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Aberrant expression of cyclin-dependent kinase 5 (Cdk5) has been reported in pituitary adenomas. However, the role of Cdk5 in the tumorigenesis remains unclear. We show that prenatal p25-activated Cdk5 phosphorylates minichromosome maintenance protein 2 (Mcm2), enhancing minichromosome maintenance (MCM) family proteins and driving intermediate lobe-located melanotrope-originated pituitary tumorigenesis. In a mouse model with CaMKII promoter-driven transgenic induction of p25, we observed intermediate lobe-originated pituitary adenoma producing non-functional proopiomelanocortin (POMC)-derived peptides under persistent p25 overexpression. Single-cell RNA sequencing revealed Mcm2 may play an important role during tumor progression. Subsequently, Mcm2 was identified as a potential phosphorylated substrate of Cdk5, mediating the tumorous proliferation of melanotrope cells. Silencing Cdk5 or Mcm2 suppressed cell proliferation and colony formation in the 293T cell lines. Therefore, our findings provide a new mouse model of intermediate lobe-originated pituitary adenoma induced by p25/Cdk5 and unveil a previously unappreciated role of Cdk5 and Mcm2 in pituitary adenoma tumorigenesis., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Objective: Understanding the differences of suprasellar papillary and adamantinomatous craniopharyngiomas (PCPs/ACPs) is pivotal for target therapy, surgical strategy or postoperative management. Here, the clinical features, surgical nuances and postoperative hypothalamic outcomes of PCPs were systematically recapitulated., Methods: 24 PCPs and 52 ACPs underwent initial surgery were retrospectively reviewed. Clinical data, quantified third ventricle (3rd V) occupation and optic chiasm distortion were compared, as well as intra-operative findings, operating notes and prognosis. Moreover, analysis of tumor/3rd V relationship and hypothalamic outcomes were also performed., Results: Tumors were more likely to occupies the 3rd V cavity in PCPs. Chiasm distortion of "compressed forward" was the most common pattern (45.8 %) in PCPs, whereas "stretched forward" pattern accounted the highest (42.5 %) in ACPs. Besides, round-shaped with less calcification, duct-like recess, solid consistency, rare subdiaphragmatic invasion, visible lower stalk and improved postoperative visual outcome were more frequently observed in PCPs. The basal membranes of the tumor epithelium and the reactive gliosis were separated by a layer of collagen fibers in most PCPs, which differs from ACPs in the morphological examination of tumor/3rd V floor interface. In daytime sleepiness and memory difficulty, the PCPs showed significantly better outcomes than the ACPs groups, and PCPs suffered less postoperative weight gain (p < 0.05) than ACPs among adult-onset cases., Conclusion: PCPs are different from ACPs regards the clinical features, operative techniques and outcomes. If necessary, PCPs are suggested more amenable to total removal since its less invasiveness to the 3rd V floor and better hypothalamic outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Papillary craniopharyngiomas harbor the BRAF V600E mutation, which paves the way for using BRAF inhibitor molecules to treat tumors refractory to standard therapies. Single case reports confirmed the efficacy of targeted therapy. However, most reports were limited by the short follow-up. We describe the long-term course of a patient treated with dual-agent BRAF and MEK inhibitors and review the available literature., Case Report: A 75-year-old male patient had recurrence of a papillary craniopharyngioma after transsphenoidal surgery and Gamma Knife radiosurgery. Review of the pathologic specimen confirmed the presence of the BRAF V600E mutation. Because of the few therapeutic options, we decided to initiate BRAF/MEK inhibitor combined therapy for six months. Rapid reduction of the tumor occurred, but three months after quitting combined medical therapy the tumor recurred. BRAF/MEK inhibitor therapy was resumed and the tumor again showed a marked reduction. The second course was maintained for 20 months and the tumor showed another recurrence within three months, which, again, responded to a third course of targeted therapy., Conclusions: Our study confirms the excellent response of papillary craniopharyngioma to combined BRAF and MEK inhibitors. However, rapid tumor recurrence is the rule when medical therapy is stopped. Resistance to a second and third course of targeted therapy did not occur, suggesting that tumor mutations affecting the response to drugs seems an uncommon event in papillary craniopharyngioma. The exact role of targeted therapy in the treatment algorithm of papillary craniopharyngiomas has still to be refined., (© 2024. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

The existence, composition, and continuity of the medial wall of the cavernous sinus (MWCS) have been extensively studied and debated. However, the precise nature of this membrane remains unknown. Understanding the anatomical characteristics of the MWCS is crucial, notably in relation to pituitary adenomas, which often invade the cavernous sinus. Indeed, surgical treatment of those tumors is frequently incomplete because of such invasion. The anatomical and molecular basis of the peculiar and often lateralized tropism of adenomatous cells to the cavernous sinus is not yet understood and it has been suggested repeatedly that the MWCS is physiologically frail. During the past three decades, there have been several conflicting accounts of the existence, composition, and continuity of this medial wall, but methodological differences and varying definitions could have contributed to the current lack of consensus regarding it. The aim of this systematic review was to summarize previously published data concerning the existence, anatomy, composition, and continuity of the MWCS., (© 2024 American Association of Clinical Anatomists and British Association of Clinical Anatomists.)

Objective: Rathke's cleft cysts (RCCs) exhibit variable growth patterns, thus posing a challenge in predicting progression. While some RCCs may not cause symptoms, others can insidiously cause pituitary dysfunction, which is often irreversible, even following surgery. Hence, it is crucial to identify asymptomatic RCCs that grow rapidly and pose a higher risk of causing endocrinologic dysfunction. This enables timely surgical intervention to prevent permanent damage. Our study examines the growth rate of RCCs, identifies factors that accelerate growth, and discusses the clinical implications of these findings., Methods: A retrospective analysis of a prospectively maintained electronic database revealed 45 patients aged 18-80 years who underwent endoscopic endonasal surgery (EEA) for RCCs between 2010 and 2022 at our center. Of these, 20 required early operative intervention. The remaining 25 patients were followed closely clinically and radiologically before requiring surgery (initial conservative management group). We conducted an analysis of the factors predicting growth over time in this group. Using a regression model, we constructed a risk score system to predict RCC growth over time., Results: Patients in the initial conservative group had smaller cysts and were generally older than those in the early surgery group. Patients with preoperative pituitary dysfunction showed a higher median growth of 1.0 mm in the longest diameter compared to those with normal pituitary function, with an increase of 0.5 mm. A sum of annual cyst growth of all (z, y, x) diameters, at a rate of 3 mm or greater, was associated with a clinically significant increase in the risk of pituitary dysfunction, exceeding 50%.The most significant factors predicting rapid growth in RCCs were smoking status, age, and T1-weighted magnetic resonance imaging (MRI) intensity of cysts. Smoking was the most critical risk factor for rapid cyst growth (p =  < .001). Our risk score system accurately predicted RCC growth with a 74% accuracy rate, 73% sensitivity, and 75% specificity., Conclusion: Our analysis showed a strong link between active smoking and the rapid growth of RCC. This novel finding has significant preventive implications but needs validation by a large population database. Surgical intervention for RCC currently is often reserved for symptomatic cases. However, utilizing our risk-based scoring system to predict rapidly growing cysts may indicate early surgery in minimally symptomatic patients, thereby potentially preserving pituitary function., (© 2024. The Author(s).)

Purpose: Growth hormone (GH)-secreting pituitary neuroendocrine tumors (PitNETs) are the most common cause of acromegaly. The endoscopic endonasal transsphenoidal approach (EEA) is commonly employed to remove them. Although morphological differences in the nasal cavity exist between acromegaly patients and those with other types of PitNET, few quantitative studies have been performed. This study aimed to evaluate the anatomical features of the nasal cavity and paranasal sinuses in patients with acromegaly., Methods: Preoperative computed tomography images of the nasal cavity and paranasal sinuses were compared between 20 patients with a GH-secreting PitNET (acromegaly group) and 22 with a non-functioning PitNET (control group). In the acromegaly group, the relationships between preoperative GH and/or insulin-like growth factor 1 (IGF-1) levels and anatomical characteristics were assessed., Results: In the acromegaly group, the distance between the nostril and dorsum sellae was significantly longer and the distance between the parasellar internal carotid arteries was significantly shorter (p = 0.0022 and 0.0092, respectively). Pneumatization volume in the nasal cavity did not differ between the groups. Nasal mucosa and bony hypertrophy were observed in the acromegaly group. Preoperative GH level was correlated with the width of the piriform aperture (p = 0.0171)., Conclusion: The nasal and paranasal changes associated with acromegaly can make EEA challenging to perform. Widening the surgical corridor anterior to the sphenoid sinus is important in these patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Papillary craniopharyngioma (PCP) and adamantinomatous craniopharyngioma (ACP) are distinct, slow-growing tumors of the suprasellar region. Their location, composition, and biology have historically evaded successful surgical radiation and medical therapy. Meanwhile compromise of critical structures either by tumor or treatments increase morbidity, impacting patient and carer quality of life. There has been a paradigm shift in the management of PCP, stemming from the discovery of BRAFV600E mutation in its tumorigenesis. Such a treatment breakthrough may soon be the case for ACP, changing the landscape of craniopharyngioma management. We use a case of ACP partially responding to ERK inhibitor therapy to demonstrate chronicity of disease progression and discuss modern management strategies highlighting the importance of access to tumor agnostic clinical trials, and future directions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Context: CHEK2 is a cell cycle checkpoint regulator gene with a long-established role as a clinically relevant, moderate risk breast cancer predisposition gene, with greater risk ascribed to truncating variants than missense variants., Objective: To assess the rate and pathogenicity of CHEK2 variants amongst individuals with pituitary adenomas (PAs)., Methods: We assessed 165 individuals with PAs for CHEK2 variants. The study population comprised a primary cohort of 29 individuals who underwent germline and tumor whole-exome sequencing, and a second, independent cohort of 136 individuals who had a targeted next-generation sequencing panel performed on both germline and tumor DNA (n = 52) or germline DNA alone (n = 84)., Results: We identified rare, coding, nonsynonymous germline CHEK2 variants amongst 3 of 29 (10.3%) patients in our primary cohort, and in 5 of 165 (3.0%) patients overall, with affected patients having a range of PA types (prolactinoma, thyrotropinoma, somatotropinoma, and nonfunctioning PA). No somatic variants were identified. Two variants were definitive null variants (c.1100delC, c.444 + 1G > A), classified as pathogenic. Two variants were missense variants (p.Asn186His, p.Thr476Met), classified as likely pathogenic. Even when considering the null variants only, the rate of CHEK2 variants was higher in our cohort compared to national control data (1.8% vs 0.5%; P = .049)., Conclusion: This is the first study to suggest a role for the breast cancer predisposition gene, CHEK2, in pituitary tumorigenesis, with pathogenic/likely pathogenic variants found in 3% of patients with PAs. As PAs are relatively common and typically lack classic autosomal dominant family histories, risk alleles-such as these variants found in CHEK2-might be a significant contributor to PA risk in the general population., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: Pituitary adenomas (PAs) are benign tumors with high prevalence and, occasionally, aggressive course. The tumorigenesis of these lesions is not completely understood at the molecular level. BAK1 and BAX proteins play fundamental roles in apoptosis and seem to interact with VDAC proteins, whose expressions have been markedly altered in cancer, impacting their prognosis., Objective: to evaluate the gene expression of VDAC1, VDAC2, BAK1 and BAX and their association with clinical and imaging characteristics in PA., Methods: Clinical-epidemiological data were collected from 117 tumor samples from patients affected by PA. Invasiveness was assessed by the Knosp scale. Gene expression was examined by real-time PCR. Relative expression analysis was performed by 2^(-DDCt) method., Results: The sample was mainly composed of women (69/117 - 57.2%). Tumor subtypes observed were Non-Functioning (NF) (73/117 - 62.4%), Acromegaly (24/117 - 20.5%) and Cushing's Disease (CD) (20/117 - 17.1%). Compared to normal tissue, there was a significant reduction in VDAC1 expression in the Acromegaly (p=0.029) and NF (p=0.002) groups. BAX expression was lower in all groups (p <0.001; p=0.007; P =0.005). No difference was found in VDAC2 and BAK1 expression, compared to normal pituitary. Overexpression of VDAC2 occurred in PAs with post-surgical regrowth (p=0.042). A strongly negative correlation was observed in BAX and BAK1 expression in CD., Conclusion: The results indicated that downregulations of VDAC1 and BAX may be related to resistance to apoptosis. In contrast, overexpression of VDAC2 in regrowing PAs suggests an antiapoptotic role for this gene. In summary, the genes evaluated might be involved in the biopathology of PAs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Facundo, Magalhães, Nascimento, Azulay, Santos, Freitas, Nascimento, Rodrigues, Santos, Beckman, Abreu, Silva, Carneiro, Oliveira Neto, Gil da Costa, Corcoy, Mato and Faria.)

Acromegaly due to ectopic secretion of growth hormone-releasing hormone (GHRH) is a rare disorder. The signs and symptoms of ectopic acromegaly are indistinguishable from acromegaly due to a somatotroph adenoma. A 35-year-old female presented with secondary amenorrhea for 10 years, intermittent headache, and reduced vision in both eyes for 4 years, which worsened over 4 months before presentation. Additionally, she was diagnosed with uncontrolled diabetes mellitus. On examination, she had coarse facial features, a fleshy nose, and acral enlargement. She had diminished visual acuity (left>right) and bitemporal hemianopia on perimetry. Biochemical investigations revealed elevated IGF-1 [588 ng/ml, reference range (RR) 100-242], markedly elevated basal growth hormone (>80 ng/ml; RR, 0.12-9.88), and hyperprolactinemia in the tumoral range (832 ng/ml; RR, 5-25). MRI sella demonstrated a 22×30×34mm sellar-suprasellar mass with T2 hypointensity. Chest imaging revealed a 75×87×106mm left lung mass, which was found to be a well-differentiated neuroendocrine tumor (NET) on biopsy. Plasma GHRH levels were elevated [38,088 ng/l; RR, <250-300], and a diagnosis of ectopic acromegaly secondary to lung neuroendocrine tumor was considered. During workup, the patient developed in-hospital pituitary apoplexy, which improved with medical management. After a left pneumonectomy, her clinical features of acromegaly improved, her diabetes underwent remission, and there was a marked reduction in plasma GHRH and pituitary size. Histopathology was suggestive of a neuroendocrine tumor, with immunohistochemistry positive for GHRH and negative for prolactin. Her final diagnosis was ectopic acromegaly due to GHRH secreting a lung NET with pituitary somatotroph and lactotroph pituitary hyperplasia and apoplexy in the hyperplastic pituitary., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gupta, Kasaliwal, Das, Sharma, Kaur, Vasiljevic, Raverot, Korbonits and Dutta.)

Pituitary adenomas that extend to the ventricular system are extremely rare. We present a 5-year natural history of a giant null cell pituitary adenoma with invasion into the cavernous sinus extending to the third ventricle. MRI series that were available could be useful for neurosurgeons, ophthalmologists, and endocrinologists as well as radiologists. Patients with the diagnosis of pituitary adenoma that are certain according to the radiological and clinical examination should be consulted by a neurosurgeon experienced in endoscopic endonasal surgery, a neuroendocrinologist, and an ophthalmologist. The surgery postponement in such cases results in disability and quality of life worsening. At that time, the surgery of giant pituitary adenomas demands high skills, and the risk of postoperative complications is high. The proper treatment modality including earlier surgery seems to be favorable for patient outcome.

Introduction: Historically, Multiple Endocrine Neoplasia type 1 (MEN1)-related pituitary adenomas (PAs) were considered more aggressive and treatment-resistant than sporadic PAs. However, recent studies suggest similarities in their behavior. This study aimed to evaluate the long-term outcomes of MEN1 PAs and identify predictive factors., Methods: Nationwide multicenter retrospective cohort study of MEN1-related PAs with a minimum 1-year follow-up, collecting patient demographics, germline MEN1 pathogenic variants (PV), PA size, secretory profile, radiological characteristics, treatments, and outcomes., Results: We analyzed 84 PAs, 69%in females and 31% in males (P<0.001), diagnosed at a mean age of 35.2±14.9 years, mostly through screening (60.7%). Median follow-up was 9 years (IQR:4-16). Prolactin-secreting PAs (PRLomas) (53.5%) and microadenomas (65.5%) were most common. Dopamine agonist treatment was first line for 16 macroPRLomas and 25 microPRLomas, 60.9% of them achieved PRL normalization. There was no significant association observed with tumor size, sex, treatment duration or MEN1 PV. The risk of progression from micro-PA to invasive macro-PA was 7.2% (4/55), after 8 years (IQR:4-13), all of them were microPRLomas. Kaplan-Meier estimation curve showed significantly higher progression probability in microPRLomas than in other microadenomas subtypes (P=0.017) or microNFPAs (P=0.032). No differences were found between sex, age, or germline MEN1 PV., Conclusion: MEN1-related micro-PAs have a low risk of progressing to invasive macro-PAs, regardless of sex, age at diagnosis, or MEN1 germline PV. The risk is higher for microPRLomas over the long term. Therefore, long-term surveillance with reduced frequency, rather than intensive short-term monitoring, may be appropriate for patients with MEN1-related PAs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Valdés, Romero, Diego, Calatayud, Lamas, Araujo-Castro, Álvarez-Escolá, Díaz, Alcázar, Sastre, Martínez, Oriola, Paja, Sánchez-Sobrino, Salinas, Recio-Córdova, Navarro, Chiara, Castaño and Casterás.)

Background: Pituitary adenomas (PAs) are the second most common intracranial tumor. While current diagnostic practices rely primarily on histological testing, they often fail to capture the molecular complexities of pituitary adenomas, underscoring the need for a molecular-based classification to refine therapeutic strategies and prognostic assessments. This study aims to provide a molecularly unbiased classification of pituitary adenomas and explore their unique gene expression patterns and clinical features., Methods: We performed unsupervised hierarchical clustering of the gene expression profiles of 117 PA samples to identify three distinct molecular subtypes. Subsequently, we analyzed the compiled transcriptomic profiles of each individual subtype for pathway enrichment. We also validated the new classification with a validation set containing 158 PAs and 24 pituitary adenoma stem cells (PASCs)., Results: Consensus clustering of transcriptomic data from 117 pituitary adenoma (PA) samples identified three distinct molecular subtypes, each showing unique gene expression patterns and associated biological processes: Group I is enriched in signaling pathways, such as the cAMP signaling pathway and the calcium signaling pathway. Group II is primarily related to metabolic processes, including nitrogen metabolism and arginine biosynthesis in cancer. Group III predominantly shows enrichment in immune responses and potential malignant transformation of the disease, especially through cancer-related pathways such as the JAK-STAT signaling pathway and the PI3K-Akt signaling pathway. The immune profiling revealed distinct patterns for each subtype: Group I had higher dendritic cells and fewer CD8+ T cells, Group II had more monocytes and macrophages, and Group III had elevated levels of T cells. Additionally, there were differences in clinical characteristics and prognosis among the subtypes, with Group III having a worse prognosis, despite the smaller tumor size compared to other groups. Notably, differences in PASCs correlated with the molecular subtypes, with Group III stem cells being enriched in tumorigenesis pathways, PI3K-Akt signaling pathway and Ras signaling pathway., Conclusion: Our study introduces a novel molecular classification for pituitary adenomas, independent of traditional histological methods. Each subtype features distinct genetic, molecular, and immunological profiles. We have isolated pituitary adenoma stem-like cells (PASCs), pairing them with tumor tissues for detailed transcriptomic analysis. These PASCs exhibit diverse molecular traits consistent with the new classification., (© 2024. The Author(s).)

Pituitary adenomas (PAs) are an array of tumors originating from the pituitary gland. PAs are sorted as functional or nonfunctional according to their hormonal activity and classified according to size into microadenomas and macroadenomas. Still, the cellular events that trigger the transformations in pituitary neoplasms are not fully understood, and the current classification methods do not precisely predict clinical behavior. A rising number of researches have emphasized the role of miRNAs, that drawn more attention as oncogenic molecules or tumor suppressors. The etiopathological mechanisms of PAs include multiple molecular cascades that are influenced by different miRNAs. miRNAs control the cell cycle control, pro- or antiapoptotic processes, and tumor invasion and metastasis. miRNAs offer a novel perspective on tumor features and behaviors and might be valuable in prognostication and therapeutic plans. In pituitary adenomas, miRNAs showed a specific expression pattern depending on their size, cell origin, remission, and treatments. Screening miRNA expression patterns is promising to monitor and evaluate recurrence, as well as to investigate the efficacy of radiation and chemotherapy for PAs exhibiting aggressive behavior. Thus, the current review investigated the interplay of the miRNAs' pivotal role in offering new opportunities to translate these innovative epigenetic tools into healthcare applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Pituitary apoplexy (PA) is a rare clinical syndrome due to acute/subacute pituitary hemorrhage and/or infarction; data on PA in functioning pituitary adenoma (FPA) is scarce., Methods: A retrospective record-review of details of PA in non-functioning (NFPA) and FPA managed at tertiary endocrine center., Results: 93 patients [56 males; 33.3% FPA: 5 acromegaly, 14 prolactinoma, and 12 Cushing's Disease (CD)] diagnosed with PA were included. Median age was 40 years, with younger age of presentation in FPA. Type A (acute) [49.5%] and headache (78.5%) were the commonest presentations, with PA being the initial manifestation in 98.4% of NFPA. Median (range) Pituitary Apoplexy Score (PAS) was 2 (0-8). Median tumor diameter was 2.5 cm, with larger tumors in FPA (3.2 cm vs. 2.3 cm). 29 (46.7%) NFPA-PA and 14 (45.2%) FPA-PA patients [71% prolactinoma, 33% in CD, and none in acromegaly] were conservatively managed. In the NFPA cohort, those managed surgically had significantly higher PAS (4 vs. 1) and larger tumor size (2.6 vs. 1.8 cm); however, both arms had comparable recovery of neuro-visual, radiological, and hormonal outcomes. In FPA cohort, CD and acromegaly required definitive treatment, whereas prolactinomas were effectively managed (clinical and biochemical recovery) with oral cabergoline and glucocorticoids. Matching PAS cohorts (to overcome allocation bias for management approach) in macroadenomas (excluding prolactinoma) showed comparable neuro-deficit and hormonal recovery between surgical and conservative approaches., Conclusion: PA in FPA has distinct features and management issues. Carefully selected patients (PAS guided) in NFPA with PA for conservative management have comparable outcomes to surgery., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: This study investigates the rare occurrence of tumor-to-tumor metastasis in Pituitary Neuroendocrine Tumors (PitNETs), also known as pituitary adenomas, aiming to enhance understanding of its diagnostic and therapeutic challenges. We report two cases from our institution of tumor-to-tumor metastasis involving PitNETs, followed by a systematic literature review., Methods: We conducted a comprehensive literature review using PubMed and Google Scholar databases. This review provides insights into patient demographics, clinical presentations, primary tumor origin, management approaches and outcomes., Results: We identified 38 documented cases of tumor-to-tumor metastasis involving the pituitary gland in the literature. This revealed a diverse range of primary tumor origins, with lung, breast, and renal carcinomas being the most prevalent. Clinical presentations varied, with visual disturbances emerging as the most frequently reported symptom. Surgical interventions predominantly resulted in subtotal resection. Kaplan-Meier survival analysis demonstrated that endoscopic endonasal approaches (EEA) are associated with longer median survival times compared to other surgical methods., Conclusion: Tumor-to-tumor metastasis to PitNETs must be considered in differential diagnoses of sellar masses. Prompt and accurate diagnosis, coupled with a multidisciplinary treatment strategy, is essential. Our study contributes to the scarce literature on such metastases, providing a foundation for further understanding of this complex pathological entity., (© 2024. The Author(s).)

Introduction: Silent corticotroph tumors (siACTH) represent a rare entity of pituitary tumors (PT), usually more aggressive than other PT. Few predictor factors of recurrence in the post-operative period have been proposed until now. This study aimed (1) to evaluate the clinical outcome of siACTH after surgery according to a five-tiered clinicopathological classification (2) to compare siACTH characteristics to ACTH-secreting macroadenomas (macroCD), and silent gonadotropinomas (siLH/FSH)., Patients and Methods: Between 2008 and 2022, 29 siACTH out of 865 PT cases operated in one tertiary center were included. Clinical, paraclinical, histological, and surgical data were collected and compared to 25 macroCD and 143 siLH/FSH cases, respectively. The tumor grading was established according to both invasion (no = 1; yes = 2) and proliferation (no = a; yes = b). Progression-free survival was estimated using Kaplan-Meier method and log-rank test., Results: We identified 15 (51.7%) grade 1a, 11 (37.9%) grade 2a and 3 (10.3%) grade 2b siACTH with a trend for a 7-fold-time higher risk of progression/recurrence in grade 2b as compared to 1a (p = 0.06). The repartition of tumor grades was similar between the three subgroups, however a 5.7-fold-higher risk of progression was observed in grade 1a siACTH than in grade 1a siLH/FSH (p = 0.02). Compared to siLH/FSH, higher ACTH levels may help to preoperatively identify siACTH., Conclusion: The five-tiered clinicopathological classification contribute to predict the risk of recurrence of operated siACTH tumors. Noteworthy, non-invasive and non-proliferative siACTH exhibit a less favorable outcomes than their siLH/FSH counterparts, which should prompt for a personalized follow up., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Recently, bispecific T-cell engagers (BiTEs) and chimeric antigen receptor-modified T cells (CAR-Ts) have been shown to have high therapeutic efficacy in hematological tumors. CD87 is highly expressed in solid tumors with an oncogenic function. To assess their cytotoxic effects on invasive nonfunctioning pituitary adenomas (iNFPAs), we first examined CD87 expression and its effects on the metabolism of iNFPA cells. We generated CD87-specific BiTE and CAR/IL-12 T cells, and their cytotoxic effects on iNFPAs cells and in mouse models were determined. CD87 had high expression in iNFPA tissue and cell samples but was undetected in noncancerous brain samples. CD87×CD3 BiTE and CD87 CAR/IL-12 T-cells showed antigenic specificity and exerted satisfactory cytotoxic effects, decreasing tumor cell proliferation in vitro and reducing existing tumors in experimental mice. Overall, the above findings suggest that CD87 is a promising target for the immunotherapeutic management of iNFPAs using anti-CD87 BiTE and CD87-specific CAR/IL-12 T cells., (© 2024. Science China Press.)

Purpose: For asymptomatic non-functioning pituitary adenomas (NFPAs), conservative approaches such as observation are preferred. However, some NFPAs exhibit poor prognoses. Thus, the purpose of this study was to investigate clinicopathological characteristics of tumors for identifying those with unfavorable prognoses., Methods: A total of 125 patients with NFPAs who underwent surgery between November 2017 and December 2022 at our institution were retrospectively analyzed. Clinical, radiological, and pathological data, including hormone profiles, tumor size, presence of cavernous sinus invasion, and Ki-67 index levels, were reviewed. High-risk PAs were identified according to 2022 WHO criteria. Statistical analyses including Kaplan-Meier survival analysis and Cox regression were performed to evaluate factors associated with tumor progression or recurrence., Results: A high-risk group demonstrated a significantly higher rate of tumor progression/recurrence than a low-risk group (p-value = 0.004). In multivariate analysis, the high-risk group at the time of diagnosis remained as an independent prognostic factor for NFPAs (p-value = 0.0148). The high-risk group also had a higher percentage of younger patients (80.0% in the high-risk group vs. 62.2% in the low-risk group, p-value = 0.016) and female patients (91.4% vs. 34.4%, p< 0.001). The presence of cavernous sinus invasion and higher Ki-67 index levels were more commonly observed in the high-risk group, although these factors did not significantly impact the overall prognosis., Conclusion: Our findings indicate that patients with high-risk NFPAs have a more aggressive disease course and a higher rate of progression or recurrence. This high-risk group has higher prevalence of younger and female patients. They may benefit from closer monitoring and possibly more aggressive treatment approaches., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Since the first description of Nelson syndrome 60 years ago, the way to consider corticotroph pituitary neuroendocrine tumors (PitNETs) after bilateral adrenalectomy has evolved. Today, it is globally acknowledged that only a subset of corticotroph PitNETs is aggressive.After adrenalectomy, corticotroph tumor progression (CTP) occurs in about 30 to 40% of patients during a median follow-up of 10 years. When CTP occurs, various CTP speeds (CTPS) can be observed. Using simple metrics in patients with CTP, CTPS was reported to vary from a few millimeters to up to 40 mm per year. Rapid CTPS/ Nelson's syndrome was associated with more severe Cushing's disease, higher adrenocorticotropic hormone (ACTH) in the year following adrenalectomy, and higher Ki67 on pituitary pathology. Complications such as apoplexy, cavernous syndrome, and visual defects were associated with higher CTPS. During follow-up, early morning ACTH, absolute variations properly reflected CTPS. Finally, CTPS was not higher after than before adrenalectomy, suggesting that cortisol deprivation after adrenalectomy does not impact CTPS in a majority of patients.Taken together, rapid CTPS/ Nelson's syndrome probably reflects the intrinsic aggressiveness of some corticotroph PitNETs. The precise molecular mechanisms related to corticotroph PitNET aggressiveness remain to be deciphered. Regular MRIs combined with intermediate morning ACTH measurements probably provide a reliable way to detect early and manage fast-growing tumors and, therefore, limit the complications., Competing Interests: We declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (Thieme. All rights reserved.)

Purpose: In a patient with elevated thyroid stimulating hormone (TSH, >50 µIU/ml) with sellar mass, it is crucial to differentiate isolated pituitary hyperplasia (IPH) from primary hypothyroidism coexisting with nonfunctioning pituitary adenoma (PHCNFPA) pre-operatively to avoid unwarranted surgery in the former condition. Here, we describe patients having pituitary mass/enlargement with markedly elevated TSH (>50 µIU/ml) and attempt to find the differentiating features between IPH and PHCNFPA., Methods: This is a retrospective study conducted at a tertiary care center. Case records of patients presenting between January 2020 and December 2022 with elevated TSH (>50 µIU/ml) for whom magnetic resonance imaging (MRI) of the sella was available were reviewed. Demographic details, symptomatology, clinical examination findings, thyroid function tests, data on pituitary hormonal excess and deficiencies, MRI findings, and details regarding levothyroxine supplementation were noted. Based on the final diagnosis, the patients were categorized into two groups: PHCNFPA and IPH., Results: Five and 11 patients were diagnosed with PHCNFPA and IPH, respectively. The median (IQR) age at presentation of patients with PHCNFPA was significantly higher than that of IPH patients [37 (28-60.5) vs. 21 (10-21.5) years, p: 0.002]. A longer duration of hypothyroid symptoms was noted in the IPH group whereas visual field defects and corticotropin deficiency were more frequent and the pituitary lesion size was greater in PHCNFPA. Thyroid function tests were not different between the two groups. The pituitary enlargement in IPH was initially an increase in pituitary height that progressed to symmetrical nipple-, dome- or tent-shaped enlargement. Besides this characteristic enlargement pattern, isointense appearance on T1-weighted and T2-weighted images, homogeneous contrast enhancement, and prompt regression of pituitary lesion with levothyroxine replacement were characteristic of IPH whereas heterogeneous enhancement, cystic/hemorrhagic change, and ≥Knosp III invasion were characteristic of PHCNFPA. Peripheral rim enhancement and Knosp I-II parasellar extension were not uncommon in patients with IPH and did not distinguish it from PHCNFPA., Conclusions: The present study reports the radiological evolution of IPH and a unique series of PHCNFPA along with the distinguishing characteristics between them., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To assess the utility of [ 18 F]fluoroethyl-L-tyrosine PET co-registered with magnetic resonance imaging ([ 18 F]FET-PET/MRI CR ) in patients with difficult-to-localize prolactinoma to inform clinical decision-making and (surgical) treatment planning., Methods: Retrospective cohort study of 17 consecutive patients with prolactinoma undergoing [ 18 F]FET-PET/MRI CR between October 2020 and September 2022 for either (1) additional information in case of difficult-to-visualize remnants after prior transsphenoidal surgery (TSS), or pharmacological treatment, or (2) radiological diagnosis in absence of a (clear) adenoma on diagnostic/post-treatment conventional MRI., Results: [ 18 F]FET-PET/MRI CR identified a lesion in 14/17 patients, yet failed to identify active lesions in 2 patients with negative conventional MRI despite prolactin > 7.5 times upper limit of normal. [ 18 F]FET-PET/MRI CR results were inconclusive in 1 patient due to diffuse tracer uptake 10 weeks post-surgery. [ 18 F]FET-PET/MRI CR was completely concordant with a suspected lesion on conventional MRI in 10/17 patients, and partially concordant in 3/17 patients. New foci were identified in 4/17 patients. The [ 18 F]FET-PET/MRI CR conclusions influenced clinical shared decision-making in 15/17 patients, of whom 7 patients underwent TSS and 8 refrained from TSS. One patient underwent TSS despite negative [ 18 F]FET-PET/MRI CR , and one patient underwent additional imaging. Intraoperative findings corresponded with [ 18 F]FET-PET/MRI CR in 5/8 patients, and immunohistochemistry was positive in 5/8 patients. The treatment goal was achieved in 7/8 patients, and remission was achieved in 5/7 patients in whom total resection was considered feasible., Conclusion: [ 18 F]FET-PET/MRI CR can be of added value in the preoperative decision-making process for selected patients with difficult-to-localize prolactinoma (remnants), or patients lacking a substrate on conventional MRI., (© 2024. The Author(s).)

Background: In surgical practice during endoscopic endonasal approach, growth hormone-secreting pituitary neuroendocrine tumor (GH-secreting PitNET) patients show morphologic differences in the nasal cavities and sinuses, leading to a narrower surgical field and a carotid prominence and potentially increasing the complexity of the surgical and the risk of complications. The aim of the study is to evaluate the anatomical differences of the sphenoid sinus between patients with GH-secreting PitNETs and patients with nonfunctioning pituitary neuroendocrine tumor (NF-PitNET) who underwent endoscopic endonasal approach., Methods: This is a monocentric retrospective study conducted at the author's institution. The minimum intercarotid distance, the largest diameter of the sphenoid sinus (DSS), and the distance between vomer and clivus (VCD) were collected and compared. Presence, localization, and course of intersphenoid sinus septum were also evaluated., Results: One hundred consecutive patients were identified: 57 males (57%) and 43 females (43%), with a mean age of 55 years. Sixty patients had NF-PitNET (60%) and 40 had GH-secreting PitNET (40%). GH-secreting PitNET group presented inferior values of intercarotid distance (16.8 ± 3.94 mm vs. 20.4 ± 3.94 mm, P < 0.001), DSS (32.5 ± 9.81 mm vs. 38.6 ± 11.03 mm, P = 0.006), and VCD (25.5 ± 6.96 mm vs. 29.6 ± 8.47 mm, P = 0.012) compared to NF-PitNET group. Intersphenoid sinus septum showed no differences between the 2 groups., Conclusions: Intercarotid distance, DSS, and VCD resulted smaller in acromegalic patients, confirming that patients with GH-secreting PitNETs have a narrower surgical field. A meticulous anatomical preoperative planning and neuronavigation are important to recognize the sphenoid anatomical landmarks in order to reduce the risk of complications, especially in acromegalic patients., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: In children with giant cystic solid craniopharyngioma (CP), the Ommaya reservoir was implanted in the CP cavity, and the cystic fluid was continuously drained for 5 days before the tumor resection., Methods: An 11-year-old male patient was admitted to the hospital due to vision loss for 1 year, intermittent headache, vomiting for 6 months, and frequent urination for 2 months. Besides, magnetic resonance imaging of the head showed cystic solid lesions in the sellar region, suprasellar, and bilateral frontal lobes, with a size of 96.0×82.6×76.0 mm. Before the surgical resection, an Ommaya reservoir was implanted within the tumor cavity. The drainage was continued for 5 days and was 39 to 50 mL (43.80 ± 4.67 mL). Following the tumor shrank, a craniotomy was performed., Results: Following surgical treatment, the CP was entirely removed. The child subsequently developed hypothyroidism and hypocortisolism, for which hormone replacement therapy was administered. No tumor recurrence was observed after 3 years of follow-up., Conclusion: The treatment of giant cystic solid CP in children is challenging. Preoperative implantation of the Ommaya reservoir, continuous drainage of cystic fluid, shrinkage of the tumor, and reduction of tumor tension are beneficial for tumor resection., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)

Nerves and blood vessels must be protected during brain tumor surgery, which has traditionally relied on microscopes. In the 2000s, endoscopes and related equipment were developed for neurosurgery. In this review, we aim to outline the role of endoscopes in brain tumor surgery and discuss the emerging use of exoscopes. The primary use of endoscopes in brain tumor surgery is in endoscopic endonasal surgery for pituitary tumors. By using the space within the sphenoid sinus, surgeons can insert an endoscope and instruments such as forceps or scissors through the nose to access and remove the tumor. Compared to microscopes, endoscopes can get closer to tumors, nerves, and blood vessels. They enable wide-angle observation of the skull base, making them valuable for skull base tumors as well as pituitary tumors. Endoscopes are also used in cases where a brain tumor is associated with hydrocephalus, allowing surgeons to correct obstructive hydrocephalus and perform tumor biopsies simultaneously. Exoscopy, a newer technique introduced in recent years, involves surgeons wearing special glasses and removing the tumor while viewing a three-dimensional monitor. This approach reduces surgeon fatigue and allows for more natural positioning during lengthy brain tumor surgeries. Future brain tumor surgeries will likely involve robotic surgery, which is already used for other organs. This is expected to make brain tumor removal safer and more accurate., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Introduction: AMPK (AMP-activated protein kinase) is an enzyme that acts as a metabolic sensor and regulates multiple pathways via phosphorylating proteins in metabolic and proliferative pathways. The aim of this work was to study the activated cellular AMPK (phosphorylated-AMPK at Thr172, pAMPK) levels in pituitary tumor samples from patients with sporadic and familial acromegaly, as well as in samples from normal human pituitary gland., Methods: We studied pituitary adenoma tissue from patients with sporadic somatotroph adenomas, familial acromegaly with heterozygote germline variants in the aryl hydrocarbon receptor interacting protein (AIP) gene (p.Q164*, p.R304* and p.F269&#95;H275dup) and autopsy from normal pituitary glands without structural alterations., Results: Cellular levels of pAMPK were significantly higher in patients with sporadic acromegaly compared to normal pituitary glands (p < 0.0001). Tissues samples from patients with germline AIP mutations also showed higher cellular levels of pAMPK compared to normal pituitary glands. We did not observe a significant difference in cellular levels of pAMPK according to the cytokeratin (CAM5.2) pattern (sparsely or densely granulated) for tumor samples of sporadic acromegaly., Conclusion: Our data show, for the first time in human cells, an increase of cellular levels of pAMPK in sporadic somatotropinomas, regardless of cytokeratin pattern, as well as in GH-secreting adenomas from patients with germline AIP mutations., Competing Interests: Declaration of competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. MFB and AROJr are current full-time employees at Ipsen in Brazil and USA, respectively. AROJr has stock shares from Ipsen., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: To evaluate clinical, laboratory, radiological, therapeutic, and prognostic characteristics of patients with acromegaly according to the size of the growth hormone (GH)-secreting pituitary adenoma at diagnosis., Methods: Observational, retrospective, single-center study of patients with acromegaly followed at a tertiary center. Data were collected regarding clinical presentation, characteristics of the adenoma in the magnetic resonance imaging, GH and IGF-1 levels, and disease control after surgery or adjuvant treatment (normal IGF-1 levels). Patients were divided according to the adenoma size at diagnosis in: group I < 10 mm; II 10-19 mm; III 20-29 mm; IV 30-39 mm; and V ≥ 40 mm. Comparisons were made between the groups, and correlations of tumor size with disease parameters, ROC curves, and logistic regression analyses were performed to investigate tumor size and confounding factors that could impact the outcomes., Results: 117 patients were studied [59 women, age at diagnosis 43 ± 13 years; group I = 11 patients (9%); group II 54 (46%); group III 34 (29%); group IV 10 (9%); group V 8 (7%)]. Hypopituitarism, cavernous sinus invasion, GH levels, and use of somatostatin receptor ligands had their prevalence increased according to the adenoma size. Age showed a negative correlation with tumor size. A tumor diameter around 20 mm was the best predictor for the presence of hypopituitarism, invasiveness, need of adjuvant therapies, and poorer disease control., Conclusion: Adenomas < 20 mm showed lower morbidity and better therapeutic response in acromegaly, while those ≥ 20 mm had similar clinical, therapeutic, and prognostic behavior., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Craniopharyngioma (CP) is an intracranial congenital epithelial tumor that can occur at any age. CP tumors are histologically benign (WHO grade I), and childhood‑onset CP (CO-CP) patients have a high rate of survival. The major concern for CO-CP patients is delayed diagnosis. Delayed diagnosis can further lead to serious adverse consequences such as acute and chronic complications, thereby endangering the life of the patient.We evaluated the early-stage clinical characteristics of CO-CP patients to provide clues for making rapid and accurate diagnoses., Methods: This was a retrospective, single-center study. We retrospectively reviewed all pediatric patients (<18 years of age) undergoing CP surgery between 2012 and 2019 at a single institution. Data including demographic data, clinical presentation, neuroendocrine dysfunction, and tumor imaging characteristics at diagnosis were analyzed., Results: The average age of the 192 children in this study was 7.32±3.94 (0-16) years, 91.0% were diagnosed when under 14 years old, and 92.7% of patients had at least one clinical symptom, and 90.7% of tumors have a diameter greater than 2cm, and 95.9% of tumor consistency was mixed or cystic, and 89.0% of tumors found calcification. The patients with hydrocephalus had higher BMI values than those without hydrocephalus (P = .006), and the incidence of calcification of tumors significantly decreased with age (P = .027)., Conclusions: For pediatric patients with calcification, >2 cm, cystic or mixed intracranial mass lesions, CP tumors should be considered, and early neuroendocrine function evaluation and further surgical treatment should be performed to avoid delayed diagnosis.

Background and Objectives: The cavernous internal carotid artery (cICA) and its branches can make it challenging to approach the lateral portion of the retrocarotid area of the cavernous sinus (RcACS) and surrounding areas during the endoscopic endonasal approach (EEA). This can sometimes require more invasive transcranial approaches, causing a higher risk of complications. We sought to explore the feasibility of adding a contralateral transmaxillary (CTM) corridor to improve access to the RcACS during EEA., Methods: We performed EEA and CTM extensions on 6 cadavers (12 sides) using image guidance. The depth of the surgical corridor, the surgical exposure, the angle of attack, and the trajectory to the anterior genu of the cICA were measured. Two illustrative clinical cases are presented., Results: Compared with the contralateral transnasal approach, the CTM corridor provided a 10.76 (5.32)-mm shorter distance ( P < .001), 36.23% (20.70%) larger surgical exposure ( P < .001), and a 24.6° (3.4°) more parallel trajectory to the anterior genu of the cICA ( P < .001). The mean angle of the lateral nasal wall line and the middle eye line was equal to the mean angle of the contralateral transnasal ( P = .075) and CTM ( P = .262) approaches, respectively. The CTM corridor allowed us to achieve near-total resection of the RcACS and beyond in 2 invasive adenomas with significant lateral extension., Conclusion: The CTM corridor is a feasible addition to standard EEA to access the RcACS and beyond, providing a more medial-to-lateral trajectory and improved access. The middle eye line can be used as a reference to help select patients for this approach., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Purpose: Molecular mechanisms involved in the pathogenesis and tumor progression of pituitary adenomas (PA) remain incompletely understood. Corticotroph and somatotroph PA are associated with a high clinical burden, and despite improved surgical outcomes and medical treatment options, they sometimes require multiple surgeries and radiation. Preliminary data suggested a role for O-GlcNAc Transferase (OGT), the enzyme responsible for the O-GlcNAcylation of proteins. O-GlcNAcylation and OGT have been found elevated in other types of tumors., Methods: We evaluated 60 functioning and nonfunctioning PA (NFPA) from operated patients and postmortem normal and tumoral pituitary tissue by immunohistochemistry. We performed transcriptomic analyses to explore the relevance of the O-GlcNAc Transferase (OGT) in PAs. We detected OGT in immunobiological analysis and define its level in PA tissue in patients., Results: OGT was strongly associated with PA hormone secretory capacity in functioning PA and with tumor growth in NFPAs. In NFPAs, OGT was positively associated with tumor size but not with cavernous sinus invasion (Knosp grading). In GH-secreting PA, OGT expression was negatively correlated with circulating Insulin-like Growth Factor 1 level. In adrenocorticotropic hormone (ACTH)-secreting PA, OGT expression was positively associated with circulating ACTH levels. OGT did not correlate with tumor size in secreting PAs. OGT levels were higher in gonadotroph PA compared to normal glands., Conclusion: O-GlcNAcylation can be downregulated in non-cancerous tumors such as GH-secreting adenomas. Future studies are warranted to elucidate the role of OGT in the pathogenesis of PAs., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Double pituitary adenoma is a rare entity that can pose a significant challenge. The incidence of double or multiple pituitary adenomas is ∼1% in autopsy cases and 0.4-1.3% in surgical series. Its definition varies, including 'double adenomas' in the literature in contrast to 'multiple adenomas', which is more specific and suitable. While some authors require separating topographically unique tumours, others have used a looser definition of separate immunohistochemistry., Case Presentation: We presented the case of a 26-year-old patient with recurrent carpal tunnel syndrome symptoms, with double pituitary adenomas secreting growth hormone (GH) and thyroid-stimulating hormone (TSH). To date, 89 patients have been reported in the literature with symptomatic carpal tunnel syndrome, but only five had GH-TSH secretion., Conclusions: Double adenoma resection is of great importance for ensuring successful biochemical treatment. To ensure a successful operation, a careful preoperative 3T MRI examination is of great importance.

Medical treatment of acromegaly is generally positioned as a second line of treatment after pituitary adenoma surgery. With the rising availability and variety of medications for acromegaly increases our understanding of their effectiveness and safety. Volume of the published data on the impact of medical therapy on biochemical control of acromegaly, contrasts a relative lack of publications which comprehensively address pituitary tumor alterations under different drug modalities. Assessment of changes in GH-secreting adenoma volume is often overshadowed by clinicians' focus on GH and IGF-I levels during acromegaly treatment. Close analysis of studies published in the last two decades, reveals that both an increase and decrease in somatotropinoma volume are possible during treatment with any of available drugs for acromegaly. Changes in pituitary tumor size may arise from the biological nature of adenoma itself, independently of the administered medications. Therefore, an individual approach is necessary in the treatment of patients with acromegaly, based on repeated insight to their clinical, biochemical, pathological and imaging characteristics. In this review, we summarize and comment how pituitary tumor size is affected by the treatment with all currently available drugs in acromegaly: long-acting somatostatin receptor ligands of the first generation (octreotide LAR and lanreotide autogel) and the second generation (pasireotide-LAR), as well as pegvisomant (PEG) and cabergoline (CAB)., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The diagnosis of pituitary microprolactinomas is often obscured by relatively low levels of elevated prolactin compared to macroprolactinomas. This may lead to varying patterns of medical therapy versus observation. We sought to correlate prolactin levels in suspected microprolactinomas with tumor volumes and clinical outcomes. This was a multicenter retrospective study of patients with pituitary microadenomas with baseline prolactin levels > 18ng/ml for males and > 30ng/ml for females. A linear-mixed model was used to depict changes in tumor volume over time. There were 65 patients with a mean tumor volume of 95.9mm 3 and mean prolactin level of 59.4ng/ml. There were significantly higher prolactin levels in patients with tumors above the mean volume versus below (74.0 versus 53.4ng/ml, p = 0.027). 26 patients were observed, 31 were treated with anti-dopaminergic therapy, and 8 had surgery. There were significantly greater baseline prolactin levels for patients who were treated surgically (mean 86.4ng/ml) than those treated medically (mean 61.7 g/ml) or observed (mean 48.5ng/ml) (p = 0.02). Among the 26 patients who were surveilled, 13 patients demonstrated spontaneous tumor shrinkage, 12 remained stable, and 1 patient's tumor grew but was lost to follow-up. Linear mixed modeling demonstrated a statistically significant rate of tumor shrinkage over time of 3.67mm 3 /year (p = 0.03). When analyzing patients who were observed versus those requiring surgery after initially being surveilled, there were significantly greater baseline PRL/volume ratios in surgical patients versus those observed (8.1 ng/ml/mm 3 versus 2.4 ng/ml/mm 3 , p = 0.025). Suspected microprolactinomas may demonstrate more convincingly elevated prolactin levels when measuring over 95.9mm 3 . Tumors with baseline prolactin levels over 50ng/ml may be more inclined to undergo medical treatment. In tumors with levels below 50ng/ml, it may be reasonable to undergo surveillance as these tumors tend to spontaneously shrink over time. In tumors that are surveilled, an elevated baseline PRL/volume ratio of > 8 ng/ml/mm 3 may be indicate serial tumor growth that may necessitate medical and/or surgical intervention., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This study aimed to predict arginine vasopressin deficiency (AVP-D) following transsphenoidal pituitary adenoma surgery using machine learning algorithms. We reviewed 452 cases from December 2013 to December 2023, analyzing clinical and imaging data. Key predictors of AVP-D included sex, tumor height, preoperative and postoperative changes in sellar diaphragm height and pituitary stalk length, preoperative ACTH levels, changes in ACTH levels, and preoperative cortisol levels. Six machine learning algorithms were tested: logistic regression (LR), support vector classification (SVC), random forest (RF), decision tree (DT), k-nearest neighbors (KNN), and extreme gradient boosting (XGBoost). After cross-validation and parameter optimization, the random forest model demonstrated the highest performance, with an accuracy (ACC) of 0.882 and an AUC of 0.96. The decision tree model followed, achieving an accuracy of 0.843 and an AUC of 0.95. Other models showed lower performance: LR had an ACC of 0.522 and an AUC of 0.54; SVC had an ACC of 0.647 and an AUC of 0.67; KNN achieved an ACC of 0.64 and an AUC of 0.70; and XGBoost had an ACC of 0.794 and an AUC of 0.91. The study found that a shorter preoperative pituitary stalk length, significant intraoperative stretching, and lower preoperative ACTH and cortisol levels were associated with a higher likelihood of developing AVP-D post-surgery., (© 2024. The Author(s).)

In the clinical diagnosis and treatment of pituitary adenomas, MRI plays a crucial role. However, traditional manual interpretations are plagued by inter-observer variability and limitations in recognizing details. Radiomics, based on MRI, facilitates quantitative analysis by extracting high-throughput data from images. This approach elucidates correlations between imaging features and pituitary tumor characteristics, thereby establishing imaging biomarkers. Recent studies have demonstrated the extensive application of radiomics in differential diagnosis, subtype identification, consistency evaluation, invasiveness assessment, and treatment response in pituitary adenomas. This review succinctly presents the general workflow of radiomics, reviews pertinent literature with a summary table, and provides a comparative analysis with traditional methods. We further elucidate the connections between radiological features and biological findings in the field of pituitary adenoma. While promising, the clinical application of radiomics still has a considerable distance to traverse, considering the issues with reproducibility of imaging features and the significant heterogeneity in pituitary adenoma patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zheng, Zhao, Zheng, Liu, Li, Jiang, Huang, Ye and Wang.)

Background: Growth hormone-secreting pituitary neuroendocrine tumors can be pathologically classified into densely granulated (DGGH) and sparsely granulated types (SGGH). SGGH is more aggressive and associated with a poorer prognosis. While epigenetic regulation is vital in tumorigenesis and progression, the role of N 6 -methyladenosine (m 6 A) in aggressive behavior has yet to be elucidated., Methods: We performed m 6 A-sequencing on tumor samples from 8 DGGH and 8 SGGH patients, complemented by a suite of assays including ELISA, immuno-histochemistry, -blotting and -fluorescence, qPCR, MeRIP, RIP, and RNA stability experiments, aiming to delineate the influence of m 6 A on tumor behavior. We further assessed the therapeutic potential of targeted drugs using cell cultures, organoid models, and animal studies., Results: We discovered a significant reduction of m 6 A levels in SGGH compared to DGGH, with an elevated expression of fat mass and obesity-associated protein (FTO), an m 6 A demethylase, in SGGH subtype. Series of in vivo and in vitro experiments demonstrated that FTO inhibition in tumor cells robustly diminishes hypoxia resistance, attenuates growth hormone secretion, and augments responsiveness to octreotide. Mechanically, FTO-mediated m 6 A demethylation destabilizes desmoplakin (DSP) mRNA, mediated by the m 6 A reader FMR1, leading to prohibited desmosome integrity and enhanced tumor hypoxia tolerance. Targeting the FTO-DSP-SSTR2 axis curtailed growth hormone secretion, therefor sensitizing tumors to octreotide therapy., Conclusion: Our study reveals the critical role of FTO in the aggressive growth hormone-secreting pituitary neuroendocrine tumors subtype and suggests FTO may represent a new therapeutic target for refractory/persistent SGGH., (© 2024. The Author(s).)

The Editors of Medical Science Monitor wish to inform you that the above manuscript has been retracted from publication due to concerns with the credibility and originality of the study, the manuscript content, and the Figure images. Reference: Yihua Zhang, Yang Tan, Hao Wang, Minhui Xu, Lunshan Xu. Long Non-Coding RNA Plasmacytoma Variant Translocation 1 (PVT1) Enhances Proliferation, Migration, and Epithelial-Mesenchymal Transition (EMT) of Pituitary Adenoma Cells by Activating ß-Catenin, c-Myc, and Cyclin D1 Expression. Med Sci Monit, 2019; 25: 7652-7659. DOI: 10.12659/MSM.917110.

This paper aims to analyze the risk factors for the recurrence or progression of non-functioning pituitary adenomas (NFPAs) in male patients after transnasal sphenoidal surgery and to develop a predictive model for prognosis. Clinical and follow-up data of 126 male patients with NFPAs treated by transnasal sphenoidal surgery from January 2011 to January 2021 in Fuzhou 900th Hospital were retrospectively analyzed. Lasso regression analysis was used to screen the best predictors, and the predictors were further screened by multivariate logistic regression analysis, and the nomogram prediction model was constructed. The performance of the model was verified by three aspects: discrimination, calibration and clinical utility by using the consistency index (C-index), receiver operating characteristic curve (ROC), calibration curve, clinical decision curve (DCA) and Clinical impact curve (CIC). Out of 126 cases, 7 (5.56%) showed postoperative tumor recurrence, and 18 (14.29%) exhibited postoperative residual regrowth (progression). Age (P = 0.024), maximum tumor diameter (P < 0.001), modified Knosp grade (P < 0.001), resection extent (P < 0.001), Ki67 (P < 0.001), pressure symptom (P < 0.001), Pre-op hypopituitarism (P = 0.048), Post-op new hypopituitarism (P = 0.017) showed significant differences among the recurrence group, the progression group, and the alleviation group. Three independent risk factors (Ki67, modified Knosp grade, and resection extent) affecting postoperative remission were used to construct a predictive model for long-term postoperative failure to remit. The C-index of the nomogram model was 0.823, suggesting that the model had a high discriminatory power, and the AUC of the area under the ROC curve was 0.9[95% CI (0.843, 0.958)]. A nomogram prediction model based on modified Knosp grading (grades 3B-4), resection extent (partial resection), and Ki-67 (≥ 3%) predicts the recurrence or progression of NFPAs in men after transnasal sphenoidal surgery., (© 2024. The Author(s).)

Introduction: Studies addressing the methylation pattern in adamantinomatous craniopharyngioma (ACP) are lacking., Objective: To identify methylation signatures in ACPs regarding clinical presentation and outcome., Methods: Clinical and pathology data were collected from 35 patients with ACP (54% male; 18.1 years [2-68]). CTNNB1 mutations and methylation profile (MethylationEPIC/Array-Illumina) were analyzed in tumoral DNA. Unsupervised machine learning analysis of this comprehensive methylome sample was achieved using hierarchical clustering and multidimensional scaling. Statistical associations between clusters and clinical features were achieved using the Fisher test and global biological process interpretations were aided by Gene Ontology enrichment analyses., Results: Two clusters were revealed consistently by all unsupervised methods (ACP-1: n = 18; ACP-2: n = 17) with strong bootstrap statistical support. ACP-2 was enriched by CTNNB1 mutations (100% vs 56%, P = .0006), hypomethylated in CpG island, non-CpG Island sites, and globally (P < .001), and associated with greater tumor size (24.1 vs 9.5 cm3, P = .04). Enrichment analysis highlighted pathways on signaling transduction, transmembrane receptor, development of anatomical structures, cell adhesion, cytoskeleton organization, and cytokine binding, and cell type-specific biological processes as regulation of oligodendrocytes, keratinocyte, and epithelial cells differentiation., Conclusion: Two clusters of patients with ACP were consistently revealed by unsupervised machine learning methods, with one of them significantly hypomethylated, enriched by CTNNB1 mutated ACPs, and associated with increased tumor size. Enrichment analysis reinforced pathways involved in tumor proliferation and in cell-specific tumoral microenvironment., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

According to numerous studies, the most common pituitary tumors are prolactinomas, reaching 60% of all clinically significant adenomas, the next in order are non-functional pituitary adenomas, somatotropinomas, corticotropinomas and thyrotropinomas. Plurigormonal tumors occur in less than 1% of all pituitary adenomas. The most common form of mixed secretion adenoma in this patient population, derived from the Pit-1 cell line, produces various combinations of hormones: growth hormone (GH), prolactin (PRL), thyroid-stimulating hormone (TSH). This article presents a patient with a plurihormonal two-component pituitary macroadenoma with a rare and exceptional combination of secreted hormones - GH / adrenocorticotropic hormone (ACTH) / TSH / follicle-stimulating hormone (FSH) / luteinizing hormone (LH) with minimal nonspecific clinical manifestations such as diabetes mellitus and poorly controlled arterial hypertension.

Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) have the potential application in evaluating pathological structural change of the optic nerve. We aimed to evaluate the value of the OCT and OCTA parameters of the optic disk and macular in differentiating early chronic primary angle-closure glaucoma (CPACG) and early pituitary adenoma (PA) in case of mild visual field defects (the mean defect (MD) > 6 dB). The results showed that regarding OCTA parameters, CPACG patients had lower retinal blood flow density of most layers of the optic disk and macular than PA patients. Regarding OCT parameters, CPACG patients had thinner circumpapillary retinal nerve fiber layer (CP-RNFL) in all quadrants and average CP-RNFL, ganglion cell layer (GCL) and macular ganglion cell complex (GCC) in each quadrant of macular inner and outer rings, and inner plexus layer (IPL) of macular inner ring, superior-outer ring and temporal-outer ring than PA patients. The Z test indicated that OCTA parameters and OCT parameters had similar value in the diagnosis of disease. In conclusion, in the case of similar visual field damage, early CPACG patients have smaller blood flow density and thinner optic disk and macular than early PA. OCTA has similar performance to OCT in diagnosing CPACG and PA., (© 2024. The Author(s).)

Brain tumors pose significant global health concerns due to their high mortality rates and limited treatment options. These tumors, arising from abnormal cell growth within the brain, exhibits various sizes and shapes, making their manual detection from magnetic resonance imaging (MRI) scans a subjective and challenging task for healthcare professionals, hence necessitating automated solutions. This study investigates the potential of deep learning, specifically the DenseNet architecture, to automate brain tumor classification, aiming to enhance accuracy and generalizability for clinical applications. We utilized the Figshare brain tumor dataset, comprising 3,064 T1-weighted contrast-enhanced MRI images from 233 patients with three prevalent tumor types: meningioma, glioma, and pituitary tumor. Four pre-trained deep learning models-ResNet, EfficientNet, MobileNet, and DenseNet-were evaluated using transfer learning from ImageNet. DenseNet achieved the highest test set accuracy of 96%, outperforming ResNet (91%), EfficientNet (91%), and MobileNet (93%). Therefore, we focused on improving the performance of the DenseNet, while considering it as base model. To enhance the generalizability of the base DenseNet model, we implemented a fine-tuning approach with regularization techniques, including data augmentation, dropout, batch normalization, and global average pooling, coupled with hyperparameter optimization. This enhanced DenseNet model achieved an accuracy of 97.1%. Our findings demonstrate the effectiveness of DenseNet with transfer learning and fine-tuning for brain tumor classification, highlighting its potential to improve diagnostic accuracy and reliability in clinical settings., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Aziz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Unlike somatotroph tumors, the data on correlates of tumor granulation patterns in functional TPIT lineage pituitary neuroendocrine tumors (corticotroph tumors) have been less uniformly documented in most clinical series. This study evaluated characteristics of 41 well-characterized functional corticotroph tumors consisting of 28 densely granulated corticotroph tumors (DGCTs) and 13 sparsely granulated corticotroph tumors (SGCTs) with respect to preoperative clinical and radiological findings, tumor proliferative activity (including mitotic count and Ki-67 labeling index), and postoperative early biochemical remission rates. The median (interquartile range (IQR)) tumor size was significantly larger in the SGCT group [16.00 (16.00) mm in SGCT vs 8.5 (9.75) mm in DGCT, p = 0.049]. T2-weighted signal intensity and T2 intensity (quantitative) did not yield statistical significance based on tumor granulation; however, the T2 intensity-to-white matter ratio was significantly higher in SGCTs (p = 0.049). The median (IQR) Ki-67 labeling index was 2.00% (IQR 1.00%) in the DGCT group and 4.00% (IQR 7.00%) in the SGCT group (p = 0.043). The mitotic count per 2 mm 2 was higher in the SGCT group (p = 0.001). In the multivariate analysis, the sparse granulation pattern (SGCT) remained an independent predictor of a lower probability of early biochemical remission irrespective of the tumor size and proliferative activity (p = 0.012). The current study further supports the impact of tumor granulation pattern as a biologic variable and warrants the detailed histological subtyping of functional corticotroph tumors as indicated in the WHO classification of pituitary neuroendocrine tumors. More importantly, the assessment of the quantitative T2 intensity-to-white matter ratio may serve as a preoperative radiological harbinger of SGCTs., (© 2024. The Author(s).)

The aim of this multicenter prospective survey called PIT-EASY was to assess the relevance of the European Pituitary Pathology Group (EPPG) diagnostic tools for pituitary neuroendocrine tumors (PitNETs) to improve the quality of their histological diagnosis. Each center performed at least 30 histological cases of PitNETs using the EPPG tools and assessed their value using a scorecard with 10 questions. For each center, the histological cases were carried out by pathologists with varying levels of expertise in pituitary pathology defined as junior, intermediate, and expert. Two hundred and ninety histological cases were collected from six French and Italian centers. The three EPPG tools were validated and regarded as helpful for a more accurate and time-efficient diagnosis. The usefulness of level 2 and level 3 of the "EPPG's multi-step approach for immunohistochemistry" including pituitary transcription factors (PIT1, TPIT, and SF1) and chromogranin, SSTRs, and P53 respectively was higher in "other non-functioning" (silent plurihormonal PIT1, silent corticotroph, and null cell): 88% vs 32%, p < 10-6 and 42% vs 14%, p = 0.002, respectively. The diagnostic algorithm proved more useful for junior pathologists (p = 0.0001) and those with intermediate experience. PIT-EASY survey confirmed the importance of a standardized approach to PitNETs for an accurate and reproducible diagnosis and served as validation of the EPPG proposal. The tool appeared to be of practical value to junior participants and staff with intermediate experience for safe routine diagnostic reporting., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)