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Background: To report the long-term outcome of patients undergoing re-irradiation (re-RT) for a recurrent or second primary head and neck cancer (RSPHNCs) in seven Italian tertiary centers, while testing the Multi-Institution Reirradation (MIRI) recursive partitioning analysis (RPA) recently published., Methods: We retrospectively analyzed 159 patients. Prognostic factors for overall survival (OS) selected by a random forest model were included in a multivariable Cox analysis. To externally validate MIRI RPA, we estimated the Kaplan-Meier group-stratified OS curves for the whole population., Results: Five-year OS was 43.5% (median follow-up: 49.9 months). Nasopharyngeal site, no organ dysfunction, and re-RT volume <36 cm 3 were independent factors for better OS. By applying the MIRI RPA to our cohort, a Harrell C-Index of 0.526 was found indicating poor discriminative ability., Conclusion: Our data reinforce the survival benefit of Re-RT for selected patients with RSPHNC. MIRI RPA was not validated in our population., (© 2019 Wiley Periodicals, Inc.)

The aim of this study is to find a correlation between tumoral heterogeneity of squamous cell carcinoma of the oropharynx and human papillomavirus (HPV) status and to determine whether analysis of texture features of primary lesion on contrast-enhanced CT (CECT) images can be useful in predicting the HPV positivity. Fifty patients with diagnosis of oropharyngeal carcinoma and pre-treatment CECT were included; tumoral heterogeneity of each lesion was evaluated by extracting quantitative texture parameters of first and higher orders. T test and logistic regression were conducted to evaluate the effects of different textural characteristics. There were 35 HPV+ and 15 HPV- lesions. Statistically significant (p < 0.05) differences were seen in multiple higher-order extracted parameters. The logistic regression model correctly classified lesions with an accuracy of 95.2%. CT texture analysis of primary oropharyngeal cancer may be used as a tool for predicting the HPV status.

Purpose: To report on the safety and clinical benefit of robotic stereotactic radiotherapy (SBRT) for liver oligometastatic colorectal cancer (CRC)., Methods: Robotic SBRT was applied to oligometastatic CRC patients, defined as having 1-4 liver metastases and absent or controlled extrahepatic disease. The intended prescription dose was 37.5 Gy in three fractions. Treatment efficacy was estimated by clinical benefit rate (CBR), progression-free survival (PFS) and overall survival (OS). Toxicity was graded according to CTC-AE scale, v. 4.03. Regression analysis was performed to search for the presence of any predictive factors., Results: Between 2012 and 2017, 38 patients (66 lesions) were irradiated. The median delivered biological effective maximum dose (maxBED 10 ) was 142 Gy. At a median follow-up of 11.8 months (range 3.2-58.8), the 1- and 2-year OS were 67.3% and 44.1%, respectively. Actuarial LC rates for all patients at 6 and 12 months were 64.2% and 60.4%, respectively. Local or distant progression occurred in 28 (77.8%) patients, with a 1- and 2-year PFS of 19.3% and 12.2%, respectively. The CBR was 71.4%, with no significant association with maxBED 10 . At multivariate analysis, the presence of extrahepatic disease had a detrimental impact on PFS (HR 3.98, 95% CI 1.77-8.93; p < 0.001) and OS (HR 3.58, 95% CI 1.06-12.07; p < 0.04). No acute grade 3 gastrointestinal toxicity was observed., Conclusions: Our analysis underlines the importance of patients' selection to identify the oligometastatic scenario most likely to benefit from SBRT. Prospective studies are needed to further assess its role among locoregional treatment options for liver metastases from CRC.

Aim: Functional and molecular imaging, including positron emission tomography with computed tomography imaging (PET/CT) is increasing for radiotherapy (RT) definition of the target volume. This expert review summarizes existing data of functional imaging modalities and RT management, in terms of target volume delineation, for the following anatomical districts: brain (for primary and secondary tumors), head/neck and lung., Materials and Methods: A collection of available published data was made, by PubMed a search. Only original articles were carefully and critically revised., Results: For primary and secondary brain tumors, amino acid PET radiotracers could be useful to identify microscopic residual areas and to differ between recurrence and treatment-related alterations in case of re-irradiation. As for head and neck neoplasms may benefit from precise PET/CT-based target delineation, due to the major capability to identify high-risk RT areas. In primary and secondary lung cancer, PET/CT could be useful both to delimit a tumor and collapsed lungs and as a predictive parameter of treatment response., Conclusion: Taken together, molecular and functional imaging approaches offer a major step to individualize radiotherapeutic care going forward. Nevertheless, several uncertainties remain on the standard method to properly assess the target volume definition including PET information for primary and secondary brain tumors., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: Severe bio-radiation dermatitis may develop in patients treated with concurrent radiotherapy and cetuximab for head and neck squamous cell carcinoma. The aim of our work was to report on the impact of a grade-specific management approach on treatment tolerability., Methods: Concomitant radiotherapy and cetuximab was prescribed for patients deemed ineligible for cisplatin-based chemoradiation. Since 2014, an advanced wound care nursing team was established in our clinic to implement a standardized policy for skin toxicity. A central role of calcium alginate dressings was defined in our management algorithm. The correlation between patient, disease, and treatment features with severe bio-radiation dermatitis and treatment tolerability was evaluated., Results: Between 2007 and 2018, 51 patients were treated at our center with radiotherapy and cetuximab. The incidence of G3/G4 bio-radiation dermatitis was 43.1%. Comparing two consecutive cohorts of 26 and 25 patients treated before and after January 2014, respectively, the adoption of a grade-specific dermatitis management allowed to improve treatment tolerability. A mean radiation treatment interruption of 8.42 days (SD, 6.73; 95% CI 5.7-11.1) was reduced to 0.86 days (SD, 2.66; 95% CI - 0.28-2.02) in the more recent group (p < 0.0001). Mean relative dose intensity of cetuximab was also significantly higher (86.3% vs 74.5%, p = 0.0226)., Conclusions: Routine involvement of an advanced wound care management team and early consideration for calcium alginate dressings in case of moist desquamation should be warranted to ensure high compliance to radiotherapy and cetuximab in patients with head and neck cancer.

Purpose: Here, we present the results from a retrospective analysis, with the purpose of evaluating the safety and feasibility of nivolumab and radiotherapy (RT) concomitant association in metastatic kidney and lung cancer patients., Materials and Methods: From August 2015 until September 2017, we retrospectively observed 20 patients with metastatic lung and renal cell carcinoma who had been initiated therapy with nivolumab and underwent concomitant RT. RT was administered either as an ablative therapy in the oligometastatic/oligoprogressive setting or as palliative-only treatment for symptomatic patients. Data on progression-free and overall survival (PFS and OS), treatment response and adverse events were collected and reported. Comparison between palliative-only and ablative treatments was performed., Results: PFS and OS were 7 and 12.5 months in the entire population, respectively. Oligoprogressive patients treated with ablative intent, compared to patients undergoing RT with palliative-only intent, had statistically longer PFS (11.5 vs 5.2 months, HR 0.42, CI 0.18-0.98, p 0.03) and OS (17.9 vs 10.31 months, HR 0.41 CI 0.16-1.02, p 0.04). Considering only patients treated with ablative intent, 87.5% showed response to treatment, and complete response was reported in 37.5% of cases. Adverse G2-G3 related to combination treatment were reported as follows: 1 gastrointestinal (nausea), 4 breakthrough pain., Conclusions: Our data showed significant advantage for oligoprogressive patients treated with RT during nivolumab therapy. No safety alert emerged. These results underline the potential synergistic effects of RT and Immune therapy combination. Our analysis prompts further prospective studies exploring the benefit of integrated treatment strategies.

Aim: Positron Emission Tomography with Computed Tomography (PET/CT) has been proven to be useful in the definition of Radiotherapy (RT) target volume. In this regard, the present expert review summarizes existing data for pancreas, prostate, gynecological and rectum/anal cancer., Methods: A comprehensive search of published original article was made, based on SCOPUS and PubMed database, selecting the paper that evaluated the role of PET/CT in the definition of RT volume., Results: FDG-PET has an important and promising role for pancreatic cancer. Choline PET/CT could be useful for identifying high-risk volumes for prostate cancer; while PSMA PET/CT is still under evaluation. FDG PET/CT in gynecological cancers has been shown to impact external-beam RT planning. The role of FDG-PET for Gross Tumor volume identification is crucial, representing a useful and powerful tool for anal and rectal cancer., Conclusion: Taken together, molecular and functional imaging approaches offer a major step to individualize radiotherapeutic approach., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: Oligometastatic head and neck squamous cell carcinoma (HNSCC) is a rare entity with no evidence-based treatment recommendations available to support the use of local ablative therapies. The aim of our study was to report on the clinical benefit of stereotactic body radiotherapy (SBRT) for patients with lung-only oligometastases, defined by the presence of 1 to 5 pulmonary lesions., Material and Methods: SBRT was applied in case of single lesions deemed amenable to local treatment only ("de novo" pattern) or after first line chemotherapy at time of disease oligoprogression ("induced" pattern). To assess the potential deferral of systemic therapy in both time points, we analyzed time to progression (TTP) defined as the time from the last day of SBRT to disease progression or death from any cause. Cox regression analysis was performed to identify predictive factors of better outcome., Results: Twenty-seven patients were retrospectively evaluated. The majority (81.5%) had HPV negative disease and a "de novo" oligometastatic pattern (78.6%). The median maximum lesion diameter and target size were 1.5 cm and 22.7 cc, respectively. At a median follow-up of 22 months (range 6-73), the median TTP was 10 months (95% CI: 9.5-21.1), with 1- and 2-year rates of 56.2% and 35%, respectively. The objective response rate at 3 months after SBRT was 75%. At multivariate analysis baseline T3/T4 stage had a HR for worse outcome of 5.38 (p = 0.033). Acute toxicity was minimal (G1/G2 of 14.8%)., Conclusion: In properly selected oligometastatic patients, SBRT has potential for sustained deferral of systemic treatment., (Copyright © 2019. Published by Elsevier Ltd.)

Introduction: For a long time, accelerated partial breast irradiation (APBI) effectiveness for ductal carcinoma in situ (DCIS) has been debated, due to conflicting published results. Recent encouraging data from phase 3 trials reopened new perspectives for this radiation approach. The aim of the present study was to analyze the long-term efficacy and safety results of the series of patients with DCIS enrolled in the APBI arm of the APBI-IMRT-Florence phase 3 trial (NCT02104895)., Methods: Patients were treated in a phase 3 randomized trial comparing whole breast irradiation (50 Gy in 25 fractions to the whole breast, plus 10 Gy in 5 fractions to the tumor bed) to APBI (30 Gy in 5 nonconsecutive fractions) using the intensity-modulated radiotherapy technique., Results: Overall, 22 patients were treated in the APBI arm. Median age was 62 years (mean 59; range 42-75 years). At a median follow-up of 9.2 years (mean 8.8; range 3.8-12.1 years), no contralateral invasive/DCIS occurrence, distant metastasis, or breast cancer-related death were recorded. The 5- and 10-year local recurrence, distant metastasis-free survival, and breast cancer-specific survival were 100%. The 10-year overall survival rate was 90.9%. No late toxicity at 5 and 10 years was recorded., Conclusions: Waiting for pending studies and mature follow-up, we confirmed the efficacy and safety of APBI for low-risk DCIS.

Radiotherapy treatment of moving lesions is a challenging task in which different strategies can be used. The clinical implementation of the variety of complex technical solutions pursued to treat cancer, while sparing healthy tissues, requires accurate quality assurance tests and adequate phantoms. The aim of this work is to report on the anthropomorphic dynamic breathing model (ADAM) and on its applications to test image quality and dose delivery for four-dimensional (4D) techniques used to compensate for breathing-induced tumor motion. ADAM reproduces a male torso containing realistic ribs and spinal cord. Lungs move along circular or elliptical paths lying on sagittal planes, while the anterior chest surface moves independently up and down. Lungs host radiochromic films, a diamond detector and objects of known shape and dimensions to test 4D scanners. Markers are embedded around a target and a specific tool, hosting orthogonal radiochromic films, has been provided to perform end-to-end tests of tracking systems. To demonstrate ADAM's performance in testing techniques and methods used to image and treat moving lesions we report the results of three experiments performed to evaluate the accuracy of 4D computed tomography reconstructed volumes, the repeatability of measured dose in volumetric modulated arc treatments and tracking performances of a robotic system. The results obtained show that the percentage differences of reconstructed volumes, with respect to the known volume, depend on the breathing pattern and the pitch size (maximum 5% for breathing rate  >  10 breaths per minute). Repeatability of measured dose maps obtained comparing radiochromic films was demonstrated (GI3%/2 mm  >  99%). Differences between planned and delivered point dose measurements were  <1%. Tracking errors were all below the tolerance level (range 0.6-0.9 mm). The results of this study demonstrate that ADAM is suitable to test techniques and methods used to image and treat moving lesions.

A diagnosis of breast cancer at a young age, defined per guidelines as ≤ 40 years, represents a challenging situation requiring additional attention by the treating physicians including radiation oncologists and surgeons involved in the local treatment of these tumors. The present review aims at providing updated evidence on the state of the art about the available techniques and indications for radiation therapy in patients with early breast cancer, specifically focusing on young women. In addition, future perspectives including the ongoing trials and the potential impact of combined approaches with systemic therapies (such as immunotherapy) are reviewed. Major conclusions from this overview are that young women affected by invasive breast cancer seem to receive the greatest benefit from the boost on the tumor bed. Most young patients affected by ductal carcinoma in situ should receive postoperative whole breast irradiation (WBI). When regional node irradiation is considered, young age should be considered as a high-risk factor. Partial breast irradiation is not suitable for young patients and should be recommended within the context of a clinical trial. Importantly, robust data have already supported the efficacy and safety of hypofractionated-WBI schedules that should now replace standard fractionated-WBI as gold standard for all patients irrespective of their age. Finally, organs-at-risk sparing systems as strategy for prevention of radiation-related long-term toxicities should be strongly considered for these patients. Considering the lack of inclusion of young patients in several published trials as well as in some of the ongoing ones, robust evidence to counsel young breast cancer patients on the optimal radiation therapy approach is still lacking. Further studies and ad hoc subgroup analyses in this specific patient population are strongly warranted., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aim: Liposarcoma (LPS) is rare tumor deriving from adipocytes. LPS is classified into histological subtypes: well-differentiated (WDLPS), dedifferentiated (DDLPS), myxoid (MLPS) and pleomorphic (PLPS). A tailored approach taking into account the specificity of disease subtype and age at presentation could be helpful in delineating therapeutic management of liposarcoma. In this paper, we report a retrospective series of a single-institution cohort of patients with LPS, undergoing surgery and radiotherapy and/or chemotherapy. The aim of this study is to evaluate whether clinical characteristics, tumor- and treatment-related features affect clinical outcome in patients treated with curative intent for non-metastatic liposarcoma., Methods: Data of patients with locally advanced, non-metastatic liposarcoma treated between 1990 and 2015 were retrospectively reviewed. Data about patient, tumor and treatment features were collected. Two patients subgroups were identified according to age (cutoff: age < 65 years or > 65 years). Statistical analysis was performed to assess correlation between the above-cited variables and local recurrence-free survival (DFS-LR), distant metastasis-free survival, overall survival (OS) and disease-specific survival (DSS); moreover, differences in clinical outcome between the two age groups were identified., Results: Data of 186 patients were collected. At diagnosis, 27.4% of patients were 65 years or older. At a median follow-up of 8.6 years (range 0.1-27.3 years), Kaplan-Meier (KM) survival analysis showed that LR, DM, OS and DSS were 75.5%, 76.6%, 48.1% and 72.1%, respectively. KM analysis showed that age > 65, DDLPS and lower limb localization were related to LR (p = 0.001, p = 0.0001 and p = 0.0001, respectively). Association between LR, age and DDLPS persisted both at univariate (p = 0.003 and p = 0.0001, respectively) and multivariate Cox regression (CR) analysis (p = 0.024 and p = 0.002). Age, tumor depth and grading influenced distant recurrence, both at KM (p = 0.023, p = 0.026 and p = 0.016) and univariate CR (p = 0.026, p = 0.042 and p = 0.012). Age and grading were confirmed at multivariate analysis (p = 0.009 and p = 0.017). Patients with WDLPS and wide excision had significantly better OS (p = 0.001 and p = 0.03, respectively), while histological G3 and age > 65 were related with worse OS (p = 0.008 and p = 0.0001, respectively). Age, DDLPS and grade were related to OS at univariate (p = 0.0001, p = 0.0001 and p = 0.03, respectively) and multivariate CR analysis (p = 0.031, p = 0.0001 and p = 0.001, respectively). However, analyzing the specific causes of death, female died less often for tumor-related causes, with a DSS of 91.0% compared to 57.4% of male counterpart (p = 0.005). At Kaplan-Meier analysis, postoperative radiotherapy resulted in a statistically significant better disease-specific survival than postoperative radiotherapy (82.9% vs. 46.2%, p = 0.045). High grade correlated with poorer disease-specific survival (59.3%) than intermediate and low grade (73.4% and 91.6%, respectively) (p = 0.008). Association between DSS, sex and grade persisted both at univariate (p = 0.008 and p = 0.022, respectively) and multivariate Cox regression (CR) analysis (p = 0.014 and p = 0.038). Histotype-driven schedules of treatment should be developed to take into account biological heterogeneity of this disease. Further studies are needed to stratify patients subgroup and develop tailored treatment strategies (i.e., altered fractionations and different chemotherapy regimens in aggressive subtypes), in particular more prospective trials are needed to develop treatment guidelines in elderly STS, taking into account the frailty and the peculiarity of this subgroup.

Background: Poly(ADP-ribose) polymerases (PARP) are a large family of enzymes involved in several cellular processes, including DNA single-strand break repair via the base-excision repair pathway. PARP inhibitors exert antitumor activity by both catalytic PARP inhibition and PARP-DNA trapping, moreover PARP inhibition represents a potential synthetic lethal approach against cancers with specific DNA-repair defects. Soft tissue sarcoma (STSs) are a heterogeneous group of mesenchymal tumors with locally destructive growth, high risk of recurrence and distant metastasis., Objectives: The purpuse of this review is to provide an overview of the main preclinical and clinical data on use of PARPi in STSs and of effect and safety of combination of PARPi with irradiation., Results: Due to numerous genomic alterations in STSs, the DNA damage response pathway can offer an interesting target for biologic therapy. Preclinical and clinical studies showed promising results, with the most robust evidences of PARPi efficacy obtained on Ewing sarcoma bearing EWS-FLI1 or EWS-ERG genomic fusions. The activity of PARP inhibitors resulted potentiated by chemotherapy and radiation. Although mechanisms of synergisms are not completely known, combination of radiation therapy and PARP inhibitors exerts antitumor effect by accumulation of unrepaired DNA damage, arrest in G2/M, activity both on oxic and hypoxic cells, reoxygenation by effect on vessels and promotion of senescence. Early trials have shown a good tolerance profile., Conclusions: The use of PARP inhibitors in advanced stage STSs, alone or combined in multimodal treatments, is of great interest and warrants further investigations.

A quantitative evaluation of the performances of the deformable image registration (DIR) algorithm implemented in MIM-Maestro was performed using multiple similarity indices. Two phantoms, capable of mimicking different anatomical bending and tumor shrinking were built and computed tomography (CT) studies were acquired after applying different deformations. Three different contrast levels between internal structures were artificially created modifying the original CT values of one dataset. DIR algorithm was applied between datasets with increasing deformations and different contrast levels and manually refined with the Reg Refine tool. DIR algorithm ability in reproducing positions, volumes, and shapes of deformed structures was evaluated using similarity indices such as: landmark distances, Dice coefficients, Hausdorff distances, and maximum diameter differences between segmented structures. Similarity indices values worsen with increasing bending and volume difference between reference and target image sets. Registrations between images with low contrast (40 HU) obtain scores lower than those between images with high contrast (970 HU). The use of Reg Refine tool leads generally to an improvement of similarity parameters values, but the advantage is generally less evident for images with low contrast or when structures with large volume differences are involved. The dependence of DIR algorithm on image deformation extent and different contrast levels is well characterized through the combined use of multiple similarity indices., (© 2019 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Purpose: Adjuvant radiotherapy is the standard postoperative treatment after conservative surgery in high risk soft tissue sarcoma. The role of adjuvant chemotherapy is still debated. Therefore, a matched cohort analysis was performed in high risk soft tissue patients to analyse differences in terms of clinical outcome and toxicity between patients treated with concomitant radio-chemotherapy (RTCT) and radiotherapy (RT) alone., Materials and Methods: For each patient in RT group was selected a patient in the RTCT group matching for age, T stage and grading. Acute and late toxicity were recorded, overall survival, recurrence free survival and distant metastases free survival were analysed and compared between the two groups., Results: Ninety patients were selected, half of patients underwent radio-chemotherapy and half received radiotherapy alone. During the treatment Grade 3 dermatitis was recorded in 15 (16.7%) patients, 6 (6.7%) patients associated chemotherapy and during follow up 12 (13.3%) patients developed grade 2 late fibrosis, 3 (3.3%) joint stiffness and 1 (1.1%) patient experienced a bone fracture. There were no differences in the rate of acute and late toxicity between RTCT and RT alone group. Nineteen (21.1%) patients developed local recurrence, overall 5-year local relapse free survival was 83%. There were no differences between the two groups. 29 patients developed distant metastases, 14 (15.6%) patients in the RTCT group and 15 (16.7%) patients in the RT group. The 5-year distant metastases free survival was 67%. Age > 65 years was the only independent factor affecting distant recurrence (HR = 5.7, 95% CI 2.7-11.9; p = 0.001). At the time of analysis 15 (16.7%) patients were dead, 6 (6.7%) patients in the RTCT group and 9 (10%) patients in the RT group. 5-years overall survival was: 88%. At multivariate analysis age > 65 years was an independent prognostic factor of overall survival (HR = 3.7, 95% CI 1.2-12.1, p = 0.037)., Conclusions: Prospective randomized studies with large size population and with subgroup analysis for histological subtypes are necessary to clarify the role of adjuvant chemotherapy in soft tissue sarcoma patients. Tailored treatment has to be considered in elderly soft tissue patients to guarantee a better outcome in this high risk and fragile population.

Aim: The difficulty in conducting meaningful clinical research is a multifactorial issue, involving political, financial and cultural problems, which can lead to unexpected negative long-term consequences, in terms of knowledge advancement and impact on patient care. The aims of the present review were to evaluate the publications of Italian radiotherapy (RT) groups during a 20-year period and to verify whether research is still appealing to young radiation oncologists (ROs) in Italy., Methods: PubMed database was searched for English-language articles published by Italian groups from January 1985 to December 2005. Analyzed variables were: publication/year, kind of study, geographical area and age of the first author., Results: The systematic review identified 3291 articles: 1207 papers fulfilled the inclusion criteria. The number of Italian published papers increased during the examined period. Retrospective analyses, prospective phase I-II trials and literature reviews were 44, 20 and 14.5% of all published manuscripts, respectively. Randomized trials showed a mild increase from 2000 to 2005, but their absolute number remained low respect to other types of studies (4%). Northern Italy produced the very most of Italian research papers (58.7%). The age of the first/second author was evaluated on 716 papers: In more than 50% of cases, the first author was younger than 40., Conclusion: Despite a general gradual improvement, RT clinical research suffers in Italy (as elsewhere) from insufficient funding, with a negative impact on evidence production. It is worth noting that clinical research is still appealing and accessible to junior Italian RO.

Background and Purpose: Breast-conserving surgery (BCS) and whole breast radiation (RT) with or without endocrine therapy (ET) represent the standard of care for ductal carcinoma in situ (DCIS). The use of adjuvant treatments after surgery is still controversial in this setting. We performed a retrospective multicenter analysis on a series of DCIS patients treated with BCS and adjuvant RT., Materials and Methods: We collected clinical data from nine Italian centers on 1072 women having a diagnosis of DCIS and treated between 1997 and 2012. We reported on the 5- and 10-year local recurrence (LR) rates, overall survival, and breast cancer specific survival (BCSS) employing the Kaplan-Meier method., Results: At a median follow-up of 8.4 years, 67 LR (6.3%) and 47 deaths (4.4%) were observed. LR rates at 5 and 10 years were 3.4% and 7.6%, respectively. BCSS rates at 5 and 10 years were 99.7% and 99.1%, respectively. At univariate regression analysis, postmenopausal state (p = 0.009), estrogen receptor (ER) (p = 0.0001) and progesterone receptor (p = 0.018) positivity and ET (p = 0.006) were inversely correlated with LR. Final surgical margins (FSM) status <1 mm was significantly correlated with higher LR (p = 0.003). At multivariate regression analysis postmenopausal state (p = 0.03), and ER positive (p = 0.045) maintained the significant favorable feature, while FSM <1 mm (p = 0.024) confirmed its negative impact on LR., Conclusions: Our real-life study pointed out the significant favorable prognostic role of postmenopausal state and ER positive status on LR occurrence. FSM <1 mm was significantly correlated to a higher chance to experience LR., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aim: We present the final results of the BONADIUV trial, a single-blind, randomised, placebo-controlled phase 2 study to evaluate the impact of ibandronate treatment on bone mineral density (BMD) in osteopenic women taking aromatase inhibitors (AI)., Patients and Methods: Between 2011 and 2014, 171 osteopenic patients were randomised in a 1:1 ratio to receive either placebo or oral monthly ibandronate (150 mg). Treatment duration was 2 years, with 6-month evaluation. Primary end-point was the 2-year lumbar spine (LS) and total hip (TH) T-score mean differences as measure of BMD variation. Secondary analyses of survival outcomes have been performed at a 5-year median follow-up. CLINICALTRIALS., Gov Identifier: NCT02616744., Results: Median age of study population was 60.2 years (range 44-75). At the database cut-off time, the median follow-up was 63.3 months (range 2.7-87.3). No difference in terms of T-score was shown at baseline between arms both for TH (P = 0.61) and LS (P = 0.96). At 2-year follow up, the mean change was statistically significant in favour of ibandronate arm both at TH (P = 0.0002) and LS (P < 0.0001). No significant difference in terms of adverse events was observed between arms. At a median follow-up of 63.3 months (range 2.7-87.3), the overall survival (OS) rate was 97.5% in the placebo group and 93.0% in the ibandronate arm (P = 0.19). The invasive disease-free survival (iDFS) rates did not differ between groups (P = 0.42)., Conclusions: Ibandronate compared to placebo improved BMD change in osteopenic women treated with adjuvant AI. Five-year survival analyses showed no difference between arms in terms of OS and iDFS rates., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background and Purpose: In our institute, breast cancer patients undergoing adjuvant treatment are included in a protocol aimed to reduce cardiovascular morbidity (SAFE-2014, NCT2236806), assessing preclinical heart damage with heart speckle-tracking ultrasound. To develop a dose constraint related to subclinical heart damage, a reliable delineation of heart substructures based on a pre-existing guideline was made., Patients and Methods: Heart substructures of 16 left-sided breast cancer patients included in the SAFE protocol were delineated by five operators. For each substructure, a multi-contour delineation based on a majority vote algorithm (MCD) was created. A consensus-based delineation (CBD) was developed by an independent team of two blinded operators. Dice similarity coefficients (DSC) between volumes delineated by different operators and the MCD were collected and reported, as well as DSC between CBD and MCD., Results: Mean DSCs between heart chambers delineated by each operator and the corresponding MCDs ranged between 0.78 and 0.96. Mean DSC between substructures delineated by all single operators and the corresponding MCD ranged between 0.84 and 0.94. Mean DSC between CBD and the corresponding MCD ranged from 0.89 to 0.97., Conclusion: Results showed low inter-observer variability of heart substructure delineation. This constitutes an external validation of the contouring atlas used, allowing a reliable dosimetric assessment of these volumes within the SAFE-2014 trial.

Purpose: Aim of the present review is to assess present data about the use of the association of Radiotherapy (RT) and targeted therapy/immunotherapy (TT/IT) in elderly people., Design: PubMed database was searched for English literature published up to December 2017 using the keywords "radiotherapy" combined with "bevacizumab", "cetuximab", "trastuzumab", "erlotinib", "gefitinib", "sorafenib", "sunitinib", "vismodegib", "sonidegib", "ipilimumab", "pembrolizumab", "nivolumab". Studies performing RT and TT/IT in people aged >65-years were evaluated focusing on safety, toxicity and efficacy. Studies eligible for inclusion were: case reports, retrospective/prospective studies in which RT and new drugs were used concomitantly or sequentially, focusing on elderly sub-group., Results: The systematic search identified 626 records. After exclusion of duplicates, full-text review, cross-referencing and paper that did not respect the inclusion criteria, 81 studies were included in this review. In elderly patients the combination of RT with cetuximab or bevacizumab seems feasible but with higher reported side effects. Patients' age should not limit the association of trastuzumab and RT in HER2 positive breast cancer. The concurrent administration of TKIs and RT appears to be feasible and effective. Regarding the Immune Check Point inhibitors and RT, tolerance seems similar among older and younger people but definitive data are lacking. Instead, the association of RT and vismodegib/sonidegib remains investigational., Conclusion: TT/IT in association of RT seems to be safe, but in elderly patients data concerning safety and toxicity are limited. Specific clinical trials on this population are encouraged., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Orbital lesions are rare, but are likely to become symptomatic and can impact on patients' quality of life. Local control is often difficult to obtain, because of proximity to critical structures. CyberKnife stereotactic robotic radiotherapy could represent a viable treatment option., Materials and Methods: Data on patients treated for intraorbital lesions from solid malignancies were retrospectively collected. All patients underwent treatment with CyberKnife system. We analyzed local control, response rate, symptoms control, progression-free survival and overall survival, acute and late toxicity., Results: From January 2012 to May 2017, 20 treatments on 19 patients were performed, with dose ranging from 24 to 35 Gy in 1 to 5 fractions, prescribed at an average isodose line of 79.5% (range: 78-81). After a mean follow-up of 14.26 months (range: 0-58), overall response rate was 75%, with 2 and 4 patients presenting a partial and complete response, respectively. Mean time to best measured response was 15.16 months (range: 2-58). Thirteen patients were alive, with a local control rate of 79%. Mean time to local progression was 5 months (range: 3-7). Three patients reported improvement in symptoms after treatment. Mean planning target volume dose coverage was 97.2% (range: 93.5-99.7). Mean maximum dose (D max) to eye globe, optic nerve, optic chiasm, and lens was 2380.8 cGy (range: 290-3921), 1982.82 cGy (range: 777.3-2897.8), 713.14 cGy (range: 219.5-2273), and 867.9 cGy (range: 38-3118.5). Four patients presented acute toxicity., Conclusion: This current retrospective series demonstrated that CyberKnife robotic stereotactic radiotherapy is a feasible and tolerable approach for intraorbital lesions.

Ribociclib is a CDK4-6 inhibitor recently approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as first-line treatment for metastatic breast cancer (MBC). The pivotal trial showed a significant improvement in progression-free survival when compared to endocrine therapy alone. However, having a challenging toxicity profile in comparison with exclusive endocrine therapy, safety may be a concern when combined to radiotherapy (RT) with palliative approach. There are no available published data regarding the combination of ribociclib and palliative RT. We reported our preliminary experience on the first five patients treated at the Radiation Oncology Unit of the Florence University (Florence, Italy) giving palliative RT concomitant to ribociclib plus letrozole as first-line treatment for MBC., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Soft tissue sarcomas (STS) are aggressive tumors with a poor prognosis. Poly(ADP-ribose) polymerase (PARP)-1 inhibitors (PARPi) enhance the cytotoxic effects of radiation. In this study, we evaluated the effect of PARPi on survival and DNA damage of irradiated STS cells. For clonogenic assays, STS cell lines were irradiated with or without olaparib, iniparib or veliparib pretreatment. The effect of PARP inhibition on γ-H2AX and Rad51 foci formation, on PARP-1, phospho-ERK and cleaved caspase-3 protein expression and on cell cycle progression was evaluated on irradiated rhabdomyosarcoma cells pretreated with olaparib. The results from this work showed that PARPi induced significant radiosensitization in STS cells. Rhabdomyosarcoma cells showed the highest increase in radiosensitivity, with a radiosensitization enhancement ratio at 50% survival (ER50) of 3.41 with veliparib. All PARPi exerted a synergistic effect when combined with radiation. Fibrosarcoma cells showed an ER50 of 2.29 with olaparib. Leiomyosarcoma and liposarcoma cells showed their highest ER50 with veliparib (1.71 and 1.84, respectively). In rhabdomyosarcoma, olaparib enhanced the formation of radiation-induced γ-H2AX/Rad51 foci and PARP-1 cleavage, induced slightly increased expression of cleaved caspase-3 and reduced phospho-ERK expression. Moreover, the combination of olaparib and radiation resulted in a significantly enhanced cell cycle arrest in the G 2 /M phase compared to the two treatments alone. In conclusion, we have shown that PARPi are potent radiosensitizers of human STS cells. These results support the pursuit of further investigations into the effects of PARPi combined with radiation on STS.

BRCA1/2 mutations are involved in breast cancer (BC) susceptibility but their influence on outcome is unclear. We reviewed BC patients tested for BRCA to determine biological features and influence on outcome. BRCA-1 was correlated to younger age (P = 0.035), nodal involvement (P = 0.030), higher tumor grade (P = 0.0022) and Ki-67 (P = 0.014), ER/PgR negative status (P = 0.00042 and 0.0091, respectively), and use of adjuvant chemotherapy (P = 0.000038); BRCA was neither predictive for chemotherapy administration nor resulted in impaired outcome or occurrence of secondary BC. BRCA status did not influence outcome despite higher biological aggressiveness and younger age at presentation., (© 2018 Wiley Periodicals, Inc.)

Background: Invasive triple negative apocrine carcinoma (TNAC) of the breast is a rare type of triple negative breast cancer. Several studies reported significantly distinct prognosis for TNAC when compared with most of the non-apocrine triple negative (NATN) tumors. This is a case-control study reporting onoutcomes from our long-term single-center experience., Patients and Methods: We analyzed the clinicopathologic features of a series of 46 TNAC tumors treated in a 15-year period. Tumor characteristics and outcomes have been compared with a homogeneous control series of 43 NATN tumors treated during the same follow-up period. Local relapse-free survival (LRFS), distant metastases-free survival (DMFS), and overall survival (OS) have been evaluated., Results: LRFS in the TNAC group was 85% and 78% at 5 and 10 years, respectively. LRFS in the NATN group was 90% and 79% at 5 and 10 years, respectively (hazard ratio [HR], 1.14; 95% confidence interval [CI], 0.41-3.19; P = .80). DMFS in the TNAC group was 85% and 85% at 5 and 10 years, respectively. DMFS in the NATN group was 85% and 75% at 5 and 10 years, respectively (HR, 0.39; 95% CI, 0.14-1.08; P = .071). OS in the TNAC group was 86% and 83% at 5 and 10 years, respectively. OS in the NATN group was 86% and 63% at 5 and 10 years, respectively. OS was significantly better in the TNAC group (HR, 0.45; 95% CI, 0.20-0.99; P = .049)., Conclusions: TNAC seems to represent a distinct group of triple negative breast cancer, characterized by a favorable long-term outcome when compared with NATN tumors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: This study aimed to evaluate the diagnostic accuracy of panoramic radiography (PAN) for the detection of clinically/surgically confirmed apical periodontitis (AP) in root canal-treated teeth using cone-beam computed tomographic (CBCT) imaging as the reference standard., Methods: Two hundred forty patients with endodontically treated AP (diseased group) were detected via CBCT imaging using the periapical index system. They were divided into groups of 20 each according to lesion size (2-4.5 mm and 4.6-7 mm) and anatomic area (incisor, canine/premolar, and molar) in both the upper and lower arches. Another 240 patients with root filling and a healthy periapex (healthy group) were selected. All diseased and healthy patients underwent PAN first and a CBCT scan within 40 days. The periapical index system was also used to assess AP using PAN. Sensitivity, specificity, diagnostic accuracy, positive predictive value, and negative predictive value for PAN images with respect to CBCT imaging were analyzed. The k value was calculated to assess both the interobserver reliability for PAN and the agreement between PAN and CBCT., Results: PAN showed low sensitivity (48.8), mediocre negative predictive value (64.7), good diagnostic accuracy (71.3), and high positive predictive value (88.6) and specificity (93.8). Both interobserver reliability for PAN and agreement between PAN and CBCT were moderate (k = 0.58 and 0.42, respectively). The best identified AP was located in the lower canine/premolar and molar areas, whereas the worst identified AP was located in the upper/lower incisor area and upper molar area., Conclusions: PAN showed good diagnostic accuracy, high specificity, and low sensitivity for the detection of endodontically treated AP., (Copyright © 2018 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Introduction:: This retrospective study analyzes the safety and feasibility of concurrent chemoradiotherapy (CRT) in adjuvant treatment of soft tissue sarcoma (STS)., Methods:: A total of 158 patients with STS were retrospectively analyzed. Anthracycline-based computed tomography was performed in high-risk patients. Acute radiotherapy toxicity and chemotherapy-related toxicity were assessed according to the Common Terminology Criteria for Adverse Events 4.0; late radiotherapy toxicity was recorded according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria., Results:: Fifty-four (34.2%) patients received CRT. Mean follow up was 5.4 years (range .2-21.1 years). Local DFS-recurrence-free survival, distant DFS-relapse-free survival, and overall survival were 79.1%, 76.4%, and 64.6%, respectively, at last follow-up. Leukopenia occurred in 11.4% of patients. Skin acute toxicity developed in 60.1% of patients and determined interruption of radiotherapy treatment in 19 (12%) patients. Nineteen patients (12%) experienced moderate fibrosis (grade 2). Mild and moderate joint stiffness was recorded in 16 (10.1%) patients. Size ≥5 cm was the only predictor of local recurrence at multivariate analysis (hazard ratio [HR] 9.65, 95% confidence interval [CI] 1.28-72.83, p = .028). Age and stage resulted as independent distant relapse predictors (HR 4.77, 95% CI 1.81-12.58, p = .002 and HR 4.83, CI 1.41-16.57, p = .012, respectively). At Cox regression univariate analysis, Karnofsky Performance Status, size, and stage were significant survival predictors (HR 2.23, 95% CI 1.02-4.87, p = .045; HR 2.88, 95% CI 1.10-7.52, p = .031; HR 2.59, 95% CI 1.11-6.04, p = .028)., Conclusions:: Concurrent CRT is a well-tolerated treatment option with no additional toxicity compared to exclusive radiotherapy or sequential CRT.

Candidemia is a major cause of in-hospital mortality. Antifungal stewardship programme (AFSP) providing infectious diseases consultation (IDC) might improve the outcome. We evaluate the impact on candidemia mortality of IDC as part of AFSP restricting the use of all antifungals with exception of fluconazole. We retrospectively reviewed the charts of patients with documented candidemia in our hospital during the period 2012-2014 evaluating the impact of several variables on 30-days in-hospital mortality. We reviewed data on 276 patients with documented candidemia: 200 (72%) were treated without IDC and 76 (28%) with IDC. In the group without IDC, 52 patients (26%) received no antifungal therapy. Antifungals used for treating candidemia were (no IDC/IDC): azoles (74%/42%); echinocandins (0%/46%); liposomal and lipidic complex amphotericin B (0%/12%). The 30-day in-hospital mortality was respectively (no IDC/IDC) 37% vs. 20% (p = 0.011). The multivariate analysis confirmed IDC as independent factor protecting from death (OR 0.511, 95% CI 0.251-0.994; p = 0.046), together with fungemia due to non-albicans Candida (OR 0.565, 95% CI 0.327-0.977; p = 0.042). Age >65 years was associated with a higher risk of death (OR 1.989, 95% CI 1.055-3.895; p = 0.038). The additional cost for the use of echinocandins driven by IDC in the study period was €207,000. IDC, as a part of a restrictive front-end antimicrobial stewardship programme (ASP), providing a timely right choice of antifungal therapy, increases the cost of antifungal drugs but might be a contributing protective factor from mortality due to candidemia. Efforts to increase the number of IDC in patients with candidemia seems to be warranted.

Background: Whole pelvic irradiation in prostate cancer patients might prevent metastatic spread of cancer cells through lymphatic drainages in patients eligible for definitive radiotherapy, but its use has declined in the last decades in favor of prostate-only irradiation (POI). The aim of our study is to assess the incidence of pelvic lymph nodal relapse and outcome in prostate cancer patients receiving POI., Materials and Methods: Data from 207 consecutive patients were collected. Clinical and treatment variables were collected. Biochemical relapse-free survival (BRFS), pelvic nodal relapse-free survival (PNRFS), distant metastasis-free survival (DMFS), disease-specific survival (DSS) and overall survival (OS) were calculated; analysis of prognostic variables was performed., Results: Five-year BRFS, PNRFS, DMFS, DSS and OS were, respectively, 90, 98, 96, 97 and 91%. On multivariate analysis, independent negative predictors of BRFS were Gleason score ≥ 7 (HR: 3.25) and PSA nadir ≥ 0.08 (HR: 4.86). Pelvic nodal relapse was not correlated to impaired outcome., Conclusions: Lymph nodal pelvic relapse occurs in 2% of patients at 5 years and does not correlate with impaired outcome, suggesting the lack of theoretical benefit of a prophylactic nodal irradiation. Tumor biology and response to treatment are the main determinants of outcome.

Objectives: Swallowing and voice dysfunctions are common side effects following head-and-neck squamous-cell carcinoma (HNSCC) treatment. Our aim was to analyze the relationships between quality of life, swallowing, and phonatory problems in patients with an advanced-stage HNSCC and to prospectively evaluate the effects of a prophylactic swallowing program., Methods: First, we retrospectively studied 60 advanced HNSCC patients treated with exclusive or adjuvant radiotherapy/chemoradiotherapy (RT/CRT). Subjects were classified according to general and clinical-therapeutic features. Outcome measures included EORTC QLQ-C30, EORTC QLQ-H&N35, Dysphagia Handicap Index (DHI), M.D.Anderson Dysphagia Inventory (MDADI), and Voice Handicap Index (VHI). Then, we conducted a prospective evaluation of a prophylactic swallowing counselling in 12 consecutive advanced-stage HNSCC patients by a two-arm case-control analysis. These patients were treated with exclusive or adjuvant RT/CRT., Results: 71% of the retrospective population studied reported swallowing dysfunction as a major side effect. No differences were detected in the severity of dysphagia or dysphonia according to type of treatment or staging of the primary tumour, while hypopharyngeal and laryngeal cancer patients showed significantly better swallowing ability and better QoL compared to oral cavity and oropharyngeal localisation (p < 0.05). In addition, a relevant correlation between swallowing and voice problems emerged (p < 0.05). In the prospective part, while no statistical correlation was evident before the start of RT/CRT in the experimental group compared to the control one, the former showed better performances at MDADI (p = 0.006) and DHI (p = 0.002) test 3 months after its end., Conclusion: Dysphagia is both an acute-and-long-term side effect which greatly affects QoL of HNSCC patients undergoing multimodality treatment. Our data show that a prophylactic swallowing program could actually produce a beneficial effect on patients' outcomes., Level of Evidence: 1b and 2b.

The primary aim of this review is to provide practical recommendations in terms of fractionation, dose, constraints and selection criteria to be used in the daily clinical routine. Based on the analysis of the literature reviewed, in order to keep the risk of severe side effects ≤3,5%, patients should be stratified according to the target volume. Thus, patients should be treated with different fractionation and total EQD2 (<12.5 ml: EQD2 < 65 Gy with radiosurgery; >12.5 ml and <35 ml: EQD2 < 50 Gy with hypofractionated stereotactic radiotherapy; >35 ml and <50 ml: EQD2 < 36 Gy with conventionally fractionated radiotherapy). Concurrent approaches with temozolomide or bevacizumab do not seem to improve the outcomes of reirradiation and may lead to a higher risk of toxicity but these findings need to be confirmed in prospective series., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Oral mucositis is a side effect of treatment regimens containing 5-fluorouracil (5-FU). The purpose of this study was to present our evaluation to see if rosiglitazone (RGZ) protected normal tissues from chemotherapy-induced oral mucositis., Methods: C57BL/6J mice were treated with 5-FU for 5 days, with or without RGZ. Mice were euthanized after 5, 8, 11, or 15 days, and mucosal segments were collected., Results: The RGZ did not affect the 5-FU-induced decrease in mouse body weight. The 5-FU caused loss of epithelial architecture, collagen fiber impairment, and inflammatory infiltration. The RGZ reduced leukocyte infiltration, preserved tissue structure, and dampened the 5-FU-induced expression of p53 and matrix metalloproteinase (Mmp)-2 after 5 days, and of Mmp-2 and interleukin (Il-1β after 15 days. The RGZ inhibited the 5-FU-induced increase of transforming growth factor-beta (TGF-β) and nuclear factor-kappa B (NF-κB) proteins and restored collagen protein levels., Conclusion: The RGZ had a protective effect on oral mucosa damaged by chemotherapy. These data encourage the further study of RGZ for the prevention of 5-FU-induced mucositis in patients with cancer., (© 2017 Wiley Periodicals, Inc.)

Introduction and Background: Head and neck squamous cell carcinoma (HNSCC) has been increasingly recognized as an immune suppressive malignancy. The efficacy of immune checkpoint inhibitors (ICI's) in the context of recurrent/metastatic (R/M) setting anticipates the possible integration of immunotherapy into the therapeutic armamentarium of locally advanced disease. Durvalumab (DUR) is a humanized monoclonal IgG1, anti-PD-L1 antibody with promising data in R/M HNSCC. The aim of our study is to test the antitumor activity of a combined regimen incorporating an immune checkpoint inhibitor into a conventional bio-radiation strategy for the cure of unfavorable locally advanced HNSCC., Methods/design: In this open label, multi-center, single-arm, phase I/II study, enrolled patients will receive Radiotherapy (RT) (69.9 Gy/2.12 Gy in 33 fractions) with concurrent Cetuximab (CTX) (400 mg/m 2 1 week before RT start followed by 250 mg/m 2 weekly) and DUR (fixed dose of 1500 mg every 4 weeks starting from RT-CTX week 1) followed by adjuvant DUR (to a maximum of 6 months after completion of RT-CTX). Primary endpoint of the study is 2-year progression-free survival (PFS). A safety run-in is planned after the enrollment of first 12, 24 and 36 patients. Patients affected by high-risk (≥N2a or ≥T3, any N) larynx, hypopharynx and HPV negative oropharynx or HPV-positive oropharynx (≥T2, ≥N2b, ≥10 pack/years) will be eligible., Discussion: Conventional intensification strategies failed to provide any benefit for the cure of locally advanced HNSCC. For the still prevalent HPV-negative population and the high risk-HPV positive disease, there is an unmet need for alternative treatment paradigms. Potentially, the inhibition of the PD-1/PD-L1 checkpoint may synergize with both CTX and RT through immunologic interplay, ultimately aiming to reverse the HNSCC-induced immune suppression. The DUCRO study will seek to demonstrate if such a strategy may be safe and active., Trial Registration: NCT number: NCT03051906Eudract number: 2016-004668-20.

Background and Purpose: There is currently no health-related quality of life (HRQoL) measure specific to anal cancer. Our objective was to develop an anal cancer HRQoL module to supplement the EORTC QLQ-C30 questionnaire using EORTC Quality of Life Group Guidelines., Materials and Method: In order to generate a list of HRQoL issues facing anal cancer patients treated with chemoradiotherapy (CRT), we systematically reviewed the literature and conducted semi-structured interviews with patients and health care professionals (HCPs). Our list was then operationalised into questions using the EORTC Item Library. The provisional question list was pilot tested alongside the EORTC QLQ-C30 with patients from 11 centres across 8 countries., Results: From our literature review and interviews with 43 patients, we generated a list of 197 issues. The list was then refined to 134 issues and reviewed by 34 HCPs and 10 patients. This review resulted in the retention of 65 issues which were used in the draft questionnaire tested by 100 patients. Our analyses led to the modification and removal of questions resulting in a 27 item questionnaire, the EORTC QLQ-ANL27., Conclusion: We have developed a 27 item questionnaire to supplement the EORTC QLQ-C30, for use with patients treated for anal cancer. This has been pilot tested and is now available upon request for use in clinical trials as well as clinical practice in 8 languages (http://groups.eortc.be/qol/)., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Stereotactic body radiotherapy (SBRT) emerged as a treatment option in oligometastatic (≤3 metastases) patients experiencing lymph node relapse from treated prostate cancer. No recommendations are available concerning dose schedule, and available studies report the use of multiple-fraction regimens due to theoretical lower toxicity and higher cumulative dose delivered to the target. The aim of the present study was to evaluate the safety and efficacy of a dose-intensive, single-fraction SBRT regimen., Patients and Methods: Retrospective data on outcome and toxicity from 27 treatments on 23 consecutive patients were collected. Statistical analysis was performed., Results: Median follow-up was 22 months (range 6-63, interquartile range 15-28). Biochemical progression-free survival (bPFS) at 6 months, 1 year, and 2 years were 65%, 40%, and 26%, respectively. In 2 cases acute toxicity of grade 1 were observed., Conclusion: Single-fraction SBRT for lymph node relapse of oligometastatic prostate cancer resulted in promising biochemical control with minimal toxicity., (© 2018 S. Karger GmbH, Freiburg.)

Purpose: Radiotherapy plus cetuximab is an effective combination therapy for locally advanced head and neck squamous cell carcinoma. The aim of our study was to determine the frequency of skin toxicity in patients receiving the combined treatment., Results: Forty-eight studies were included in our analysis, for a total of 2152 patients. The mean rates of G3/G4 radiation dermatitis and acneiform rash were 32.5% (SD: 20.4; 95% CI: 28.5-36.5) and 13.4% (SD: 11.5; 95% CI: 11.2-15.6), respectively. The majority of studies referred to CTCAE scales for reporting both side effects (85.7% and 92.1%, respectively). Data on the management of skin toxicity were available in only 35.4% of the reviewed literature., Conclusions: severe radiation dermatitis is a frequent side effect induced by the combination of radiotherapy and cetuximab in head and neck cancer. The lack of predictive biomarkers of toxicity hampers the possibilty to design preventive measures on a personalized basis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: The 11-gauge (11G) stereotactic vacuum-assisted breast biopsy (VABB) showed a better profile than 14G-VABB in terms of feasibility, safety, microcalcification sampling, and accuracy. Underestimation rates were significantly lower with 11G-VABB than with 14G-VABB. Thus, the introduction of an even larger needle at the VABB procedure could reduce this rate further. The purpose of this study was to compare the overall performance of stereotactic VABB with 8G and 11G needles., Materials and Methods: Four hundred and three VABBs performed between July 2012 and February 2015 at the Breast Diagnostic Unit of Careggi Hospital in Florence were retrospectively analyzed; 197 were performed with 11G-VABB and 206 with 8G-VABB. Lesions were classified according to mammographical patterns in microcalcifications, architectural distortions, or opacities, and all biopsy targets were classified according to BIRADS classification as BIRADS III, IV or V. Data were collected on radiological classification of targets, imaging presentation, procedure time, number of specimens per procedure, and microcalcification retrieval on histological findings. Surgery was always performed when high-risk or malignant lesions (B3 or B5) were detected; the final diagnosis was made on surgical pathology., Results: Compared to VABB with an 11G needle, 8G-VABB allows a reduction in the time needed to complete the procedure (20.6 versus 27.4, P < 0.00001) and the number of specimens collected per lesion (21.6 versus 12.2, P < 0.00001). Moreover, 8G-VABB resulted in the same diagnostic accuracy, and the underestimation rates were comparable between the two groups for both B3 and DCIS lesions., Conclusions: The 8G needle should be considered as a valid alternative option in VABB for breast lesions., (Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objectives: The aim of our work was to report on the clinical outcome of a moderately hyprofractionated radiotherapy regimen in elderly patients affected by head and neck squamous cell carcinoma (HNSCC)., Material and Methods: HNSCC aged ≥65 deemed unsuitable for curatively-intended concurrent chemo-radiotherapy or high-dose radiotherapy by clinical judgement were further evaluated with the Geriatric 8 (G8) questionnaire and Charlson comorbidity index (CCI). In case of a G8 score ≤14, a de-intensified radiation schedule of 40 Gy delivered in 16 fractions was prescribed., Results: Thirty-six patients were treated between 2011 and 2016. The median age of the cohort was 77.5 (range: 65-91 years) with a combined ECOG PS of 2-3 in 77.8% and CCI of ≥8 in 25% patients, respectively. At a median follow-up of 13 months (range 2-62 months), the 6-month and 1-year rates of loco-regional control and progression-free survival were 42%, 28% and 36% and 20%, respectively. At univariate analysis, log-rank test showed that age >75 years (p=0.036), worse PS (ECOG≥2; p=0.027), lower G8 score (<9; p=0.027) and PTV volume greater than 200 cc (p=0.038) had a significant correlation with PFS. The negative impact of the PTV volume on PFS was the only parameter confirmed in the multivariate analysis (HR 2.68; 95% CI: 1.24-5.81, p=0.013). No grade 4-5 toxicity was observed, while 13/36 patients (36%) had G3 acute side effects., Conclusion: The hypofractionated radiation schedule evaluated provides clinical benefit with low toxicity in frail, elderly patients affected by locally advanced HNSCC., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: This study aimed to evaluate the diagnostic accuracy of orthopantomography (OPT) for the detection of clinically/surgically confirmed apical periodontitis (AP) without endodontic treatment using cone-beam computed tomographic (CBCT) imaging as the reference standard., Methods: One hundred twenty patients without endodontically treated AP (diseased group) were detected via CBCT imaging using the periapical index system. They were divided into groups of 10 each according to the size of the lesion (2-4.5 mm and 4.6-7 mm) and the anatomic area (incisor, canine/premolar, and molar) in both the upper and lower arches. Another 120 patients with a healthy root and periapex (healthy group) were selected. Each diseased and healthy patient underwent OPT first and a CBCT scan within 40 days of the OPT. The periapical index system was also used to assess AP by OPT. Sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy for OPT images with respect to CBCT imaging were analyzed. The k value was calculated to assess both the interobserver reliability for OPT and the agreement between OPT and CBCT imaging., Results: OPT showed low sensitivity (34.2), negative predictive value (59.3), and diagnostic accuracy (65.0) and high specificity (95.8) and positive predictive value (89.1). Interobserver reliability for OPT was substantial (k = 0.71), and agreement between OPT and CBCT imaging was fair (k = 0.30). The best and worst identified AP were located in the lower molar area and the upper/lower incisor area, respectively., Conclusions: OPT showed high specificity and positive predictive value. However, overall, it was not an accurate imaging technique for the detection of untreated AP, especially in the incisor area., (Copyright © 2017 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Background: Ductal carcinoma in situ (DCIS) is a heterogeneous disease, for which the best adjuvant treatment is still uncertain. Many attempts of risk-groups stratification have been made over time, developing prognostic scores to predict risk of local recurrence (LR) on the basis of features such as age, final surgical margins (FSM) status, grade, and tumor size. The aim of our analysis was to evaluate the patterns of recurrence from a two large-institutional retrospective series., Patients and Methods: We collected data on 457 patients treated with BCS and adjuvant RT between 1990 and 2012. Final analysis was performed on 278 patients, due to missing data about hormonal status (HS). Patients were treated at the Radiation Oncology Unit of the University of Florence (n = 195), and S. Maria Annunziata Hospital (n = 83) (Florence, Italy)., Results: At a median follow up time of 10.8 years (range 3-25), we observed 20 LR (7.2%). The 5-year and 10-year LR rates were 4.9% and 10.2%, respectively. At Cox regression univariate analysis, estrogen receptor (ER) positive status (p = 0.001), HS positive (p = 0.003), and FSM <1 mm (p = 0.0001) significantly impacted on LR. At Cox regression multivariate analysis positive ER status maintained a protective role (p = 0.003), and FSM status <1 mm its negative impact (p = 0.0001) on LR rate., Conclusions: Our experience confirmed the wide heterogeneity of DCIS. Inadequate FSM and negative ER status negatively influenced LR rates. Tumor biology should be integrated in adjuvant treatment decision-making process., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Accelerated partial breast irradiation (APBI) represents a valid option for selected early breast cancer (BC). We recently published the 5-year results of the APBI-IMRT-Florence phase 3 randomised trial (NCT02104895), showing a very low rate of disease failure, with acute and early-late toxicity in favour of APBI. We present the early and 2-year follow-up health-related quality of life (HRQoL) results., Methods: Eligible patients were women aged more than 40 years with early BC suitable for breast-conserving surgery. APBI consisted of 30 Gy in five fractions delivered with IMRT technique. Standard whole breast irradiation (WBI) consisted of 50 Gy in 25 fractions plus a 10 Gy in five fractions boost on tumour bed. A total of 520 patients were enrolled in the phase 3 trial. Overall, 205 patients (105 APBI and 100 WBI) fully completed all the given questionnaires and were therefore included in the present analysis. As HRQoL assessment, patients were asked to complete the European Organisation for Research and Treatment of Cancer QLQ-C30, and the BR23 questionnaires at the beginning (T0), at the end (T1) and after 2 years from radiation (T2)., Findings: No significant difference between the two arms at QLQ-C30 and BR23 scores emerged at T0. Global health status (p = 0.0001), and most scores of the functional and symptom scales of QLQ-C30 at T1 showed significant differences in favour of the APBI arm. Concerning the BR23 functional and symptom scales, the body image perception, future perspective and breast and arm symptoms were significantly better in the APBI group. Similar significant results emerged at T2: significant differences in favour of APBI emerged for GHS (p = 0.0001), and most functional and symptom QLQ-C30 scales. According to QLQ-BR23 module, among the functional scales, the body image perception and the future perspective were significantly better in the APBI group (p = 0.0001), whereas among the symptom scales significant difference emerged by breast and arm symptoms with better outcomes in APBI arm (p < 0.01)., Interpretation: Early BC treated with APBI showed an improved short-term, and 2-year follow-up HRQoL outcome as compared with WBI. Early BC treated with APBI showed an improved short-term, and 2-year follow-up HRQoL outcome as compared with WBI. APBI should be strongly considered in the treatment choice for selected low-risk patients. Mature local control results from ongoing adequately powered randomised trials are awaited., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: Radiosurgery (RS) is a well-established treatment in selected patients with brain metastasis. The aim of this study is to compare the differences between CyberKnife (CK) and TomoTherapy (HT) treatment plans of RS of single brain metastasis (BM) to define when HT should be used in cases beyond Cyberknife-when both systems are readily available for the radiation oncologist., Methods and Materials: Nineteen patients with single brain metastasis treated with CK were re-planned for radiosurgery using TomoTherapy Hi-ART system. Two planning approaches have been used for TomoTherapy plans: the classical one (HT) and the improved conformity (icHT) that produces dose distributions more similar to those of RS plans. PTV coverage, Conformity Index (CI), Paddick Conformity Index (nCI), Homogeneity Index (HI), Gradient Index (GI), and beam on time of CK, HT, and icHT plans were evaluated and compared., Results: A good coverage was found for CK, HT, and icHT plans. A difference between mean HI of CK and icHT plans was observed (p = 0.007). Better dose gradients compared to both icHT and HT modalities were observed in CK plans. icHT modality showed improved mean CI respect to HT modality, similar to that obtained in CK plans., Conclusions: CK plans show higher conformity and lower GI than icHT and HT plans. TomoTherapy demonstrates the advantage of being a device capable to reach different clinical objectives depending on the different planning modality employed. CyberKnife and TomoTherapy are both optimal RS devices, the choice to use one over another has to be clinically guided.

Over the years, thanks to the addition of new generation systemic agents, as well as the use of more advanced and precise radiotherapy techniques, it was able to obtain a high curability rate for breast cancer. Anthracyclines play a key role in the treatment of breast disease, with a well-known benefit on disease-free survival of patients with positive nodal status. Trastuzumab have shown a significant outcome advantage after 1-year administration in case of HER2-positive disease. Unfortunately, significant increase in cardiotoxicity has been observed after anthracyclines and trastuzumab therapies. Even though the cardiology and oncology community strongly recommend a cardiotoxicity prevention strategy for this subset of patients, there is still no consensus on the optimal patient's approach. We aimed to review the published and ongoing researches on cardioprevention strategies and to present the SAFE trial (CT registry ID: NCT2236806; EudraCT number: 2015-000914-23). It is a randomized phase 3, four-arm, single-blind, placebo-controlled study that aims to evaluate the effect of bisoprolol, ramipril or both drugs, compared to placebo, on subclinical heart damage evaluated by speckle tracking cardiac ultrasound in non-metastatic breast cancer patients.

Both endocrine and chemotherapy can be utilized for breast cancer patients' management, in multiple setting (i.e., primary systemic therapy, adjuvant, metastatic treatment). Health-related quality of life in breast cancer survivors can be significantly influenced by cognitive impairment, which has been related in several previously reported experiences to systemic therapies administration. However, although the growing body of literature, the impact of both chemo- and endocrine therapy on cognitive function is currently unclear, due to many confounding factors (i.e., multiple therapies, duration of therapy, comorbidity, age). The aim of the present review is to present an overview of the current literature concerning the possible influence of endocrine and systemic therapy on breast cancer patients' cognitive impairment.

Major advances in the knowledge of cancer biology and its interactions with tumor immune environment led to the emergence, in the last five years of new immunotherapy-based treatment strategies in cancer patients. At the same time, improvement in radiation technique and progress in radiobiology allowed in the last decade to expand the applications of radiotherapy in a growing number of settings. At present, there are strong theoretical basis to propose immune-enhanced radiation therapy that may represent in the future a new paradigm of treatment, combining the intrinsic power of radiotherapy to elicit a specific, systemic, tumor-directed immune response with modern highly conformal and precise dose delivery, in order to maximize response at the major site of disease and obtain durable disease control. The aim of this review is to describe the principal mechanisms of immune modulation of response to radiation and investigational strategies to harness the potential of radiation-inducible immune response: radiation therapy is expected to be not just a local treatment but the cornerstone of a multimodal strategy that might achieve long-lasting tumor remission at the primary site and systemic efficacy metastatic lesions., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Because of its anti-inflammatory, anti-fibrotic, anti-apoptotic and anti-neoplastic properties, the PPAR-γ agonist rosiglitazone is an interesting drug for investigating for use in the prevention and treatment of radiation-induced intestinal damage. We aimed to evaluate the radioprotective effect of rosiglitazone in a murine model of acute intestinal damage, assessing whether radioprotection is selective for normal tissues or also occurs in tumour cells., Methods: Mice were total-body irradiated (12 Gy), with or without rosiglitazone (5 mg/kg/day). After 24 and 72 hours, mice were sacrificed and the jejunum was collected. HT-29 human colon cancer cells were irradiated with a single dose of 2 (1000 cells), 4 (1500 cells) or 6 (2000 cells) Gy, with or without adding rosiglitazone (20 µM) 1 hour before irradiation. HT-29-xenografted CD1 mice were irradiated (16 Gy) with or without rosiglitazone; tumour volumes were measured for 33 days., Results: Rosiglitazone markedly reduced histological signs of altered bowel structures, that is, villi shortening, submucosal thickening, necrotic changes in crypts, oedema, apoptosis, and inflammatory infiltrate induced by irradiation. Rosiglitazone significantly decreased p-NF-kB p65 phosphorylation and TGFβ protein expression at 24 and 72 hours post-irradiation and significantly decreased gene expression of Collagen1 , Mmp13 , Tnfα and Bax at 24 hours and p53 at 72 hours post-irradiation. Rosiglitazone reduced HT-29 clonogenic survival, but only produced a slight reduction of xenograft tumour growth., Conclusion: Rosiglitazone exerts a protective effect on normal tissues and reduces alterations in bowel structures and inflammation in a radiation-induced bowel toxicity model, without interfering with the radiation effect on HT-29 cancer cells. PPAR-γ agonists should be further investigated for their application in abdominal and pelvic irradiation.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major clinical problem associated with a number of cytotoxic agents. OPERA ® (GAMFARMA srl, Milan, Italy) is a new dietary supplement where α-lipoic acid, Boswellia Serrata, methylsulfonylmethane and bromelain are combined in a single capsule. The aim of this prospective study was to determine the efficacy and safety of OPERA ® supplementation in a series of patients affected by CIPN. We selected 25 subjects with CIPN evolving during or after chemotherapy with potentially neurotoxic agents. Patients were enrolled at the first clinical manifestation of neuropathy. CIPN was assessed at the enrollment visit and subsequently repeated every 3 weeks until 12 weeks. Primary endpoint was the evaluation of changes of measured scores after 12 weeks of therapy compared to baseline evaluation. Secondary endpoints were the evaluation of neuropathy reduction at 12 weeks after beginning of therapy with OPERA ® . Analysis of VAS data showed reduction in pain perceived by patients. According to NCI-CTC sensor and motor score, mISS scale and TNSc scale, both pain and both sensor and motor neuropathic impairment decreased after 12 weeks of treatments. Treatment with OPERA supplement was well tolerated; no increase in the toxicity profile of any of the therapeutic regimen that the patients were undergoing was reported. OPERA ® was able to improve CIPN symptoms in a prospective series of patients treated with neurotoxic chemotherapy, with no significant toxicity or interaction. Prospective RCT in a selected patients' population is warranted to confirm its promising activity.

Background: Due to its anti-inflammatory, antifibrotic and antineoplastic properties, the PPAR gamma agonist rosiglitazone is of interest in prevention and therapy of radiation-induced toxicities. We aimed to evaluate the radioprotective effect of rosiglitazone in a mouse model of radiation-induced oral mucositis., Material and Methods: Oral mucositis was obtained by irradiation of the oral region of C57BL/6J mice, pretreated or not with rosiglitazone. Mucositis was assessed by macroscopic scoring, histology and molecular analysis. Tumor xenograft was obtained by s.c. injection of Hep-2 cells in CD1 mice. Tumor volume was measured twice a week to evaluate effect of rosiglitazone alone and combined with radiotherapy., Results: Irradiated mice showed typical features of oral mucositis, such as oedema and reddening, reaching the peak of damage after 12-15days. Rosiglitazone markedly reduced visible signs of mucositis and significantly reduced the peak. Histological analysis showed the presence of an inflammatory cell infiltrate after irradiation; the association with rosiglitazone noticeably reduced infiltration. Rosiglitazone significantly inhibited radiation-induced tnfα, Il-6 and Il-1β gene expression. Rosiglitazone controlled the increase of TGF-β and NF-kB p65 subunit proteins induced by irradiation, and enhanced the expression of catalase. Irradiation and rosiglitazone significantly reduced tumor volume as compared to control. Rosiglitazone did not protect tumor from the therapeutic effect of radiation., Conclusion: Rosiglitazone exerted a protective action on normal tissues in radiation-induced mucositis. Moreover, it showed antineoplastic properties on head-neck carcinoma xenograft model and selective protection of normal tissues. Thus, PPAR gamma agonists should be further investigated as radioprotective agents in head and neck cancer., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aim: This study evaluates, for the first time, the safety of eribulin in metastatic breast cancer patients concomitantly treated with palliative radiotherapy (RT). Patients & materials: A total of 17 patients were pretreated for metastatic breast cancer. Patients received eribulin mesylate and bone RT., Results: The most frequent grade 3 hematologic adverse events were neutropenia (56%) and anemia (20%). Mean pain score decreased from 2 (baseline) to 0.7 (end of observation). Analgesic score remained stable (1.8 vs 1.6). Bone pain scores dropped within a few weeks and remained below baseline values throughout the analysis. The overall response rate was 29%, and the clinical benefit rate was 59%., Conclusion: Eribulin is characterized by a manageable safety profile also when combined with palliative RT.

Near 75% of all breast cancers (BC) express estrogen receptors (ER) and/or progesterone receptors (PgR), while up to 20% of BC show an overexpression/amplification of Human Epidermal Growth Factor Receptor 2 (HER2). Around 50% of all HER2-overexpressing BC show the coexistence of both HER2 overexpression/amplification and ER and/or PgR overexpression. Numerous in vitro and in vivo studies suggest the existence of a cross-talk between their downstream pathways, which seem to affect the natural history, response to therapy and outcome of patients affected by this subset of BC. Meta-analyses or subgroup analysis of numerous neo-/adjuvant trials demonstrated significant clinical implications deriving from ER/HER2 co-existence, consisting in a different pattern of relapse and dissimilar outcome in response to anti-HER2 therapy. However, only two randomized trials in early disease and three in advanced disease specifically addressed the issue whether a combined approach with both hormonal and anti-HER2 therapy would have a better therapeutic impact in this subset of BC compared to the lone anti-HER2 or hormonal therapies (HT). None of these trials demonstrated improvements in overall survival, even though several efficacy end-points such as progression free survival, in advanced setting, or pCR rates in neoadjuvant setting, often favored the combined hormonal and anti-HER2 therapeutic approach. In the next few years, a certain number of ongoing randomized trials, both in neoadjuvant and advanced setting, will evaluate the efficacy of new anti-HER2 drugs, T-DM1 and pertuzumab, in combination with HT, helping to improve the therapeutic strategy for this specific subtype of breast tumors., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)