Hormone-secreting Pituitary Tumors Research Articles

Mixed Gangliocytoma-Pituitary Adenoma: Incidental Discovery During Eye Injury Evaluation: A Case Study

Abstract Introduction/Objective Mixed gangliocytoma-adenoma is exceedingly rare, representing less than 0.5% of sellar tumors. We present a unique case of mixed gangliocytoma-pituitary adenoma incidentally diagnosed during the evaluation of traumatic eye injury. We aim to clarify the diagnostic process using real clinical data, stressing how such cases might be missed without careful histopathological examination Methods/Case Report A 32-year-old male presented for elective transsphenoidal resection (TSR) due to a suspected growth hormone (GH) secreting pituitary tumor. Surprisingly, the adenoma was discovered incidentally during an eye injury evaluation. Referred from an ophthalmology clinic, initial concerns were a possible blood clot or foreign body in the left eye, following a forceful encounter with a tree branch Results (if a Case Study enter NA) Imaging incidentally identified a 2 cm pituitary mass. Further evaluation showed elevated levels of insulin-like growth factor 1 (IGF1) at 1162 ng/ml and GH at 10.2 ng/ml. Remarkably, the patient had not observed signs of acromegaly, until photographic comparison between past and present appearances was made. TSR of the pituitary mass was done. Microscopic examination revealed monomorphic cells with round nuclei with the typical speckled chromatin pattern of neuroendocrine cells with cytoplasm ranging from chromophobic to eosinophilic, consistent with pituitary adenoma. An additional unexpected finding was the presence of large gangliocytic cells (large neurons), dispersed throughout the tumor as single or clustered cells. In some regions, distinct patches of fine neuropil stroma were associated with the clustered ganglion cells. IHC staining with synaptophysin and neurofilament highlighted the gangliocytic component. CAM 5.2 IHC stain showed perinuclear dot-like expression in the adenoma cells, GH IHC showed patchy expression, and prolactin IHC was expressed in scattered cells. Ki67 index was ~ 2%. There was no evidence of necrosis nor mitosis. The coexistence of sellar gangliocytoma with pituitary adenoma, as observed in this case, represents a rare entity known as mixed gangliocytoma-pituitary adenoma Conclusion The adenomatous component of mixed gangliocytoma-pituitary adenoma often secrete GH, leading to its classification as pituitary somatotroph adenoma. This poses a diagnostic challenge due to the lack of specific symptoms or unique brain imaging features, necessitating thorough histological evaluation for precise diagnosis and to ensure the gangliocytoma component is not overlooked

12353 Differential Gene Expression And Pathway Analysis In Growth Hormone Secreting Pituitary Tumors According To Granulation Pattern

Abstract Disclosure: H. Shin: None. Differential gene expression and pathway analysis in growth hormone-secreting pituitary tumors according to granulation pattern. Hye Ju Shin [1], Kyung Won Kim[2], Chan Woo Kang[2], Eun Jig Lee[2], Cheol Ryong Ku[2]. [1]Department of Clinical Drug Discovery & Development, Yonsei University College of Medicine, Seoul, Republic of Korea, [2]Endocrinology, Institute of Endocrine Research, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea Objective: The purpose of this research is to explain clinical variations in patients with acromegaly by exploring gene expression differences according to granulation patterns in growth hormone (GH)-secreting pituitary tumors. Materials & methods: Transcriptome analysis was conducted on 6 normal pituitary tissues and 15 GH-secreting pituitary tumors, including 9 densely granulated somatotroph tumors (DGSTs) and 6 sparsely granulated somatotroph tumors (SGSTs). Results: The median age at diagnosis was 50 years, with a predominance of female patients (60%). We identified 3111 differentially expressed genes (DEGs) in tumors compared to normal pituitaries, with 1117 DEGs unique to a specific granulation within tumors. SGST showed enriched the pathways involved in neuronal development (axon development, axonogenesis, axon guidance, synapse and presynapse organization, gliogenesis, glial cell differentiation, nerve development, synaptic membrane adhesion, semaphorin-plexin signaling pathway involved in neuron projection guidance) and acute inflammatory response. No pathways were significantly downregulated in SGST compared with those in DGST. Three signaling pathways (JAK-STAT, phosphatidylinositol 3-kinase, and MAP cascade) and three neuronal development processes (generation of neurons, nerve development, and neurogenesis) were significantly enriched in both GO and GSEA analysis. The PPI networks constructed with the up- and downregulated DEGs consisted of 128 and 132 PPI pairs, respectively. There were 10 hub proteins, top highly connected DEGs: ANLN, TLE3, TLE2, DMD, ADRA1A, RBFOX1, MMP2, LMO1, RUNX1T1, and NPPA. Conclusion: The results indicate that granulation-specific gene expression may underpin diverse clinical characteristics in acromegaly. Overall, this study emphasizes the potential for further investigation into these transcriptomic variations and their roles in disease pathology, particularly the involvement of genes linked to neuronal development, inflammatory response, and JAK-STAT signaling in SGST. Presentation: 6/3/2024

FTO-mediated DSP m6A demethylation promotes an aggressive subtype of growth hormone-secreting pituitary neuroendocrine tumors

BackgroundGrowth 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 N6-methyladenosine (m6A) in aggressive behavior has yet to be elucidated.MethodsWe performed m6A-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 m6A on tumor behavior. We further assessed the therapeutic potential of targeted drugs using cell cultures, organoid models, and animal studies.ResultsWe discovered a significant reduction of m6A levels in SGGH compared to DGGH, with an elevated expression of fat mass and obesity-associated protein (FTO), an m6A 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 m6A demethylation destabilizes desmoplakin (DSP) mRNA, mediated by the m6A 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.ConclusionOur 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.

Anatomical Differences in Sphenoid Sinus During Endoscopic Transsphenoidal Surgery: Comparison Between Nonfunctioning Pituitary Neuroendocrine Tumor (PiTNET) and Growth Hormone-Secreting PiTNET

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. 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. One hundred consecutive patients were identified: 57 males (57%) and 43 females (43%), with a mean age of 55years. 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 ± 3.94mm vs. 20.4 ± 3.94mm, P < 0.001), DSS (32.5 ± 9.81mm vs. 38.6 ± 11.03mm, P= 0.006), and VCD (25.5 ± 6.96mm vs. 29.6 ± 8.47mm, P= 0.012) compared to NF-PitNET group. Intersphenoid sinus septum showed no differences between the 2 groups. 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.

AB092. Imaging the histopathology subtypes of the growth hormone-secreting pituitary neuroendocrine tumor.

Sparsely granulated (SG) growth hormone-secreting pituitary neuroendocrine tumors (GH-PitNETs) often present with a more aggressive clinical course compared to densely granulated (DG) tumors. These subtypes exhibit distinct biological and imaging characteristics. Thus, this study aims to differentiate between the histopathological subtypes of GH-PitNETs using pre-operative magnetic resonance imaging (MRI). A retrospective analysis was conducted on 83 acromegalic patients treated at our institution between 2000 and 2010. Tumor volumes were segmented from preoperative MRIs, including T1-weighted, T2-weighted, T1 with contrast, and T2 fluid attenuated inversion recovery (FLAIR) sequences. Reference regions of interest (ROIs) were delineated using gray and white matter from the same sequences. Two pathologists reviewed pathology specimens for anti-cytokeratin (CAM 5.2) and Pit-1 expression. Clinical and radiological biomarkers were compared between SG and DG patients. A total of 83 patients with complete histopathology and 51 patients with complete MRIs were included in the analysis. SG PitNETs exhibited higher rates of supra-sellar invasion (61.5%, P<0.001), larger tumor sizes, lower pre-operative GH levels, and increased post-operative residual tumor (65.4%, P<0.001) compared to DG PitNETs. Additionally, SG PitNETs showed greater hyperintensity on T2-weighted images and enhanced contrast, whereas DG PitNETs exhibited less contrast enhancement. Utilization of these imaging biomarkers demonstrated an 94.1% accuracy in T2 FLAIR and overall of 78.7% predicting the histopathological subtypes of GH-PitNETs. Distinct histopathological subtypes of GH-PitNETs represent crucial prognostic factors. Utilizing multimodal pre-operative MRIs, clinicians can accurately identify sparsely granulated GH-PitNETs, facilitating improved treatment planning strategies.

Differential gene expression and pathway analysis in growth hormone-secreting pituitary tumors according to granulation pattern.

This study investigated differential gene expression between granulation patterns in growth hormone (GH)-secreting pituitary tumors, aiming to elucidate novel transcriptomes that explain clinical variances in patients with acromegaly. Transcriptome analysis was conducted on 6 normal pituitary tissues and 15 GH-secreting pituitary tumors, including 9 densely granulated somatotroph tumors (DGSTs) and 6 sparsely granulated somatotroph tumors (SGSTs). We identified 3111 differentially expressed genes (DEGs) in tumors compared to normal pituitaries, with 1117 DEGs unique to a specific granulation within tumors. SGST showed enrichment of neuronal development and acute inflammatory response pathways, along with a significant enhancement of JAK-STAT, phosphatidylinositol 3-kinase, and MAPK signaling. The results suggest that granulation-specific gene expression may underpin diverse clinical presentations in acromegaly, highlighting the potential for further investigation into these transcriptomic variations and their roles in disease pathology, particularly the involvement of genes linked to neuronal development, inflammatory response, and JAK-STAT signaling in SGST.

Impact of medical therapy for hormone-secreting Pituitary tumors on bone.

Bone health is often impaired in patients with hormone-secreting pituitary tumors. Since medical therapy is central to their care, understanding how its use impacts on this is highly important. This review summarizes a systemmatic review of the literature on the effects of medical therapies for hormone-secreting pituitary tumors on bone. In acromegaly, medical therapy lowers bone turnover marker (BTM) levels, consistent with correction of the high bone turnover of active disease, and overall, areal bone mineral density (aBMD) does not change or increases. Somatostatin-receptor ligand (SRL) and pegvisomant-treated acromegaly patients have persistently reduced volumetric BMD and microarchitectural abnormalities of the peripheral skeleton, deficits that are similar to those in surgically-treated patients. Fracture risk remains elevated in medically-treated acromegaly patients but in conjunction with biochemical control the risk is lessened. Treatment of prolactin-secreting tumors with dopamine agonists is associated with improvements in aBMD, but this does not always fully normalize despite effective medical treatment of the prolactinoma. In one cross-sectional study, prolactinoma patients had lower total volumetric BMD and impaired microarchitecture suggesting that bone microstructure does not fully normalize despite dopamine agonist therapy. Cross-sectional studies show a high rate of VF in patients with prolactin-secreting tumors that is lowered on cabergoline therapy, but still the fracture rate of men and postmenopausal women is higher than that of controls in some studies. Studies on the effects of modern-day medical therapy for Cushing's disease on bone are lacking. More research is needed on the effectsof medical therapies for hormone secreting pituitary tumors on bone health.

Clinical Characteristics, Diagnosis, and Treatment of Thyroid Stimulating Hormone-Secreting Pituitary Neuroendocrine Tumor (TSH PitNET): A Single-Center Experience.

Thyroid-stimulating hormone (TSH)-secreting pituitary neuroendocrine tumor (TSH PitNET) is a rare subtype of PitNET. We investigated the comprehensive characteristics and outcomes of TSH PitNET cases from a single medical center. Also, we compared diagnostic methods to determine which showed superior sensitivity. A total of 17 patients diagnosed with TSH PitNET after surgery between 2002 and 2022 in Samsung Medical Center was retrospectively reviewed. Data on comprehensive characteristics and treatment outcomes were collected. The sensitivities of diagnostic methods were compared. Seven were male (41%), and the median age at diagnosis was 42 years (range, 21 to 65); the median follow-up duration was 37.4 months. The most common (59%) initial presentation was hyperthyroidism-related symptoms. Hormonal co-secretion was present in four (23%) patients. Elevated serum alpha-subunit (α-SU) showed the greatest diagnostic sensitivity (91%), followed by blunted response at thyrotropin-releasing hormone (TRH) stimulation (80%) and elevated sex hormone binding globulin (63%). Fourteen (82%) patients had macroadenoma, and a specimen of one patient with heavy calcification was negative for TSH. Among 15 patients who were followed up for more than 6 months, 10 (67%) achieved hormonal and structural remission within 6 months postoperatively. A case of growth hormone (GH)/TSH/prolactin (PRL) co-secreting mixed gangliocytoma-pituitary adenoma (MGPA) was discovered. The majority of the TSH PitNET cases was macroadenoma, and 23% showed hormone co-secretion. A rare case of GH/TSH/PRL co-secreting MGPA was discovered. Serum α-SU and TRH stimulation tests showed great diagnostic sensitivity. Careful consideration is needed in diagnosing TSH PitNET. Achieving remission requires complete tumor resection. In case of nonremission, radiotherapy or medical therapy can improve the long-term remission rate.

Asynchronous, double, growth hormone-secreting pituitary neuroendocrine tumor of a variable proliferative potential.

Asynchronous, double, growth hormone-secreting pituitary neuroendocrine tumor of a variable proliferative potential.

Clinical Characteristics, Diagnosis, and Treatment of Thyroid Stimulating Hormone-Secreting Pituitary Neuroendocrine Tumor (TSH PitNET): A Single-Center Experience.

Thyroid-stimulating hormone (TSH)-secreting pituitary neuroendocrine tumor (TSH PitNET) is a rare subtype of Pit- NET. We investigated the comprehensive characteristics and outcomes of TSH PitNET cases from a single medical center. Also, we compared diagnostic methods to determine which showed superior sensitivity. A total of 17 patients diagnosed with TSH PitNET after surgery between 2002 and 2022 in Samsung Medical Center was retrospectively reviewed. Data on comprehensive characteristics and treatment outcomes were collected. The sensitivities of diagnostic methods were compared. Seven were male (41%), and the median age at diagnosis was 42 years (range, 21 to 65); the median follow-up duration was 37.4 months. The most common (59%) initial presentation was hyperthyroidism-related symptoms. Hormonal co-secretion was present in four (23%) patients. Elevated serum alpha-subunit (α-SU) showed the greatest diagnostic sensitivity (91%), followed by blunted response at thyrotropin-releasing hormone (TRH) stimulation (80%) and elevated sex hormone binding globulin (63%). Fourteen (82%) patients had macroadenoma, and a specimen of one patient with heavy calcification was negative for TSH. Among 15 patients who were followed up for more than 6 months, 10 (67%) achieved hormonal and structural remission within 6 months postoperatively. A case of growth hormone (GH)/TSH/prolactin (PRL) co-secreting mixed gangliocytoma-pituitary adenoma (MGPA) was discovered. The majority of the TSH PitNET cases was macroadenoma, and 23% showed hormone co-secretion. A rare case of GH/TSH/PRL co-secreting MGPA was discovered. Serum α-SU and TRH stimulation tests showed great diagnostic sensitivity. Careful consideration is needed in diagnosing TSH PitNET. Achieving remission requires complete tumor resection. In case of nonremission, radiotherapy or medical therapy can improve the long-term remission rate.

Collision sellar lesion: coexistence of growth hormone-secreting pituitary neuroendocrine tumor and pituicytoma.

Collision sellar lesion: coexistence of growth hormone-secreting pituitary neuroendocrine tumor and pituicytoma.

Exploring the role of the tumor microenvironment in refractory pituitary tumor pathogenesis.

Treatment-refractory pituitary tumors demonstrate characteristics resembling those of highly aggressive tumors, in which the local tumor microenvironment (TME) plays a dominant role in promoting aggressiveness and refractoriness. However, role of the TME in pituitary tumors is not well studied. Literature on the TME and development of refractory pituitary tumors was reviewed RESULTS: TME harbors tumorigenic immune cells, cancer-associated fibroblasts (CAF), extracellular matrix, and other factors that have been shown to affect behavior of tumor tissue. For example, tumor-associated macrophages and tumor-infiltrating lymphocytes correlate with aggressive and invasive tumor behavior in nonfunctioning and growth hormone-secreting (GH) pituitary tumors, while CAF release of TGFβ, FGF2, cytokines, chemokines, and growth factors may promote treatment resistance, tumor fibrosis, and inflammation in prolactinomas and GH-secreting tumors. In turn, Wnt pathway activation can further promote cell growth in dopamine-resistant prolactinomas. Finally, proteins secreted by extracellular matrix are associated with increased angiogenesis in invasive tumors. It is likely that multiple mechanisms, including TME, contribute to the development of aggressive refractory pituitary tumors. Given the increased morbidity and mortality associated with pituitary tumor refractoriness, more research on the role of TME is warranted.

The Prognostic-Based Approach in Growth Hormone-Secreting Pituitary Neuroendocrine Tumors (PitNET): Tertiary Reference Center, Single Senior Surgeon, and Long-Term Follow-Up

Postoperative deserved outcomes in acromegalic patients are to normalize serum insulin-like growth factor (IGF-1), reduce the tumoral mass effect, improve systemic comorbidities, and reverse metabolic alterations. Pituitary neuroendocrine tumors (PitNET) are characterized to present a heterogeneous behavior, and growth hormone (GH)-secreting PitNET is not an exception. Promptly determining which patients are affected by more aggressive tumors is essential to guide the optimal postoperative decision-making process [prognostic-based approach]. From 2006 to 2019, 394 patients affected by PitNET were intervened via endoscopic endonasal transsphenoidal approach by the same senior surgeon. A total of 44 patients that met the criteria to be diagnosed as acromegalic and were followed up at least for 24 months (median of 66 months (26-156) were included in the present study. Multiple predictive variables [age, gender, preoperative GH and IGF-1 levels, maximal tumor diameter, Hardy's and Knosp's grade, MRI. T2-weighted tumor intensity, cytokeratin expression pattern, and clinicopathological classification] were evaluated through uni- and multivariate statistical analysis. Sparse probability of long-term remission was related to younger age, higher preoperative GH and- or IGF-1, group 2b of the clinicopathological classification, and sparsely granulated cytokeratin expression pattern. Augmented recurrence risk was related to elevated preoperative GH levels, tumor MRI T2-weighted hyperintensity, and sparsely granulated cytokeratin expression pattern. Finally, elevated risk for reintervention was related to group 2b of the clinicopathological classification, Knosp's grade IV, and tumor MRI T2-weighted hyperintensity. In this study, the authors determined younger age, higher preoperative GH and- or IGF-1 levels, group 2b of the clinicopathological classification, Knosp's grade IV, MRI T2-weighted tumor hyperintensity and sparsely granulated cytokeratin expression pattern are related to worse postoperative outcomes in long-term follow-up patients affected with GH-secreting PitNET.

Attention and working memory in patients with prolactinomas: a case–control study

Prolactinomas (prolactin-secreting adenomas) are the most common type of hormone-secreting pituitary tumor. Mounting evidence indicates that excess prolactin impairs cognitive function, but specific assessments of attention in patients with prolactinomas are lacking. Case–control study gathered 54 participants—27 patients with prolactinoma and 27 healthy controls. Neuropsychological assessment included a comprehensive set of diagnostic methods for the evaluation of attention and working memory. Patients showed slower information processing, expressed as a longer working time on the d2 Test of Attention and Color Trails Test (CTT-2), and lower attention-switching shown in the CTT-2 and in two subtests of the Tests of Everyday Attention (Visual Elevator), and Telephone Search While Counting. Working memory disturbances were observed in Digit Span and Symbol Span tests. A level of prolactin correlated negatively with scores in some of the neuropsychological tests measuring attentional switching (Visual Elevator), spatial screening and working memory (CTT-2), spatial working memory (Symbol Span) and auditory-verbal working memory (Digit Span backwards). There were no significant correlations between cognitive performance and tumor size. In conclusion, patients with prolactinoma suffer from impaired cognitive functions, including attention and working memory. Comprehensive neuropsychological assessment should be a permanent element of the diagnostics of this group of patients.

Genome wide analysis of circulating miRNAs in growth hormone secreting pituitary neuroendocrine tumor patients' plasma.

BackgroundCirculating plasma miRNAs have been increasingly studied in the field of pituitary neuroendocrine tumor (PitNET) research. Our aim was to discover circulating plasma miRNAs species associated with growth hormone (GH) secreting PitNETs versus assess how the plasma levels of discovered miRNA candidates are impacted by SSA therapy and whether there is a difference in their levels between GH secreting PitNETs versus other PitNET types and healthy individuals.DesignWe compared plasma miRNA content and levels before and after surgery focusing on GH secreting PitNET patients. Selected miRNA candidates from our data and literature were then tested in a longitudinal manner in somatostatin analogues (SSA) treatment group. Additionally, we validated selected targets in an independent GH secreting PitNET group.MethodsmiRNA candidates were discovered using the whole miRNA sequencing approach and differential expression analysis. Selected miRNAs were then analyzed using real-time polymerase chain reaction (qPCR).ResultsWhole miRNA sequencing discovered a total of 16 differentially expressed miRNAs (DEMs) in GH secreting PitNET patients’ plasma 24 hours after surgery and 19 DEMs between GH secreting PitNET patients’ plasma and non-functioning (NF) PitNET patients’ plasma. Seven miRNAs were selected for further testing of which miR-625-5p, miR-503-5p miR-181a-2-3p and miR-130b-3p showed a significant downregulation in plasma after 1 month of SSA treatment. mir-625-5p was found to be significantly downregulated in plasma of GH secreting PitNET patients vs. NF PitNET patients. miR-625-5p alongside miR-130b-3p were also found to be downregulated in GH PitNETs compared to healthy individuals.ConclusionsOur study suggests that expression of plasma miRNAs miR-625-5p, miR-503-5p miR-181a-2-3p and miR-130b-3p in GH secreting PitNETs is affected by SSA treatment. Additionally, miR-625-5p can distinguish GH secreting PitNETs from other PitNET types and healthy controls warranting further research on these miRNAs for treatment efficacy.

Intraoperative Alcoholization of the Pituitary Gland Does Not Reduce the Recurrence Rate of Growth Hormone Secreting Pituitary Adenomas.

Objective Although the role of intraoperative alcoholization of the pituitary gland has been examined for the management of malignant tumor metastases and Rathke's cleft cysts, no such studies have been conducted relating to growth hormone (GH) secreting pituitary tumors, despite the high rate of recurrence in this cohort of patients. Here, we sought to understand the impact of adjunctive intraoperative alcoholization of the pituitary gland on recurrence rates and perioperative complications associated with resection of GH-secreting tumors. Methods This is a single-institution retrospective cohort study analyzing recurrence rates and complications among patients with GH-secreting tumors who received intraoperative alcoholization of the pituitary gland postresection versus those that did not. Welch's t -tests and analysis of variance (ANOVA) analyses were employed to compare continuous variables between groups, whereas chi-squared tests for independence or Fisher's exact tests were used for comparing categorical variables. Results A total of 42 patients ( n = 22 no alcohol and n = 20 alcohol) were included in the final analysis. The overall recurrence rates did not significantly differ between the alcohol and no alcohol groups (35 and 22.7%, respectively; p = 0.59). The average time to recurrence in the alcohol and no alcohol groups was 22.9 and 39 months, respectively ( p = 0.63), with a mean follow-up of 41.2 and 53.5 months ( p = 0.34). Complications, including diabetes insipidus, were not significantly different between the alcohol and no alcohol groups (30.0 vs. 27.2%, p = 0.99). Conclusion Intraoperative alcoholization of the pituitary gland after resection of GH-secreting pituitary adenomas does not reduce recurrence rates or increase perioperative complications.

RET signalling provides tumorigenic mechanism and tissue specificity for AIP-related somatotrophinomas

It is unclear how loss-of-function germline mutations in the widely-expressed co-chaperone AIP, result in young-onset growth hormone secreting pituitary tumours. The RET receptor, uniquely co-expressed in somatotrophs with PIT1, induces apoptosis when unliganded, while RET supports cell survival when it is bound to its ligand. We demonstrate that at the plasma membrane, AIP is required to form a complex with monomeric-intracellular-RET, caspase-3 and PKCδ resulting in PIT1/CDKN2A-ARF/p53-apoptosis pathway activation. AIP-deficiency blocks RET/caspase-3/PKCδ activation preventing PIT1 accumulation and apoptosis. The presence or lack of the inhibitory effect on RET-induced apoptosis separated pathogenic AIP variants from non-pathogenic ones. We used virogenomics in neonatal rats to demonstrate the effect of mutant AIP protein on the RET apoptotic pathway in vivo. In adult male rats altered AIP induces elevated IGF-1 and gigantism, with pituitary hyperplasia through blocking the RET-apoptotic pathway. In females, pituitary hyperplasia is induced but IGF-1 rise and gigantism are blunted by puberty. Somatotroph adenomas from pituitary-specific Aip-knockout mice overexpress the RET-ligand GDNF, therefore, upregulating the survival pathway. Somatotroph adenomas from patients with or without AIP mutation abundantly express GDNF, but AIP-mutated tissues have less CDKN2A-ARF expression. Our findings explain the tissue-specific mechanism of AIP-induced somatotrophinomas and provide a previously unknown tumorigenic mechanism, opening treatment avenues for AIP-related tumours.

MicroRNA-Mediated Drug Repurposing Unveiled Potential Candidate Drugs for Prolactinoma Treatment

Introduction: Prolactinomas, also called lactotroph adenomas, are the most encountered type of hormone-secreting pituitary neuroendocrine tumors in the clinic. The preferred first-line therapy is a medical treatment with dopamine agonists (DAs), mainly cabergoline, to reduce serum prolactin levels, tumor volume, and mass effect. However, in some cases, patients have displayed DA resistance with aggressive tumor behavior or are faced with recurrence after drug withdrawal. Also, currently used therapeutics have notorious side effects and impair the life quality of the patients. Methods: Since the amalgamation of clinical and laboratory data besides tumor histopathogenesis and transcriptional regulatory features of the tumor emerges to exhibit essential roles in the behavior and progression of prolactinomas; in this work, we integrated mRNA- and microRNA (miRNA)-level transcriptome data that exploit disease-specific signatures in addition to biological and pharmacological data to elucidate a rational prioritization of pathways and drugs in prolactinoma. Results: We identified 8 drug candidates through drug repurposing based on mRNA-miRNA-level data integration and evaluated their potential through in vitro assays in the MMQ cell line. Seven repurposed drugs including 5-fluorocytosine, nortriptyline, neratinib, puromycin, taxifolin, vorinostat, and zileuton were proposed as potential drug candidates for the treatment of prolactinoma. We further hypothesized possible mechanisms of drug action on MMQ cell viability through analyzing the PI3K/Akt signaling pathway and cell cycle arrest via flow cytometry and Western blotting. Discussion: We presented the transcriptomic landscape of prolactinoma through miRNA and mRNA-level data integration and proposed repurposed drug candidates based on this integration. We validated our findings through testing cell viability, cell cycle phases, and PI3K/Akt protein expressions. Effects of the drugs on cell cycle phases and inhibition of the PI3K/Akt pathway by all drugs gave us promising output for further studies using these drugs in the treatment of prolactinoma. This is the first study that reports miRNA-mediated repurposed drugs for prolactinoma treatment via in vitro experiments.

Pre- and postoperative 68 Ga-DOTATOC positron emission tomography for hormone-secreting pituitary neuroendocrine tumours.

Somatostatin receptors (SSTRs) are potential targets for detecting pituitary neuroendocrine tumours (PitNETs) that can be visualized effectively with 68 Ga-labelled PET tracers. With this study, we have evaluated the diagnostic properties of such a tracer, 68 Ga-DOTATOC, in patients with hormone-producing PitNETs before and after surgery. This prospective case-control study presents preoperative positron emission tomography (PET) and histopathological data in 18 patients with somatotroph (n=8), corticotroph (n=7) and thyrotroph (n=3) PitNETs. Patients were scanned pre- and postoperatively with 68 Ga-DOTATOC PET. For the postoperative part of the study, patients with gonadotroph tumours (n=7) were also included. Fifteen pituitary healthy controls underwent the same protocol once. The maximum standard uptake value (SUVmax ) was analysed in manually outlined regions around the tumour in patients and around the pituitary gland in controls. specimens were collected during surgery in subjects for assessment of adenohypophyseal tumour cell type and the SSTR expression. Thyrotroph tumours showed higher uptake (median SUVmax 41.1; IQR 37.4-60.0) and corticotroph tumours lower uptake (SUVmax 6.8; 2.6-9.3) than normal pituitary gland (SUVmax 13.8; 12.1-15.5). The uptake in somatotroph tumours (SUVmax 15.9; 11.6-19.7) was similar to the uptake in the pituitary gland. There was a strong correlation between SUVmax and SSTR2 expression (r=.75 (P<.01)). In the postoperative evaluation, PET was able to correlate tracer uptake with biochemical cure and noncure in patients with an abnormal postoperative magnetic resonance image and a preoperative tumour uptake SUVmax >13.8. 68 Ga-DOTATOC PET can be used to detect thyrotroph tumours in the pre- and postoperative imaging assessment. Corticotroph tumours had a significantly lower uptake compared to the pituitary gland but without a distinct increased tumour uptake the clinical postoperative value is limited.

Oncogene-induced DNA damage: cyclic AMP steps into the ring.

Growth hormone-secreting (GH-secreting) pituitary tumors are driven by oncogenes that induce cAMP signaling. In this issue of the JCI, Ben-Shlomo et al. performed a whole-exome study of pituitary adenomas. GH-secreting tumors had a high frequency of whole chromosome or chromosome arm copy number alterations and were associated with an increase in the tumor protein p53 and the cyclin-dependent kinase inhibitor p21WAF1/CIP1, which are findings consistent with induction of a response to DNA damage. Further, treatment of mouse pituitary cells with cAMP pathway agonists in vitro and in vivo elicited biomarkers of DNA replication stress or double-strand breaks. The findings of Ben Shlomo et al. indicate that oncoproteins that drive constitutively high cAMP signaling pathway output in susceptible cell types can elicit DNA replication stress and may promote genomic instability.