Tufts Medical Center Experience With Long-Term Follow-Up of Vestibular Schwannoma Treated With Gamma Knife Stereotactic Radiosurgery: Novel Finding of Delayed Pseudoprogression.

PURPOSE: Our purpose was to evaluate the long-term outcomes of patients with vestibular schwannoma (VS) treated with Gamma Knife stereotactic radiosurgery (GKSRS) with modern techniques, with attention to posttreatment tumor growth dynamics, dosimetric predictors, and late toxicities. METHODS AND MATERIALS: One hundred twelve patients with VS were treated with GKSRS with a median dose of 12.5 Gy to the 50% isodose line treated between 2004 and 2015, with patients followed up to 15 years. Target and organ-at-risk doses were recorded, and tumor diameter/volume, audiologic decline, and trigeminal/facial nerve preservation were tracked from treatment onward. RESULTS: GKSRS yielded local control of 5, 10, and 15 years at 96.9%, 90.0%, and 87.1% respectively. Pseudoprogression was found in 45%, with a novel pattern detected with peak swelling at 31 months. Pseudoprogression was associated with smaller tumor diameter at treatment and fewer treatment isocenters, but not with the development of any toxicity, nor was it predicted by any dosimetric factor. Median time to hearing loss was 3.4 years with actuarial hearing preservation at 2, 5, and 10 years of 66.5%, 43.1%, and 37.6%, with rate of hearing loss correlating with maximum cochlea and modiolus doses. Trigeminal and facial nerve preservation rates were 92.7% and 97.6%, respectively. Increasing maximum tumor dose was associated with facial paresthesia. CONCLUSIONS: Modern GKSRS is a safe and effective treatment for VS on long-term follow-up, with high levels of facial and trigeminal nerve preservation. A novel pattern of pseudoprogression has been identified suggesting longer imaging follow-up may be needed before initiating salvage in those without symptomatic progression. Several tumor and dosimetric predictors have been suggested for the development of different toxicities, requiring further evaluation.

Corrigendum to "Particle Radiation-Induced Nontargeted Effects in Bone-Marrow-Derived Endothelial Progenitor Cells".

[This corrects the article DOI: 10.1155/2015/496512.].

Tumor-host signaling interaction reveals a systemic, age-dependent splenic immune influence on tumor development.

The concept of age-dependent host control of cancer development raises the natural question of how these effects manifest across the host tissue/organ types with which a tumor interacts, one important component of which is the aging immune system. To investigate this, changes in the spleen, an immune nexus in the mouse, was examined for its age-dependent interactive influence on the carcinogenesis process. The model is the C57BL/6 male mice (adolescent, young adult, middle-aged, and old or 68, 143, 551 and 736 days old respectively) with and without a syngeneic murine tumor implant. Through global transcriptome analysis, immune-related functions were found to be key regulators in the spleen associated with tumor progression as a function of age with CD2, CD3ε, CCL19, and CCL5 being the key molecules involved. Surprisingly, other than CCL5, all key factors and immune-related functions were not active in spleens from non-tumor bearing old mice. Our findings of age-dependent tumor-spleen signaling interaction suggest the existence of a global role of the aging host in carcinogenesis. Suggested is a new avenue for therapeutic improvement that capitalizes on the pervasive role of host aging in dictating the course of this disease.

Proton irradiation impacts age-driven modulations of cancer progression influenced by immune system transcriptome modifications from splenic tissue.

Age plays a crucial role in the interplay between tumor and host, with additional impact due to irradiation. Proton irradiation of tumors induces biological modulations including inhibition of angiogenic and immune factors critical to 'hallmark' processes impacting tumor development. Proton irradiation has also provided promising results for proton therapy in cancer due to targeting advantages. Additionally, protons may contribute to the carcinogenesis risk from space travel (due to the high proportion of high-energy protons in space radiation). Through a systems biology approach, we investigated how host tissue (i.e. splenic tissue) of tumor-bearing mice was altered with age, with or without whole-body proton exposure. Transcriptome analysis was performed on splenic tissue from adolescent (68-day) versus old (736-day) C57BL/6 male mice injected with Lewis lung carcinoma cells with or without three fractionations of 0.5 Gy (1-GeV) proton irradiation. Global transcriptome analysis indicated that proton irradiation of adolescent hosts caused significant signaling changes within splenic tissues that support carcinogenesis within the mice, as compared with older subjects. Increases in cell cycling and immunosuppression in irradiated adolescent hosts with CDK2, MCM7, CD74 and RUVBL2 indicated these were the key genes involved in the regulatory changes in the host environment response (i.e. the spleen). Collectively, these results suggest that a significant biological component of proton irradiation is modulated by host age through promotion of carcinogenesis in adolescence and resistance to immunosuppression, carcinogenesis and genetic perturbation associated with advancing age.

Particle Radiation-Induced Nontargeted Effects in Bone-Marrow-Derived Endothelial Progenitor Cells.

Bone-marrow- (BM-) derived endothelial progenitor cells (EPCs) are critical for endothelial cell maintenance and repair. During future space exploration missions astronauts will be exposed to space irradiation (IR) composed of a spectrum of low-fluence protons ((1)H) and high charge and energy (HZE) nuclei (e.g., iron-(56)Fe) for extended time. How the space-type IR affects BM-EPCs is limited. In media transfer experiments in vitro we studied nontargeted effects induced by (1)H- and (56)Fe-IR conditioned medium (CM), which showed significant increase in the number of p-H2AX foci in nonirradiated EPCs between 2 and 24 h. A 2-15-fold increase in the levels of various cytokines and chemokines was observed in both types of IR-CM at 24 h. Ex vivo analysis of BM-EPCs from single, low-dose, full-body (1)H- and (56)Fe-IR mice demonstrated a cyclical (early 5-24 h and delayed 28 days) increase in apoptosis. This early increase in BM-EPC apoptosis may be the effect of direct IR exposure, whereas late increase in apoptosis could be a result of nontargeted effects (NTE) in the cells that were not traversed by IR directly. Identifying the role of specific cytokines responsible for IR-induced NTE and inhibiting such NTE may prevent long-term and cyclical loss of stem and progenitors cells in the BM milieu.