Purpose ATR inhibitors (ATRi) are in early phase clinical trials and have been shown to sensitise to chemotherapy and radiotherapy preclinically. Limited data have been published about the effect of these drugs on the tumor microenvironment. Experimental Design We used an immunocompetent mouse model of HPV-driven malignancies to investigate the ATR inhibitor AZD6738 in combination with fractionated radiation (RT). Gene expression analysis and flow cytometry were performed post-therapy. Results Significant radiosensitization to RT by ATRi was observed alongside a marked increase in immune cell infiltration. We identified increased numbers of CD3+ and NK cells but most of this infiltrate was composed of myeloid cells. ATRi plus radiation produced a gene expression signature matching a type I/II interferon response with upregulation of genes playing a role in nucleic acid sensing. Increased MHC I levels were observed on tumor cells, with transcript-level data indicating increased antigen processing and presentation within the tumor. Significant modulation of cytokine gene expression (particularly CCL2, CCL5 and CXCL10) was found in vivo, with in vitro data indicating CCL3, CCL5 and CXCL10 are produced from tumor cells after ATRi + RT. Conclusions We show that DNA damage by ATRi and RT leads to an interferon response through activation of nucleic acid sensing pathways. This triggers increased antigen presentation and innate immune cell infiltration. Further understanding of the effect of this combination on the immune response may allow modulation of these effects to maximise tumor control through anti-tumor immunity.
SummaryBackgroundPatient-reported outcomes (PROs) might detect more toxic effects of radiotherapy than do clinician-reported outcomes. We did a quality of life (QoL) substudy to assess PROs up to 24 months after conventionally fractionated or hypofractionated radiotherapy in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy in Prostate Cancer (CHHiP) trial.MethodsThe CHHiP trial is a randomised, non-inferiority phase 3 trial done in 71 centres, of which 57 UK hospitals took part in the QoL substudy. Men with localised prostate cancer who were undergoing radiotherapy were eligible for trial entry if they had histologically confirmed T1b–T3aN0M0 prostate cancer, an estimated risk of seminal vesicle involvement less than 30%, prostate-specific antigen concentration less than 30 ng/mL, and a WHO performance status of 0 or 1. Participants were randomly assigned (1:1:1) to receive a standard fractionation schedule of 74 Gy in 37 fractions or one of two hypofractionated schedules: 60 Gy in 20 fractions or 57 Gy in 19 fractions. Randomisation was done with computer-generated permuted block sizes of six and nine, stratified by centre and National Comprehensive Cancer Network (NCCN) risk group. Treatment allocation was not masked. UCLA Prostate Cancer Index (UCLA-PCI), including Short Form (SF)-36 and Functional Assessment of Cancer Therapy-Prostate (FACT-P), or Expanded Prostate Cancer Index Composite (EPIC) and SF-12 quality-of-life questionnaires were completed at baseline, pre-radiotherapy, 10 weeks post-radiotherapy, and 6, 12, 18, and 24 months post-radiotherapy. The CHHiP trial completed accrual on June 16, 2011, and the QoL substudy was closed to further recruitment on Nov 1, 2009. Analysis was on an intention-to-treat basis. The primary endpoint of the QoL substudy was overall bowel bother and comparisons between fractionation groups were done at 24 months post-radiotherapy. The CHHiP trial is registered with ISRCTN registry, number ISRCTN97182923.Findings2100 participants in the CHHiP trial consented to be included in the QoL substudy: 696 assigned to the 74 Gy schedule, 698 assigned to the 60 Gy schedule, and 706 assigned to the 57 Gy schedule. Of these individuals, 1659 (79%) provided data pre-radiotherapy and 1444 (69%) provided data at 24 months after radiotherapy. Median follow-up was 50·0 months (IQR 38·4–64·2) on April 9, 2014, which was the most recent follow-up measurement of all data collected before the QoL data were analysed in September, 2014. Comparison of 74 Gy in 37 fractions, 60 Gy in 20 fractions, and 57 Gy in 19 fractions groups at 2 years showed no overall bowel bother in 269 (66%), 266 (65%), and 282 (65%) men; very small bother in 92 (22%), 91 (22%), and 93 (21%) men; small bother in 26 (6%), 28 (7%), and 38 (9%) men; moderate bother in 19 (5%), 23 (6%), and 21 (5%) men, and severe bother in four (<1%), three (<1%) and three (<1%) men respectively (74 Gy vs 60 Gy, ptrend=0.64, 74 Gy vs 57 Gy, ptrend=0·59). We saw no differences between treatment groups in change...
Diverse extracellular matrix patterns are observed in both normal and pathological tissue. However, most current tools for quantitative analysis focus on a single aspect of matrix patterning. Thus, an automated pipeline that simultaneously quantifies a broad range of metrics and enables a comprehensive description of varied matrix patterns is needed. To this end, we have developed an ImageJ plugin called TWOMBLI, which stands for The Workflow Of Matrix BioLogy Informatics. This pipeline includes metrics of matrix alignment, length, branching, end points, gaps, fractal dimension, curvature, and the distribution of fibre thickness. TWOMBLI is designed to be quick, versatile and easy-to-use particularly for non-computational scientists. TWOMBLI can be downloaded from https://github.com/wershofe/TWOMBLI together with detailed documentation and tutorial video. Although developed with the extracellular matrix in mind, TWOMBLI is versatile and can be applied to vascular and cytoskeletal networks. Here we present an overview of the pipeline together with examples from a wide range of contexts where matrix patterns are generated.
This study derived anorectal dose constraints using 12 clinician-reported or patientreported bowel symptoms in the CHHiP trial of Purpose: The CHHiP trial randomized 3216 men with localized prostate cancer (1:1:1) to 3 radiation therapy fractionation schedules: 74 Gy in 37 fractions over 7.4 weeks; 60 Gy in 20 fractions over 4 weeks; and 57 Gy in 19 fractions over 3.8 weeks. Literaturebased dose constraints were applied with arithmetic adjustment for the hypofractionated arms. This study aimed to derive anorectal dose constraints using prospectively collected clinician-reported outcomes (CROs) and patient-reported outcomes (PROs) and to assess the added predictive value of spatial dose metrics.
E 7 2 7What ' s known on the subject? and What does the study add? Diethylstilbestrol (DES) was the fi rst hormone treatment used for prostate cancer and has also shown effectiveness in castration-resistant disease in small studies; however, concerns over thromboembolic toxicity have restricted its use in the past.Over 200 elderly men with castration-resistant prostate cancer were treated with 1 -3 mg of DES, given with 75 mg aspirin and breast bud irradiation. Almost 30% of men showed a signifi cant PSA response and the median time to PSA progression was 4.6 months. Almost 20% of patients with pain had a signifi cant analgesic benefi t. The most important toxicity was thromboembolism in 10% of men. Overall the drug has an acceptable toxicity profi le and offers a palliative benefi t in frail elderly men who may not be fi t for chemotherapy. OBJECTIVE• To assess the effi cacy and toxicity of diethylstilbestrol (DES) in the management of castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS• A total of 231 patients with CRPC received treatment with DES at the Royal Marsden Hospital between August 1992 and August 2000.• The median pre-treatment prostatespecifi c antigen (PSA) level was 221 ng/mL.• DES was used at a dose of 1 -3 mg daily, with aspirin 75 mg.• The primary endpoint was PSA response rate. RESULTS• The PSA response rate (using PSA Working Group criteria) was 28.9%.• The median time to PSA progression was 4.6 months.• Of patients with bone pain, 18% had an improvement in their European Organisation for the Research and Treatment of Cancer pain score.• Thromboembolic complications were seen in 9.9% of all patients. CONCLUSIONS• DES has signifi cant activity in CRPC and can be of palliative benefi t.• DES has an acceptable toxicity profi le in the management of patients with symptomatic CRPC when used at a dose of 1 -3 mg, combined with aspirin and prophylactic breast bud radiotherapy. KEYWORDS
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