Gamma Knife Radiosurgery for Pituitary Tumors: A Systematic Review and Meta-Analysis.

Simple SummaryPituitary tumors represent approximately 10–15% of all brain neoplasms. Gamma Knife, the most commonly used stereotactic radiosurgery technique worldwide, plays an important role in the treatment of several pituitary neoplasm. It is currently used in cases of residual or recurrent tumors after surgery or as primary treatment when surgery is contraindicated. Its goals are long-term tumor control, preservation of visual function, and, for secreting pituitary adenomas, endocrine remission. Several retrospective case-series (level of evidence IV) on Gamma Knife for pituitary tumors have been published describing encouraging outcomes; only one systematic review and meta-analysis on non-functioning pituitary adenoma has been recently reported. We provide a systematic review of the literature and meta-analysis from the last two decades on Gamma Knife radiosurgery for several pituitary tumors with the aim of describing and confirming safety and effectiveness of this technique.To describe and evaluate outcomes of Gamma Knife radiosurgery (GK) for the treatment of pituitary tumors over the past twenty years, a systematic review and meta-analysis according to PRISMA statement was performed. Articles counting more than 30 patients were included. A weighted random effects models was used to calculate pooled outcome estimates. From 459 abstract reviews, 52 retrospective studies were included. Among them, 18 reported on non-functioning pituitary adenomas (NFPA), 13 on growth hormone (GH)-secreting adenomas, six on adrenocorticotropic hormone (ACTH)-secreting adenomas, four on prolactin hormone (PRL)-secreting adenomas, and 11 on craniopharyngiomas. Overall tumor control and five-year progression free survival (PFS) estimate after one GK procedure for NFPA was 93% (95% CI 89–97%) and 95% (95% CI 91–99%), respectively. In case of secreting pituitary adenomas, overall remission (cure without need for medication) estimates were 45% (95% CI 35–54%) for GH-secreting adenomas, 64% (95% CI 0.52–0.75%) for ACTH-secreting adenomas and 34% (95% CI: 19–48%) for PRL-secreting adenomas. The pooled analysis for overall tumor control and five-year PFS estimate after GK for craniopharyngioma was 74% (95% CI 67–81%) and 70% (95% CI: 64–76%), respectively. This meta-analysis confirms and quantifies safety and effectiveness of GK for pituitary tumors.

The bromodomain inhibitor JQ1+ reduces calcium-sensing receptor activity in pituitary cell lines.

Corticotrophinomas represent 10% of all surgically removed pituitary adenomas, however, current treatment options are often not effective, and there is a need for improved pharmacological treatments. Recently, JQ1+, a bromodomain inhibitor that promotes gene transcription by binding acetylated histone residues and recruiting transcriptional machinery, has been shown to reduce proliferation in a murine corticotroph cell line, AtT20. RNA-Seq analysis of AtT20 cells following treatment with JQ1+ identified the calcium-sensing receptor (CaSR) gene as significantly downregulated, which was subsequently confirmed using real-time PCR and Western blot analysis. CaSR is a G protein-coupled receptor that plays a central role in calcium homeostasis but can elicit non-calcitropic effects in multiple tissues, including the anterior pituitary where it helps regulate hormone secretion. However, in AtT20 cells, CaSR activates a tumour-specific cAMP pathway that promotes ACTH and PTHrP hypersecretion. We hypothesised that the Casr promoter may harbour binding sites for BET proteins, and using chromatin immunoprecipitation (ChIP)-sequencing demonstrated that the BET protein Brd3 binds to the promoter of the Casr gene. Assessment of CaSR signalling showed that JQ1+ significantly reduced Ca2+e-mediated increases in intracellular calcium (Ca2+i) mobilisation and cAMP signalling. However, the CaSR-negative allosteric modulator, NPS-2143, was unable to reduce AtT20 cell proliferation, indicating that reducing CaSR expression rather than activity is likely required to reduce pituitary cell proliferation. Thus, these studies demonstrate that reducing CaSR expression may be a viable option in the treatment of pituitary tumours. Moreover, current strategies to reduce CaSR activity, rather than protein expression for cancer treatments, may be ineffective.

Drug resistance in pituitary tumours: from cell membrane to intracellular signalling.

The pharmacological treatment of pituitary tumours is based on the use of stable analogues of somatostatin and dopamine. The analogues bind to somatostatin receptor types 2 and 5 (SST2 and SST5) and dopamine receptor type 2 (DRD2), respectively, and generate signal transduction cascades in cancerous pituitary cells that culminate in the inhibition of hormone secretion, cell growth and invasion. Drug resistance occurs in a subset of patients and can involve different steps at different stages, such as following receptor activation by the agonist or during the final biological responses. Although the expression of somatostatin and dopamine receptors in cancer cells is a prerequisite for these drugs to reach a biological effect, their presence does not guarantee the success of the therapy. Successful therapy also requires the proper functioning of the machinery of signal transduction and the finely tuned regulation of receptor desensitization, internalization and intracellular trafficking. The present Review provides an updated overview of the molecular factors underlying the pharmacological resistance of pituitary tumours. The Review discusses the experimental evidence that supports a role for receptors and intracellular proteins in the function of SSTs and DRD2 and their clinical importance.

Use of a Surgical Stepdown Protocol for Cost Reduction After Transsphenoidal Pituitary Adenoma Resection: A Case Series

No established standard of care currently exists for the postoperative management of patients with surgically resected pituitary adenomas. Our objective was to quantify the efficacy of a postoperative stepdown unit protocol for reducing patient cost. In 2018-2020, consecutive patients undergoing transsphenoidal microsurgical resection of sellar lesions were managed postoperatively in the full intensive care unit (ICU) or an ICU-based surgical stepdown unit based on preset criteria. Demographic variables, surgical outcomes, and patient costs were evaluated. Fifty-four patients (27 stepdown, 27 full ICU; no difference in age or sex) were identified. Stepdown patients were also compared with 634 historical control patients. The total hospital length of stay was no different among stepdown, ICU, and historical patients (4.8 ± 1.0 vs. 5.9 ± 2.8 vs. 4.4 ± 4.3 days, respectively, P= 0.1). Overall costs were 12.5% less for stepdown patients (P= 0.01), a difference mainly driven by reduced facility utilization costs of -8.9% (P= 0.02). The morbidity and complication rates were similar in the stepdown and full ICU groups. Extrapolation of findings to historical patients suggested that ∼$225,000 could have been saved from 2011 to2016. These results suggest that use of a postoperative stepdown unit could result in a 12.5% savings for eligible patients undergoing treatment of pituitary tumors by shifting patients to a less acute unit without worsened surgical outcomes. Historical controls indicate that over half of all pituitary patients would be eligible. Further refinement of patient selection for less costly perioperative management may reduce cost burden for the health care system and patients.

COVID-19 Testing in the Era of Modern Neurosurgery: Mitigating Risk in Our Vulnerable Patient Populations

BackgroundThe respiratory illness identified as coronavirus disease 2019 (COVID-19) has resulted in a pandemic illness that has changed the face of healthcare. As the COVID-19 pandemic continues, patients have continued to require neurosurgical interventions, and the endoscopic endonasal approach for surgery has continued to be a mainstay treatment of pituitary tumors and anterior skull base lesions.MethodsWe sought to highlight the current lack of recommendations regarding testing protocols for neurosurgical patients.ResultsWe implemented a novel testing protocol for our patient populations at increased risk and have proposed a model that can be used at other institutions to mitigate the risk of complications associated with some forms of COVID-19 testing.ConclusionPatients with anterior skull base defects may be at risk with current COVID-19 testing protocols, and may benefit from alternative specimen collection strategies.

LncRNA MEG3 inhibits pituitary tumor development by participating in cell proliferation, apoptosis and EMT processes.

Pituitary tumors do not pose a threat to life but can cause visual disturbances and serious clinical syndromes, such as infertility and metabolic syndrome. Therefore, screening of key genes involved in the occurrence and development of pituitary tumors can provide new targets for the treatment of pituitary tumors. The aim of the present study was to investigate the molecular mechanism of long non-coding (lnc.) RNA maternally expressed 3 (MEG3) in cell proliferation, apoptosis and epithelial-mesenchymal transition (EMT) processes of pituitary tumor. Tissue samples were obtained from 34 patients who underwent surgical treatment of pituitary tumors. Pituitary tumor cells (GH3 and MMQ) were transfected with pcDNA3.1(+)-MEG3, short hairpin (sh)MEG3, microRNA (miR)-23-3p inhibitor or their controls using Lipofectamine® 2000. Reverse transcription-quantitative PCR and western blot analyses were used to detect the levels of MEG3, miR-23b-3p and FOXO4, as well as proliferation-, apoptosis- and EMT-associated genes and proteins. Cell Counting Kit-8 and flow cytometry assays were performed to detect proliferation and apoptosis, and Transwell assay was undertaken to assess invasion and migration. Luciferase reporter and RNA pulldown assays were performed to verify the binding between lncRNA MEG3, miR-23b-3p and FOXO4. Pearson's correlation analysis was used to analyze the correlation between expression levels of MEG3, miR-23b-3p and FOXO4. lncRNA MEG3 was expressed at lower levels in pituitary tumor tissues and cells. Overexpression of lncRNA MEG3 inhibited proliferation, invasion and migration and accelerated apoptosis of pituitary tumor cells. lncRNA MEG3 negatively regulated miR-23b-3p expression levels, while miR-23b-3p negatively regulated FOXO4 expression levels. Overexpression of lncRNA MEG3 inhibited the EMT process in pituitary tumor cells. miR-23-3p inhibitor rescued the effect of shMEG3 on proliferation, invasion, migration, apoptosis and the EMT process in pituitary tumor cells. lncRNA MEG3 inhibited pituitary tumor development by participating in cell proliferation, apoptosis and the EMT process, which may present a novel target for pituitary tumor treatment.

Update on pituitary adenomas in the 2017 World Health Organization classification: innovations and perspectives.

The World Health Organization (WHO) classifications of tumors offer invaluable support in the diagnosis of tumors, with every new edition including novel information and diagnostic updates. The new 2017 WHO Classification of Tumors of Endocrine Organs, 4th edition, includes innovations in both terminology and diagnostic guidelines for pituitary adenomas, along with new entities, molecular information, and novel treatment modalities. The recommended reporting system of pituitary adenomas is based on morphology and assessment of the hormonal content by immunohistochemistry. Electron microscopy and immunohistochemistry for Ki-67 and p53 and transcription factors, while presenting additional information, are not recommended for routine diagnosis. Other markers may also yield information of prognostic and predictive significance. In sum, the 2017 WHO classification provides pathologists and clinicians with new and comprehensive information of great use for the diagnosis and treatment of pituitary tumors.