Emerging and Novel Treatments for Pituitary Tumors

A subset of pituitary neuroendocrine tumors (PitNETs) have an aggressive behavior, showing resistance to treatment and/or multiple recurrences in spite of the optimal use of standard therapies (surgery, conventional medical treatments, and radiotherapy). To date, for aggressive PitNETs, temozolomide (TMZ) has been the most used therapeutic option, and has resulted in an improvement in the five-year survival rate in responders. However, given the fact that roughly only one third of patients showed a partial or complete radiological response on the first course of TMZ, and even fewer patients responded to a second course of TMZ, other treatment options are urgently needed. Emerging therapies consist predominantly of peptide receptor radionuclide therapy (20 cases), vascular endothelial growth factor receptor-targeted therapy (12 cases), tyrosine kinase inhibitors (10 cases), mammalian target of rapamycin (mTOR) inhibitors (six cases), and more recently, immune checkpoint inhibitors (one case). Here, we present the available clinical cases published in the literature for each of these treatments. The therapies that currently show the most promise (based on the achievement of partial radiological response in a certain number of cases) are immune checkpoint inhibitors, peptide receptor radionuclide therapy, and vascular endothelial growth factor receptor-targeted therapy. In the future, further improvement of these therapies and the development of other novel therapies, their use in personalized medicine, and a better understanding of combination therapies, will hopefully result in better outcomes for patients bearing aggressive PitNETs

The Microenvironment of Pituitary Tumors—Biological and Therapeutic Implications

International audienceThe tumor microenvironment (TME) includes resident and infiltrative non-tumor cells, as well as blood and lymph vessels, extracellular matrix molecules, and numerous soluble factors, such as cytokines and chemokines. While the TME is now considered to be a prognostic tool and a therapeutic target for many cancers, little is known about its composition in pituitary tumors. This review summarizes our current knowledge of the TME within pituitary tumors and the strong interest in TME as a therapeutic target. While we cover the importance of angiogenesis and immune infiltrating cells, we also address the role of the elusive folliculostellate cells, the emerging literature on pituitary tumor-associated fibroblasts, and the contribution of extracellular matrix components in these tumors. The cases of human pituitary tumors treated with TME-targeting therapies are reviewed and emerging concepts of vascular normalization and combined therapies are presented. Together, this snapshot overview of the current literature pinpoints not only the underestimated role of TME components in pituitary tumor biology, but also the major promise it may offer for both prognosis and targeted therapeutics

Immunotherapy in aggressive pituitary tumors and carcinomas: a systematic review

International audienceOnce 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

Biological and Therapeutic Implications of the Tumor Microenvironment in Pituitary Adenomas

International audienceAbstract 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

Gonadotroph Tumors Show Subtype Differences that Might Have Implications for Therapy

Gonadotroph tumors, although frequent, are poorly studied and understood, being usually included in the larger nonfunctioning pituitary neuroendocrine tumors (PitNETs) group. Moreover, in comparison to the other types of PitNETs, no established medical treatment is currently available for gonadotroph tumors. Here, we performed a retrospective study and analyzed the clinicopathological characteristics of 98 gonadotroph tumors operated in a single large pituitary center. Although being larger in men (p = 0.01), the aggressiveness of gonadotroph tumors did not appear to be sex-related. LH tumors were rare (4/98) and exclusively encountered in men. Somatostatin receptor type 5 (SST5) was absent in all analyzed tumors. The immunoreactive score (IRS) of somatostatin receptor type 2 (SST2) and of estrogen receptor alpha (ERα) was associated with the histological subtype (p = 0.01 and p = 0.02). IRS ERα correlated moderately with IRS SST2 in all (rho = 0.44, adjusted p-value = 0.0001) and in male (rho = 0.51, adjusted p-value = 0.0002) patients, and with follicle-stimulating hormone (FSH) percentage in all (rho = 0.40, adjusted p-value = 0.0005) and in female (rho = 0.58, adjusted p-value = 0.004) patients. In conclusion, gonadotroph tumors exhibit histological characteristics pinpointing the existence of several subtypes. Their heterogeneity warrants further investigations and may have to be taken into account when studying these tumors and investigating treatment options

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

Consumer Choice for Milk and Dairy in Romania: Does Income Really Have an Influence?

Milk and dairy are basic food products and their importance in healthy human development is well known. However, this does not mean that the consumers’ requests for these products are not evolving and fitting into the new context of sustainable development. By conducting a quantitative analysis on 847 answers regarding milk and dairy consumption offered by Romanian consumers, the objective of this study is to reveal what are the main factors of influence for respondents when choosing a milk or dairy product, and to see if these factors are evolving towards including sustainability-related aspects. The results point out that while price and store availability are still present as choice criteria, new aspects that might be related to a sustainable behavior, such as ecologic certification, country of origin or traditional products, are considered by the respondents when purchasing milk and dairy. However, this depends on the level of income; higher incomes allow respondents to consider new criteria