***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: ABSTRACT The predominant mode of radiation-induced cell death for solid tumours is mitotic catastrophe , which is in part dependent on sublethal damage repair being complete at around 6 h. Circadian variation appears to play a role in normal cellular division , and this could influence tumour response of radiation treatment depending on the time of treatment delivery . We tested the hypothesis that radiation treatment later in the day may improve tumour response and nodal downstaging in rectal cancer patients treated neoadjuvantly with radiation therapy .  Recruitment was by retrospective review of 267 rectal cancer patients treated neoadjuvantly in the Department of Radiation Oncology at the Canberra Hospital between January 2010 and November 2015 . One hundred and fifty-five patients met the inclusion criteria for which demographic , pathological and imaging data were collected , as well as the time of day patients received treatment with each fraction of radiotherapy . Data analysis was performed using the Statistical Package R with nonparametric methods of significance for all tests set at p < 0.05 . Of the 45 female and 110 male patients , the median age was 64 . Seventy-three percent had cT3 disease and there was a mean tumour distance from the anal verge of 7 cm . Time to surgical resection following radiotherapy ranged from 4 to 162 days with a median of 50 days , with a complete pathological response seen in 21 % of patients . Patients exhibiting a favourable pathological response had smaller median pre- and postradiotherapy tumour size and had a greater change in tumour size following treatment ( p < 0.01 ) . Patients who received the majority of their radiotherapy fractions after 12:00 pm were more likely to show a complete or moderate pathological response ( p = 0.035 ) and improved nodal downstaging . There were also more favourable responses amongst patients with longer time to surgical resection postradiotherapy ( p < 0.004 ) , although no relationship was seen between response and tumour distance from the anal verge . Females were less likely to exhibit several of the above responses . Neoadjuvant radiotherapy for locally advanced rectal cancer performed later in the day coupled with a longer time period to surgical resection may improve pathological tumour response rates and nodal downstaging . A prospect i ve study in chronomodulated radiotherapy in this disease is warranted The safety and efficacy of chemotherapeutics can vary as a function of the time of their delivery during the day . This study aim ed to improve the treatment of glioblastoma ( GBM ) , the most common brain cancer , by testing whether the efficacy of the DNA alkylator temozolomide ( TMZ ) varies with the time of its administration . We found cell-intrinsic , daily rhythms in both human and mouse GBM cells . Circadian time of treatment affected TMZ sensitivity of murine GBM tumor cells in vitro . The maximum  TMZ-induced DNA damage response , activation of apoptosis , and growth inhibition occurred near the daily peak in expression of the core clock gene Bmal1 . Deletion of Bmal1 ( Arntl ) abolished circadian rhythms in gene expression and TMZ-induced activation of apoptosis and growth inhibition . These data indicate that tumor cell-intrinsic circadian rhythms are common to GBM tumors and can regulate TMZ cytotoxicity . Optimization of GBM treatment by timing TMZ administration to daily rhythms should be evaluated in prospect i ve clinical trials Mucositis , a radiotherapy‐associated toxicity , is an important factor determining morbidity and treatment compliance . Gastrointestinal mucositis in patients undergoing radiotherapy  may also depend on time of administration of radiation in addition to several other factors . The presence of any correlation between the severity of acute gastrointestinal mucositis in cervical carcinoma patients and the time of irradiation was prospect ively evaluated 1 . The circadian timing system has been implicated in age-related changes in sleep structure , timing and consolidation in humans . 2 . We investigated the circadian regulation of sleep in 13 older men and women and 11 young men by forced desynchrony of polysomnographically recorded sleep episodes ( total , 482 ; 9 h 20 min each ) and the circadian rhythms of plasma melatonin and core body temperature . 3 . Stage 4 sleep was reduced in older people . Overall levels of rapid eye movement ( REM ) sleep were not significantly affected by age . The latencies to REM sleep were shorter in older people when sleep coincided with the melatonin rhythm . REM sleep was increased in the first quarter of the sleep episode and the increase of REM sleep in the course of sleep was diminished in older people . 4 . Sleep propensity co-varied with the circadian rhythms of body temperature and plasma melatonin in both age groups . Sleep latencies were longest just before the onset of melatonin secretion and short sleep latencies were observed close to the temperature nadir . In older people  sleep latencies were longer close to the crest of the melatonin rhythm . 5 . In older people sleep duration was reduced at all circadian phases and sleep consolidation deteriorated more rapidly during the course of sleep , especially when the second half of the sleep episode occurred after the crest of the melatonin rhythm . 6 . The data demonstrate age-related decrements in sleep consolidation and increased susceptibility to circadian phase misalignment in older people . These changes , and the associated internal phase advance of the propensity to awaken from sleep , appear to be related to the interaction between a reduction in the homeostatic drive for sleep and a reduced strength of the circadian signal promoting sleep in the early morning BACKGROUND Smoking is a risk factor for several cancers and may also limit the efficacy of treatment . In this study , we evaluated the influence of cigarette smoking during radiation therapy on the efficacy of treatment in patients with head and neck cancer . METHODS Using a question naire , we obtained information on smoking behavior at base line and weekly during therapy in 115 patients with head and neck cancer who were treated with radiation therapy with or without fluorouracil .  The side effects of therapy were evaluated weekly , and response was assessed 13 weeks after treatment was completed . The main outcomes measured were treatment response and survival . RESULTS The prognostic variables were similar among the patients who smoked and those who did not smoke during treatment . The 53 patients who continued to smoke during radiation therapy had a lower rate of complete response ( 45 percent vs. 74 percent , P = 0.008 ) and poorer two-year survival ( 39 percent vs. 66 percent , P = 0.005 ) than the 62 patients who did not smoke or who had quit before treatment . Among the nonsmoking patients , mortality was influenced by the length of time between quitting and treatment , with a risk reduction ( relative to that for patients who continued to smoke ) of 40 percent for patients who had quit less than 12 weeks before diagnosis and of 70 percent for patients who had quit more than 1 year before diagnosis . After adjustment for other variables with proportional-hazards regression analysis , smoking remained an independent prognostic factor ( P = 0.002 ) , with a relative risk of 2.5 ( 95 percent confidence interval , 1.4 to 4.4 ) favoring the patients who abstained from smoking . The results could not be explained by the type of chemotherapy received , the presence of coexisting morbid conditions , differences in the side effects of radiation , or the number of interruptions of treatment . CONCLUSIONS Patients with head and neck cancer who continue to smoke during  radiation therapy have lower rates of response and survival than patients who do not smoke during radiation therapy PURPOSE To investigate the radiation effects and acute damage in inoperable cervical cancer patients irradiated at different times as well as the underlying mechanisms . METHODS 67 patients were r and omized to a morning group ( MG , 9:00 - 11:00 AM ) and an evening group ( EG , 9:00 - 11:00 PM ) and both received external beam radiotherapy ( RT ) ( 50 Gy in 25 fractions ) at different times . Brachytherapy ( 36 - 42 Gy in 6 - 7 fractions ) was also performed to enhance the radiation response twice every week in all patients at the same time . Clinical therapeutic effects and acute toxicities were evaluated after RT . Flow cytometry was analyzed before and after RT . RESULTS Patients ' response to radiation was similar in the two groups . Incidences of overall and high- grade ( III - IV ) diarrhea in the MG vs. the EG were 75.0 % vs. 57.6 % and 12.5 % vs. 6.1 % , respectively . The incidence of severe hematological toxicity in the EG was significantly increased compared to the MG group . Cell apoptosis in the EG was significantly higher at 9:00 - 11:00 PM than that at 9:00 - 11:00 AM after RT . No significant differences were found in Gap Phase 0/Gap Phase 1 ( G0/G1 ) , Gap Phase 2/Metaphase Phase ( G2/M ) , and Synthesis Phase ( S ) phase between different times and groups , nor were expressions of Per1 , Per2 , and Clock . But expressions of Per1 , Per2 , and Clock were significantly negative with G2/M phase and positively correlated with cell apoptosis . CONCLUSION RT at different time intervals results in similar efficacy . However , RT in the morning reduces severe hematological toxicity . Radiation responses may be associated with circadian genes by influence of cell cycles and apoptosis . AIMS Radiotherapy is an important treatment for many types of cancer , but a minority of patients suffer long-term side-effects of treatment . Multiple lines of evidence suggest a role for circadian rhythm in the development of radiotherapy late side-effects . MATERIAL S AND METHODS We carried out a study to examine the effect of radiotherapy timing in two breast cancer patient cohorts . The retrospective LeND cohort comprised 535 patients scored for late effects using the Late Effects of Normal Tissue-Subjective Objective Management Analytical ( LENT-SOMA ) scale . Acute effects were assessed prospect ively in 343 patients from the REQUITE study using the CTCAE v4 scales . Genotyping was carried out for c and i date circadian rhythm variants . RESULTS In the LeND cohort , patients who had radiotherapy in the morning had a significantly increased incidence of late toxicity in univariate ( P = 0.03 ) and multivariate analysis ( P = 0.01 ) . Acute effects in the REQUITE group were also significantly increased in univariate analysis after morning treatment ( P = 0.03 ) but not on multivariate analysis . Increased late effects in the LeND group receiving morning radiotherapy were associated with carriage of the PER3 variable number t and em repeat 4/4 genotype ( P = 6 × 10 - 3 ) and the NOCT rs131116075 AA genotype ( P = 5 × 10 - 3 ) . CONCLUSION Our results suggest that it may be possible to reduce toxicity associated with breast cancer radiotherapy by identifying gene variants that affect circadian rhythm and scheduling for appropriate morning or afternoon radiotherapy PURPOSE Based on our demonstration of a circadian rhythm in the human oral mucosa cell cycle , with most cells in the G(1 ) phase in the morning and M phase at night , we hypothesized that morning radiotherapy ( RT ) would lead to less oral mucositis than afternoon RT . METHODS AND MATERIAL S A total of 216 patients were r and omized to morning ( 8 - 10 AM ) vs. afternoon ( 4 - 6 PM ) RT  and stratified by radiation dose , smoking status , and center . Patients receiving primary or postoperative RT alone were eligible .  Oral mucositis was scored using the Radiation Therapy Oncology Group ( RTOG ) criteria and a vali date d scoring system . RESULTS Of 205 evaluable patients , 52.9 % vs. 62.4 % developed RTOG Grade 3 or greater mucositis after morning vs. afternoon RT , respectively ( p = 0.17 ) . Morning RT was also associated with significantly less weight loss after 5 months ( p = 0.024 ) . In a subgroup of 111 patients treated to a dose of 66 - 70 Gy in 33 - 35 fractions , exploratory analyses revealed a significant reduction in Grade 3 or greater mucositis with morning RT ( 44.6 % vs. 67.3 % , p = 0.022 ) and a longer interval to the development of Grade 3 or greater mucositis ( median , > 7.9 vs. 5.6 weeks , p = 0.033 ) . In 53 patients , who smoked during therapy , a significant reduction was found in Grade 3 or greater mucositis with morning RT ( 42.9 % vs. 76 % , p = 0.025 ) . CONCLUSION In this proof of principle study , morning RT was associated with significantly less weight loss after 5 months and an apparent reduction in oral mucositis in a subset of patients receiving > /=66 Gy and in patients who smoked during therapy Purpose : Patients of head and neck cancer undergoing radiotherapy  develop oral mucositis . The severity of mucositis may also depend on the time of administration of radiation apart from patient-related factors . The most radiosensitive phase of the cell cycle ( G2-M ) occurs in the late afternoon and evening in human oral mucosa ; therefore , it is more vulnerable to radiation injury in the evening . The present study evaluated prospect ively the severity of acute oral mucositis in head and neck carcinoma patients irradiated  in  the morning ( 08:00–11:00 h ) versus late afternoon/evening ( 15:00–18:00 h ) . Method : A total of 212 patients of head and neck carcinoma were r and omised to morning 
    Output:
    
Existing literature suggests that the application of radiation chronotherapy may reduce negative symptom outcome within highly proliferative tissues .