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Radiotherapy can be limited by pneumonitis, which is impacted by innate immunity, including pathways regulated by TRAIL death receptor DR5. We investigated whether DR5 agonists could rescue mice from toxic effects of radiation and found that 2 different agonists, parenteral PEGylated trimeric TRAIL (TLY012) and oral TRAIL-inducing compound (TIC10/ONC201), could reduce pneumonitis, alveolar wall thickness, and oxygen desaturation. Lung protection extended to late effects of radiation including less fibrosis at 22 weeks in TLY012-rescued survivors versus unrescued surviving irradiated mice. Wild-type orthotopic breast tumor-bearing mice receiving 20 Gy thoracic radiation were protected from pneumonitis with disappearance of tumors. At the molecular level, radioprotection appeared to be due to inhibition of CCL22, a macrophage-derived chemokine previously associated with radiation pneumonitis and pulmonary fibrosis. Treatment with anti-CCL22 reduced lung injury in vivo but less so than TLY012. Pneumonitis severity was worse in female versus male mice, and this was associated with increased expression of X-linked TLR7. Irradiated mice had reduced esophagitis characterized by reduced epithelial disruption and muscularis externa thickness following treatment with the ONC201 analog ONC212. The discovery that short-term treatment with TRAIL pathway agonists effectively rescues animals from pneumonitis, dermatitis, and esophagitis following high doses of thoracic radiation exposure has important translational implications.

Background Prone breast positioning reduces skin reaction and heart and lung dose, but may also reduce radiation dose to axillary lymph nodes (ALNs). Methods Women with early stage breast cancer treated with whole breast irradiation (WBI) in the prone position were identified. Patients treated in the supine position were matched for treating physician, laterality, and fractionation. Ipsilateral breast, tumor bed, and Level I, II, and III ALNs were contoured according to the RTOG breast atlas. Clips marking surgically removed sentinel lymph nodes (SLN)s were contoured. Treatment plans developed for each patient were retrospectively analyzed. V90 % and V95 % was calculated for each axillary level. When present, dose to axillary surgical clips was calculated. Results Treatment plans for 46 women (23 prone and 23 supine) were reviewed. The mean V90 % and V95 % of ALN Level I was significantly lower for patients treated in the prone position (21% and 14%, respectively) than in the supine position (50% and 37%, respectively) ( p  < 0.0001 and p  < 0.0001, respectively). Generally, Level II & III ALNs received little dose in either position. Sentinel node biopsy clips were all contained within axillary Level I. The mean V95 % of SLN clips was 47% for patients treated in the supine position and 0% for patients treated in the prone position ( p  < 0.0001). Mean V90 % to SLN clips was 96% for women treated in the supine position but only 13% for women treated in the prone position. Conclusions Standard tangential breast irradiation in the prone position results in substantially reduced dose to the Level I axilla as compared with treatment in the supine position. For women in whom axillary coverage is indicated such as those with positive sentinel lymph node biopsy who do not undergo completion axillary dissection, treatment in the prone position may be inappropriate.

Jayant Vaidya and colleagues claim that TARGIT treatment results in increased survival since the number of non-breast cancer deaths are higher in the external beam radiotherapy (EBRT) cohort. The investigators cite higher incidences of cardiac toxic effects and deaths from non-breast cancers in the EBRT group as the major cause for the difference in overall survival, even though the TARGIT group currently has a higher, although not significantly breast cancer death rate (2·6% vs 1·9%, p=0·56).

To evaluate the effectiveness of Leksell Gamma Knife stereotactic radio-surgery (Elekta, Stockholm, Sweden) with respect to local tumor control, visual acuity, and radiation side effects for uveal melanoma. Retrospective, non-comparative case series of 23 patients with uveal melanoma treated with Gamma Knife stereotactic radiosurgery at Tufts Medical Center from 2000 to 2012. Patients received single-fraction stereotactic radiation therapy of 20-25 gray (Gy) (mean: 21.7 Gy), primarily at the 50% isodose line. Follow-up was 4 to 121 months (median: 41.5 months). Main outcome measures included local tumor control, metastasis, visual acuity, and complications of therapy. In 21 of 23 patients (91%), local control was achieved with a single session of Gamma Knife therapy. Both patients who did not have local control, as well as a third patient (three of 23, 13%) developed liver metastases. Visual acuity was 20/200 or better in eight of 23 patients (35%) at last follow-up. Radiation side effects severe enough to cause vision loss were present in 14 of 23 patients (61%). Gamma Knife therapy may be an effective alternative to enucleation in patients with uveal melanoma who are deemed less satisfactory candidates for brachytherapy or wish to avoid surgery.

Publisher's Note: Products purchased from 3rd Party sellers are not guaranteed by the Publisher for quality, authenticity, or access to any online entitlements included with the product.For more than 30 years, Perez and Brady's Principles and Practice of Radiation Oncology has been the must-have standard reference for radiation oncologists and radiation oncology residents who need a comprehensive text covering both the biological and physical science aspects of this complex field as well as disease site-specific information on the integrated, multidisciplinary management of patients with cancer. The book has established itself as the discipline's \"text-of-record,\" belonging on the shelf of all of those working in the field. The Seventh Edition continues this tradition of excellence with extensive updates throughout, many new chapters, and more than 1,400 full-color illustrations that highlight key concepts in tumor pathogenesis, diagnosis, and targeted radiation therapy.

Multiple mammary epithelial cell (MEC) types are observed both in mammary ducts in vivo and in primary cultures in vitro; however, the oncogenic potential of different cell types remains unknown. Here, we used human papilloma virus 16 E6 and E7 oncogenes, which target p53 and Rb tumor suppressor proteins, respectively, to immortalize MECs present in early or late passages of human mammary tissue-derived cultures or in milk. One MEC subtype was exclusively immortalized by E6; such cells predominated in late-passage cultures but were rare at early passages and apparently absent in milk. Surprisingly, a second cell type, present only in early-passage tissue-derived cultures, was fully immortalized by E7 alone. A third cell type, observed in tissue-derived cultures and in milk, showed a substantial extension of life span with E7 but eventually senesced. Finally, both E6 and E7 were required to fully immortalize milk-derived MECs and a large proportion of MECs in early-passage tissue-derived cultures, suggesting the presence of another discrete subpopulation. Identification of MECs with distinct susceptibilities to p53- and Rb-targeting human papillomavirus oncogenes raises the possibility that these cells may serve as precursors for different forms of breast cancer.

Ratsch, S. B., Gao, Q., Srinivasan, S., Wazer, D. E. and Band, V. Multiple Genetic Changes Are Required for Efficient Immortalization of Different Subtypes of Normal Human Mammary Epithelial Cells. Breast cancer is the second leading cause of cancer-related deaths of women in the U.S. About 180,000 new cases of breast cancer are diagnosed each year, a quarter of them fatal. Early detection is the key to the survival of these patients. However, there are no molecular markers to detect breast cancer at very early stages. A hurdle in understanding the early molecular changes in breast cancer has been the difficulty in establishing premalignant lesions and primary breast tumors as in vitro cell cultures. Normal epithelial cells grow for a finite life span and then senesce. Immortalization is defined by continuous growth of otherwise senescing cells and is believed to represent an early stage in tumor progression. To examine these early stages, we and others have developed in vitro models of mammary epithelial cell immortalization. These models have been extremely important in understanding the role of various tumor suppressor pathways that maintain the normal phenotypes of mammary epithelial cells. In this paper, we describe the establishment of these models and their relevance to understanding the molecular changes that occur in early breast cancer. These models have helped to identify molecular changes that occur in early breast cancers and appear to be well suited to identify novel markers for early diagnosis of breast cancer.

We evaluated the necessity of a tumor bed boost after whole-breast radiotherapy for early-stage breast cancer after breast-conserving surgery and negative re-excision. Of patients treated at the Virginia Commonwealth and Tufts Universities with breast-conservation therapy for early-stage breast cancer between 1983 and 1999, 205 required re-excision of the tumor cavity to obtain clear margins and were found to be without residual disease. Adjuvant conventionally fractionated whole-breast radiotherapy was given to a total dose of 50 Gy in 25 fractions. The tumor bed boost was omitted. The median follow-up was 98 months (range, 6-229 months). The tumor histological diagnosis was primarily infiltrating ductal carcinoma (183 cases; 89%). Nodal involvement was documented in 49 cases (24%). There were four documented recurrences at the tumor bed site. Five in-breast recurrences were documented to be in a location removed from the tumor bed. The overall Kaplan-Meier 15-year in-breast control rate was 92.4%, and the freedom from true recurrence rate was 97.6%. The findings support the concept that postlumpectomy radiotherapy can be tailored according to the degree of surgical resection. There is an easily identifiable subgroup of patients who can avoid a tumor bed boost, thus resulting in a reduced treatment time and improved cosmesis, while maintaining local control rates that approach 100%. The data suggest that in patients who undergo a negative re-excision, treatment with whole-breast radiotherapy to 50 Gy is a sufficient dose to maximally reduce the risk of local recurrence.

Wazer comments on a study by Vicini et al that evaluate the outcome of using MammoSite breast brachytherapy catheter in delivering accelerated partial breast irradiation. In the current registry trial, factors found to be significantly associated with short-term favorable cosmetic outcome were balloon-to-skin spacing, both as a continuous variable as well as at a cut-off value of more than or equal to seven mm, larger bra size, and the absence of post-procedure infection. The use of chemotherapy was not found to adversely affect cosmetic outcome, but was associated with an increased incidence of radiation recall reaction.

Rivard, M. J., Melhus, C. S., Zinkin, H. D., Stapleford, L. J., Evans, K. E., Wazer, D. E. and Odlozilíková, A. A Radiobiological Model for the Relative Biological Effectiveness of High-Dose-Rate 252Cf Brachytherapy. Radiat. Res. 164, 319– 323 (2005). While there is significant clinical experience using both low- and high-dose-rate 252Cf brachytherapy, there are minimal data regarding values for the neutron relative biological effectiveness (RBE) with both modalities. The aim of this research was to derive a radiobiological model for 252Cf neutron RBE and to compare these results with neutron RBE values used clinically in Russia. The linear-quadratic (LQ) model was used as the basis to characterize cell survival after irradiation, with identical cell killing rates (SN = Sγ) between 252Cf neutrons and photons used for derivation of RBE. Using this equality, a relationship among neutron dose and LQ radiobiological parameter (i.e., αN, βN, αγ, βγ) was obtained without the need to specify the photon dose. These results were used to derive the 252Cf neutron RBE, which was then compared with Russian neutron RBE values. The 252Cf neutron RBE was determined after incorporating the LQ radiobiological parameters obtained from cell survival studies with fast neutrons and teletherapy photons. For single-fraction high-dose-rate neutron doses of 0.5, 1.0, 1.5 and 2.0 Gy, the total biologically equivalent doses were 1.8, 3.4, 4.7 and 6.0 RBE Gy with 252Cf neutron RBE values of 3.2, 2.9, 2.7 and 2.5, respectively. Using clinical data for late-responding reactions from 252Cf, Russian investigators created an empirical model that predicted high-dose-rate 252Cf neutron RBE values ranging from 3.6 to 2.9 for similar doses and fractionation schemes and observed that 252Cf neutron RBE increases with the number of treatment fractions. Using these relationships, our results were in general concordance with high-dose-rate 252Cf RBE values obtained from Russian clinical experience.