Signaling Pathways of AXL Receptor Tyrosine Kinase Contribute to the Pathogenetic Mechanisms of Glioblastoma.

Brain tumors are a diverse collection of neoplasms affecting the brain with a high prevalence rate in people of all ages around the globe. In this pathological context, glioblastoma, a form of glioma that belongs to the IV-grade astrocytoma group, is the most common and most aggressive form of the primary brain tumors. Indeed, despite the best treatments available including surgery, radiotherapy or a pharmacological approach with Temozolomide, glioblastoma patients' mortality is still high, within a few months of diagnosis. Therefore, to increase the chances of these patients surviving, it is critical to keep finding novel treatment opportunities. In the past, efforts to treat glioblastoma have mostly concentrated on customized treatment plans that target specific mutations such as epidermal growth factor receptor (EGFR) mutations, Neurotrophic Tyrosine Receptor Kinase (NTRK) fusions, or multiple receptors using multi-kinase inhibitors like Sunitinib and Regorafenib, with varying degrees of success. Here, we focused on the receptor tyrosine kinase AXL that has been identified as a mediator for tumor progression and therapy resistance in various cancer types, including squamous cell tumors, small cell lung cancer, and breast cancer. Activated AXL leads to a significant increase in tumor proliferation, tumor cell migration, and angiogenesis in different in vitro and in vivo models of cancer since this receptor regulates interplay with apoptotic, angiogenic and inflammatory pathways. Based on these premises, in this review we mainly focused on the role of AXL in the course of glioblastoma, considering its primary biological mechanisms and as a possible target for the application of the most recent treatments.

Innovations in Positron Emission Tomography and State of the Art in the Evaluation of Breast Cancer Treatment Response.

The advent of hybrid Positron Emission Tomography/Computed Tomography (PET/CT) and PET/Magnetic Resonance Imaging (MRI) scanners resulted in an increased clinical relevance of nuclear medicine in oncology. The use of [18F]-Fluorodeoxyglucose ([18F]FDG) has also made it possible to study tumors (including breast cancer) from not only a dimensional perspective but also from a metabolic point of view. In particular, the use of [18F]FDG PET allowed early confirmation of the efficacy or failure of therapy. The purpose of this review was to assess the literature concerning the response to various therapies for different subtypes of breast cancer through PET. We start by summarizing studies that investigate the validation of PET/CT for the assessment of the response to therapy in breast cancer; then, we present studies that compare PET imaging (including PET devices dedicated to the breast) with CT and MRI, focusing on the identification of the most useful parameters obtainable from PET/CT. We also focus on novel non-FDG radiotracers, as they allow for the acquisition of information on specific aspects of the new therapies.

Target Therapy in Thyroid Cancer: Current Challenge in Clinical Use of Tyrosine Kinase Inhibitors and Management of Side Effects.

Thyroid cancer (TC) is the most common endocrine malignancy. TC is classified as differentiated TC (DTC), which includes papillary and follicular subtypes and Hürthle cell variants, medullary TC (MTC), anaplastic TC (ATC), and poorly differentiated TC (PDTC). The standard of care in DTC consists of surgery together with radioactive iodine (131I) therapy and thyroid hormone, but patients with MTC do not benefit from 131I therapy. Patients with advanced TC resistant to 131I treatment (RAI-R) have no chance of cure, as well as patients affected by ATC and progressive MTC, in which conventional therapy plays only a palliative role, representing, until a few years ago, an urgent unmet need. In the last decade, a better understanding of molecular pathways involved in the tumorigenesis of specific histopathological subtypes of TC has led to develop tyrosine kinase inhibitors (TKIs). TKIs represent a valid treatment in progressive advanced disease and were tested in all subtypes of TC, highlighting the need to improve progression-free survival. However, treatments using these novel therapeutics are often accompanied by side effects that required optimal management to minimize their toxicities and thereby enable patients who show benefit to continue treatment and obtain maximal clinical efficacy. The goal of this overview is to provide an update on the current use of the main drugs recently studied for advanced TC and the management of the adverse events.

Ribociclib efficacy in special populations and analysis of patient-reported outcomes in the MONALEESA trials.

INTRODUCTION: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors abemaciclib, palbociclib, and ribociclib radically modified the treatment of hormone receptor-positive/human epidermal growth factor 2-negative advanced breast cancer. Ribociclib efficacy was proved in the phase III MONALEESA-2, -3, and -7 trials. In the first-line setting, ribociclib plus endocrine therapy determined statistically significant improvements in progression-free (PFS) and overall survival (OS) in pre-menopausal (MONALEESA-7) and post-menopausal (MONALEESA-2) women. Likewise, ribociclib and fulvestrant induced a significant PFS and OS benefit in post-menopausal women previously treated with endocrine therapy (MONALEESA-3). Additionally, ribociclib did not affect patients health-related quality of life in all the MONALEESA trials. AREAS COVERED: We reviewed the results of the available randomized phase III trials testing ribociclib and endocrine therapy in advanced breast cancer, focusing on different patient subgroups and then on health-related quality of life. EXPERT OPINION: The benefit of ribociclib is consistent across patient subgroups and is maintained in populations with unfavorable features, such as those with endocrine resistance or visceral metastases. Furthermore, the addition of ribociclib to endocrine therapy delays quality of life deterioration and improves pain scores. These results represent a pivotal improvement for the treatment of advanced breast cancer patients receiving CDK4/6 inhibitors.

Whole Brain Irradiation or Stereotactic RadioSurgery for five or more brain metastases (WHOBI-STER): A prospective comparative study of neurocognitive outcomes, level of autonomy in daily activities and quality of life.

AIMS: To evaluate neurocognitive performance, daily activity and quality of life (QoL), other than usual oncologic outcomes, among patients with brain metastasis ≥5 (MBM) from solid tumors treated with Stereotactic Brain Irradiation (SBI) or Whole Brain Irradiation (WBI). METHODS: This multicentric randomized controlled trial will involve the enrollment of 100 patients (50 for each arm) with MBM ≥ 5, age ≥ 18 years, Karnofsky Performance Status (KPS) ≥ 70, life expectancy > 3 months, known primary tumor, with controlled or controllable extracranial disease, baseline Montreal Cognitive Assessment (MoCA) score ≥ 20/30, Barthel Activities of Daily Living score ≥ 90/100, to be submitted to SBI by LINAC with monoisocentric technique and non-coplanar arcs (experimental arm) or to WBI (control arm). The primary endpoints are neurocognitive performance, QoL and autonomy in daily-life activities variations, the first one assessed by MoCa Score and Hopkins Verbal Learning Test-Revised, the second one through the EORTC QLQ-C15-PAL and QLQ-BN-20 questionnaires, the third one through the Barthel Index, respectively. The secondary endpoints are time to intracranial failure, overall survival, retreatment rate, acute and late toxicities, changing of KPS. It will be considered significant a statistical difference of at least 30% between the two arms (statistical power of 80% with a significance level of 95%). DISCUSSION: Several studies debate what is the decisive factor accountable for the development of neurocognitive decay among patients undergoing brain irradiation for MBM: radiation effect on clinically healthy brain tissue or intracranial tumor burden? The answer to this question may come from the recent technological advancement that allows, in a context of a significant time saving, improved patient comfort and minimizing radiation dose to off-target brain, a selective treatment of MBM simultaneously, otherwise attackable only by WBI. The achievement of a local control rate comparable to that obtained with WBI remains the fundamental prerequisite. TRIAL REGISTRATION: NCT number: NCT04891471.

Role of Calixarene in Chemotherapy Delivery Strategies.

Since cancer is a multifactorial disease with a high mortality rate, the study of new therapeutic strategies is one of the main objectives in modern research. Numerous chemotherapeutic agents, although widely used, have the disadvantage of being not very soluble in water or selective towards cancerous cells, with consequent side effects. Therefore, in recent years, a greater interest has emerged in innovative drug delivery systems (DDSs) such as calixarene, a third-generation supramolecular compound. Calixarene and its water-soluble derivatives show good biocompatibility and have low cytotoxicity. Thanks to their chemical-physical characteristics, calixarenes can be easily functionalized, and by itself can encapsulate host molecules forming nanostructures capable of releasing drugs in a controlled way. The encapsulation of anticancer drugs in a calixarene derivate improves their bioavailability and efficacy. Thus, the use of calixarenes as carriers of anticancer drugs could reduce their side effects and increase their affinity towards the target. This review summarizes the numerous research advances regarding the development of calixarene nanoparticles capable of encapsulating various anticancer drugs.

Role of the Combination of Cyclin-Dependent Kinase Inhibitors (CDKI) and Radiotherapy (RT) in the Treatment of Metastatic Breast Cancer (MBC): Advantages and Risks in Clinical Practice.

Targeting cell cycle has become the gold standard for metastatic breast cancer (MBC), being cyclin-dependent kinase inhibitors (CDKIs) cornerstones of its treatment, alongside radiotherapy (RT). To date, no definite evidence regarding safety and efficacy of the combination of CDKIs plus radiotherapy (RT) is currently available. Purpose of this review is to collect data in favor or against the feasibility of the association of CDKIs + RT, describing its potential adverse events. Our review shows how CDKI + RT allows an overall satisfying disease control, proving to be effective and causing a grade of toxicity mainly influenced by the site of irradiation, leaning to favourable outcomes for sites as liver, spine or brain and to poorer outcomes for thoracic lesions or sites close to viscera; controversial evidence is instead for bone treatment. Toxicity also varies from patient to patient. To sum up, our contribution enriches and enlightens a still indefinite field regarding the feasibility of CDKIs + RT, giving cues for innovative clinical management of hormone-responsive MBC.

Eribulin efficacy based on type of metastatic site: a real-life study in heavily pretreated metastatic breast cancer.

AIM: The halichondrin B analog, eribulin, exerts an anticancer effect, as reported by several clinical and real-life studies on metastatic breast cancer patients. Here, we evaluated efficacy and safety of eribulin, focusing on response to treatment per metastasis type. PATIENTS & METHODS: This monocentric, real-life study was conducted on 31 heavily pretreated patients with metastatic breast cancer. RESULTS: The median progression-free survival and overall survival were 2.0 and 5.5 months, respectively. All patients (12.9%) responding to eribulin were treated in fourth-line setting. Considering response per metastasis type, bone lesions (13.6%) responded more frequently than other metastases to eribulin. CONCLUSION: Eribulin exhibited a good overall response rate, with the highest response observed for bone metastases.

New treatment in advanced thyroid cancer.

Thyroid cancer is the most common endocrine tumor. Thyroidectomy, radioactive iodine, and TSH suppression represent the standard treatment for differentiated thyroid cancer. Since chemotherapy has been shown to be unsuccessful in case of advanced thyroid carcinomas, the research for new therapies is fundamental. In this paper, we reviewed the recent literature reports (pubmed, medline, EMBASE database, and abstracts published in meeting proceedings) on new treatments in advanced nonmedullary and medullary thyroid carcinomas. Studies of many tyrosine kinase inhibitors as well as antiangiogenic inhibitors suggest that patients with thyroid cancer could have an advantage with new target therapy. We summarized both the results obtained and the toxic effects associated with these treatments reported in clinical trials. Reported data in this paper are encouraging, but further trials are necessary to obtain a more effective result in thyroid carcinoma treatment.