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Purpose: Hydrogen peroxide (H 2 O 2) plays a vital role in normal cellular processes but at supraphysiological concentrations causes oxidative stress and cytotoxicity, a property that is potentially exploitable for the treatment of cancer in combination with radiation therapy (RT). We report the first phase 1 trial testing the safety and tolerability of intratumoral H 2 O 2 þ external beam RT as a novel combination in patients with breast cancer and exploratory plasma marker analyses investigating possible mechanisms of action. Methods and Materials: Twelve patients with breast tumors !3 cm (surgically or medically inoperable) received intratumoral H 2 O 2 with either 36 Gy in 6 twice-weekly fractions (n Z 6) or 49.5 Gy in 18 daily fractions (n Z 6) to the whole breast AE

Aims: Moderately hypofractionated breast irradiation has been evaluated in several prospective studies, resulting in wide acceptance of shorter treatment protocols for postoperative breast irradiation. Reimbursement for radiation therapy varies between private and public systems and between countries, impacting variably financial considerations in the use of hypofractionation. The aim of this study was to evaluate the financial impact of moderately hypofractionated breast irradiation by reimbursement system in different countries. Materials and methods:The study was designed by an international group of radiation oncologists. A web-questionnaire was distributed to representatives from each country. The participants were asked to involve the financial consultant at their institution. Results: Data from 13 countries from all populated continents were collected (Europe:

Background IMPORT HIGH is a randomised, multi-centre phase III trial testing dose escalated simultaneous integrated boost (SIB) against sequential boost each delivered by intensity modulated radiotherapy (IMRT) for early stage breast cancer with higher risk of local relapse. The primary endpoint was initially breast induration at 3 years, requiring 840 patients; accrual was extended (target 2568) with the new primary endpoint of local relapse. We report adverse effects (AE) at 3 years. Methods Women age ≥18 after breast conservation surgery for pT1-3 pN0-pN3a M0 invasive carcinoma were eligible. Randomisation was 1:1:1 between 40Gy/15F to whole breast (WB) + 16Gy/8F sequential photon boost to tumour bed (40+16Gy), 36Gy/15F to WB, 40Gy to partial breast + 48Gy (48Gy) or + 53Gy (53Gy) in 15F SIB to tumour bed. AEs were assessed annually by clinicians in all patients and in a planned sub-set (840) of patients by photographs at 3 years and by patients at 6 months, 1 and 3 years. AE scores were dichotomised as none/mild vs marked for photographs and none/mild vs moderate/marked for patients and clinicians. Fisher's exact tests compared groups; principal comparison (protocol-specified) between 53Gy and 48Gy (p<0.01 defined as statistical significance). Results 2617 women consented between 03/2009 and 09/2015 from 39 UK radiotherapy centres. Median follow-up was 49.1 (IQR 36.8-63.2) months. Median age was 49 (IQR 44-56); 9%, 38% & 53% were tumour grade 1, 2 & 3 respectively; 30% were node positive. 66% received chemotherapy and 73% endocrine therapy. 3-year AE data were available for 2017 clinician assessments, 641 photographs and 842 patient assessments. Proportions of patients with marked AEs were low overall. Rates of moderate/marked AEs at 3 years were broadly similar between the randomised groups; with a suggestion of a slightly increased risk for breast induration in 53Gy compared with control (borderline significance). AE at 3 years 40+16Gy n(%)48Gy n(%)53Gy n(%)ClinicianBreast induration;N656668654None451 (69)483 (72)445 (68)Mild167 (25)141 (21)146 (22)Moderate32 (5)42 (6)56 (9)Marked6 (1)2 (1)7 (1)P-value 0.57010.0102  0.0443Breast shrinkage;N655669654None442 (68)472 (71)448 (69)Mild167 (26)161 (24)166 (25)Moderate40 (6)33 (5)35 (5)Marked6 (1)3 (1)5 (1)P-value 0.25410.5772  0.6373Breast distortion;N656669654None451 (69)464 (69)442 (68)Mild169 (26)170 (25)170 (26)Moderate33 (5)32 (5)38 (6)Marked3 (1)3 (1)4 (1)P-value 0.90310.4862  0.4113PatientChange in breast appearance;N287264285None38 (13)50 (19)58 (20)Mild164 (57)151 (57)142 (50)Moderate57 (20)45 (17)54 (19)Marked28 (10)18 (7)31 (11)P-value 0.14910.9992  0.1243PhotographChange in breast appearance;N218210213None183 (84)185 (88)177 (83)Mild25 (11)23 (11)32 (15)Marked10 (5)2 (1)4 (2)P-value 0.03610.1732  0.6853148Gy v 40+16Gy; 253Gy v 40+16Gy; 353Gy v 48Gy Conclusions These results represent the largest and most mature reported AE outcomes of breast SIB within a clinical trial. At 3 years, rates of moderate/marked AEs were similar between SIB IMRT and WB + sequential boost IMRT delivered over 3 and 4.5 weeks respectively. Citation Format: Coles CE, Griffin CL, Kirby AM, Haviland JS, Titley JC, Benstead K, Brunt AM, Chan C, Ciurlionis L, Din OS, Donovan EM, Eaton DJ, Harnett AN, Hopwood P, Jefford ML, Jenkins PJ, Lee CE, McCormack M, Sherwin L, Syndikus I, Tsang Y, Twyman NI, Ventikaraman R, Wickers S, Wilcox MH, Bliss JM, Yarnold JR. Dose escalated simultaneous integrated boost radiotherapy for women treated by breast conservation surgery for early breast cancer: 3-year adverse effects in the IMPORT HIGH trial (CRUK/06/003) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS4-05.

Mild cognitive impairment (MCI) and early Alzheimer’s disease (AD) are characterized by blood–brain barrier (BBB) breakdown leading to abnormal BBB permeability ahead of brain atrophy or dementia. Previous findings in AD mouse models have reported the beneficial effect of extra-virgin olive oil (EVOO) against AD, which improved BBB and memory functions and reduced brain amyloid-β (Aβ) and related pathology. This work aimed to translate these preclinical findings to humans in individuals with MCI. We examined the effect of daily consumption of refined olive oil (ROO) and EVOO for 6 months in MCI subjects on BBB permeability (assessed by contrast-enhanced MRI), and brain function (assessed using functional-MRI) as the primary outcomes. Cognitive function and AD blood biomarkers were also assessed as the secondary outcomes. Twenty-six participants with MCI were randomized with 25 participants completed the study. EVOO significantly improved clinical dementia rating (CDR) and behavioral scores. EVOO also reduced BBB permeability and enhanced functional connectivity. While ROO consumption did not alter BBB permeability or brain connectivity, it improved CDR scores and increased functional brain activation to a memory task in cortical regions involved in perception and cognition. Moreover, EVOO and ROO significantly reduced blood Aβ42/Aβ40 and p-tau/t-tau ratios, suggesting that both altered the processing and clearance of Aβ. In conclusion, EVOO and ROO improved CDR and behavioral scores; only EVOO enhanced brain connectivity and reduced BBB permeability, suggesting EVOO biophenols contributed to such an effect. This proof-of-concept study justifies further clinical trials to assess olive oil’s protective effects against AD and its potential role in preventing MCI conversion to AD and related dementias.

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