3D bone texture analysis as a potential predictor of radiationinduced insufficiency fractures

Background: The aim of our work is to assess the potential role of texture analysis (TA), applied to computed tomography (CT) simulation scans, in relation to the development of insuffciency fractures (IFs) in patients undergoing radiation therapy (RT) for pelvic malignancies. Methods: We analyzed patients undergoing pelvic RT from Jan-2010 to Dec-2016, 31 of whom had developed IFs of the pelvis. We analyzed CT simulation scans using LifeX Software, and in particular we selected three regions of interest (ROI): L5 body, the sacrum and both the femoral heads. The ROI were automatically contoured using the treatment planning software Raystation. TA parameters included parameters from the gray-level histogram, indices from sphericity and from the matrix of GLCM (gray level co-occurrence matrix). The IFs patients were matched (1:1 ratio) with control patients who had not developed IFs, and were matched for age, sex, type of tumor, menopausal status, RT dose and use of chemotherapy. Univariate and multivariate analyses (logistic regression) were used for statistical analysis. Results: Signifcant TA parameters on univariate analysis included both parameters from the histogram distribution, as well from the matrix of GLCM. On logistic regression analysis the signifcant parameters were L5-energy [P=0.033, odds ratio (OR): 1.997, 95% CI: 1.0593.767] and FH-Skewness (P=0.014, OR: 2.338, 95% CI: 1.1914.591), with a R2: 0.268. A ROC curve was generated from the binary logistic regression, and the AUC was 0.741 (95% CI: 0.6270.855, P=0.001, S.E.: 0.058). Conclusions: In our experience, 3D-bone CT TA can be used to stratify the risk of the patients to develop radiation-induced IFs. A prospective study will be conducted to validate these fndings

Patients Affected by Unmethylated O(6)-Methylguanine-DNA Methyltransferase Glioblastoma Undergoing Radiochemotherapy May Benefit from Moderately Dose-Escalated Radiotherapy

Purpose. To compare the therapeutic results of two radiotherapy (RT) dose schedules in combined temozolomide- (TMZ-) RT treatment in newly diagnosed glioblastoma (GB), according to the O(6)-methylguanine-DNA methyltransferase (MGMT) methylation status. Material and Method. Patients received either standard (60 Gy) or moderately escalated dose (70 Gy) radiotherapy (RT) with concomitant and adjuvant TMZ between June 2006 and October 2013. We retrospectively evaluated the therapeutic effectiveness of RT schedules in terms of Overall Survival (OS) and Progression-Disease Free Survival (PDFS) analyzing the MGMT methylation status. Results. One hundred and seventeen patients were selected for the present analysis. Seventy-two out of the selected cases received the standard RT-TMZ course (SDRT-TMZ) whereas the remaining 45 underwent the escalated schedule (HDRT-TMZ). The analysis according to the MGMT promoter methylation status showed that, in unmethylated-MGMT GB patients, HDRT-TMZ and SDRT-TMZ groups had different median OS () and PDFS (), that is, 8 months and 5 months for the SDRT-TMZ group and 14 months and 9 months for the HDRT-TMZ group, respectively. No difference in survival outcomes was found in methylated MGMT patients according to the two RT schedules (). Conclusions. In our experience, unmethylated-MGMT GB patients benefited from a moderately escalated dose of RT plus TMZ

Systemic inflammatory status predict the outcome of k-RAS WT metastatic colorectal cancer patients receiving the thymidylate synthase poly-epitope-peptide anticancer vaccine

TSPP is an anticancer poly-epitope peptide vaccine to thymidylate synthase, recently investigated in the multi-arm phase Ib TSPP/VAC1 trial. TSPP vaccination induced immune-biological effects and showed antitumor activity in metastatic colorectal cancer (mCRC) patients and other malignancies. Progression-free and overall survival of 41 mCRC patients enrolled in the study correlated with baseline levels of CEA, immune-inflammatory markers (neutrophil/lymphocyte ratio, CRP, ESR, LDH, ENA), IL-4 and with post-treatment change in p-ANCA and CD56dimCD16brightNKs (p < 0.04). A subset of 19 patients with activating k-ras mutations showed a different immune-inflammatory response to TSPP as compared to patients with k-ras/wt and a worse outcome in term of PFS (p = 0.048). In patients with k-ras/mut, inflammatory markers lost their predictive value and their survival directly correlated with the baseline levels of IL17/A over the median value (p = 0.01). These results provide strong hints for the design of further clinical trials aimed to test TSPP vaccination in mCRC patients

Anti-cancer activity of dose-fractioned mPE +/- bevacizumab regimen is paralleled by immune-modulation in advanced squamous NSLC patients

Background: Results from the BEVA2007 trial, suggest that the metronomic chemotherapy regimen with dose-fractioned cisplatin and oral etoposide (mPE) +/- bevacizumab, a monoclonal antibody to the vascular endothelial growth factor (VEGF), shows anti-angiogenic and immunological effects and is a safe and active treatment for metastatic non-small cell lung cancer (mNSCLC) patients. We carried out a retrospective analysis aimed to evaluate the antitumor effects of this treatment in a subset of patients with squamous histology. Methods: Retrospective analysis was carried out in a subset of 31 patients with squamous histology enrolled in the study between September 2007 and September 2015. All of the patients received chemotherapy with cisplatin (30 mg/sqm, days 1-3q21) and oral etoposide (50 mg, days 1-15q21) (mPE) and 14 of them also received bevacizumab 5 mg/kg on the day 3q21 (mPEBev regimen). Results: This treatment showed a disease control rate of 71% with a mean progression free survival (PFS) and overall survival (OS) of 13.6 and 17 months respectively. After 4 treatment courses, 6 patients showing a remarkable tumor shrinkage, underwent to radical surgery, attaining a significant advantage in term of survival (P=0.048). Kaplan-Meier and log-rank test identified the longest survival in patients presenting low baseline levels in neutrophil-to-lymphocyte ratio (NLR) (P=0.05), interleukin (IL) 17A (P=0.036), regulatory-T-cells (Tregs) (P=0.020), and activated CD83+ dendritic cells (DCs) (P=0.03). Conclusions: These results suggest that the mPE +/- bevacizumab regimen is feasible and should be tested in comparative trials in advanced squamous-NSCLC (sqNSCLC). Moreover, its immune-biological effects strongly suggest the investigation in sequential combinations with immune check-point inhibitors

Radiotherapy prolongs the survival of advanced non-small-cell lung cancer patients undergone to an immune-modulating treatment with dose-fractioned cisplatin and metronomic etoposide and bevacizumab (mPEBev).

Radiotherapy (RT), together with a direct cytolytic effect on tumor tissue, also elicits systemic immunological events, which sometimes result in the regression of distant metastases (abscopal effect). We have shown the safety and anti-tumor activity of a novel metronomic chemotherapy (mCH) regimen with dose-fractioned cisplatin, oral etoposide and bevacizumab, a mAb against the vasculo-endothelial-growth-factor (mPEBev regimen), in metastatic non-small-cell-lung cancer (mNSCLC). This regimen, designed on the results of translational studies, showed immune-modulating effects that could trigger and empower the immunological effects associated with tumor irradiation. In order to assess this, we carried out a retrospective analysis in a subset of 69 consecutive patients who received the mPEBev regimen within the BEVA2007 trial. Forty-five of these patients, also received palliative RT of one or more metastatic sites. Statistical analysis (a Log-rank test) revealed a much longer median survival in the group of patients who received RT [mCH vs mCH + RT: 12.1 +/-2.5 (95%CI 3.35-8.6) vs 22.12 +/-4.3 (95%CI 11.9-26.087) months; P=0.015] with no difference in progression-free survival. In particular, their survival correlated with the mPEBev regimen ability to induce the percentage of activated dendritic cells (DCs) (CD3-CD11b+CD15-CD83+CD80+) [Fold to baseline value (FBV) ≤1 vs >1: 4+/-5.389 (95%CI,0- 14.56) vs 56+/-23.05 (95%CI,10.8-101.2) months; P:0.049)] and central-memory- T-cells (CD3+CD8+CD45RA-CCR7+) [FBV ≤ 1 vs >1: 8+/-5.96 (95%CI,0-19.68) vs 31+/-12.3 (95%CI,6.94-55.1) months; P:0.045]. These results suggest that tumor irradiation may prolong the survival of NSCLC patients undergone mPEBev regimen presumably by eliciting an immune-mediated effect and provide the rationale for further perspective clinical studies

The effects of radiotherapy on the survival of patients with unresectable non-small cell lung cancer

Introduction: Lung cancer represents the leading cause of cancer mortality across the worlds. At present, less than 30% of the patients can undergo curative surgery, while the majority of them (65%) are diagnosed with metastatic disease and directed to systemic treatments. In this context there is a subset of patients (25%) with locally advanced stage disease whose outcome might be improved by using combined strategies of treatment including chemotherapy, radiotherapy and surgery. Areas covered: Here we reviewed possible combination strategies aimed to improve the outcome of lung cancer patients, focusing on the role of radiotherapy both in the adjuvant and oligo-metastatic setting and in synergy with immunotherapy, and finally, we afforded the new challenges concerning the advanced RT and precision oncology. We carried out a focused analysis concerning the key clinical management weaknesses as well as the potential that current research holds. Expert commentary: We believe that the most promising clinical trials in this specific patient subset will build their rationale on the results of well-designed translational models aimed to test the combination of cytotoxic drugs, radiobiology, and immune-pharmacology. In this context, remarkable investigational fields are focused on the attempt to combine radiotherapy with chemo-immunological strategies and precision medicine protocols

In Regard to Kubicek et al

We read the article “Stereotactic radiosurgery for poor performance status patients” by Kubicek et al recently published in your journal. The authors concluded that patients with poor performance status (PS) could be ideal candidates for stereotactic radiosurgery (SRS), given the favorable logistics of singlefraction treatment and a potential survival advantage. From our point of view, however, further consideration needs to be given regarding the use of these technologies in poor PS patients