Search

Although early detection and treatment of colorectal cancer (CRC) have improved, it remains a significant health‐care problem with high morbidity and mortality. Data indicate that long‐term intake of low‐dose aspirin reduces the risk of CRC; however, the mechanisms underlying this chemopreventive effect are still unclear. Different mouse models for inflammation‐associated, sporadic, and hereditary CRC were applied to assess the efficacy and mechanism of low‐dose aspirin on tumor prevention. An initial dosing study performed in healthy mice indicates that aspirin at a dose of 25 mg/kg/d has a similar pharmacodynamic effect as low‐dose aspirin treatment in human subjects (100 mg/d). Chronic low‐dose aspirin treatment suppresses colitis‐associated and to a lesser extent spontaneous tumorigenesis in mice. Aspirin's antitumor effect is most pronounced in a preventive approach when aspirin administration starts before the tumor‐initiating genotoxic event and continues for the duration of the experiment. These effects are not associated with alterations in cell proliferation, apoptosis, or activation of signaling pathways involved in CRC. Aspirin‐induced reduction in tumor burden is accompanied by inhibition of thromboxane B2 formation, indicating reduced platelet activation. Aspirin treatment also results in decreased colonic prostaglandin E2 formation and tumor angiogenesis. With respect to colitis‐triggered tumorigenesis, aspirin administration is associated with a reduction in inflammatory activity in the colon, as indicated by decreased levels of pro‐inflammatory mediators, and tumor‐associated iNOS‐positive macrophages. Our results suggest that low‐dose aspirin represents an effective antitumor agent in the context of colon tumorigenesis primarily due to its well‐established cyclooxygenase inhibition effects., Using three different mouse models of intestinal tumorigenesis, this study clearly establishes a colon tumor‐protective effect of low‐dose aspirin. Aspirin‐induced reduction in tumor burden is accompanied by inhibition of TXB2 and PGE2 formation, as well as a decrease in tumor angiogenesis and inflammatory activity in the colon. These findings argue toward a classical prostanoid‐dependent antitumor effect of low‐dose aspirin.

Background Clinical heterogeneity, a hallmark of systemic autoimmune diseases (SADs) impedes early diagnosis and effective treatment, issues that may be addressed if patients could be grouped into a molecular defined stratification. Methods With the aim of reclassifying SADs independently of the clinical diagnoses, unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data of 918 patients with 7 SADs and 263 healthy controls was undertaken. An inception cohort prospectively followed for 6 and 14 months was studied to validate the results in early cases and analyze if cluster assignment was modified with time. Results Four clusters were identified Three aberrant clusters were ‘acute phase inflammatory’, ‘T cell immunity’, and ‘interferon’, each including all diagnoses, were defined by genetic, clinical, serological and cellular features. A fourth cluster showed no specific molecular pattern, to which 74% of healthy controls clustered with patients. The inception cohort showed that most patients were either assigned always to the same cluster or moved from the healthy-like cluster to a single aberrant cluster resembling the relapsing-remitting dynamic of these diseases, showing that single aberrant molecular signatures characterize each individual patient. Conclusions Patients with SADs share molecular signatures and can be therefore stratified into three disease clusters differentiating each patient into a specific molecular disease pathway. Such assignment is stable with time. These results have important implications for understanding disease progression and therapy design marking a paradigm shift in our view of SADs. Acknowledgment This work has been supported through a grant from the Innovative Medicines Initiative Joint Undertaking No. 115565 and in-kind and in-cash contributions from the EFPIA partners. G.B. is supported by the Instituto de Salud Carlos III (ISCIII, Spanish Health Ministry), through the Sara Borrell subprogram (CD18/00153). The authors would like to particularly express their gratitude to the patients, nurses and many others who helped directly or indirectly in the consecution of this study.

SUMMARYBackgroundClinical heterogeneity, a hallmark of systemic autoimmune diseases (SADs) impedes early diagnosis and effective treatment, issues that may be addressed if patients could be grouped into a molecular defined stratification.MethodsWith the aim of reclassifying SADs independently of the clinical diagnoses, unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data of 918 patients with 7 SADs and 263 healthy controls was undertaken. In addition, an inception cohort was prospectively followed for 6 and 14 months to validate the results and analyze if cluster assignment changed or not with time.ResultsFour clusters were identified. Three clusters were aberrant, representing ‘inflammatory’, ‘lymphoid’, and ‘interferon’ patterns each including all diagnoses and defined by genetic, clinical, serological and cellular features. A fourth cluster showed no specific molecular pattern and accumulated also healthy controls. An independent inception cohort showed that with time, the molecular clusters remain stable, showing that single aberrant molecular signatures characterize each individual patient.ConclusionsPatients with SADs can be jointly stratified into three stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of therapy non-responsiveness marking a paradigm shift in the view of SADs.

PurposeImage guided adaptive radiation therapy offers individualized solutions to improve target coverage and reduce normal tissue irradiation, allowing the opportunity to increase the radiation tumor dose and spare normal bladder tissue.Methods and MaterialsA library of 3 intensity modulated radiation therapy plans were created (small, medium, and large) from planning computed tomography (CT) scans performed at 30 and 60 minutes; treating the whole bladder to 52 Gy and the tumor to 70 Gy in 32 fractions. A “plan of the day” approach was used for treatment delivery. A post-treatment cone beam CT (CBCT) scan was acquired weekly to assess intrafraction filling and coverage.ResultsA total of 18 patients completed treatment to 70 Gy. The plan and treatment for 1 patient was to 68 Gy. Also, 1 patient's plan was to 70 Gy but the patient was treated to a total dose of 65.6 Gy because dose-limiting toxicity occurred before dose escalation. A total of 734 CBCT scans were evaluated. Small, medium, and large plans were used in 36%, 48%, and 16% of cases, respectively. The mean ± standard deviation rate of intrafraction filling at the start of treatment (ie, week 1) was 4.0 ± 4.8 mL/min (range 0.1-19.4) and at end of radiation therapy (ie, week 5 or 6) was 1.1 ± 1.6 mL/min (range 0.01-7.5; P=.002). The mean D98 (dose received by 98% volume) of the tumor boost and bladder as assessed on the post-treatment CBCT scan was 97.07% ± 2.10% (range 89.0%-104%) and 99.97% ± 2.62% (range 96.4%-112.0%). At a median follow-up period of 19 months (range 4-33), no muscle-invasive recurrences had developed. Two patients experienced late toxicity (both grade 3 cystitis) at 5.3 months (now resolved) and 18 months after radiation therapy.ConclusionsImage guided adaptive radiation therapy using intensity modulated radiation therapy to deliver a simultaneous integrated tumor boost to 70 Gy is feasible, with acceptable toxicity, and will be evaluated in a randomized trial.

Background and purpose The latency of a multileaf collimator (MLC) tracking system used to overcome respiratory motion causes misalignment of the treatment beam with respect to the gross tumour volume, which may result in reduced target coverage. This study investigates the magnitude of this effect. Material and methods Simulated superior–inferior breathing motion was used to construct histograms of isocentre offset with respect to the gross tumour volume (GTV) for a variety of tracking latencies. Dose distributions for conformal volumetric modulated arc therapy (VMAT) arcs were then calculated at a range of offsets and summed according to these displacement histograms. The results were verified by delivering the plans to a Delta4 phantom on a motion platform. Results In the absence of an internal target margin, a tracking latency of 150 ms reduces the GTV D95% by approximately 2%. With a margin of 2 mm, the same drop in dose occurs for a tracking latency of 450 ms. Lung V13Gy is unaffected by a range of latencies. These results are supported by the phantom measurements. Conclusions Assuming that internal motion can be modelled by a rigid translation of the patient, MLC tracking of conformal VMAT can be effectively accomplished in the absence of an internal target margin for substantial breathing motion (4 s period and 20 mm peak–peak amplitude) so long as the system latency is less than 150 ms.

In countries with the best cancer outcomes, approximately 60% of patients receive radiotherapy as part of their treatment, which is one of the most cost-effective cancer treatments. Notably, around 40% of cancer cures include the use of radiotherapy, either as a single modality or combined with other treatments. Radiotherapy can provide enormous benefit to patients with cancer. In the past decade, significant technical advances, such as image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic radiotherapy, and proton therapy enable higher doses of radiotherapy to be delivered to the tumour with significantly lower doses to normal surrounding tissues. However, apart from the combination of traditional cytotoxic chemotherapy with radiotherapy, little progress has been made in identifying and defining optimal targeted therapy and radiotherapy combinations to improve the efficacy of cancer treatment. The National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) formed a Joint Working Group with representatives from academia, industry, patient groups and regulatory bodies to address this lack of progress and to publish recommendations for future clinical research. Herein, we highlight the Working Group's consensus recommendations to increase the number of novel drugs being successfully registered in combination with radiotherapy to improve clinical outcomes for patients with cancer.

Radiotherapy remains the cornerstone of curative treatment for inoperable locally advanced lung cancer, given concomitantly with platinum-based chemotherapy. With poor overall survival, research efforts continue to explore whether integration of advanced radiation techniques will assist safe treatment intensification with the potential for improving outcomes. One advance is the integration of magnetic resonance imaging (MRI) in the treatment pathway, providing anatomical and functional information with excellent soft tissue contrast without exposure of the patient to radiation. MRI may complement or improve the diagnostic staging accuracy of F-18 fluorodeoxyglucose position emission tomography and computerized tomography imaging, particularly in assessing local tumour invasion and is also effective for identification of nodal and distant metastatic disease. Incorporating anatomical MRI sequences into lung radiotherapy treatment planning is a novel application and may improve target volume and organs at risk delineation reproducibility. Furthermore, functional MRI may facilitate dose painting for heterogeneous target volumes and prediction of normal tissue toxicity to guide adaptive strategies. MRI sequences are rapidly developing and although the issue of intra-thoracic motion has historically hindered the quality of MRI due to the effect of motion, progress is being made in this field. Four-dimensional MRI has the potential to complement or supersede 4D CT and 4D F-18-FDG PET, by providing superior spatial resolution. A number of MR-guided radiotherapy delivery units are now available, combining a radiotherapy delivery machine (linear accelerator or cobalt-60 unit) with MRI at varying magnetic field strengths. This novel hybrid technology is evolving with many technical challenges to overcome. It is anticipated that the clinical benefits of MR-guided radiotherapy will be derived from the ability to adapt treatment on the fly for each fraction and in real-time, using 'beam-on' imaging. The lung tumour site group of the Atlantic MR-Linac consortium is working to generate a challenging MR-guided adaptive workflow for multi-institution treatment intensification trials in this patient group.

Although early detection and treatment of colorectal cancer (CRC) have improved in recent years, it remains a significant healthcare problem with high morbidity and mortality. Published data indicate that long-term intake of low dose aspirin reduces the risk of CRC, however the molecular mechanisms underlying this effect are still unclear. The aim of this study was to investigate the efficacy of low dose equivalent aspirin treatment in a mouse colon carcinogenesis model, including evaluation of potential mechanistic contributors. An initial PK/PD study in healthy mice indicated that aspirin 25 mg/kg/day given via drinking water had a similar PD effect - reduction in plasma thromboxane B2 (TXB2), as an indicator of cyclooxygenase-1 (COX-1) inhibition - as did 5-day low-dose aspirin treatment (100 mg/day) in healthy human volunteers. Male and female C57BL/6J mice were treated with the carcinogen azoxymethane (AOM) 10 mg/kg once i.p. combined with three 5-day cycles (at 14 day intervals) of dextran sodium sulphate (DSS) 2% in drinking water. Aspirin treatment was started concomitant with AOM administration and continued for 12 weeks, at which time the data outlined below were obtained. Aspirin 25 mg/kg/day significantly reduced tumor burden in 3 independent experiments (total tumor number reduced by 43 - 51%; tumor area per mouse reduced by 59 - 65%; mean tumor area reduced by 22 - 27%). Increasing the dose to 50 mg/kg/day did not show better inhibition of tumorigenesis. Aspirin-induced reduction in tumorigenesis in this model was accompanied by reduction in systemic plasma TXB2 by about 70%, indicating reduced platelet activation. TXB2 production by colon explants was also reduced, by 30-50%. Aspirin treatment reduced inflammatory activity (fecal blood; IL-1β and IL-6 production by colon explant cultures; iNOS-positive tumor macrophage infiltration). Immunohistological analysis of tumor tissue showed no reduction in proliferation (BrdU staining) by aspirin but there was a trend towards increased apoptosis (caspase-3 positive cells) and a significant reduction in CD31-positive microvessel density. Aspirin treatment did not result in significant modulation of the Wnt/β-catenin, NF-κB or HIF-1 pathways as assessed by mRNA expression of several of their target genes in tumor tissue. The results show that aspirin can inhibit tumor development in this established model of colon carcinogenesis, primarily by reducing tumor number with a less marked effect on the size of individual tumors. This effect is associated with COX-1 inhibition of a similar magnitude to that seen with low dose aspirin in humans. The influence of aspirin on intestinal inflammation and platelet activation as well as on tumor cell apoptosis and tumor angiogenesis might all contribute to the beneficial effects seen in this model. Additional studies are planned to further elucidate aspirin's mechanism of action in inhibiting tumor development. Citation Format: Nadine Rohwer, Anja Kuehl, Dieter Zopf, Fiona M. McDonald, Karsten-Heinrich Weylandt. Effects of chronic low dose aspirin treatment in the mouse AOM/DSS model of colon carcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5244.

Purpose Given the large number of adolescents and young adults (AYAs) impacted by parental cancer and the potential for negative psychosocial outcomes in this vulnerable population, this study examined the mediating role of offspring unmet needs with regard to parental cancer and the relation between AYAs psychosocial adjustment and perceived illness unpredictability. Methods A total of 113 AYAs (aged 11–24 years) living with a parent diagnosed with cancer completed a questionnaire assessing illness unpredictability, offspring unmet needs, and psychosocial adjustment (i.e., health-related quality of life and internalizing problems). Results Higher offspring unmet needs were associated with lower health-related quality of life (r = –0.24**) and higher internalizing problems (r = 0.21*). Offspring unmet needs mediated the relation between illness unpredictability and health-related quality of life (standardized indirect effect = –0.100* [–0.183, –0.018]) but not internalizing problems (standardized indirect effect = 0.067 [–0.015, 0.148]). In particular, higher illness unpredictability was related to higher unmet needs (β = 0.351**) which, in turn, predicted lower health-related quality of life (β = –0.286**). Conclusion These findings identify offspring unmet needs and illness unpredictability as implicated in AYAs positive psychosocial adjustment to parental cancer. Given that AYAs are at greater risk of elevated psychosocial difficulties, interventions should target offspring unmet needs and perception of illness unpredictability to mitigate the adverse effects of parental cancer.