Chromosomal instability (CIN) is a hallmark of cancer and it results from ongoing errors in chromosome segregation during mitosis. While CIN is a major driver of tumor evolution, its role in metastasis has not been established. Here we show that CIN promotes metastasis by sustaining a tumor-cell autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signaling. Genetic suppression of CIN significantly delays metastasis even in highly aneuploid tumor models, whereas inducing continuous chromosome segregation errors promotes cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumor cells co-opt chronic activation of innate immune pathways to spread to distant organs.

Breast cancer is a common diagnosis in women. Breast radiation has become critical in managing patients who receive breast conserving surgery, or have certain high-risk features after mastectomy. Most patients have an excellent prognosis, therefore understanding the late effects of radiation to the chest is important. Radiation-induced heart disease (RIHD) comprises a spectrum of cardiac pathology including myocardial fibrosis and cardiomyopathy, coronary artery disease, valvular disease, pericardial disease, and arrhythmias. Tissue fibrosis is a common mediator in RIHD. Multiple pathways converge with both acute and chronic cellular, molecular, and genetic changes to result in fibrosis. In this article, we review the pathophysiology of cardiac disease related to radiation therapy to the chest. Our understanding of these mechanisms has improved substantially, but much work remains to further refine radiation delivery techniques and develop therapeutics to battle late effects of radiation.

BACKGROUND: Radiation-induced fatigue is a common side effect of breast cancer radiotherapy (RT). This study compares the induction and persistence of radiation-induced fatigue in accelerated partial breast irradiation (APBI), accelerated hypofractionated RT, and standard whole breast RT. METHODS: Eighty patients were treated with a novel, 3-week accelerated regimen with 333 centigrays (cGy) for 15 fractions to 4995 cGy; of these, 45 were treated using APBI, whereas 35 patients were treated using accelerated hypofractionated RT. These patients were matched with patients receiving 200 cGy for 30 fractions using standard whole breast irradiation. Fatigue score, using Common Terminology Criteria for Adverse Events version 4.0, was obtained at 5 time points: consultation before RT, first on-treatment visit, halfway through treatment, last on-treatment visit, and first follow-up. RESULTS: Maximum fatigue and average fatigue since treatment were calculated. Maximum fatigue was 1.5, 2.4, and 2.3, and average fatigue was 0.46, 0.81, and 0.92 for the APBI, accelerated hypofractionated RT, and standard whole breast RT groups, respectively. The accelerated schedules did not have significantly less fatigue than standard whole breast RT at first ontreatment visit. Maximum fatigue in APBI was reduced compared with standard whole breast RT. Accelerated hypofractionated RT had fatigue trajectory similar to standard whole breast RT. Multivariate analysis found that increased age and whole breast treatment are associated with more fatigue. Chemotherapy, hormone therapy, race, and T stage were not significant predictors of maximum fatigue. Results were similar for average fatigue, except that magnitudes were smaller. CONCLUSIONS: Field sizes and age in breast RT were positively associated with maximum radiationinduced fatigue. Accelerated hypofractionated RT and standard whole breast RT had similar fatigue trajectories compared with APBI, which reduced fatigue at all times. Cancer 2011;117:4116-

Three-dimensional (3D) conformal radiation therapy is the standard technique used for adjuvant breast radiation. We report the clinical use of a novel 6-MV flattening-filter-free O-ring linear accelerator (6X-FFF ORL) for breast cancer that may improve upon 3D conformal radiation therapy with its higher dose rate and faster rotation and leaf speed than traditional C-arm gantries. Methods and Materials: We retrospectively identified consecutive women with breast cancer who underwent surgery followed by radiation therapy to the breast or chest wall on Halcyon (Varian Medical Systems, Palo Alto, CA), a novel 6X-FFF ORL. We report their clinicopathologic information, radiation therapy details, acute toxicities, dose-volume histogram data, couch corrections, and treatment times. Results: Thirty-four women were treated for breast cancer on a 6X-FFF ORL between February 2018 and September 2018. All patients underwent lumpectomy (92%) or mastectomy (8%). Tumors were left sided in 44% and bilateral in 9%, and 9% included comprehensive nodal radiation therapy. Twelve percent of patients were treated prone and 29% with deep-inspiration breath hold. Standard target and normal-tissue constraints were met in nearly all plans. The 3D vector couch correction average was 0.77 AE 0.05 cm. The mean beam-on time was 2.0 AE 0.3 minutes, and mean treatment time from start of imaging to beam-off was 4.4 AE 0.4 minutes. Grade 2 dermatitis, fatigue, and breast pain occurred in 18%, 9%, and 3% of patients, respectively. Conclusions: In this first clinical report of breast radiation therapy with a 6X-FFF ORL, treatment was versatile and fast for complex setups and techniques, with acceptable toxicity and organ-at-risk doses. Thus, a 6X-FFF ORL can increase throughput or reduce length of day compared with a conventional C-arm linear accelerator in departments with a busy breast service.

SUMMARYGlioblastoma is a common aggressive primary malignant brain tumor, and is nearly universal in progression and mortality after initial treatment. Re-irradiation presents a promising treatment option for progressive disease, both palliating symptoms and potentially extending survival. Highly conformal radiation techniques such as stereotactic radiosurgery and hypofractionated radiosurgery are effective short courses of treatment that allow delivery of high doses of therapeutic radiation with steep dose gradients to protect normal tissue. Patients with higher performance status, younger age, and longer interval between primary treatment and progression represent the best candidates for re-irradiation. Multiple studies are also underway involving combinations of radiation and systemic therapy to bend the survival curve and improve the therapeutic index. In the multimodal treatment of recurrent high-grade glioma, the use of surgery, radiation, and systemic therapy should be highly individualized. Here we comprehensively review radiation therapy and techniques, along with discussion of combination treatment and novel strategies.

Superficial dose is an important parameter in breast cancer radiation therapy. When treated with conventional linacs, bolus is commonly applied to improve target coverage near the surface while also managing the risk of severe skin reactions and negative cosmesis. With the introduction of modern linacs with 6X flattening filter free (FFF) photon beams, the effect on superficial dose and the need for bolus must be evaluated. Methods and Materials:In vivo measurements of superficial dose were made with optically stimulated luminescence dosimeters on 11 breast cancer patients treated with the Halcyon 6X FFF linac (Varian Medical Systems, Palo Alto, CA). Additionally, measurements were made with the Halycon 6X FFF beam and a 6X beam with flattening filter (FF) delivered to an anthropomorphic phantom. A planning study was carried out in which 14 patients treated on the Halcyon were replanned with a conventional linac to determine the difference in superficial dose predicted by the treatment planning system. Measures were taken to increase the accuracy of the treatment planning system superficial dose.

Posttreatment Ktrans SD may be used as an early posttreatment imaging biomarker to help predict long-term response of lung cancer brain metastases to SRS. This can help identify patients who will ultimately fail SRS and allow for timelier adjustment in treatment approach. These data should be prospectively validated in larger patient cohorts and other histologies.

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