Soft extracellular matrix drives endoplasmic reticulum stress-dependent S quiescence underlying molecular traits of pulmonary basal cells.

Cell culture on soft matrix, either in 2D and 3D, preserves the characteristics of progenitors. However, the mechanism by which the mechanical microenvironment determines progenitor phenotype, and its relevance to human biology, remains poorly described. Here we designed multi-well hydrogel plates with a high degree of physico-chemical uniformity to reliably address the molecular mechanism underlying cell state modification driven by physiological stiffness. Cell cycle, differentiation and metabolic activity could be studied in parallel assays, showing that the soft environment promotes an atypical S-phase quiescence and prevents cell drift, while preserving the differentiation capacities of human bronchoepithelial cells. These softness-sensitive responses are associated with calcium leakage from the endoplasmic reticulum (ER) and defects in proteostasis and enhanced basal ER stress. The analysis of available single cell data of the human lung also showed that this non-conventional state coming from the soft extracellular environment is indeed consistent with molecular feature of pulmonary basal cells. Overall, this study demonstrates that mechanical mimicry in 2D culture supports allows to maintain progenitor cells in a state of high physiological relevance for characterizing the molecular events that govern progenitor biology in human tissues. STATEMENT OF SIGNIFICANCE: This study focuses on the molecular mechanism behind the progenitor state induced by a soft environment. Using innovative hydrogel supports mimicking normal human lung stiffness, the data presented demonstrate that lung mechanics prevent drift while preserving the differentiation capabilities of lung epithelial cells. Furthermore, we show that the cells are positioned in a quiescent state in the atypical S phase. Mechanistically, we demonstrate that this quiescence: i) is driven by calcium leakage from the endoplasmic reticulum (ER) and basal activation of the PERK branch of ER stress signalling, and ii) protects cells from lethal ER stress caused by metabolic stress. Finally, we validate using human single-cell data that these molecular features identified on the soft matrix are found in basal lung cells. Our results reveal original and relevant molecular mechanisms orchestrating cell fate in a soft environment and resistance to exogenous stresses, thus providing new fundamental and clinical insights into basal cell biology.

Pasireotide: potential treatment option for McCune-Albright-associated acromegaly.

Only 30% of patients with McCune-Albright syndrome (MAS)-associated acromegaly achieve biochemical control under first-generation somatostatin receptor ligands (fg-SRLs), while pegvisomant fails to normalize insulin-like growth factor 1 (IGF-I) in >20% of cases. Here, we report all the patients with MAS-associated acromegaly treated with pasireotide long-acting release (LAR) in our center. Pasireotide LAR 20 mg/month resulted in rapid and long-term IGF-I normalization in patients #1 and #3. Patient #3 was resistant to fg-SRLs, while patient #1 was also controlled on fg-SRLs. In patient #2, resistant to fg-SRLs and uncontrolled on pegvisomant 40 mg/day combined with cabergoline 0.5 mg/day, pegvisomant was replaced with pasireotide LAR 40 mg/month, resulting in the near normalization of IGF-I levels. All 3 patients developed intermittent impaired fasting glucose, without the need for glucose-lowering drugs. Thus, pasireotide LAR is clearly useful as third-line therapy, and potentially even as second-line therapy, in MAS-associated acromegaly.

scAN1.0: A reproducible and standardized pipeline for processing 10X single cell RNAseq data.

Single cell transcriptomics has recently seen a surge in popularity, leading to the need for data analysis pipelines that are reproducible, modular, and interoperable across different systems and institutions.To meet this demand, we introduce scAN1.0, a processing pipeline for analyzing 10X single cell RNA sequencing data. scAN1.0 is built using the Nextflow DSL2 and can be run on most computational systems. The modular design of Nextflow pipelines enables easy integration and evaluation of different blocks for specific analysis steps.We demonstrate the usefulness of scAN1.0 by showing its ability to examine the impact of the mapping step during the analysis of two datasets: (i) a 10X scRNAseq of a human pituitary gonadotroph tumor dataset and (ii) a murine 10X scRNAseq acquired on CD8 T cells during an immune response.

Therapeutic targeting of the pituitary tumor microenvironment.

The tumor microenvironment (TME), the complex environment in which tumors develop, has been increasingly targeted for cancer treatment in recent years. Aggressive pituitary tumors and pituitary carcinomas have been so far targeted with immune-checkpoint inhibitors (28 cases, including a large cohort), and anti-angiogenic drugs (34 cases), specifically bevacizumab (30 cases), sunitinib (three cases), and apatinib (one case). Here, we reviewed all these cases, reporting tumor response, potential predictors of response, as well as adverse events. Given that the histological type could potentially influence treatment response, we present the existing data separately for each type. Briefly, under ICIs, complete response was noted in one case, partial response in a third of cases, stable disease in 10% of cases, while 54% of tumors progressed. Under BVZ monotherapy, most cases (57%) showed stable disease, while 36% of tumors progressed; partial response was reported in only one case. The three cases treated with sunitinib monotherapy progressed. Regarding predictive factors of response, the tumor type (aggressive pituitary tumor versus pituitary carcinoma) appears as the strongest predictor of response to ICIs. To date, no predictor of response to anti-angiogenic drugs in the treatment of pituitary carcinomas and aggressive pituitary tumors has been identified. The interest of BZV add-on to first- or second-line chemotherapy warrants further investigation. In addition, we discuss perspectives regarding the TME-targeting in aggressive pituitary tumors and pituitary carcinomas, including perspectives on immunotherapy, anti-angiogenic drugs, as well as on other TME components, namely stromal cells, extracellular matrix, and secreted molecules.

Outcome and prognostic factors for pituitary carcinomas: lessons from a systematic review.

Purpose: The purpose of this work was toinvestigate the clinicopathological characteristics at the initial diagnosis of the pituitary tumor and at pituitary carcinoma (PC) diagnosis, alongside with the management and outcomes of PCs, and identify potential prognostic factors and therapeutic strategies associated with the clinical outcome. Methods: PubMed was searched in May 2021 for articles in English and French reporting PCs, the diagnosis of which was made on the presence of metastases. The cases without histological proof and with either another cancer present or an atypical history for a pituitary tumor were excluded. Results: One hundred and eighty-one articles reporting 207 cases were included, which included 38% corticotroph and 29% lactotroph carcinomas. An initial Ki67 index ≥10% was associated with shorter survival after the initial diagnosis (P = 0.01). Cases with early metastases were associated with both higher initial Ki67 index (P = 0.01) and shorter survival after PC diagnosis (P = 0.001). Interestingly, cases with short survival after PC diagnosis were associated with shorter time between the initial diagnosis and PC diagnosis (P = 0.0006) and had both higher initial Ki67 index (P = 0.003) and higher Ki67 index of the metastasis (P = 0.03). In addition, cases with long survival after PC diagnosis had received more frequently both systemic treatment after PC diagnosis (P = 0.0005) and local treatment for metastases (P < 0.0001). Conclusions: An initial Ki67 index ≥10% is associated with worse outcome and appears as a promising early marker of future metastasis. Its presence should lead to an intensified surveillance and to a more timely management. Clinicians should not hesitate to use local treatment, independent of whether systemic treatment is used.

Inhibition of activin signalling reduces the growth of LßT2 gonadotroph pituitary tumours in mouse.

Pituitary tumours are benign neoplasms that derive from hormone-producing cells of the pituitary gland. While medical treatments have emerged for most subtypes, gonadotroph tumours that express follicle-stimulating hormone (FSH) and/or luteinizing hormone still lack therapeutic options apart from surgery and radiotherapy. Activin ligands are physiological regulators of production and secretion of FSH by gonadotroph cells, but their role in gonadotroph tumourigenesis remains little explored. Using the LßT2 mouse gonadotroph cell line which produces FSH under activin stimulation, we first tested whether subcutaneous xenografts of LßT2 cells resulted in tumour formation in Rag2KO mice. Histological analysis confirmed the presence of LßT2 tumours with endothelial cells and macrophages in their microenvironment. FSH expression was found in a subset of clusters of LßT2 cells in the tumours. We subsequently addressed the consequences of targeting activin signalling via injection of a soluble activin decoy receptor (sActRIIB-Fc). sActRIIB-Fc treatment resulted in significantly decreased LßT2 tumour volume. Reduced Smad2 phosphorylation as well as inhibition of tumour-induced FSH production confirmed the efficient targeting of activin-downstream signalling in treated tumours. More interestingly, treated tumours showed significantly fewer endothelial cells associated with reduced Vegfa expression. In vitro treatment of LßT2 cells with sActRIIB-Fc had no effect on cell proliferation or apoptosis, but Vegfa expression was inhibited, pointing to a likely paracrine effect of LßT2 cells on endothelial cells through activin-mediated Vegfa regulation. Further in vitro and in vivo studies are now needed to pinpoint the exact roles of activin signalling in these processes prior to translating these observations to the clinic.

Biological and Therapeutic Implications of the Tumor Microenvironment in Pituitary Adenomas.

Pituitary adenomas (PAs) are neoplasms derived from the endocrine cells of the anterior pituitary gland. Most frequently, they are benign tumors, but may sometimes display an aggressive course, and in some cases metastasize. Their biology, including their wide range of behavior, is only partly understood. In terms of therapeutic targeting, most PAs are easily treated with available medical treatments, surgery, and sometimes radiotherapy. Nevertheless, gonadotroph adenomas lack medical therapeutic options, and treatment of aggressive PAs and pituitary carcinomas remains challenging. Here, we present an overview of the implications of the tumor microenvironment in PAs, reviewing its composition and function, as well as published cases that have been treated thus far using tumor microenvironment-targeting therapies. Additionally, we discuss emerging views, such as the concept of nonangiogenic tumors, and present perspectives regarding treatments that may represent future potential therapeutic options. Tumor-infiltrating lymphocytes, tumor-associated macrophages, folliculostellate cells, tumor-associated fibroblasts, angiogenesis, as well as the extracellular matrix and its remodeling, all have complex roles in the biology of PAs. They have been linked to hormone production/secretion, size, invasion, proliferation, progression/recurrence, and treatment response in PAs. From a therapeutic perspective, immune-checkpoint inhibitors and bevacizumab have already shown a degree of efficacy in aggressive PAs and pituitary carcinomas, and the use of numerous other tumor microenvironment-targeting therapies can be foreseen. In conclusion, similar to other cancers, understanding the tumor microenvironment improves our understanding of PA biology beyond genetics and epigenetics, and constitutes an important tool for developing future therapies.

Immunotherapy in pituitary carcinomas and aggressive pituitary tumors.

After temozolomide failure, no evidence-based treatment option is currently available for aggressive pituitary tumors (APTs) and pituitary carcinomas (PCs). Moreover, once temozolomide has failed, the survival of these patients is very poor. The use of immune-checkpoint inhibitors (ICIs) has been so far reported in a large cohort, a small phase 2 clinical trial, and in another five isolated cases (24 cases in total). Here, we review the available evidence on the efficacy and potential predictors of response to ICIs in PCs and APTs, namely the histological type (corticotroph versus lactotroph), the tumor type (PC versus APT), the presence of uncontrolled endogenous hypercortisolism, the type of protocol (combined ICIs versus monotherapy), programmed death-ligand 1 (PD-L1) expression, CD8+ cell infiltration, tumor mutational burden (TMB), microsatellite instability (MSI), and mismatch repair (MMR) status. We also discuss key clinical aspects that can already be implemented in the everyday practice and identify future research needs.

Predictive Factors of Somatostatin Receptor Ligand Response in Acromegaly-A Prospective Study.

CONTEXT: Somatostatin receptor ligands (SRLs) are the cornerstone medical treatments for acromegaly; however, many patients remain unresponsive to SRLs. Well-established predictive markers of response are needed. OBJECTIVE: We aimed to explore the relationship between responsiveness to SRLs relative to somatostatin (SST)2A and 5 receptor expression, adenoma granularity, and T2-weighted magnetic resonance imaging (MRI) signal intensity (T2WSI). METHODS: We conducted a multicentric, prospective, observational cohort study, in France. Forty-nine naïve patients (ie, patients without preoperative SRL treatment) with active acromegaly following surgery were treated with octreotide (group 1; n = 47), or pasireotide if uncontrolled under first-generation SRLs (group 2; n = 9). Data were collected at baseline and months 3 and 6. Biochemical measurements, immunohistochemistry studies, and MRI readings were centralized. RESULTS: In group 1, IGF-I decrease from baseline to month 6 positively correlated with SST2A immunoreactive score (IRS), P = 0.01. Densely granulated/intermediate adenomas had a greater IGF-I and GH decrease under octreotide compared with sparsely granulated adenomas (P = 0.02 and P = 0.006, respectively), and expressed greater levels of SST2A (P < 0.001), coupled with lower levels of SST5 (P = 0.004). T2WSI changed between preoperative MRI and month 6 MRI in one-half of the patients. Finally, SST5 IRS was higher in preoperative hyperintense compared with preoperative hypointense adenomas (P = 0.04), and most sparsely granulated and most hyperintense adenomas expressed high SST5 levels. CONCLUSION: We prospectively confirm that SST2A and adenoma granularity are good predictors of response to octreotide. We propose the IRS for scoring system harmonization. MRI sequences must be optimized to be able to use the T2WSI as a predictor of treatment response.

Real-life efficacy and predictors of response to immunotherapy in pituitary tumors: a cohort study.

Objective: After temozolomide failure, no evidence-based treatment is available for pituitary carcinomas (PCs) and aggressive pituitary tumors (APTs). To date, only 12 cases treated with immune-checkpoint inhibitors (ICIs) have been published, showing encouraging efficacy. Predictive factors of response are lacking. Here, we aimed to assess the real-life efficacy and predictors of response to ICIs in PCs and APTs. Design and methods: This study is a multicentric, retrospective, observational cohort study, including all PCs and APTs treated with ICIs in France up to March 2022. PD-L1 immunohistochemistry and CD8+ T cell infiltration were evaluated centrally. Results: Six PCs (four corticotroph and two lactotroph) and nine APTs (five corticotroph and four lactotroph) were included. The real-life efficacy of ICIs was lower than previously published data. Three corticotroph tumors (33.3%) showed partial response, one (11.1%) stable disease, while five (55.6%) progressed. One lactotroph tumor (16.7%) showed partial response, one (16.7%) stable disease, while four (66.7%) progressed. PCs responded far better than APTs, with 4/6 PCs showing partial response compared to 0/9 APTs. Corticotroph tumors responded slightly better than lactotroph tumors. In the four responsive corticotroph tumors, PD-L1 staining was negative and CD8+ T cell infiltration attained a maximum of 1% in the tumor center. Conclusions: Confirmation of the presence or absence of metastases is necessary before starting ICIs. After temozolomide failure, ICIs appear as a good therapeutic option for PCs, especially for corticotroph carcinomas. Negative PD-L1 staining and very low CD8+ T cell infiltration in the tumor center should not preclude ICI administration in corticotroph carcinomas. Significance statement: This is the first study to assess the real-life efficacy of ICIs in pituitary carcinomas (PCs) and aggressive pituitary tumors. We also assessed potential predictors of response and are the first to assess the predictive value of CD8+ cell infiltration. We identified the tumor type as a major predictor, ICIs proving far more effective in treating PCs. Our study provides evidence that ICIs are a good option after temozolomide failure for PCs (four of six responded), especially for corticotroph carcinomas (three of four responded). We also provide evidence that negative PD-L1 staining and very low CD8+ cell infiltration in the tumor center should not preclude ICI administration in corticotroph carcinomas. Moreover, our findings point toward the need to systematically perform extension workup before starting ICIs.

Aggressive corticotroph tumors and carcinomas.

Pituitary tumors are generally benign, although in rare cases aggressive pituitary tumors (APTs) and carcinomas present important diagnostic and therapeutic challenges and are associated with a high mortality rate. Almost half of these APTs and carcinomas are corticotroph tumors, suggesting a specific prognosis. Clinical, pathological and molecular prognostic markers are limited and do not allow early management of these tumors. Temozolomide remains the first-line treatment once a diagnosis of aggressive pituitary tumor or carcinoma has been made. Novel alternative treatments exist, including immune checkpoint inhibitors, which can be used in the case of temozolomide treatment failure. The aim of this review is to present the clinical, pathological and molecular characteristics of aggressive corticotroph tumors and carcinomas, and to describe the results obtained with currently available treatments.

Immunotherapy in aggressive pituitary tumors and carcinomas: a systematic review.

Once temozolomide has failed, there is no recommended treatment option for pituitary carcinomas and aggressive pituitary tumors. Immune-checkpoint inhibitors (ICIs) represent the most recent therapeutic avenue, having raised hope with the publication of the first successful case in 2018. Here, we present an overview of immunotherapy in pituitary carcinomas and aggressive pituitary tumors, starting with the rationale for using ICIs and the implications of tumor-infiltrating lymphocytes in anterior pituitary tumors, followed by a systematic review of all published cases, analyzing both treatment response and potential predictors of response and finishing with research and clinical perspectives. Seven corticotroph and four lactotroph tumors have been so far treated with ICIs. Corticotroph tumors showed radiological partial response in 57% of cases, followed by stable disease in 29% of cases, which was accompanied by biochemical partial or complete response in 83% of cases. Half of lactotroph tumors showed radiological complete or partial response, accompanied by biochemical complete response in 33% of the cases. In the case of a dissociate response, continuation of immunotherapy combined with local treatment represents a good option. At this time, a high tumor mutational burden appears to be the most promising predictive marker of response. MMR deficiency does not guarantee a response. Negative PD-L1 staining should not preclude ICIs administration. Therefore, ICIs are a promising option after temozolomide failure. This review highlights key clinical aspects that can already be implemented into practice and also discusses tumor biology concepts and perspectives expected to improve immunotherapy outcomes.

Intratumoural spatial distribution of S100B + folliculostellate cells is associated with proliferation and expression of FSH and ERα in gonadotroph tumours.

Folliculostellate cells are S100B-expressing cells with numerous functions in the normal anterior pituitary. These cells have also been identified in pituitary neuroendocrine tumours (PitNETs), where their precise role remains elusive. Here, we aimed to build a refined cartography of S100B-expressing cells to characterise their interpatient and intratumoural spatial distribution, and to start identifying their potential functions in PitNETs. High-throughput histological analysis of S100B-stained tumour sections of 54 PitNETs revealed a significant decrease in S100B + cells in PitNETs compared to the normal anterior pituitary. A Ki67 index ≥ 3, a mitosis count > 2/10 per high power fields, and a proliferative status, were all associated with fewer S100B + cells in gonadotroph tumours. Gonadotroph tumours also showed interpatient and intratumoural heterogeneity in the spatial distribution of S100B + cells. The existence of an intratumoural heterogeneity was further confirmed by the incorporation to our spatial analysis of additional markers: Ki67, FSH, LH, ERα and SSTR2. The tumour areas with fewer S100B + cells displayed a higher percentage of Ki67 + cells, whereas strong positive correlations were observed between S100B + , FSH + , and ERα + cells. Such spatial associations suggest that S100B + folliculostellate cells could play a role in gonadotroph tumorigenesis, and may contribute to the maintenance of tumour cells in a low proliferating, FSH + /ERα + differentiated state. Albeit, further in-depth functional studies are required to decipher the mechanisms underlying these spatial associations and to potentially identify a therapeutic use.

First case of chronic post-traumatic anterior pituitary dysfunction in a professional rugby player: A case report.

BACKGROUND: Post-traumatic hypopituitarism has been reported as a complication in a number of contact sports. Although rugby is a sport with a high risk and high incidence of concussion, no such cases have been reported to date. CASE PRESENTATION: A 35-year-old professional rugby player presented with fatigue and reduced libido complaints after nearly 300 professional games during his 15-year career. At the end of the season, biological monitoring was performed and revealed low total testosterone level associated with a low luteinizing hormone, suggestive of central hypogonadism. Brain magnetic resonance imaging (MRI) revealed the presence of a 10-mm sequel lesion in the right medial temporal lobe and two additional punctiform lesions, all suggestive of post-traumatic brain injury lesions. Testosterone replacement therapy was initiated and the player perceived an overall decrease in fatigue and complete restoration of his libido after only a couple of weeks of treatment. During follow-up, thyrotropic deficiency was diagnosed 2 years after initial diagnosis treated by l-Thyroxin. CONCLUSIONS: In conclusion, this case report highlights a new post-traumatic brain injury complication in a professional rugby player, namely chronic post-traumatic anterior pituitary dysfunction. STUDY DESIGN: Case report; level of evidence 4.

Aggressive pituitary tumours and pituitary carcinomas.

Although usually benign, anterior pituitary tumours occasionally exhibit aggressive behaviour, with invasion of surrounding tissues, rapid growth, resistance to conventional treatments and multiple recurrences. In very rare cases, they metastasize and are termed pituitary carcinomas. The time between a 'classical' pituitary tumour and a pituitary carcinoma can be years, which means that monitoring should be performed regularly in patients with clinical (invasion and/or tumour growth) or pathological (Ki67 index, mitotic count and/or p53 detection) markers suggesting aggressiveness. However, although both invasion and proliferation have prognostic value, such parameters cannot predict outcome or malignancy without metastasis. Future research should focus on the biology of both tumour cells and their microenvironment, hopefully with improved therapeutic outcomes. Currently, the initial therapeutic approach for aggressive pituitary tumours is generally to repeat surgery or radiotherapy in expert centres. Standard medical treatments usually have no effect on tumour progression but they can be maintained on a long-term basis to, at least partly, control hypersecretion. In cases where standard treatments prove ineffective, temozolomide, the sole formally recommended treatment, is effective in only one-third of patients. Personalized use of emerging therapies, including peptide receptor radionuclide therapy, angiogenesis-targeted therapy and immunotherapy, will hopefully improve the outcomes of patients with this severe condition.

Immune Landscape of Pituitary Tumors Reveals Association Between Macrophages and Gonadotroph Tumor Invasion.

PURPOSE: Pituitary neuroendocrine tumors (PitNETs) are frequent intracranial neoplasms that present heterogenic characteristics. Little is known about the immune cell network that exists in PitNETs and its contribution to their aggressive behavior. METHODS: Here we combined flow cytometry, t-SNE analysis, and histological approaches to define the immune landscape of surgically resected PitNETs. Xenografts of rodent pituitary tumor cells and resected PitNETs were performed in Rag2KO mice, in combination with in vitro analysis aimed at dissecting the role of pituitary tumor-cells in monocyte recruitment. RESULTS: We report that gonadotroph PitNETs present an increased CD68+ macrophage signature compared to somatotroph, lactotroph, and corticotroph PitNETs. Transcriptomic and histological characterizations confirmed gonadotroph infiltrating macrophages expressed CD163, MRC-1, ARG1, and CSF1R M2 macrophage markers. Use of growth hormone (GH)3/GH4 somatotroph and LßT2/αT3.1 gonadotroph cells drove THP1 macrophage migration through respective expression of CCL5 or CSF1. Although both LßT2 and GH3 cells recruited F4/80 macrophages following their engraftment in mice, only LßT2 gonadotroph cells showed a capacity for M2-like polarization. Similar observations were performed on patient-derived xenografts from somatotroph and gonadotroph tumors. Analysis of clinical data further demonstrated a significant correlation between the percentage of CD68+ and CD163+ infiltrating macrophages and the invasive character of gonadotroph tumors. CONCLUSIONS: Gonadotroph tumor drive the recruitment of macrophages and their subsequent polarization to an M2-like phenotype. More importantly, the association between infiltrating CD68+/CD163+ macrophages and the invasiveness of gonadotroph tumors points to macrophage-targeted immunotherapies being a potent strategy to limit the progression of gonadotroph PitNETs.

Immunotherapy in Corticotroph and Lactotroph Aggressive Tumors and Carcinomas: Two Case Reports and a Review of the Literature.

Once temozolomide has failed, no other treatment is recommended for pituitary carcinomas and aggressive pituitary tumors. Recently, the use of immune checkpoint inhibitors (ICIs) has raised hope, but so far, only one corticotroph carcinoma and one aggressive corticotroph tumor treated with immunotherapies have been reported in the literature. Here, we present two cases, one corticotroph carcinoma and one aggressive prolactinoma (the first one reported in the literature) treated with ipilimumab (1 mg/kg) and nivolumab (3 mg/kg) every three weeks, followed by maintenance treatment with nivolumab (3 mg/kg every 2 weeks) in the case of the corticotroph carcinoma, and we compare them with the two previously reported cases. Patient #1 presented a biochemical partial response (plasma ACTH decreased from 13,813 to 841 pg/mL) and dissociated radiological response to the combined ipilimumab and nivolumab-the pituitary mass decreased from 37 × 32 × 41 to 29 × 23 × 42 mm, and the pre-existing liver metastases decreased in size (the largest one from 45 to 14 mm) or disappeared, while a new 11-mm liver metastasis appeared. The maintenance nivolumab (21 cycles) resulted in a stable disease for the initial liver metastases, and in progressive disease for the newly appeared metastasis (effectively treated with radiofrequency ablation) and the pituitary mass. Patient #2 presented radiological and biochemical progressive disease after two cycles of ICIs-the pituitary mass increased from 38 × 42 × 26 to 53 × 57 × 44 mm, and the prolactin levels increased from 4410 to 9840 ng/mL. In conclusion, ICIs represent a promising therapeutic option for aggressive pituitary tumors and carcinomas. The identification of subgroups of responders will be key.

Aggressive Pituitary Adenomas and Carcinomas.

A subset of pituitary tumors present an aggressive behavior that remains difficult to predict, and in rare cases they metastasize. The current European Society for Endocrinology (ESE) guidelines for the management of aggressive pituitary tumors and carcinomas provide valuable guidance, but several issues remain unaddressed because of the scarcity of data in the literature. This article presents key clinical aspects regarding aggressive pituitary tumors and carcinomas, and also discusses some of the unanswered questions of the ESE guidelines, focusing on both diagnosis and treatment.

Treatment Options for Gonadotroph Tumors: Current State and Perspectives.

CONTEXT: Gonadotroph tumors represent approximatively one-third of anterior pituitary tumors, but despite their frequency, no medical treatment is currently recommended for them. This would be greatly needed because following surgery, which is the first-line treatment, a significant percentage of gonadotroph tumors regrow. EVIDENCE ACQUISITION: We performed PubMed searches in March 2020 using the term "gonadotroph" in combination with 36 different keywords related to dopamine type 2 receptor agonists, somatostatin receptor (SST) ligands, temozolomide, peptide receptor radionuclide therapy (PRRT), immunotherapy, vascular endothelial growth factor receptor (VEGFR)-targeted therapy, mammalian target of rapamycin (mTOR) inhibitors, and tyrosine kinase inhibitors. Articles resulting from these searches, as well as relevant references cited by these articles were reviewed. EVIDENCE SYNTHESIS: SST2 analogs have demonstrated only very limited antitumor effect, while high-dose cabergoline has been more effective in preventing tumor regrowth, but still in only a minority of cases. In the setting of an aggressive gonadotroph tumor, temozolomide is the recommended medical treatment, but has demonstrated also only limited efficacy. Still, its efficacy has been so far better than that of PRRT. No case of a gonadotroph tumor treated with pasireotide, VEGFR-targeted therapy, mTOR inhibitors, tyrosine kinase inhibitors, or immune checkpoint inhibitors is reported in literature. CONCLUSIONS: Gonadotroph tumors need better phenotyping in terms of both tumor cells and associated tumor microenvironment to improve their treatment. Until formal recommendations will be available, we provide the readers with our suggested approach for the management of gonadotroph tumors, management that should be discussed within multidisciplinary teams.