IntroductionMaturity Onset Diabetes of the Young (MODY) remains an underdiagnosed condition with remarkable genetic variability across populations. While diagnostic tools are based on Caucasian cohorts, Whole Exome Sequencing (WES) studies are needed to identify new genes in non-Caucasians, as up to 77% of patients do not harbor variants of significance in MODY-known genes. No WES studies have addressed the genomic landscape of MODY beyond its canonical genes in Latino populations. We aimed to characterize the genomic landscape of MODY through WES in a Mexican cohort, comparing cases with type 2 diabetes mellitus (T2DM) patients and healthy controls (HC).MethodsWES was performed in 17 patients with MODY, 17 with T2DM and 17 HC. We compared the single nucleotide variant landscape across groups in MODY-known genes and searched for genetic variants with differential enrichment across groups.ResultsMODY genes used for routine diagnosis showed low discrimination utility, as patients with MODY, T2DM and HC harbored genetic variants in MODY-known genes at similar frequencies in most cases. We found 14 genes with variants capable of distinguishing MODY from T2DM and HC. Variants in genes such as MAP2K3, SYT15, KCNJ12, PEX5, and TPTE were found in 75-100% of MODY cases while absent in T2DM and HC. Enrichment analysis revealed involvement in synaptic vesicle trafficking, insulin/IGF pathway-mitogen activated protein kinase kinase/MAPK, and insulin/IGF pathway-protein kinase B/AKT signaling.DiscussionMODY presents a complex genetic architecture in the Mexican population. Besides improving our understanding of glycemic regulation pathways, identified genes may serve as diagnostic biomarkers.

Growth hormone (GH), a 191-amino acid peptide produced by the anterior pituitary gland, plays a central role in linear growth, body composition, metabolism, and homeostasis. Exogenous GH has been used to treat GH deficiency (GHD) in children and adults since the early 1960s. GH used to be purified from human pituitaries obtained at autopsy, with the consequent limited availability and risk of Creutzfeld Jacob disease due to prion contamination. Since the mid 1980s all the GH used to treat humans is synthesized by recombinant DNA technologies (rhGH). rhGH is currently used in several conditions besides GHD, to promote linear growth in children with chronic kidney disease, patients with Turner syndrome, and in children with intrauterine growth retardation. Because of its metabolic effects, rhGH has been tried with varying results to improve the functional capacity of patients with cystic fibrosis, heart failure and critical illness, as well as the severe muscle wasting and lipodystrophy seen in patients with human immunodeficiency virus infection. Finally, rhGH has been used as an antiaging therapy and to improve athletic performance. Many of these unconventional uses of GH are certainly off label and can cause serious side effects. In the present review, we critically analyzed available data regarding these unconventional indications of rhGH.

Introduction: Predicting resistance to cabergoline in prolactinomas remains a challenge. While prolactin (PRL)-based ratios help differentiate prolactinomas from non-functioning pituitary adenomas (NFPAs), their role in forecasting therapeutic response is unclear.Objectives: To assess the usefulness of PRL-based ratios and tumor volume in distinguishing between prolactinomas and NFPAs, as well as in predicting cabergoline resistance.Methods: We conducted a retrospective study of 86 patients (46 NFPAs, 40 prolactinomas). Resistance was reclassified according to the updated 2023 Pituitary Society criteria, and PRL, tumor volume (software-measured and ellipsoid-calculated), and PRL-derived ratios (PRL/maximum diameter [MD)], PRL/volume [V)]) were evaluated using ROC analysis.Results: PRL and PRL/MD ratio excelled at differentiating prolactinomas from NFPAs (AUC = 0.999). Calculated tumor volume demonstrated moderate discriminative capacity for predicting cabergoline resistance (AUC = 0.668, p = 0.084), with an exploratory cutoff of 65.64 cm3 yielding a sensitivity of 64.3% and a specificity of 69.2%. PRL levels and PRL-based ratios were not predictive of resistance.Discussion: Calculated tumor volume showed exploratory predictive value but did not reach statistical significance. Importantly, baseline structural parameters should not be interpreted as substitutes for the early biochemical and radiological response at three to six months, as these responses remain the most reliable predictors of long-term responsiveness to dopamine agonists. Rather, tumor volume may represent a preliminary pre-treatment structural risk marker that requires further prospective validation.

Introduction:Pituitary tumors (PT) constitute the second most frequent intracranial tumor. A subset of PT can behave aggressively despite multimodal treatment. Hallmarks such as cellular senescence, epithelial-mesenchymal transition (EMT), and stemness have been implicated in tumor progression, but their role in PT pathogenesis remains is unclear. Methods:We performed spatial transcriptomics (ST) in dopamine agonist resistant prolactin secreting PT, as well as single nucleus RNAseq (snRNAseq) in growth hormone secreting and non-functioning of gonadotropic differentiation PT to describe the senescence, proliferative and stemness landscapes. Bioinformatic analyses included clustering, senescence scoring (SenePy), cell cycle inference (ccAFv2), differentiation potential (CytoTRACE2), and EMT signature evaluation. Primary tumor cell cultures were established to validate senescence (β-galactosidase activity) and to assess the senolytic effect of dasatinib. Result:All PT included in the study were transcriptomically heterogeneous, showing between three and ten transcriptional clusters. Senescence analysis reveals two main clusters regardless of PT lineage: One with a high and the other one with low senescence score. Most spots contain terminally differentiated cells at phase G1/G0 of the cell cycle. Distinct alteration in different signaling pathways were found in clusters with low senescence score: PI3K-cascade-FGFR1 and inositol phosphate metabolism among prolactin secreting tumors, phosphatidyl inositol signaling system and serine/threonine kinase activity the in GH-secreting PT, sphingolipid signaling pathway and serine/threonine kinase alterations among non-functioning of gonadotropic differentiation PT. Dasatinib treatment of primary cell cultures of pituitary tumors of different lineages showed significant dose-dependent cell death, accompanied by caspase-3/7 activation and morphological changes consistent with apoptosis. Conclusion:Our data show that PT may contain senescent and terminally differentiated cells without any EMT evidence, and dasatinib could represent an alternative for therapy resistant PT.

The epigenetic landscape and tumor microenvironment (TME) interactions of non-functioning pituitary adenomas (NFPAs), benign tumors with high morbidity and recurrence rates, are not well characterized. We completed single-nucleus (sn) multiomics assays on 4 gonadotrope NFPAs (34,819 cells) and 11 non-diseased postmortem control pituitaries (51,535 cells), finding decreased proportions of tumor-associated endothelial cells and pericytes and increased proportions of macrophages. We identified bidirectional tumor-macrophage crosstalk comprising nine ligand-receptor interactions and experimentally validated the macrophage-initiated SFRP1-FZD6 interaction, whose predicted target genes CCND1, CDK6, SGK1, and TGFBR2 were linked to tumorigenesis. We uncovered coordinated gene expression and chromatin accessibility programs, which distinguished adenoma cells from gonadotropes. Integrated transcriptome-chromatin modeling revealed gene regulatory circuits (GRCs) that showed altered activity in adenoma cells and were regulated by transcription factors (TFs), including PBX3 and MEF2C. Our study provides insight into the altered epigenetic gene control landscape and TME processes of the NFPA tumor phenotype. Our data are freely available at https://rstudio-connect.hpc.mssm.edu/nfpa_browser/.

Familial partial lipodystrophy type 2 is a rare disease, particularly when it is caused by nonclassical gene variants. A high index of suspicion is essential for a timely diagnosis. We present the case of a 32-year-old woman, referred to evaluation of a possible Cushing syndrome, which was clinically and biochemically ruled out. Yet, due to the finding of a rather abnormal fat distribution during physical examination, the diagnosis of lipodystrophy was cogitated. Whole-exome sequencing revealed a missense variant of exon 11 R582H of the gene encoding Laminin A (rs57830985,c.1745G>A, p.Arg582His). The patient presented some clinical and biochemical characteristics discordant with those previously reported in patients harboring other classical variants of this gene.

Disclosure: K. Taniguchi-Ponciano: None. F. Martinez-Mendoza: None. S. Andonegui-Elguera: None. E. Sosa-Eroza: None. E. Gomez-Apo: None. A. Escobar-España: None. G. Guinto-Nishimura: None. B. Lopez-Felix: None. E. Zepeda-Fernandez: None. E. Estrada-Estrada: None. E. Cantu-Chavez: None. R. Arreola-Rosales: None. D. Marrero-Rodríguez: None. M. Mercado: None. Resistant and sensitive GH pituitary neuroendocrine tumors resolved by spatial transcriptomics Acromegaly results from a growth hormone secreting pituitary neuroendocrine tumor (GH-PitNET) in more than 98% of cases. GH-PitNET are the second most common functioning pituitary adenomas. Acromegaly is a chronic and systemic condition that significantly compromises life expectancy and quality of life as a consequence of its metabolic, cardiovascular, cerebrovascular and respiratory comorbidities. Surgical removal of the adenoma is the treatment of choice, yet over 30% of these patients require adjuvant pharmacological treatment with first generation somatostatin receptor ligands (fgSRL) to achieve disease control. SRL normalize IGF-1 levels in 30-50% of patients; thus, a significant proportion of patients are resistant to this treatment. The molecular mechanisms underlying such resistance to fgSRL are largely unknown. This study aimed to identify molecular markers of aggressiveness and SRL resistance using spatial transcriptomics in patients with GH-PitNET. WE also performed bulk RNAseq on a second group of SRL-resistant and SRL-sensitive GH-PitNET. Ethical approval was obtained from our institutional review board, and patients were recruited with signed informed consent. High intratumoral heterogeneity was observed in patients with SRL-sensitive tumors with 8 and 10 transcriptomic clusters, whereas the SRL-resistant patients had 8 and 9 transcriptomic clusters. Differential gene expression revealed a distinct profile of SRL-sensitive and SRL-resistant patients. The 3 predominantly expressed genes were HLA-A, LMO3 and PCP4L1 in SRL-resistant patients, and CBLN1, NF1 and PRL in SRL-sensitive patients. Enrichment analysis showed that ECM-receptor interaction, MAPK signaling pathway and WNT signaling pathway are altered in SRL-resistant, whereas Sphingolipid signaling pathway, various types of N-glycan biosynthesis and Cell adhesion molecules are altered in SRL-sensitive PitNET. Similar findings were observed in the second group. We then performed a cell cycle analysis, showing that most spots/clusters are in G0/G1 cell cycle phase with very low number of spots in S, G2/M and early G1, this results in disregard of the SA-response status. We previously showed that sphingolipid and MAPK signaling pathways are altered in aggressive and recurrent PitNET and could represent an attractive molecular target. Presentation: Monday, July 14, 2025

Context Genetic tests are part of the routine clinical approach to syndromic and nonsyndromic phenotypes of neuroendocrine neoplasms (NENs). Current data on phenotype-genotype associations in NENs, however, do not accurately represent all populations.Objective To describe the frequency, inventory, and clinical associations of germline defects associated with multiple types of NENs in a Mexican cohort.Methods Blood DNA from Mexican adults with NENs was analyzed with a 53-gene next-generation sequencing panel developed ad hoc (n = 90) or Sanger sequencing (n = 2). Single nucleotide variants, indels, and structural variants were identified, classified, and subjected to orthogonal confirmation. When possible, tumor samples and blood DNA from additional family members were tested using Sanger sequencing.Results Ninety-two probands (70.7% women, 51.5% sporadic) were included; 16 carried pathogenic or likely pathogenic (P/LP) variants and were significantly younger at disease onset than the rest (29.6 +/- 10.7 vs 40 [21.5-51.5] years, P = .0384). Likely driving variants were identified in three-quarters of Von Hippel Lindau syndrome cases, one-third of multiple endocrine neoplasia (MEN) type 1, one-quarter of early-onset acromegaly/gigantism, and individual cases of Cushing's disease, MEN2A, and medullary thyroid carcinoma. One patient with clinical MEN1 associated with an SDHA variant and 1 with a pituitary tumor and neurofibromatosis type 1 were also identified. Probands with familial disease were more likely to carry P/LP variants than sporadic cases (26.7 vs 8.5%, P = .0282).Conclusion P/LP variants were identified in 17.4% of individuals with NENs. Our research provides a view of the landscape of NEN drivers in a population not previously characterized.

The 15th Acromegaly Consensus Conference in September 2023 updated recommendations on therapeutic outcomes for acromegaly. Since the publication of medical management guidelines in 2018, new pharmacological agents and new treatment approaches have been developed. Fifty-two experts in the management of acromegaly reviewed the current literature and assessed changes in drug approvals, clinical practice standards and management. Current outcome goals were considered, with a focus on the effect of current and emerging somatostatin receptor ligands, the growth hormone receptor antagonist pegvisomant and the dopamine agonist cabergoline on biochemical control, clinical control, adenoma mass and surgical outcomes. Participants assessed factors that determine pharmacological choices, as well as the proposed use of each agent. Here, we present consensus recommendations highlighting how an evidence-based acromegaly management algorithm could be optimized in clinical practice. In this Consensus Statement, an international group of experts provide updated recommendations on the treatment of acromegaly, including discussion of treatment outcomes.

Disclosure: D. Marrero-Rodríguez: None. K. Taniguchi-Ponciano: None. F. Martinez-Mendoza: None. S. Andonegui-Elguera: None. E. Sosa-Eroza: None. E. Gomez-Apo: None. A. Escobar-España: None. A. Moscona Nissan: None. G. Guinto-Nishimura: None. B. Lopez-Felix: None. E. Zepeda-Fernandez: None. C. Victor: None. P. Gonzalez-Zavala: None. M. Asenscio-Montiel: None. M. Garcia-Vargas: None. E. Cantu-Chavez: None. R. Arreola-Rosales: None. M. Mercado: None. Lactotroph pituitary neuroendocrine tumors (PRL-PitNET) are the most common functioning pituitary neoplasm, accounting for 50% of all pituitary tumors. About 15% behave aggressively with rapid growth despite dopamine agonist (DA) therapy. Lactotroph carcinomas resemble aggressive PRL-PitNET but feature craniospinal or distant metastases. This study aimed to identify molecular markers of aggressiveness and DA resistance using spatial transcriptomics, as well as whole exome and transcriptome sequencing in patients with aggressive, DA-resistant PRL-PitNET. Ethical approval was obtained from our institutional review board, and patients were recruited with signed informed consent.The evaluated tumors contained a few stem cells, a high number of tumor cells, and a relatively low number of endothelial cells and macrophages. Each tumor showed from 3 to 10 transcriptional clusters. Interestingly, when senescence was analyzed, tumors showed only two main clusters, one with high a senescence score and a second one with a low score. The trajectory correlated with the senescence score, indicating a transition from a high to a low senescent profile. We found a close association between the metabolic alterations and the senescence landscape. Particularly, high-score senescence clusters showed alterations in glycerolipid, phospholipid, glycerophospholipid and phosphatidylinositol metabolic processes. The high senescence metabolically altered clusters showed alteration in PI3K-AKT signaling, linking metabolism with pathways regulating senescence in aggressive PRL-PitNET. We also performed cell potency and epithelial-mesenchymal transition (EMT) analysis to identify if there was any de-differentiation process or any EMT process, showing no cell state regression. The cell proliferation analysis showed that most spots in all tumors were predominantly in G1/G0 phase of the cell cycle. Exome-seq showed SF3B1 and TP53 pathogenic variants in one tumor each. Altogether, metabolically altered, senescent clones correlate with pharmacologically-resistant and aggressive PRL-PitNET. It remains to be elucidated whether these alterations are induced by DA or are inherent to these neoplasms. Presentation: Monday, July 14, 2025

ABSTRACT A 25‐year‐old previously healthy man presents to the clinic with a severe headache after cocaine consumption. Physical examination revealed acromegaloid features, and the hormonal profile revealed an IGF‐1 of 308 ng/mL (40.8 nmol/L) (normal reference range 197–333 ng/mL; 17.8–45.6). An MRI showed a heterogeneous, cystic lesion of the pituitary gland with hematic contents, consistent with the diagnosis of a pituitary apoplexy. Considering the normal IGF‐1 level, the patient was classified to be in remission, which deems it unnecessary to initiate pharmacologic or surgical treatment. Remission of acromegaly after a pituitary apoplexy is an extremely rare event, and pituitary apoplexy after cocaine consumption is also anecdotal. We present the first case of remission of acromegaly after a cocaine‐induced pituitary apoplexy.

Clinically aggressive lactotroph pituitary neuroendocrine tumors (PitNET) are invasive tumors with an unusually rapid growth rate despite maximally tolerated doses of dopamine agonist (DA). We aimed to unravel the molecular heterogeneity of lactotroph PitNET and to identify biomarkers of aggressiveness and resistance to pharmacological treatment. A total of 13 patients harboring DA-resistant lactotroph PitNET were included in this study. Visium Spatial Transcriptomics (ST), whole transcriptome sequencing (WTS), and whole exome sequencing (WES) were performed in tumors from 4 of these patients; WTS and WES was carried out in 5; tumors from two patients underwent ST and WES and tumors from two other patients underwent only ST. Tumors were classified as null or partial responders according to their response to DA treatment. The eight PitNET analyzed by ST exhibited significant intratumoral heterogeneity, with clones showing alterations in PI3K/AKT and lipid metabolism pathways, particularly inositol phosphate, glycerophospholipid, and sphingolipid metabolism. The cell-cell communication analysis showed FGF-FGFR ligand receptor interaction whilst the transcription factors RXRA and CREM showed participation in both groups. A trajectory exploration was performed by including all PitNET together in a single analysis to determine whether there was a tendency or molecular pathway showing a differentiation pattern that would guide the transition from a partially responsive PitNET to a completely unresponsive one. We did not observe any such pattern. All of these findings were corroborated in the cohort of DA-resistant PitNETs in which only bulk WTS and WES were performed. The bulk WTS corroborated lipid metabolism and PI3K-AKT pathway alteration in PitNET, whereas the WES showed only SF3β1 and TP53 variants in one tumor each. Our work suggests that the PI3K/AKT pathway may constitute a molecular target at which to aim therapeutic strategies designed to treat aggressive and DA-resistant lactotroph PitNET.

Pituitary neuroendocrine tumors (PitNET) are known to be variably infiltrated by different immune cells. Nonetheless, their role in pituitary oncogenesis has only begun to be unveiled. The immune microenvironment could determine the biological and clinical behavior of a neoplasm and may have prognostic implications. To evaluate the expression of immune-related genes and to correlate such expression with the presence of infiltrating immune cells in forty-two PitNETs of different lineages, we performed whole transcriptome analysis and RT-qPCR. Deconvolution analysis was carried out to infer the immune cell types present in each tumor and the presence of immune cells was confirmed by immunofluorescence. We found characteristic expression profiles of immune-related genes including those encoding interleukins and chemokines for each tumor lineage. Genes such as IL4-I1, IL-36A, TIRAP, IL-17REL, and CCL5 were upregulated in all PitNETS, whereas IL34, IL20RA, and IL-2RB characterize the NR5A1-, TBX19-, and POU1F1-derived tumors, respectively. Transcriptome deconvolution analysis showed that M2 macrophages, CD4+ T cells, CD8+ T cells, NK cells, and neutrophils can potentially infiltrate PitNET. Furthermore, CD4+ and CD8+ T cells and NK cells infiltration was validated by immunofluorescence. Expression of CCL18, IL-5RA, and HLA-B as well as macrophage tumor infiltration could identify patients who can potentially benefit from treatment with immune checkpoint inhibitors.

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