Combining proton or photon irradiation with epothilone B : An in vitro study of cytotoxicity in human cancer cells

Recently, the use of proton beams in cancer therapy is becoming widespread, and tumour treatment modalities combining radiosensitizing chemical agents with irradiation are under investigation in order to achieve greater tumour local control and reduce the probability of distant failures. The combined treatment modality of radiation and the clinically relevant microtubule-stabilizing compound epothilone B is a promising approach for anticancer therapy. In the present study, we investigated the cytotoxicity of a spread out Bragg peak (SOBP) proton beam, as well as of 6 MV photons, in human glioblastoma (U251 MG) and lung adenocarcinoma (A549) cells pretreated for 24 h, or not, with epothilone B at concentrations of 0.125 and 0.075 nM respectively. Proton irradiation was performed at the middle position of an actively modulated SOBP (12\u201318 cm depth in water) and cell survival was evaluated by a colony forming assay. For both cell lines, survival curves after proton or photon irradiation alone showed linear quadratic behaviour with proton RBE (relative biological effectiveness), compared with photons at 10% survival, of 1.5 \ub1 0.2. Treatment of cells with epothilone B at subnanomolar concentration has an anticlonogenic effect. Furthermore, differently from the results found with radiation alone, the survival curves for the combined treatment epothilone B\u2013radiation showed a linear trend and analysis of the interaction of the two cytotoxic agents indicated a slight synergism. These data provide a radiobiological basis for further experiments, as well as clinical studies

factors influencing acute and late toxicity in the era of adjuvant hypofractionated breast radiotherapy

Abstract Purpose To evaluate toxicity in breast cancer patients treated with anthracycline and taxane based chemotherapy and whole breast hypofractionated radiotherapy, and to identify the risk factors for toxicity. Methods and materials 537 early breast cancer patients receiving hypofractionated radiotherapy after conservative surgery were enrolled from April 2009 to December 2014, in an Italian cancer institute. The dose was 42.4 Gy in 16 daily fractions, 2.65 Gy per fraction. The boost to the tumor bed was administered only in grade III breast cancer patients and in patients with close or positive margins. Acute and late toxicity were prospectively assessed during and after radiotherapy according to RTOG scale. The impact of patients clinical characteristics, performed treatments and dose inhomogeneities on the occurrence of an higher level of acute skin toxicity and late fibrosis has been evaluated by univariate and multivariate analysis. Results The mean age was 74 (range 46–91 yrs). 27% of patients received boost. 22% of cases (n = 119) received also chemotherapy. The median follow-up was 32 months. G1 and G2/G3 acute skin toxicity were 61.3% and 20.5% and G1 and G2/G3 late fibrosis 12.6% and 4.3% respectively. Chemotherapy (p = 0.04), diabetes (p = 0.04) and boost administration (p Conclusions The results of our study, according to the large randomized trials, confirmed that hypofractionated whole breast irradiation is safe, and only the boost administration seems to be an important predictor for toxicity. Chemotherapy does not impact on acute and late skin toxicity

Studio degli effetti dell’uso combinato di fasci terapeutici di particelle cariche e radiosensibilizzanti in cellule tumorali umane coltivate in vitro

Nell\u2019ambito delle terapie oncologiche \ue8 crescente l\u2019interesse per trattamenti che abbinino alle radiazioni l\u2019utilizzo di agenti chimici potenziali radiosensibilizzanti. L\u2019obiettivo di questo tipo di trattamenti \ue8 quello di ottenere un miglior controllo locale del tumore e di ridurre la probabilit\ue0 di formazione di metastasi. In letteratura sono stati pubblicati numerosi studi sull\u2019uso concomitante di fasci terapeutici di fotoni e diversi agenti chimici, ma attualmente ben pochi dati sono disponibili sull\u2019azione combinata di adroni e agenti chimici radiosensibilizzanti. In questo lavoro si descrivono i risultati di uno studio radiobiologico condotto su fasci terapeutici di fotoni e di protoni, ed alcuni dati preliminari relativi a fasci di ioni Carbonio, utilizzando cellule umane tumorali coltivate in vitro, trattate o meno, durante le 24 ore precedenti l\u2019irraggiamento, con il chemioterapico Epothilone B, un agente microtubulo-stabilizzante. I principali obiettivi dello studio sono: - determinare l\u2019efficacia dei fasci di adroni rispetto ai fotoni, per le linee cellulari studiate ( RBE) - studiare la modalit\ue0 di interazione delle diverse radiazioni con Epothilone B per valutare se sia additiva o sinergica. Sono stati utilizzati i fasci terapeutici di adroni di CNAO (Pavia) e di fotoni presso l\u2019Istituto Tumori di Milano. Lo studio \ue8 stato condotto su linee cellulari umane di glioblastoma multiforme (U251MG), adenocarcinoma polmonare a cellule non piccole (A549) e medulloblastoma pediatrico (DAOY). I principali effetti biologici studiati sono il mantenimento della capacit\ue0 proliferativa (sopravvivenza clonogenica), la crescita e l\u2019invasivit\ue0 cellulare. I risultati ottenuti hanno mostrato che: - l\u2019RBE dei protoni dipende fortemente dalla linea cellulare e, per glioblastoma multiforme e per adenocarcinoma polmonare, \ue8 risultata maggiore di 1.1, valore attualmente usato nella pratica clinica. - Il chemioterapico Epothilone B aumenta la citotossicit\ue0 dei fasci di protoni e di fotoni e l\u2019effetto del trattamento combinato \ue8 pi\uf9 che additivo

A microRNA prognostic signature in patients with diffuse intrinsic pontine gliomas through non-invasive liquid biopsy

Diffuse midline gliomas (DMGs) originate in the thalamus, brainstem, cerebellum and spine. This entity includes tumors that infiltrate the pons, called diffuse intrinsic pontine gliomas (DIPGs), with a rapid onset and devastating neurological symptoms. Since surgical removal in DIPGs is not feasible, the purpose of this study was to profile circulating miRNA expression in DIPG patients in an effort to identify a non-invasive prognostic signature with clinical impact. Using a high-throughput platform, miRNA expression was profiled in serum samples collected at the time of MRI diagnosis and prior to radiation and/or systemic therapy from 47 patients enrolled in clinical studies, combining nimotuzumab and vinorelbine with concomitant radiation. With progression-free survival as the primary endpoint, a semi-supervised learning approach was used to identify a signature that was also tested taking overall survival as the clinical endpoint. A signature comprising 13 circulating miRNAs was identified in the training set (n = 23) as being able to stratify patients by risk of disease progression (log-rank p = 0.00014; HR = 7.99, 95% CI 2.38–26.87). When challenged in a separate validation set (n = 24), it confirmed its ability to predict progression (log-rank p = 0.00026; HR = 5.51, 95% CI 2.03–14.9). The value of our signature was also confirmed when overall survival was considered (log-rank p = 0.0021, HR = 4.12, 95% CI 1.57–10.8). We have identified and validated a prognostic marker based on the expression of 13 circulating miRNAs that can shed light on a patient’s risk of progression. This is the first demonstration of the usefulness of nucleic acids circulating in the blood as powerful, easy-to-assay molecular markers of disease status in DIPG. This study provides Class II evidence that a signature based on 13 circulating miRNAs is associated with the risk of disease progression

Aneurysmal disease is associated with lower carotid intima-media thickness than occlusive arterial disease

Objective: Patients with aneurysmal and occlusive arterial disease have overlapping cardiovascular risk profiles. The question remains how atherosclerosis is related to the formation of aortic aneurysms. Common carotid artery intima-media thickness (CIMT) is an easily accessible and objective marker of early atherosclerosis. The aim of the current study was to investigate whether there is a difference in atherosclerotic burden as measured by CIMT between patients with aneurysmal and those with occlusive arterial disease. Methods: From 2004 to 2011, the CIMT was measured using B-mode ultrasound scanning in patients undergoing vascular surgery for aortic aneurysmal or occlusive arterial disease at the Erasmus University Medical Center. Cardiovascular risk factors, comorbidities, and medication were recorded. Patients treated for combined aneurysmal and occlusive arterial disease and patients diagnosed with a genetic aneurysm syndrome were excluded. Univariable and multivariable analyses wer