The Progress of Immunotherapy in Refractory Pituitary Adenomas and Pituitary Carcinomas.
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ABSTRACT:
SUBMITTER: Dai C
PROVIDER: S-EPMC7761748 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
The Progress of Immunotherapy in Refractory Pituitary Adenomas and Pituitary Carcinomas.
Dai Congxin C Liang Siyu S Sun Bowen B Kang Jun J
Frontiers in endocrinology 20201211
Most pituitary adenomas (PAs) are considered benign tumors, but approximately 0.2% can present metastasis and are classified as pituitary carcinomas (PCs). Refractory PAs lie between benign adenomas and true malignant PC and are defined as aggressive-invasive PAs characterized by a high Ki-67 index, rapid growth, frequent recurrence, and resistance to conventional treatments, including temozolomide. It is notoriously difficult to manage refractory PAs and PC because of the limited therapeutic op ...[more]
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Project description:PurposeTo describe quality and outcomes of patient-reported outcome (PRO) measures (PROMs) used in patients with refractory hormone-producing pituitary adenomas, and to provide an overview of PROs in these challenging pituitary adenomas.MethodsThree databases were searched for studies reporting on refractory pituitary adenomas. For the purpose of this review, refractory adenomas were defined as tumors resistant to primary therapy. General risk of bias was assessed using a component approach and the quality of PROM reporting was assessed using the International Society for Quality of Life Research (ISOQOL) criteria.Results20 studies reported on PROMs in refractory pituitary adenomas, using 14 different PROMs, of which 4 were disease specific (median general risk of bias score: 33.5% (range 6-50%) and ISOQOL score: 46% (range 29-62%)). SF-36/RAND-36 and AcroQoL were most frequently used. Health-related quality of life in refractory patients (measured by AcroQoL, SF-36/Rand-36, Tuebingen CD-25, and EQ-5D-5L) varied greatly across studies, and was not always impaired compared to patients in remission.ConclusionThere is a scarcity of data on PROs in the subset of pituitary adenomas that is more difficult to treat, e.g., refractory and these patients are difficult to isolate from the total cohort. The patients' perspective on quality of life, therefore, remains largely unknown in refractory patients. Thus, PROs in refractory pituitary adenomas require adequate analysis using properly reported disease specific PROMs in large cohorts to enable appropriate interpretation for use in clinical practice.
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Project description:The genetic landscape of pituitary adenomas (PAs) is diverse and many of the identified cases remain of unclear pathogenetic mechanism. Germline genetic defects account for a small percentage of all patients and may present in the context of relevant family history. Defects in AIP (mutated in Familial Isolated Pituitary Adenoma syndrome or FIPA), MEN1 (coding for menin, mutated in Multiple Endocrine Neoplasia type 1 or MEN 1), PRKAR1A (mutated in Carney complex), GPR101 (involved in X-Linked Acrogigantism or X-LAG), and SDHx (mutated in the so called "3 P association" of PAs with pheochromocytomas and paragangliomas or 3PAs) account for the most common familial syndromes associated with PAs. Tumor genetic defects in USP8, GNAS, USP48 and BRAF are some of the commonly encountered tissue-specific changes and may explain a larger percentage of the developed tumors. Somatic (at the tumor level) genomic changes, copy number variations (CNVs), epigenetic modifications, and differential expression of miRNAs, add to the variable genetic background of PAs.
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Project description:CONTEXT:The tumor immune microenvironment is associated with clinical outcomes and immunotherapy responsiveness. OBJECTIVE:To investigate the intratumoral immune profile of pituitary adenomas (PAs) and its clinical relevance and to explore a novel immune classification for predicting immunotherapy responsiveness. DESIGN, PATIENTS, AND METHODS:The transcriptomic data from 259 PAs and 20 normal pituitaries were included for analysis. The ImmuCellAI algorithm was used to estimate the abundance of 24 types of tumor-infiltrating immune cells (TIICs) and the expression of immune checkpoint molecules (ICMs). RESULTS:The distributions of TIICs differed between PAs and normal pituitaries and varied among PA subtypes. T cells dominated the immune microenvironment across all subtypes of PAs. The tumor size and patient age were correlated with the TIIC abundance, and the ubiquitin-specific protease 8 (USP8) mutation in corticotroph adenomas influenced the intratumoral TIIC distributions. Three immune clusters were identified across PAs based on the TIIC distributions. Each cluster of PAs showed unique features of ICM expression that were correlated with distinct pathways related to tumor development and progression. CTLA4/CD86 expression was upregulated in cluster 1, whereas programmed cell death protein 1/programmed cell death 1 ligand 2 (PD1/PD-L2) expression was upregulated in cluster 2. Clusters 1 and 2 exhibited a "hot" immune microenvironment and were predicted to exhibit higher immunotherapy responsiveness than cluster 3, which exhibited an overall "cold" immune microenvironment. CONCLUSIONS:We summarized the immune profile of PAs and identified 3 novel immune clusters. These findings establish a foundation for further immune studies on PAs and provide new insights into immunotherapy strategies for PAs.
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Project description:Background and aimAbout a third of Pituitary Neuroendocrine Tumors (PitNETs) may show aggressive behavior. Many efforts have been performed for identifying possible predictive factors to early determine the future behavior of PitNETs. Programmed cell death ligand 1 (PD-L1) expression was associated with a more aggressive biology in different solid tumors, but its role in PitNET is not well-established yet. Our study aims to analyze PD-L1 expression in a surgical cohort of PitNETs to determine its association with radiological invasion and pathology findings, as well as with long-term recurrence rates.MethodsWe performed a retrospective analysis in a series of 86 PitNETs. Clinical presentation and radiological features of the preoperative period were collected, as well as pathological data and follow-up data. The rate of PD-L1 expression was immunohistochemically evaluated and expressed as a tumor proportion score (TPS). We assessed its relationship with cavernous sinus invasion and Trouillas' classification as primary outcomes. Secondary outcomes included the TPS' relationship with histopathological markers of proliferation, hormonal expression, tumor size and long-term recurrence rates. We calculated the optimal cut-point for the primary outcomes while maximizing the product of the sensitivity and specificity and then we evaluated the significance of secondary outcomes with logistic regression analysis.ResultsEighty-six patients were included in the analysis; 50 cases were non-functional PitNETs. The TPS for PD-L1 showed a highly right-skewed distribution in our sample, as 30.2% of patients scored 0. Using Trouillas' classification, we found that "proliferative" cases have a significantly higher probability to express PD-L1 in more than 30% of tumor cells (OR: 5.78; CI 95%: 1.80-18.4). This same cut-point was also associated with p53 expression. A positive association was found between PD-L1 expression and GH expression (p = 0.001; OR: 5.44; CI 95%: 1.98-14.98), while an inverse relationship was found with FSH/LH expression (p = 0.014; OR = 0.27, CI 95%: 0.10-0.76). No association was found with CS invasion, tumor size, bone erosion or dura invasion. We could not find any association between PD-L1 expression and recurrence.ConclusionsPD-L1 expression was associated with proliferative grades of Trouillas' classification and p53 expression. We also confirmed a higher expression of PD-L1 in somatotroph tumors. Larger studies are necessary to investigate the relationship between PD-L1 expression and aggressive behaviors.
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Project description:Pituitary adenoma (PA) is prevalent in the general population. Due to its severe complications and aggressive infiltration into the surrounding brain structure, the effective management of PA is required. Till now, no drug has been approved for treating non-functional PA, and the removal of cancerous cells from the pituitary is still under experimental investigation. Due to its superior specificity and safety profile, immunotherapy stands as one of the most promising strategies for dealing with PA refractory to the standard treatment, and various studies have been carried out to discover immune-related gene markers as target candidates. However, the lists of gene markers identified among different studies are reported to be highly inconsistent because of the greatly limited number of samples analyzed in each study. It is thus essential to substantially enlarge the sample size and comprehensively assess the robustness of the identified immune-related gene markers. Herein, a novel strategy of direct data integration (DDI) was proposed to combine available PA microarray datasets, which significantly enlarged the sample size. First, the robustness of the gene markers identified by DDI strategy was found to be substantially enhanced compared with that of previous studies. Then, the DDI of all reported PA-related microarray datasets were conducted to achieve a comprehensive identification of PA gene markers, and 66 immune-related genes were discovered as target candidates for PA immunotherapy. Finally, based on the analysis of human protein⁻protein interaction network, some promising target candidates (GAL, LMO4, STAT3, PD-L1, TGFB and TGFBR3) were proposed for PA immunotherapy. The strategy proposed together with the immune-related markers identified in this study provided a useful guidance for the development of novel immunotherapy for PA.
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Project description:The present study aimed to screen potential genes associated with pituitary adenomas to obtain further understanding with regard to the pathogenesis of pituitary adenomas. The microarray GSE23207 dataset, containing 16 pituitary adenoma samples from multiple endocrine neoplasia syndrome-associated rats and 5 normal pituitary tissue samples, was downloaded from Gene Expression Omnibus. The Linear Models for Microarray Data package was used to identify the differentially-expressed genes (DEGs) with the cut-off criteria of a |log2fold change (FC)|>1 and adjusted P-values of <0.05. The potential functions of the DEGs were predicted by functional and pathway enrichment analysis with the Database for Annotation, Visualization and Integrated Discovery. Furthermore, the interaction associations of the up- and downregulated DEGs obtained from the Search Tool for the Retrieval of Interacting Genes database were respectively revealed by the protein-protein interaction networks visualized with Cytoscape. A total of 391 upregulated and 238 downregulated DEGs in were screened in the pituitary adenoma samples. The upregulated DEGs with a higher degree in the protein-protein interaction network (e.g., CCNA2, CCNB1 and CDC20) were significantly involved in cell cycle and cell division. Notably, PTTG1 was enriched in every functional term. These DEGs interacted with each other. The downregulated DEGs (e.g., GABRA1, GABRA4 and GABRB1) also interacted with each other, and were relevant to neuroactive ligand-receptor interaction; the DEG POU1F1, interacting with POMC, was correlated with the development of the pituitary gland, adenohypophysis and endocrine system. Certain DEGs, including CCNB1, CCNA2, CDC20, GABRA1, GABRA4, GABRB1, POU1F1 and POMC, and particularly PTTG1, were shown to be closely involved in the pathogenesis of pituitary adenomas.
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Project description:Giant pituitary adenomas are a subgroup of pituitary adenomas defined by a diameter greater than 4 cm, and they account for 5-14% of adenomas in surgical series. Because of their growth patterns and locations, often involving critical neurovascular structures, they represent a true surgical challenge, and gross total resection is difficult to achieve. There is no consensus on the optimal surgical strategy for giant pituitary adenomas, and, often, integrated multi-staged treatment strategies have been considered. Transcranial or transsphenoidal approaches, alone or combined, according to tumor and patient features are the two main routes. Each of these strategies has pros and cons. The conventional transcranial approach has for a long time been considered the first choice for the removal of giant pituitary adenomas. Currently, with endoscopic techniques, it is also possible to remove lesions that involve the intradural compartment and the adjacent neurovascular structures with the use of extended approaches. Our policy for the management of these lesions is to adopt the endoscopic endonasal approach as the first choice unless the tumor presents significant intracranial extension that results in it being outside the visibility and maneuverability of the endoscopic endonasal route. In these latter cases, we agree that the transcranial approach is more appropriate. However, accurate preoperative evaluation and refined treatment plans for each patient are mandatory to define a proper strategy in order to achieve the most effective long-term result.
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