Purpose Radiation-induced fibrosis (RIF) is a long-term side effect of external beam radiation therapy for the treatment of cancer. It results in a multitude of symptoms that significantly impact quality of life. Understanding the mechanisms of RIF-induced changes is essential to developing effective strategies to prevent long-term disability and discomfort following radiation therapy. In this review, we describe the current understanding of the etiology, clinical presentation, pathogenesis, treatment, and directions of future therapy for this condition. Methods A literature review of publications describing mechanisms or treatments of RIF was performed. Specific databases utilized included PubMed and clinicaltrials.gov, using keywords “Radiation-Induced Fibrosis,” “Radiotherapy Complications,” “Fibrosis Therapy,” and other closely related terms. Results RIF is the result of a misguided wound healing response. In addition to causing direct DNA damage, ionizing radiation generates reactive oxygen and nitrogen species that lead to localized inflammation. This inflammatory process ultimately evolves into a fibrotic one characterized by increased collagen deposition, poor vascularity, and scarring. Tumor growth factor beta serves as the primary mediator in this response along with a host of other cytokines and growth factors. Current therapies have largely been directed toward these molecular targets and their associated signaling pathways. Conclusion Although RIF is widely prevalent among patients undergoing radiation therapy and significantly impacts quality of life, there is still much to learn about its pathogenesis and mechanisms. Current treatments have stemmed from this understanding, and it is anticipated that further elucidation will be essential for the development of more effective therapies.

PURPOSE Reducing radiation treatment dose could improve the quality of life (QOL) of patients with good-risk human papillomavirus–associated oropharyngeal squamous cell carcinoma (OPSCC). Whether reduced-dose radiation produces disease control and QOL equivalent to standard chemoradiation is not proven. PATIENTS AND METHODS In this randomized, phase II trial, patients with p16-positive, T1-T2 N1-N2b M0, or T3 N0-N2b M0 OPSCC (7th edition staging) with ≤ 10 pack-years of smoking received 60 Gy of intensity-modulated radiation therapy (IMRT) over 6 weeks with concurrent weekly cisplatin (C) or 60 Gy IMRT over 5 weeks. To be considered for a phase III study, an arm had to achieve a 2-year progression-free survival (PFS) rate superior to a historical control rate of 85% and a 1-year mean composite score ≥ 60 on the MD Anderson Dysphagia Inventory (MDADI). RESULTS Three hundred six patients were randomly assigned and eligible. Two-year PFS for IMRT + C was 90.5% rejecting the null hypothesis of 2-year PFS ≤ 85% ( P = .04). For IMRT, 2-year PFS was 87.6% ( P = .23). One-year MDADI mean scores were 85.30 and 81.76 for IMRT + C and IMRT, respectively. Two-year overall survival rates were 96.7% for IMRT + C and 97.3% for IMRT. Acute adverse events (AEs) were defined as those occurring within 180 days from the end of treatment. There were more grade 3-4 acute AEs for IMRT + C (79.6% v 52.4%; P < .001). Rates of grade 3-4 late AEs were 21.3% and 18.1% ( P = .56). CONCLUSION The IMRT + C arm met both prespecified end points justifying advancement to a phase III study. Higher rates of grade ≥ 3 acute AEs were reported in the IMRT + C arm.

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Abstract-Vascular cell adhesion molecule-1 (VCAM-1/Vcam1) is a cytokine-inducible member of the immunoglobulin gene superfamily that is expressed by arterial endothelial cells in regions predisposed to atherosclerosis and at borders of atherosclerotic plaques. To determine whether VCAM-1 expression regulates atherosclerotic lesion formation, we crossed Vcam1 domain 4 -deficient (D4D) mice, which partially circumvent the embryonic lethality of Vcam1 null mice, with apolipoprotein E null (Apoe Ϫ/Ϫ ) mice, which spontaneously develop hypercholesterolemia and atherosclerosis. In the Apoe Ϫ/Ϫ background, mice homozygous for the Vcam1 D4D allele had markedly reduced arterial VCAM-1 expression, monocyte adherence in the aortic root, and fatty streak formation. A therosclerosis begins as a focal process at specific regions of the vasculature, so-called lesion-prone areas, where hemodynamic flow is altered. The arterial endothelium expresses numerous adhesion molecules, such as P-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), at these lesion-prone areas before lesion development 1,2 and at the borders of atherosclerotic lesions. 2,3 Whereas ICAM-1 is also abundantly expressed at lesion-prone areas in wild-type mice with normal cholesterol levels, 1,2 VCAM-1, a cytokine-inducible member of the immunoglobulin gene superfamily, 4 is specifically upregulated in arterial endothelial cells at lesion-prone areas in hypercholesterolemic mice and rabbits. 1,2,5 This specific upregulation of VCAM-1 at lesion-prone areas in hypercholesterolemic animals suggests that VCAM-1 may regulate monocyte adhesion in early atherogenesis.To circumvent the embryonic lethality of Vcam1 null mice, 6,7 mutant mice were generated with a targeted disruption of the exon encoding the fourth immunoglobulin domain of VCAM-1, which codes for an ␣ 4 integrin binding site. 8 Domain 4 -deficient (D4D) mice (Vcam1 D4D/D4D ) express only a 6-immunoglobulin domain form of Vcam1, with VCAM-1 mRNA and protein levels Ͻ10% of those found in wild-type mice. 8 Reduced expression of VCAM-1 protein resulted in decreased embryonic survival of Vcam1 D4D/D4D mice. 8 The frequency of embryonic survival was strain dependent, ranging from 29% in 129-C57BL/6 hybrids to 6% of expected in C57BL/6 Vcam1 D4D/D4D mice. 8 When Vcam1 D4D/D4D of mixed genetic background were bred with LDL receptor-deficient (Ldlr Ϫ/Ϫ ) mice, the aortic surface area occupied by atherosclerosis was reduced by 40% compared with that of Ldlr Ϫ/Ϫ mice. 8 In the present study, Vcam1 D4D/D4D mice were bred with hypercholesterolemic apoE null (Apoe Ϫ/Ϫ ) mice 9 to determine whether relative deficiency in VCAM-1 would also attenuate lesion formation in the apoE-deficient background. Mice homozygous for the Vcam1 D4D allele (Apoe Ϫ/Ϫ and Vcam1 D4D/D4D) had markedly reduced arterial VCAM-1 expression, monocyte adherence, and an 84% decrease in aortic root lesion area. We also demonstrate a significant Vcam1 gene-dosage effect on these parameters. Our da...

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SRS meningioma treatment demonstrated a low incidence of toxicity; however, large tumor volumes and single-fraction SRS treatment had an increased risk for posttreatment edema. Risk factors for edema should be considered in meningiomas treatment.