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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.

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Pituitary apoplexy (PA) is a clinical syndrome resulting from a hemorrhagic infarction of the pituitary gland. It is characterized by the sudden onset of visual disturbances, nausea, vomiting, headache and occasionally, signs of meningeal irritation and an altered mental status. The exact pathogenesis of PA remains to be elucidated, although tumor overgrowth of its blood supply remains the most popular theory. Main risk factors for the development of PA include systemic, iatrogenic, and external factors as well as the presence of an underlying pituitary tumor. The diagnostic approach of PA includes both neuroimaging and evaluation of pituitary secretory function. PA is a potentially life-threatening condition which should be managed with hemodynamic stabilization, correction of electrolyte abnormalities and replacement of hormonal deficiencies. PA treatment should be individualized based on the severity of the clinical picture which may vary widely. Treatment options include conservative management with periodic follow-up or neurosurgical intervention, which should be decided by a multidisciplinary team. We conducted a systematic review of the literature to unveil the frequency of PA predisposing factors, clinical and biochemical presentations, management strategies and outcomes.

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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.

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BACKGROUND: The tumor microenvironment (TME) includes diverse cellular components such as mesenchymal stem cells (MSC) and immune cells among others. MSC have been isolated from different tumors and they favor tumor cell growth, however, their role in pituitary tumors (PT) remains unknown. Herein we report the presence of MSCs in 2 ACTH-secreting PT causing Cushing disease (MCU), 2 nonfunctioning adenomas of gonadotrope differentiation (MNF) and 2 non tumoral pituitary glands (MS). METHODS: We have analyzed their transcriptomic profiles by RNAseq and compared MSC in terms of their immunosuppressive effects against lymphoid T cell and macrophage populations by means of co-cultures and flow cytometry. RESULTS: Our transcriptomic analysis revealed molecular differences between MSC derived from non-tumoral pituitaries and MSC derived from PT. Two distinct subpopulations of MSC, one displaying immunosuppressive properties and the other with increased pro-proliferative capabilities, regardless of their origin. MSC derived from ACTH- and nonfunctioning PT, but not those derived from non-tumoral glands significantly inhibited the proliferation of activated T cells, favored the generation of Tregs and promote 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 IL-10. Importantly, MSC derived from ACTH-PT showed a higher immunosuppressive potential than MSC isolated from nonfunctioning tumors. CONCLUSION: This study demonstrates the presence of at least two MSC subpopulations in the pituitary gland and suggests that immunosuppressive effects of MSC may have important implications in PT growth.

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GH-secreting tumors represent 15 % to 20 % of all pituitary neuroendocrine tumors (pitNETs), of which 95 % occur in a sporadic context, without an identifiable inherited cause. Recent multi-omic approaches have characterized the epigenomic, genomic, transcriptomic, proteomic and kynomic landscape of pituitary tumors. Transcriptomic analysis has allowed us to discover specific transcription factors driving the differentiation of pituitary tumors and gene expression patterns. GH-secreting, along with PRL- and TSH-secreting pitNETs are driven by POU1F1; ACTH-secreting tumors are determined by TBX19; and non-functioning tumors, which are predominantly of gonadotrope differentiation are conditioned by NR5A1. Upregulation of certain miRNAs, such as miR-107, is associated with tumor progression, while downregulation of others, like miR-15a and miR-16-1, correlates with tumor size reduction. Additionally, miRNA expression profiles are linked to treatment resistance and clinical outcomes, providing insights into potential therapeutic targets. Specific somatic mutations in GNAS, PTTG1, GIPR, HGMA2, MAST and somatic variants associated with cAMP, calcium signaling, and ATP pathways have also been associated with the development of acromegaly. This review focuses on the oncogenic mechanisms by which sporadic acromegaly can develop, covering a complex series of molecular alterations that ultimately alter the balance between proliferation and apoptosis, and dysregulated hormonal secretion.

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Pituitary tumors (PT) are highly heterogeneous neoplasms, comprising functioning and nonfunctioning lesions. Functioning PT include prolactinomas, causing amenorrhea-galactorrhea in women and sexual dysfunction in men; GH-secreting adenomas causing acromegaly-gigantism; ACTH-secreting corticotrophinomas causing Cushing disease (CD); and the rare TSH-secreting thyrotrophinomas that result in central hyperthyroidism. Nonfunctioning PT do not result in a hormonal hypersecretion syndrome and most of them are of gonadotrope differentiation; other non-functioning PT include null cell adenomas and silent ACTH-, GH- and PRL-adenomas. Less than 5% of PT occur in a familial or syndromic context whereby germline mutations of specific genes account for their molecular pathogenesis. In contrast, the more common sporadic PT do not result from a single molecular abnormality but rather emerge from several oncogenic events that culminate in an increased proliferation of pituitary cells, and in the case of functioning tumors, in a non-regulated hormonal hypersecretion. In recent years, important advances in the understanding of the molecular pathogenesis of PT have been made, including the genomic, transcriptomic, epigenetic, and proteomic characterization of these neoplasms. In this review, we summarize the available molecular information pertaining the oncogenesis of PT.

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Neutrophils infiltrate several types of cancer; however, whether their presence is associated with disease progression remains controversial. Here, we show that colon tumors overexpress neutrophil chemoattractants compared to healthy tissues, leading to their recruitment to the invasive margin and the central part of colon tumors. Of note, tumor-associated neutrophils expressing tumor necrosis factor α, which usually represents an antitumoral phenotype, were predominantly located in the invasive margin. Tumor-associated neutrophils from the invasive margin displayed an antitumoral phenotype with higher ICAM-1 and CD95 expression than neutrophils from healthy adjacent tissues. A higher neutrophil/lymphocyte ratio was found at later stages compared to the early phases of colon cancer. A neutrophil/lymphocyte ratio ≤3.5 predicted tumor samples had significantly more neutrophils at the invasive margin and the central part. Moreover, tumor-associated neutrophils at the invasive margin of early-stage tumors showed higher ICAM-1 and CD95 expression. Coculture of colon cancer cell lines with primary neutrophils induced ICAM-1 and CD95 expression, confirming our in situ findings. Thus, our data demonstrate that tumor-associated neutrophils with an antitumoral phenotype characterized by high ICAM-1 and CD95 expression infiltrate the invasive margin of early-stage colon tumors, suggesting that these cells can combat the disease at its early courses. The presence of tumor-associated neutrophils with antitumoral phenotype could help predict outcomes of patients with colon cancer.

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Over 20 years ago, Hanahan and Weinberg published a seminal review that addressed the biological processes that underly malignant transformation. This classical review, along with two revisions published in 2011 and 2022, has remain a classic of the oncology literature. Since many of the addressed biological processes may apply to non-malignant tumorigenesis, we evaluated to what extent these hallmarks pertain to the development of pituitary adenomas.Some of the biological processes analyzed in this review include genome instability generated by somatic USP8 and GNAS mutations in Cushing's diseases and acromegaly respectively; non-mutational epigenetic reprograming through changes in methylation; induction of angiogenesis through alterations of VEGF gene expression; promotion of proliferative signals mediated by EGFR; evasion of growth suppression by disrupting cyclin dependent kinase inhibitors; avoidance of immune destruction; and the promotion of inflammation mediated by alteration of gene expression of immune check points. We also elaborate further on the existence of oncogene induced senescence in pituitary tumors. We conclude that a better understanding of these processes can help us dilucidated why pituitary tumors are so resistant to malignant transformation and can potentially contribute to the development of novel anticancer treatments.

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INTRODUCTION: The prevalence of the different genotypes of human papillomavirus (HPV) varies depending on lesion severity and geographic region. OBJECTIVE: To identify multiple HPV infections in low- and high-grade cervical lesions in a group of women from the Mexican Bajío region referred with inconclusive cytology. METHODS: Pilot study of women referred from primary care units of Guanajuato, Mexico, with cytology suggestive of cervical lesion. Cervical smears were subjected to DNA extraction and HPV genotyping using microarrays. RESULTS: 100 consecutive cases were collected and 90 were analyzed; HPV positivity was observed in 26% of healthy women, and 62% had some degree of cervical lesion. The most common HPV genotypes were 59, 31, 16 and 51. Multiple infections were found in most samples. CONCLUSIONS: HPV heterogeneity was identified in the samples of the study population in contrast to worldwide reports; furthermore, multiple infections are common in precursor lesions and decrease in high-grade lesions. These data could have an impact on current HPV vaccination programs.

INTRODUCCIÓN: La prevalencia de los diferentes genotipos de virus del papiloma humano (VPH) varía dependiendo de la severidad de la lesión y región geográfica. OBJETIVO: Identificar infecciones múltiples de VPH en lesiones cervicales de bajo y alto grado en un grupo de mujeres del Bajío mexicano referidas con citología no concluyente. MÉTODOS: Estudio piloto de mujeres referidas de unidades del primer nivel de atención de Guanajuato, México, por citología sugerente de lesión cervical. Los raspados cervicales fueron sujetos a extracción de ADN y genotipificación del VPH mediante microarreglos. RESULTADOS: Se colectaron 100 casos consecutivos y fueron analizados 90; se observó 26 % de positividad a VPH en mujeres sanas y 62 % presentó algún grado de lesión. Los genotipos de VPH más frecuentes fueron 59, 31, 16 y 51. En la mayoría de las muestras se encontró infección múltiple. CONCLUSIONES: Se identificó heterogeneidad de VPH en las muestras de la población estudiada en contraste con los reportes internacionales; además, son comunes las infecciones múltiples en lesiones precursoras y disminuyen en las lesiones de alto grado. Estos datos podrían influir en los actuales programas de vacunación anti-VPH.

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