BackgroundRisk of normal tissue toxicity limits the amount of thoracic radiation therapy (RT) that can be routinely prescribed to treat non-small cell lung cancer (NSCLC). An early biomarker of response to thoracic RT may provide a way to predict eventual toxicities—such as radiation pneumonitis—during treatment, thereby enabling dose adjustment before the symptomatic onset of late effects. MicroRNAs (miRNAs) were studied as potential serological biomarkers for thoracic RT. As a first step, we sought to identify miRNAs that correlate with delivered dose and standard dosimetric factors.MethodsWe performed miRNA profiling of plasma samples obtained from five patients with Stage IIIA NSCLC at five dose-points each during radical thoracic RT. Candidate miRNAs were then assessed in samples from a separate cohort of 21 NSCLC patients receiving radical thoracic RT. To identify a cellular source of circulating miRNAs, we quantified in vitro miRNA expression intracellularly and within secreted exosomes in five NSCLC and stromal cell lines.ResultsmiRNA profiling of the discovery cohort identified ten circulating miRNAs that correlated with delivered RT dose as well as other dosimetric parameters such as lung V20. In the validation cohort, miR-29a-3p and miR-150-5p were reproducibly shown to decrease with increasing radiation dose. Expression of miR-29a-3p and miR-150-5p in secreted exosomes decreased with radiation. This was concomitant with an increase in intracellular levels, suggesting that exosomal export of these miRNAs may be downregulated in both NSCLC and stromal cells in response to radiation.ConclusionsmiR-29a-3p and miR-150-5p were identified as circulating biomarkers that correlated with delivered RT dose. miR-150 has been reported to decrease in the circulation of mammals exposed to radiation while miR-29a has been associated with fibrosis in the human heart, lungs, and kidneys. One may therefore hypothesize that outlier levels of circulating miR-29a-3p and miR-150-5p may eventually help predict unexpected responses to radiation therapy, such as toxicity.Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-016-0636-4) contains supplementary material, which is available to authorized users.

Background Older patients are poorly represented in breast cancer research and guidelines do not provide evidence based recommendations for this specific group. We compared treatment strategies and survival outcomes between European countries and assessed whether variance in treatment patterns may be associated with variation in survival. Methods Population-based study including patients aged ≥ 70 with non-metastatic BC from cancer registries from the Netherlands, Belgium, Ireland, England and Greater Poland. Proportions of local and systemic treatments, five-year relative survival and relative excess risks (RER) between countries were calculated. Results In total, 236,015 patients were included. The proportion of stage I BC receiving endocrine therapy ranged from 19.6% (Netherlands) to 84.6% (Belgium). The proportion of stage III BC receiving no breast surgery varied between 22.0% (Belgium) and 50.8% (Ireland). For stage I BC, relative survival was lower in England compared with Belgium (RER 2.96, 95%CI 1.30–6.72, P < .001). For stage III BC, England, Ireland and Greater Poland showed significantly worse relative survival compared with Belgium. Conclusions There is substantial variation in treatment strategies and survival outcomes in elderly with BC in Europe. For early-stage BC, we observed large variation in endocrine therapy but no variation in relative survival, suggesting potential overtreatment. For advanced BC, we observed higher survival in countries with lower proportions of omission of surgery, suggesting potential undertreatment.

We aimed to externally validate five normal tissue complication probability (NTCP) models for radiation-induced hypothyroidism (RIHT) in a prospectively recruited cohort of 108 patients with oropharyngeal cancer (OPC). NTCP scores were calculated using original published formulas. Plasma thyrotropin (TSH) level was additionally assessed in the short-term after RT. After a median of 28 months of follow-up, thirty one (28.7%) patients developed RIHT. Thyroid mean dose and thyroid volume were significant predictors of RIHT: odds ratio equal to 1.11 (95% CI 1.03–1.19) for mean thyroid dose and 0.87 (95%CI 0.81–0.93) for thyroid volume in univariate analyses. Two of the evaluated NTCP models, published by Rønjom et al. and by Boomsma et al., had satisfactory performance with accuracies of 0.87 (95%CI 0.79–0.93) and 0.84 (95%CI: 0.76–0.91), respectively. Three remaining models, by Cella et al., Bakhshandeh et al. and Vogelius et al., performed significantly worse, overestimating the risk of RIHT in this patient cohort. A short-term TSH level change relative to baseline was not indicative of RIHT development in the follow-up (OR 0.96, 95%CI: 0.65–1.42, p = 0.825). In conclusion, the models by Rønjom et al. and by Boomsma et al. demonstrated external validity and feasibility for long-term prediction of RIHT in survivors of OPC treated with Intensity-Modulated Radiation Therapy (IMRT).

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Abstract.Immune checkpoints refer to a plethora of inhibitory pathways built into the immune system, and recent studies have emphasized the role of these checkpoints in carcinogenesis. The aim of the present study was to evaluate two major immune checkpoints, the cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), in the serum of 35 patients with stage I and II breast cancer. Serum concentrations of CTLA-4 and PD-1 were measured at three time points: i) Preoperatively; ii) during anesthesia following the harvesting of sentinel nodes (SNs); and iii) 24 h postoperatively. Control samples were obtained from 25 healthy, age-matched females. Assessment of CTLA-4 and PD-1 expression levels was conducted using flow cytometry. A statistically significant difference in PD-1 expression was identified between breast cancer patients preoperatively and healthy controls (26.31±11.87 vs. 12.72±8.15; P<0.0001). In addition, a statistically significant association was found between CTLA-4 and PD-1 levels prior to surgery (P=0.0084). In addition, CTLA-4 expression was associated with age (P=0.0453), with elevated levels of CTLA-4 detected in older breast cancer patients. Higher PD-1 expression levels were observed in T2 tumors compared with T1 tumors prior to surgery and intraoperatively; however, the differences were not statistically significant. Furthermore, a decrease in PD-1 levels was observed subsequent to harvesting SNs with metastasis, but not in SN-negative patients (P=0.05). A negative correlation was also observed between PD-1 expression and progesterone receptor (PR) status following surgery (P=0.024). These results provided a basis for further investigation of immune checkpoints in breast cancer. Breast cancer patients exhibit an altered profile of immune checkpoint markers, with higher concentrations of PD-1 observed in larger, PR-negative tumors. IntroductionThe value of lymph node surgery in breast cancer patients has been greatly debated over the past years, resulting in a wide range of management techniques, including radical excision of three levels of axillary lymph nodes and parasternal nodes (1), axillary lymph node dissection (2), sentinel node biopsy (3), omission of axillary lymph node dissection in cases of macroor micrometastases in selected cases (4,5), and abandonment of nodal procedures in early-stage breast cancer (6,7). Despite a paradigm shift and progressive decline in the extent of lymph node surgery in recent years, the survival rates in breast cancer patients have improved and axillary recurrence remains extremely low (~1% per 5 years) (4,5). The improvement in survival rates may be due to following: i) Modern postoperative adjuvant therapies, including chemo-, endocrine, anti-human epidermal growth factor receptor 2 (HER2) and radio-therapy, may eliminate low volume axillary metastases in residual nodes in early-stage breast cancer; ii) intact axillary lymph nodes may eliminate low-volume disease by immune surveillance mechanisms in early-stage breast cancer...