Pituitary metastasis: a rare condition

Tumor metastasis to the pituitary gland is a rare, not well-documented and life-threatening condition associated with a shortened life span. A better understanding of its clinical manifestations could lead to earlier diagnosis, appropriate therapy and potentially improving quality of life. Therefore, we retrospectively studied the charts of patients with pituitary metastases who were treated at the City of Hope National Medical Center (Duarte, CA) from 1984 to 2018. We reviewed and analyzed tumor origin, primary pituitary clinical manifestation, duration between primary tumor diagnosis and pituitary metastasis, type of treatment and patient survival. A total of 11 patients were identified with a mean age of 59.2 years and median survival following the diagnosis of metastasis of 10 months. Breast cancer and lymphoma were the most common primary origins in these cases, and diabetes insipidus and panhypopituitarism were the most common clinical manifestations of their metastasis. We also compared our results with reports in the literature published between 1957 and 2018. A total 289 patients with pituitary metastasis have been reported in the literature. Breast cancer was the most frequent primary origin of the metastasis, and visual symptoms were the most common primary manifestation. The posterior part of the pituitary is more susceptible than the anterior to metastasis. Pituitary metastasis may occur as a consequence of successful primary tumor treatment prolonging the chance of seeding. Future studies are needed to determine the molecular mechanism of metastasis to the pituitary

Dynamically Programmable Magnetic Fields for Controlled Movement of Cells Loaded with Iron Oxide Nanoparticles

Cell-based therapies are becoming increasingly prominent in numerous medical contexts, particularly in regenerative medicine and the treatment of cancer. However, since the efficacy of the therapy is largely dependent on the concentration of therapeutic cells at the treatment area, a major challenge associated with cell-based therapies is the ability to move and localize therapeutic cells within the body. In this article, a technique based on dynamically programmable magnetic fields is successfully demonstrated to noninvasively aggregate therapeutic cells at a desired location. Various types of therapeutically relevant cells (neural stem cells, monocytes/macrophages, and chimeric antigen receptor T cells) are loaded with iron oxide nanoparticles and then focused at a particular site using externally controlled electromagnets. These experimental results serve as a readily scalable prototype for designing an apparatus that patients can wear to focus therapeutic cells at the anatomical sites needed for treatment

Early Changes in Tumor Perfusion from T1-Weighted Dynamic Contrast-Enhanced MRI following Neural Stem Cell-Mediated Therapy of Recurrent High-Grade Glioma Correlate with Overall Survival

Background. The aim of this study was to correlate T1-weighted dynamic contrast-enhanced MRI- (DCE-MRI-) derived perfusion parameters with overall survival of recurrent high-grade glioma patients who received neural stem cell- (NSC-) mediated enzyme/prodrug gene therapy. Methods. A total of 12 patients were included in this retrospective study. All patients were enrolled in a first-in-human study (NCT01172964) of NSC-mediated therapy for recurrent high-grade glioma. DCE-MRI data from all patients were collected and analyzed at three time points: MRI#1—day 1 postsurgery/treatment, MRI#2— day 7 ± 3 posttreatment, and MRI#3—one-month follow-up. Plasma volume (Vp), permeability (Ktr), and leakage (λtr) perfusion parameters were calculated by fitting a pharmacokinetic model to the DCE-MRI data. The contrast-enhancing (CE) volume was measured from the last dynamic phase acquired in the DCE sequence. Perfusion parameters and CE at each MRI time point were recorded along with their relative change between MRI#2 and MRI#3 (Δ32). Cox regression was used to analyze patient survival. Results. At MRI#1 and at MRI#3, none of the parameters showed a significant correlation with overall survival (OS). However, at MRI#2, CE and λtr were significantly associated with OS (p<0.05). The relative λtr and Vp from timepoint 2 to timepoint 3 (Δ32λtr and Δ32Vp) were each associated with a higher hazard ratio (p<0.05). All parameters were highly correlated, resulting in a multivariate model for OS including only CE at MRI#2 and Δ32Vp, with an R2 of 0.89. Conclusion. The change in perfusion parameter values from 1 week to 1 month following NSC-mediated therapy combined with contrast-enhancing volume may be a useful biomarker to predict overall survival in patients with recurrent high-grade glioma

Functionalized iron oxide nanoparticles for controlling the movement of immune cells

Immunotherapy is currently being investigated for the treatment of many diseases, including cancer. The ability to control the location of immune cells during or following activation would represent a powerful new technique for this field. Targeted magnetic delivery is emerging as a technique for controlling cell movement and localization. Here we show that this technique can be extended to microglia, the primary phagocytic immune cells in the central nervous system. The magnetized microglia were generated by loading the cells with iron oxide nanoparticles functionalized with CpG oligonucleotides, serving as a proof of principle that nanoparticles can be used to both deliver an immunostimulatory cargo to cells and to control the movement of the cells. The nanoparticle-oligonucleotide conjugates are efficiently internalized, non-toxic, and immunostimulatory. We demonstrate that the in vitro migration of the adherent, loaded microglia can be controlled by an external magnetic field and that magnetically-induced migration is non-cytotoxic. In order to capture video of this magnetically-induced migration of loaded cells, a novel 3D-printed “cell box” was designed to facilitate our imaging application. Analysis of cell movement velocities clearly demonstrate increased cell velocities toward the magnet. These studies represent the initial step towards our final goal of using nanoparticles to both activate immune cells and to control their trafficking within the diseased brain

Crosstalk between autophagy and metabolic regulation of (CAR) T cells: therapeutic implications

Despite chimeric antigen receptor (CAR) T cell therapy’s extraordinary success in subsets of B-cell lymphoma and leukemia, various barriers restrict its application in solid tumors. This has prompted investigating new approaches for producing CAR T cells with superior therapeutic potential. Emerging insights into the barriers to CAR T cell clinical success indicate that autophagy shapes the immune response via reprogramming cellular metabolism and vice versa. Autophagy, a self-cannibalization process that includes destroying and recycling intracellular components in the lysosome, influences T cell biology, including development, survival, memory formation, and cellular metabolism. In this review, we will emphasize the critical role of autophagy in regulating and rewiring metabolic circuits in CAR T cells, as well as how the metabolic status of CAR T cells and the tumor microenvironment (TME) alter autophagy regulation in CAR T cells to restore functional competence in CAR Ts traversing solid TMEs

Downregulation of TLX induces TET3 expression and inhibits glioblastoma stem cell self-renewal and tumorigenesis

International audienceGlioblastomas have been proposed to be maintained by highly tumorigenic glioblastoma stem cells (GSCs) that are resistant to current therapy. Therefore, targeting GSCs is critical for developing effective therapies for glioblastoma. In this study, we identify the regulatory cascade of the nuclear receptor TLX and the DNA hydroxylase Ten eleven translocation 3 (TET3) as a target for human GSCs. We show that knockdown of TLX expression inhibits human GSC tumorigenicity in mice. Treatment of human GSC-grafted mice with viral vector-delivered TLX shRNA or nanovector-delivered TLX siRNA inhibits tumour development and prolongs survival. Moreover, we identify TET3 as a potent tumour suppressor downstream of TLX to regulate the growth and self-renewal in GSCs. This study identifies the TLX-TET3 axis as a potential therapeutic target for glioblastoma

Microglia and Macrophages in Malignant Gliomas: Recent Discoveries and Implications for Promising Therapies

Malignant gliomas are the most common primary brain tumors. Their deadliest manifestation, glioblastoma multiforme (GBM), accounts for 15% of all primary brain tumors and is associated with a median survival of only 15 months even after multimodal therapy. There is substantial presence of microglia and macrophages within and surrounding brain tumors. These immune cells acquire an alternatively activated phenotype with potent tumor-tropic functions that contribute to glioma growth and invasion. In this review, we briefly summarize recent data that has been reported on the interaction of microglia/macrophages with brain tumors and discuss potential application of these findings to the development of future antiglioma therapies