Glioblastoma survival is associated with distinct proteomic alteration signatures post chemoirradiation in a large-scale proteomic panel

BackgroundGlioblastomas (GBM) are rapidly progressive, nearly uniformly fatal brain tumors. Proteomic analysis represents an opportunity for noninvasive GBM classification and biological understanding of treatment response.PurposeWe analyzed differential proteomic expression pre vs. post completion of concurrent chemoirradiation (CRT) in patient serum samples to explore proteomic alterations and classify GBM by integrating clinical and proteomic parameters.Materials and methods82 patients with GBM were clinically annotated and serum samples obtained pre- and post-CRT. Serum samples were then screened using the aptamer-based SOMAScan® proteomic assay. Significant traits from uni- and multivariate Cox models for overall survival (OS) were designated independent prognostic factors and principal component analysis (PCA) was carried out. Differential expression of protein signals was calculated using paired t-tests, with KOBAS used to identify associated KEGG pathways. GSEA pre-ranked analysis was employed on the overall list of differentially expressed proteins (DEPs) against the MSigDB Hallmark, GO Biological Process, and Reactome databases with weighted gene correlation network analysis (WGCNA) and Enrichr used to validate pathway hits internally.Results3 clinical clusters of patients with differential survival were identified. 458 significantly DEPs pre- vs. post-treatment, 316 upregulated, 142 downregulated emerged including several pathways relevant to cancer metabolism and progression. The worst survival group (median OS 13.2 months) was associated with DEPs affiliated with proliferative pathways and distinct oppositional response (including RT) as compared to better-performing groups (intermediate, median OS 22.4 months; highest, median OS 28.7 months). Opposite signaling patterns across multiple analyses in several pathways (notably fatty acid metabolism, TNFα via NF-κB, Myc target V1 signaling, UV response, unfolded protein response, peroxisome, and interferon response) were distinct between clinical survival groups and supported by WGCNA. 9 proteins were statistically signficant for OS with 1 (CEACAM16) supported by KM.ConclusionDistinct proteomic alterations with hallmarks of cancer, including progression, resistance, stemness, and invasion, were identified in serum samples obtained from GBM patients pre vs. post CRT and corresponded with clinical survival. The proteome can potentially be employed for glioma classification and biological interrogation of cancer pathways

Re-irradiation for recurrent glioma- the NCI experience in tumor control, OAR toxicity and proposal of a novel prognostic scoring system

Abstract Purpose/objectives Despite mounting evidence for the use of re-irradiation (re-RT) in recurrent high grade glioma, optimal patient selection criteria for re-RT remain unknown. We present a novel scoring system based on radiobiology principles including target independent factors, the likelihood of target control, and the anticipated organ at risk (OAR) toxicity to allow for proper patient selection in the setting of recurrent glioma. Materials/methods Thirty one patients with recurrent glioma who received re-RT (2008–2016) at NCI – NIH were included in the analysis. A novel scoring system for overall survival (OS) and progression free survival (PFS) was designed to include:1) target independent factors (age, KPS (Karnofsky Performance Status), histology, presence of symptoms), 2) target control, and 3) OAR toxicity risk. Normal tissue complication probability (NTCP) calculations were performed using the Lyman model. Kaplan-Meier analysis was performed for overall survival (OS) and progression free survival (PFS) for comparison amongst variables. Results No patient, including those who received dose to OAR above the published tolerance dose, experienced any treatment related grade 3–5 toxicity with a median PFS and OS from re-RT of 4 months (0.5–103) and 6 months (0.7–103) respectively. Based on cumulative maximum doses the average NTCP was 25% (0–99%) for the chiasm, 21% (0–99%) for the right optic nerve, 6% (0–92%) for the left optic nerve, and 59% (0–100%) for the brainstem. The independent factor and target control scores were each statistically significant for OS and the combination of independent factors plus target control was also significant for both OS (p = 0.02) and PFS (p = 0.006). The anticipated toxicity risk score was not statistically significant. Conclusion Our scoring system may represent a novel approach to patient selection for re-RT in recurrent high grade glioma. Further validation in larger patient cohorts including compilation of doses to tumor and OAR may help refine this further for inclusion into clinical trials and general practice

Pilot trial of topical MTS-01 application to reduce dermatitis in patients receiving chemoradiotherapy for stage I–III carcinoma of the anal canal

The purpose of the present trial was to determine the feasibility of the daily topical application of the piperidine nitroxide, MTS‑01, combined with chemoradiotherapy in the treatment of patients with anal carcinoma. The secondary study endpoints were the description of the effects of this agent on skin toxicity and rectal‑associated lymphoid tissue. The participants received radiotherapy concurrent with mitomycin‑C and 5‑fluorouracil for carcinoma of the anal canal. MTS‑01 was applied to the bilateral inguinal area and the gluteal cleft. Dermatologic and non‑dermatologic toxicity was graded throughout the treatment period. Circulating lymphocytes were serially collected for phenotyping. Rectal mucosal snag biopsies were collected at baseline and at 1 year of follow‑up. A total of 5 patients received topical MTS‑01. Adverse events attributed to MTS‑01 included asymptomatic grade 1 hypoglycemia and grade 1‑2 diarrhea. Dermatitis within untreated, radiated skin was not more severe than dermatitis in MTS‑01‑treated, unirradiated skin. Circulating CD4+ lymphocyte suppression was noted at >1 year following treatment in human immunodeficiency virus‑negative participants. CD4+ lymphocytes remained suppressed in the irradiated rectal mucosa at 1 year, whereas the CD8+ lymphocyte numbers recovered or increased. On the whole, the present study demonstrates that the MTS‑01 topical application was tolerable with minimal toxicity. Chemoradiation for anal cancer led to prolonged CD4+ lymphocytopenia in the circulation and gut mucosa

Additional file 1: Table S1. of Re-irradiation for recurrent glioma- the NCI experience in tumor control, OAR toxicity and proposal of a novel prognostic scoring system

A. maximum Dose and NTCP to OAR based on Maximum Dose values. B. Mean Dose (EUD) and NTCP to OAR based on Mean Dose values. (DOCX 200 kb

Additional file 3: Figure S2. of Re-irradiation for recurrent glioma- the NCI experience in tumor control, OAR toxicity and proposal of a novel prognostic scoring system

Comparison with existing scoring systems A. Carson 2007. B. Combs 2013. (DOCX 28 kb