In silico Experimentation of Glioma Microenvironment Development and Anti-tumor Therapy

Tumor cells do not develop in isolation, but co-evolve with stromal cells and tumor-associated immune cells in a tumor microenvironment mediated by an array of soluble factors, forming a complex intercellular signaling network. Herein, we report an unbiased, generic model to integrate prior biochemical data and the constructed brain tumor microenvironment in silico as characterized by an intercellular signaling network comprising 5 types of cells, 15 cytokines, and 69 signaling pathways. The results show that glioma develops through three distinct phases: pre-tumor, rapid expansion, and saturation. We designed a microglia depletion therapy and observed significant benefit for virtual patients treated at the early stages but strikingly no therapeutic efficacy at all when therapy was given at a slightly later stage. Cytokine combination therapy exhibits more focused and enhanced therapeutic response even when microglia depletion therapy already fails. It was further revealed that the optimal combination depends on the molecular profile of individual patients, suggesting the need for patient stratification and personalized treatment. These results, obtained solely by observing the in silico dynamics of the glioma microenvironment with no fitting to experimental/clinical data, reflect many characteristics of human glioma development and imply new venues for treating tumors via selective targeting of microenvironmental components

Primary hypophysitis: A single-center experience in 16 cases

Object. The authors review their experience in the treatment of 16 patients with primary hypophysitis. Methods. A retrospective study was undertaken to review cases of primary hypophysitis. The mean age of the patients was 47 years and there was an equal distribution of sexes. Recent pregnancy and underlying autoimmunity were noted in 50% of the patients. Two patients had undergone previous transsphenoidal operations at other centers, one for prolactinoma and another for hypophysitis. Headache, anterior pituitary deficiency, and suprasellar mass lesions were the most common presenting features. The initial presumptive diagnosis was pituitary adenoma in six patients (37.5%) and inflammatory hypophysitis in 10 (62.5%). Five patients received initial medical therapy for hypophysitis; although three (60%) responded satisfactorily, two (40%) did not and later underwent surgery. Altogether 13 patients (81.2%) underwent transsphenoidal surgery. The histological diagnoses were lymphocytic hypophysitis in 10 (76.9%) and granulomatous hypophysitis in three (23.1%) of the surgically treated patients. A coexistent Rathke cleft cyst was noted in one patient. There was no death in this series. One patient experienced postoperative cerebrospinal fluid leakage and meningitis. One patient had bilateral internal carotid artery occlusion secondary to inflammatory involvement of the cavernous sinuses and arteritis. This patient recovered and is capable of independent functional activities. Conclusions. All surgical patients experienced improvement in their headache and/or visual field defects and none had visual deterioration. None of the patients experienced any improvement in endocrine function and all required long-term hormone replacement. Transsphenoidal surgery was a safe and effective treatment especially for visual and pressure symptoms. A postoperative recurrence developed in two patients (15.4%) and the treatment modalities included steroid therapy, repeated surgery, and radiosurgery.link_to_subscribed_fulltex