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Objective: To explore therapeutic results of different radiotherapy (RT) dose schedules combined to Temozolomide (TMZ)-RT treatment in newly diagnosed glioblastoma (GB), according to the O (6)-methylguanine-DNA methyltransferase (MGMT) methylation status., Patients and Methods: Patients with newly diagnosed GB received either standard (60-59.4 Gy) or reduced (54-52 Gy) dose radiation therapy (RT) with concurrent and adjuvant TMZ between June 2010 and October 2016. We retrospectively evaluated the therapeutic effectiveness of the RT ranges schedules in terms of overall survival (OS) with univariate and multivariate analysis, after analyzing the MGMT methylation status., Results: One hundred and seventeen patients were selected for the present analysis out of 146 total treated patients accrued. Seventy-two out of the selected cases received the standard RT-TMZ course (SDRT-TMZ) whereas the remaining 45 underwent the reduced dose schedule (RDRT-TMZ). The analysis according to the MGMT promoter methylation status showed that, in methylated-MGMT GB patients, SDRT-TMZ and RDRT-TMZ groups did not show different median OS (p = ns) according to the two RT schedules, independently by the extent of surgical resection. Instead, a difference in survival outcomes was confirmed in unmethylated-MGMT GB patients with better survival for patients undergoing to SDRT, particularly in sub-total resection., Conclusion: In our experience, a reduction of radiation dose schedule does not seem to jeopardize survival in methylated-MGMT patients independently by the extent of resection. A therapeutic approach to a standard reduction of RT dose for the methylated subset of patients may be feasible and could deserve prospective trials for validation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In the original publication, the 6th author's first name and the last name was inverted and incorrectly published. The correct author name is Letizia Ferella.

Purpose: Skeletal muscle (Skm) plays a key role in regulating energetic metabolism through glucose homeostasis. Several hormones such as Testosterone (T) and Vitamin D (VD) have been shown to affect energy-dependent cell trafficking by determining Insulin (I)-like effects., Aim: To elucidate possible hormone-related differences on muscular metabolic control, we analyzed and compared the effects of T and elocalcitol (elo), a VD analogue, on the activation of energy-dependent cell trafficking, metabolism-related-signal transduction pathways and transcription of gene downstream targets., Methods: Human fetal skeletal muscle cells (Hfsmc) treated with T or elo were analyzed for GLUT4 localization, phosphorylation/activation status of AKT, ERK1/2, IRS-1 signaling and c-MYC protein expression., Results: T, similar to elo, induced GLUT4 protein translocation likely in lipid raft microdomains. While both T and elo induced a rapid IRS-1 phosphorylation, the following dynamic in phosphorylation/activation of AKT and ERK1/2 signaling was different. Moreover, T but not elo increased c-MYC protein expression., Conclusions: All together, our evidence indicates that whether both T and elo are able to affect upstream I-like pathway, they differently determine downstream effects in I-dependent cascade, suggesting diverse physiological roles in mediating I-like response in human skeletal muscle.

Background: Endometrial cancer (EC) is one of the most frequent tumors in women. Despite recent advances in treatment approaches, the prognosis in advanced, recurrent, or metastatic disease remains poor. The aim was to provide the clinician with an update, the current status, and the new developments in the management of EC. Based on the new EC molecular classification, we focused on the impact of immune check-point inhibitors., Methods: Pivotal trials, published literature, and conference proceedings were reviewed. PubMed and Scopus databases were searched to select English-language articles., Results: Immune check-point inhibitors are the subject of ongoing studies and their benefit seems to be related to microsatellite instability (MSI) status., Conclusions: Immune check-point inhibitors should be considered a promising treatment option to better personalize therapeutic strategies in EC.

Aim: to evaluate efficacy and late toxicity of moderate hypofractionated (HFRT) over high-dose (>76 Gy) conventional radiotherapy (CRT) in a non-inferiority perspective., Methods: Randomized controlled trials (RCTs) were included. HFRT regimens were deemed non-inferior to high-dose CRT if the computed CI for the overall RR did not exceed the non-inferiority margin of 7%., Results: When the prespecified margin, corresponding to a critical RR of 0.930 for CCS, OS and BFS, was used all efficacy outcomes satisfied the criteria for the non-inferiority analysis indicating the non-inferiority of HFRT regimens over high-dose CRT in the medium term period. Differently, the evidence concerning the late toxicity was inconclusive., Conclusions: Noninferiority analysis indicates that moderate HFRT regimes are non-inferior over high-dose CRT in the medium-term. Inconclusive is the evidence for the late toxicity. Longer follow-up will provide a more clear answer concerning the non-inferiority of HFRT regimens in the long-term period., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Single metastasis to the cranial bone represents a very uncommon occurrence that can arise from an anal canal cancer. No cases of cranial bone metastasis from anal canal carcinoma are available in the literature. Herein, we present a case of a unique metastatic lesion to the right parietal bone that occurred after curative chemoradiotherapy of primary squamous cell anal canal carcinoma. The patient received radiotherapy and systemic platinum-based chemotherapy, with optimal local control, high compliance and a well tolerable level of toxicity., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

This study was designed to evaluate the objective response after hypofractionated radiotherapy (HFRT) combined with cetuximab (HFBRT) in vulnerable elderly patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Vulnerable elderly patients with histologically proven HNSCC received HFRT (total dose 60 Gy, 3 Gy/fraction) with concurrent cetuximab (250 mg/m 2 with a loading dose of 400 mg/m 2 1 week before HFRT). Elderly patients were categorized as vulnerable based on mini-cog test and adult comorbidity evaluation-27 score. All patients completed the programmed HFRT and two patients received the planned cetuximab infusion. Severe acute toxicity, observed in four patients, was gastrointestinal (oral mucositis in four cases; nausea/vomiting in one case) and dermatological (acneiform eruption in three cases; radiation dermatitis in one case). Three serious adverse events were recorded in three out of six patients Overall, three patients had a partial response and three patients had progression disease 3 months after the end of the treatment. No complete response was observed. HFBRT seems to be not a safer alternative approach for vulnerable elderly patients with locally advanced HNSCC. Further prospective trials are needed to define better tumor control with less incidence of toxic effects in vulnerable elderly HNSCC patients.

Background: Risk factors for local recurrence after mastectomy in ductal carcinoma in situ (DCIS) emerged as a grey area during the second "Assisi Think Tank Meeting" (ATTM) on Breast Cancer., Aim: To review practice patterns of post-mastectomy radiation therapy (PMRT) in DCIS, identify risk factors for recurrence and select suitable candidates for PMRT., Methods: A questionnaire concerning DCIS management, focusing on PMRT, was distributed online via SurveyMonkey., Results: 142 responses were received from 15 countries. The majority worked in academic institutions, had 5-20 years work-experience and irradiated <5 DCIS patients/year. PMRT was more given if: surgical margins <1 mm, high-grade, multicentricity, young age, tumour size >5 cm, skin- or nipple- sparing mastectomy. Moderate hypofractionation was the most common schedule, except after immediate breast reconstruction (57% conventional fractionation)., Conclusions: The present survey highlighted risk factors for PMRT administration, which should be further evaluated., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Glioblastoma multiforme (GBM) represents one of the main frequent and aggressive primary brain neoplasms among adults worldwide. Despite a first-line multimodal treatment, including radical surgery and adjuvant radiation therapy with concomitant temozolomide-based chemotherapy, GBM prognosis continues to be unfavourable. During this decade, different research groups have explored immune check-point inhibitors role in order to improve response to therapy and subsequently prolong survival rate. The aim of this review was to analyze published literature to support immune check-point inhibitors use in the management of patients with GBM diagnosis. The hope was to help physicians for better decision-making., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The aim of this prospective cohort study was to evaluate how the radiation technique can affect crestal bone loss and the implant survival rate in head and neck cancer patients treated with radiotherapy. In this study, the type of radiotherapy treatment, i.e. three-dimensional conformal radiotherapy (3D-CRT) or intensity modulated radiation therapy (IMRT), was the predictor variable. The primary outcome variable was crestal bone loss, recorded at implant placement and after 3, 6, 12, and 24 months. A descriptive analysis and ANOVA test were performed; significance was set at P<0.05. Thirty-two patients were enrolled and a total of 113 dental implants placed in irradiated residual bone. There was no statistically significant difference in crestal bone loss levels between the groups at any of the intervals (P>0.05), except after 6 months (P=0.028). The cumulative dental implant survival rate was 94.7%. After 24 months, the mean marginal bone loss was 0.83±0.12mm in the 3D-CRT group and 0.74±0.15mm in the IMRT group (P=0.179). The data suggest that the different radiation techniques did not affect the outcomes of implant-supported prosthetic rehabilitation, as related to crestal bone loss and implant survival. However, long-term follow-up studies are necessary to evaluate the real influence of the radiotherapy technique on dental implants., (Copyright © 2018 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Purpose: To correlate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters to tumor grading and to assess their reliability in predicting pathological complete response (pCR) before neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC)., Materials and Methods: Forty patients (24 male; mean age, 67.3 ± 8.1 years) with histologically proven LARC who had undergone 3-Tesla DCE-MRI before (MRI&#95;1) and after CRT (MRI&#95;2) between August 2015 and February 2016 were included in this retrospective study. DCE-MRI parameters at MRI&#95;1 and MRI&#95;2 were extracted by two board certified radiologists in consensus reading with Olea Sphere 2.3 software using the extended Tofts model. Based on DCE-MRI results, patients were divided in complete responders (CR) and non-complete responders (nCR) and the perfusion parameters were correlated to tumor grading and pCR., Results: Wash-out and K ep at MRI&#95;1 showed significant correlation with LARC grading (P = 0.004 and 0.01, respectively). V e showed a significant increase between MRI&#95;1 (0.47 ± 0.27) and MRI&#95;2 (0.63 ± 0.23; P = 0.007). K trans measured at MRI&#95;1 was significantly higher in CR (0.66 ± 0.48) compared to nCR (0.53 ± 0.34, P = 0.02)., Conclusion: Wash-out and K ep measured before CRT correlate with LARC grading. V e changes during CRT, while K trans measured before CRT may predict the response to therapy. Therefore, DCE-MRI parameters can predict tumor aggressiveness and CRT efficacy, playing a role as imaging biomarkers in patients with LARC.

Patients with human papillomavirus- (HPV-) related oropharyngeal squamous cell carcinoma (OPSCC) have a better prognosis than HPV-negative OPSCC when treated with standard high-dose cisplatin-based chemoradiotherapy. Consistent with this assertion and due to younger age at diagnosis, novel approaches to minimize treatment sequelae while preserving survival outcomes become of paramount importance. Here, we critically reviewed the evidence-based literature supporting the deintensification strategies in HPV-related OPSCC management, including radiotherapy dose and/or volume reduction, replacement of cisplatin radiosensitising chemotherapy, and the use of transoral surgery. Undoubtedly, further researches are needed before changing the standard of care in this setting of patients.

Purpose: Intravenous (IV) chemotherapy has been compared with intraperitoneal (IP) chemotherapy in randomized clinical trials in advanced ovarian cancer (OC). The aim of this meta-analysis was to evaluate efficacy and toxicity of IV and IP and identify differences in outcomes., Methods: The preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement was applied. Random-effects models were used. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and the proportion of patients with grade ≥2 acute toxicity., Results: Four randomized clinical trials representing 2461 patients were identified. The hazard ratio (HR) of PFS was 0.88 (95% CI 0.80-0.98; p = 0.01, I 2  = 24%) in favor of IP chemotherapy. IP chemotherapy was also associated with significant OS improvement compared with IV chemotherapy, with HR of 0.79 (95% CI 0.67-0.92; p = 0.003, I 2  = 0%). Globally, grade ≥2 toxicities were reduced with IV chemotherapy., Conclusion: This meta-analysis shows the superiority of IP chemotherapy over IV infusion in terms of clinical outcomes but toxicity rates. Its precise role in the management of advanced OC remains to be determined., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: Tumor cells generally exhibit higher levels of reactive oxygen species (ROS), however, when stressed, tumor cells can undergo a process of 'Redox Resetting' to acquire a new redox balance with stronger antioxidant systems that enable cancer cells to become resistant to radiation therapy (RT). Here, we describe how RT affects the oxidant/antioxidant balance in human embryonal (RD) and alveolar (RH30) rhabdomyosarcoma (RMS) cell lines, investigating on the molecular mechanisms involved., Methods: Radiations were delivered using an x-6 MV photon linear accelerator and their effects were assessed by vitality and clonogenic assays. The expression of specific antioxidant-enzymes, such as Superoxide Dismutases (SODs), Catalase (CAT) and Glutathione Peroxidases 4 (GPx4), miRNAs (miR-22, -126, -210, -375, -146a, -34a) and the transcription factor NRF2 was analyzed by quantitative polymerase chain reaction (q-PCR) and western blotting. RNA interference experiments were performed to evaluate the role of NRF2., Results: Doses of RT higher than 2 Gy significantly affected RMS clonogenic ability by increasing ROS production. RMS rapidly and efficiently brought back ROS levels by up-regulating the gene expression of antioxidant enzymes, miRNAs as well as of NRF2. Silencing of NRF2 restrained the RMS ability to counteract RT-induced ROS accumulation, antioxidant enzyme and miRNA expression and was able to increase the abundance of γ-H2AX, a biomarker of DNA damage, in RT-treated cells., Conclusions: Taken together, our data suggest the strategic role of oxidant/antioxidant balance in restraining the therapeutic efficiency of RT in RMS treatment and identify NRF2 as a new potential molecular target whose inhibition might represent a novel radiosensitizing therapeutic strategy for RMS clinical management.

Purpose: To investigate the correlation between inflammatory-related parameters and overall survival (OS) and disease-free survival (DFS) in anal canal cancer population., Methods and Materials: Patients diagnosed with anal canal carcinoma and treated with curative intent chemoradiotherapy (CRT) were included. Data about pre-treatment complete blood count were collected. Neutrophil to lymphocyte ratio (NLR), fibrinogen (F), and a combination of these (F-NLR score) were correlated with OS., Results: A total of 58 patients were enrolled. In multivariate analysis, the strongest OS prognostic factor was NLR, with a hazard ratio (HR) for low NLR compared to high NLR of 1.30 (95% confidence interval 1.01-14.12). Kaplan-Meier survival analysis showed that patients with high NLR, F, and F-NLR had significantly shorter OS and DFS., Conclusion: To our knowledge, this is the first study providing evidence that elevated pre-treatment NLR, F, and F-NLR score significantly correlate with worse survival outcomes in patients with anal canal carcinoma. In view of our findings, future clinical trials in anal canal cancer patients are warranted to verify our results.

Objective: Endothelial dysfunction (ED) predisposes to venous thrombosis (VT) and post-thrombotic syndrome (PTS), a long-term VT-related complication. Sulodexide (SDX) is a highly purified glycosaminoglycan with antithrombotic, pro-fibrinolytic and anti-inflammatory activity used in the treatment of chronic venous disease (CVD), including patients with PTS. SDX has recently obtained clinical evidence in the "extension therapy" after initial-standard anticoagulant treatment for the secondary prevention of recurrent deep vein thrombosis (DVT). Herein, we investigated how SDX counteracts ED., Materials and Methods: Human umbilical vein endothelial cells (HUVEC) were used. Metabolic and non metabolic-induced ED was induced by treating with methylglyoxal (MGO) or irradiation (IR), respectively. Bafilomycin A1 was used to inhibit autophagy. The production of reactive oxygen species (ROS), tetrazolium bromide (MTT) assay for cell viability, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay for cell apoptosis, Real-time PCR and Western blot analysis for gene and protein expression were used., Results: SDX protected HUVEC from MGO- or IR-induced apoptosis by counteracting the activation of the intrinsic and extrinsic caspase cascades. The cytoprotective effects of SDX resulted from a reduction in a) ROS production, b) neo-synthesis and release of pro-inflammatory cytokines (TNFα, IL1, IL6, IL8), c) DNA damage induced by MGO or IR. These effects were reduced when autophagy was inhibited., Conclusions: Data herein collected indicate the ability of SDX to counteract ED induced by metabolic or non-metabolic stresses by involving the intracellular autophagy pathway. Our experience significantly increases the knowledge of the mechanisms of action of SDX against ED and supports the use of SDX in the treatment of CVD, PTS and in the secondary prevention of recurrent DVT.

Purpose: Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in childhood, rarely affects adults, preferring male. RMS expresses the receptor for androgen (AR) and responds to androgen; however, the molecular action of androgens on RMS is unknown., Methods: Herein, testosterone (T) effects were tested in embryonal (ERMS) and alveolar (ARMS) RMS cell lines, by performing luciferase reporter assay, RT-PCR, and western blotting experiments. RNA interference experiments or bicalutamide treatment was performed to assess the specific role of AR. Radiation treatment was delivered to characterise the effects of T treatment on RMS intrinsic radioresistance., Results: Our study showed that RMS cells respond to sub-physiological levels of T stimulation, finally promoting AR-dependent genomic and non-genomic effects, such as the transcriptional regulation of several oncogenes, the phosphorylation-mediated post-transductional modifications of AR and the activation of ERK, p38 and AKT signal transduction pathway mediators that, by physically complexing or not with AR, participate in regulating its transcriptional activity and the expression of T-targeted genes. T chronic daily treatment, performed as for the hormone circadian rhythm, did not significantly affect RMS cell growth, but improved RMS clonogenic and radioresistant potential and increased AR mRNA both in ERMS and ARMS. AR protein accumulation was evident in ERMS, this further developing an intrinsic T-independent AR activity., Conclusions: Our results suggest that androgens sustain and improve RMS transformed and radioresistant phenotype, and therefore, their therapeutic application should be avoided in RMS post puberal patients.

Purpose: Aberrant expression and activity of histone deacetylases (HDACs) sustain glioblastoma (GBM) onset and progression, and, therefore, HDAC inhibitors (HDACi) represent a promising class of anti-tumor agents. Here, we analyzed the effects of ITF2357 (givinostat), a pan-HDACi, in GBM models for its anti-neoplastic potential., Methods: A set of GBM- and patient-derived GBM stem-cell lines was used and the ITF2357 effects on GBM oncophenotype were investigated in in vitro and in vivo xenograft models., Results: ITF2357 inhibited HDAC activity and affected GBM cellular fate in a dose-dependent manner by inducing G 1 /S growth arrest (1-2.5 µM) or caspase-mediated cell death (≥ 2.5 µM). Chronic treatment with low doses (≤ 1 µM) induced autophagy-mediated cell death, neuronal-like phenotype, and the expression of differentiation markers, such as glial fibrillar actin protein (GFAP) and neuron-specific class III beta-tubulin (Tuj-1); this reduces neurosphere formation from patient-derived GBM stem cells. Autophagy inhibition counteracted the ITF2357-induced expression of differentiation markers in p53-expressing GBM cells. Finally, in in vivo experiments, ITF2357 efficiently passed the blood-brain barrier, so rapidly reaching high concentration in the brain tissues, and significantly affected U87MG and U251MG growth in orthotopic xenotransplanted mice., Conclusions: The present findings provide evidence of the key role played by HDACs in sustaining transformed and stem phenotype of GBM and strongly suggest that ITF2357 may have a clinical potential for the HDACi-based therapeutic strategies against GBM.

Purpose: To investigate the effects of the pretreatment neutrophil-to-lymphocyte ratio (N/L) on non-human papilloma virus (HPV)-related oropharyngeal cancer., Materials and Methods: N/L was calculated by dividing the neutrophil count by the lymphocyte count. Survival outcomes were estimated using the Kaplan-Meier method and compared by the log-rank test. Univariate and multivariate analyses were performed to evaluate the prognostic impact of N/L and other clinical factors on survival outcomes. High/low N/L groups were defined as > 4.7 and ≤4.7, respectively., Results: Data of 57 consecutive patients with non-HPV-related oropharyngeal cancer were analyzed. The 3-year disease-free survival was 79 versus 36.9% in favor of the low N/L group (p = 0.04). The 5-year overall survival was 71.6 versus 53.3% in the low N/L and high N/L group, respectively (p = 0.07)., Conclusion: N/L could play an important role in non-HPV-related oropharyngeal cancer progression and indicate prognosis., (© 2018 S. Karger AG, Basel.)

Purpose: PARP inhibitors (PARPi) are used in a wide range of human solid tumours but a limited evidence is reported in rhabdomyosarcoma (RMS), the most frequent childhood soft-tissue sarcoma. The cellular and molecular effects of Olaparib, a specific PARP1/2 inhibitor, and AZD2461, a newly synthesized PARP1/2/3 inhibitor, were assessed in alveolar and embryonal RMS cells both as single-agent and in combination with ionizing radiation (IR)., Methods: Cell viability was monitored by trypan blue exclusion dye assays. Cell cycle progression and apoptosis were measured by flow cytometry, and alterations of specific molecular markers were investigated by, Real Time PCR, Western blotting and immunofluorescence experiments. Irradiations were carried out at a dose rate of 2 Gy (190 UM/min) or 4 Gy (380 UM/min). Radiosensitivity was assessed by using clonogenic assays., Results: Olaparib and AZD2461 dose-dependently reduced growth of both RH30 and RD cells by arresting growth at G2/M phase and by modulating the expression, activation and subcellular localization of specific cell cycle regulators. Downregulation of phospho-AKT levels and accumulation of γH2AX, a specific marker of DNA damage, were significantly and persistently induced by Olaparib and AZD2461 exposure, this leading to apoptosis-related cell death. Both PARPi significantly enhanced the effects of IR by accumulating DNA damage, increasing G2 arrest and drastically reducing the clonogenic capacity of RMS-cotreated cells., Conclusions: This study suggests that the combined exposure to PARPi and IR might display a role in the treatment of RMS tumours compared with single-agent exposure, since stronger cytotoxic effects are induced, and compensatory survival mechanisms are prevented.

Firstly used in the early 90s to generate 3-dimensional projections of X-ray images, cone beam computed tomography (CBCT) has resulted in a large application in dentomaxillofacial imaging, even in children. CBCT uses ionizing radiation that may cause damage to the DNA, and children are at the greatest carcinogenesis risk due to their higher tissue radiosensitivity and their longer life expectancy compared to adults. The questions of whether the cancer risk is really increased after repeated dental CBCT in childhood and of what the underlying biological basis is have become hot topics in the field of dentistry and radiobiology. We performed an overview of the current literature to assess an acceptable role of CBCT in pediatric dentistry., (© 2019 S. Karger AG, Basel.)

Background: Spermatogenesis is a process of dynamic cell differentiation. Ionizing radiation impairs spermatogenesis, and spermatogonia are more radiosensitive than spermatocytes or spermatids. Consistent with this assumption and due to improvement in tumor curability, nowadays, fertility preservation represents a public health need., Objectives: To discuss radiotherapy-induced risk to male fertility and raise oncologic awareness of male fertility in daily clinical practice., Materials and Methods: PubMed and Clinicaltrials.gov databases were searched for papers in English., Results: We provide an overview of clinical landscape. Four main issues were proposed: (i) spermatogenesis and radiobiological general concepts; (ii) impairment of spermatogenesis; (iii) impairment of testosterone-producing Leydig cells; (iv) clinical radiotherapy evidence in oncology., Conclusion: This review can be useful in daily clinical work and offer some directions for future research., (© 2018 American Society of Andrology and European Academy of Andrology.)

To report the clinical results after definitive radiotherapy (RT) for indolent primary cutaneous B cell lymphoma (pcBCL). The data concerning all patients treated for indolent pcBCL with RT with a curative intent between 1992 and 2012 were reviewed. All cases were (re)classified according to the World Health Organization (WHO) guidelines. A total of 42 patients with biopsy-proven primary cutaneous follicle center lymphoma (pcFCL) and primary cutaneous marginal zone lymphoma (pcMZL) were included. The median follow-up is 9.5 years. Treatment with RT resulted in complete response (CR) in all patients. Eight patients showed one or multiple relapses confined to the skin. No in-field recurrences were observed. For the entire cohort, the 10-year relapse-free survival (RFS) and overall survival (OS) were 71.1% and 87.1%, respectively. Univariate (UA) and multivariate (MA) analysis revealed extra-trunk primary lesion (MA) and multiple lesions (UA) as unfavorable prognostic factors. The 5-year RFS rate for patients with trunk lesion was 89.4% versus 66.9% for those with other location (p = 0.02). The 5-year RFS rates were 83.5 and 57.1% in case of single and multiple lesions (p = 0.04). An excellent survival can be achieved with definitive RT in indolent pcBCL. Patients with multiple and extra-trunk primary cutaneous lesions probably warrants intensification of therapy. Prospective studies are mandatory.

Background: Hormone replacement therapy (HRT) has been tested in women with BRCA1 and BRCA2 mutations who underwent risk-reducing salpingo-oophorectomy (RRSO), but its effect on breast cancer (BC) risk has never been appraised using meta-analysis comparison. We performed the first meta-analysis aimed to clarify whether HRT after RRSO could negatively impact on BC risk in women carriers of BRCA1 and BRCA2 mutations., Methods and Material: Pubmed and Scopus databases were searched to retrieve articles written in the English language. Trials comparing RRSO with or without HRT were identified and only those trials with available BC events were included. BC risk was the main endpoint., Results: Three trials with 1100 patients were included. There was not a significantly higher BC risk in BRCA1 and BRCA2 mutation carriers receiving HRT after RRSO (HR = 0.98; 95% CI 0.63-1.52). There was a slightly but not significantly, benefit in BC risk reduction in favor of estrogen alone HRT versus estrogen plus progesterone HRT formulation (OR = 0.53; 95% CI 0.25-1.15)., Conclusion: HRT use after RRSO in BRCA 1 and BRCA2 mutation carries does not affect BC risk. Comparison of the different HRT types suggests that estrogen alone should be related to lowest BC risk., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Nowadays, the multidisciplinary team (MDT) is an essential component for oncologic disease management. Its benefit is also extensively recognized in head and neck cancer (HNC) community, due to tumor rarity and complex treatment. A well-defined MDT management serves as a stable point to define the better strategy and offers a chance to optimize HNC clinical outcomes and patient's quality of life. We explored both mandatory and additional requirements for establishing a high-quality MDT. Then we proposed an example of HNC MDT organization. The aim is to contribute to the best way to systematize HNC care.

Background and Purpose: Complete surgical resection remains the only curative treatment option in locally advanced gastric cancer (GC). Several studies were conducted to prevent local recurrence and to increase the chance of cure. The aim of this study was to summarize our experience in locally advanced GC patients treated with adjuvant chemoradiotherapy (CRT) and to evaluate overall survival (OS), disease-free survival (DFS), toxicity rate and compliance to treatment., Materials and Methods: Locally advanced GC stage IB-III were included. Adjuvant CRT consisted of 45-50.4 Gy (1.8 Gy/day, 5 days/week) with concomitant Macdonald regimen (Mcd) or Epirubicin, Cisplatin and 5-Fluorouracil (ECF) scheme. Univariate and multivariate analysis of several prognostic factors for OS was conducted., Results: Fourty-nine GC patients were treated: 24 received Mcd and 25 received ECF. Median follow up was 48 months. Acute grade 3-4 toxicity was observed in 6 patients. The 2-year and 5-year OS rates were 65.3% and 41.5%, respectively. The 2-year and 5-year DFS were 59.2% and 41.2%, respectively. No prognostic factors were significantly associated with OS., Conclusions: Adjuvant CRT is a feasible strategy in locally advanced GC. It has an acceptable toxicity rate and it is able to increase both DFS and OS., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest.

Background and Purpose: To report preliminary results of induction chemotherapy (IC) followed by neoadjuvant chemoradiotherapy (CRT) and surgery in locally advanced rectal cancer (LARC) patients., Materials and Methods: This is the preliminary evaluation of a phase II study. Patients with histologically proven rectal adenocarcinoma, stage II-III disease, who met the inclusion criteria, received induction FOLFOXIRI (5-FU, leucovorin, oxaliplatin and irinotecan) regimen in combination with targeted agents followed by CRT and surgery. Analysis of the first 8 patients was required to confirm the treatment feasibility before the accrual of 20 additional patients., Results: The first 8 patients were evaluated. The median follow-up time was 23 months. There were no treatment-related deaths. Trimodality strategy was well tolerated with high compliance and a good level of toxicity. There were no evidence of febrile neutropenia and any grade 4 adverse events were recorded. Three patients had pathologic complete response (pCR) and 1 patient had a nearly pCR (ypT1 ypN0)., Conclusion: Preliminary results are encouraging. FOLFOXIRI regimen plus targeted agents followed by CRT and surgery seems a safe approach. Longer follow-up and higher number of patients are mandatory to confirm such findings., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no competing interests.

Despite different treatment strategies, locally advanced cervical cancer (CC) persists as one of the most incurable cancers among women worldwide. In fact, this setting of patients are at high risk of persistent and recurrent disease. In recent years, researches have investigated immune check-point inhibitors in hopes of determining improved response to therapy with prolongation of survival. We reviewed the published literature and conference proceedings and presented pivotal trials supporting immune check-point inhibitors use in the treatment of CC., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: Prostate cancer (PCa) cell radioresistance causes the failure of radiation therapy (RT) in localized or locally advanced disease. The aberrant accumulation of c-Myc oncoprotein, known to promote PCa onset and progression, may be due to the control of gene transcription and/or MEK/ERK-regulated protein stabilization. Here, we investigated the role of MEK/ERK signaling in PCa., Methods: LnCAP, 22Rv1, DU145, and PC3 PCa cell lines were used in in vitro and in vivo experiments. U0126, trametinib MEK/ERK inhibitors, and c-Myc shRNAs were used. Radiation was delivered using an x-6 MV photon linear accelerator. U0126 in vivo activity alone or in combination with irradiation was determined in murine xenografts., Results: Inhibition of MEK/ERK signaling down-regulated c-Myc protein in PCa cell lines to varying extents by affecting expression of RNA and protein, which in turn determined radiosensitization in in vitro and in vivo xenograft models of PCa cells. The crucial role played by c-Myc in the MEK/ERK pathways was demonstrated in 22Rv1 cells by the silencing of c-Myc by means of short hairpin mRNA, which yielded effects resembling the targeting of MEK/ERK signaling. The clinically approved compound trametinib used in vitro yielded the same effects as U0126 on growth and C-Myc expression. Notably, U0126 and trametinib induced a drastic down-regulation of BMX, which is known to prevent apoptosis in cancer cells., Conclusions: The results of our study suggest that signal transduction-based therapy can, by disrupting the MEK/ERK/c-Myc axis, reduce human PCa radioresistance caused by increased c-Myc expression in vivo and in vitro and restores apoptosis signals.

Introduction: The pathogenic mechanism underlying capsular contracture is still unknown. It is certainly a multifactorial process, resulting from human body reaction, biofilm activation, bacteremic seeding, or silicone exposure. The scope of the present article is to investigate the effect of hypofractionated radiotherapy protocol (2.66 Gy × 16 sessions) both on silicone and polyurethane breast implants., Methods: Silicone implants and polyurethane underwent irradiation according to a hypofractionated radiotherapy protocol for the treatment of breast cancer. After irradiation implant shells underwent mechanical, chemical, and microstructural evaluation by means of tensile testing, infrared spectra in attenuated total reflectance mode, nuclear magnetic resonance, and field emission scanning electron microscopy., Results: At superficial analysis, irradiated silicone samples show several visible secondary and tertiary blebs. Polyurethane implants showed an open cell structure, which closely resembles a sponge. Morphological observation of struts from treated polyurethane sample shows a more compact structure, with significantly shorter and thicker struts compared with untreated sample. The infrared spectra in attenuated total reflectance mode spectra of irradiated and control samples were compared either for silicon and polyurethane samples. In the case of silicone-based membranes, treated and control specimens showed similar bands, with little differences in the treated one. Nuclear magnetic resonance spectra on the fraction soluble in CDCl3 support these observations. Tensile tests on silicone samples showed a softer behavior of the treated ones. Tensile tests on Polyurethane samples showed no significant differences., Conclusions: Polyurethane implants seem to be more resistant to radiotherapy damage, whereas silicone prosthesis showed more structural, mechanical, and chemical modifications.

Renal cell carcinoma (RCC) is classically regarded as extremely resistant to classical fractionated radiation therapy (RT). Nowadays, there is convincing data supporting RCC radiosensitivity to high fraction doses, which may represent an ideal issue for new treatment strategies in primary and oligometastatic RCC disease. This review discusses the role of RT in RCC and its potential therapeutic scenario focusing on the most interesting clinical trials., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: The aim of the study was to comparatively evaluate the psychological and functional effect of different primary treatments in patients with prostate cancer., Methods and Materials: We conducted a single-center prospective non randomized study in a real-life setting using functional and psychological questionnaires in prostate cancer cases submitted to radical prostatectomy, external radiotherapy, or active surveillance. Totally, 220 cases were evaluated at baseline and during the follow-up at 1-, 3-, 6-, and 12-month interval after therapy. Patients self-completed questionnaires on urinary symptoms and incontinence, erectile and bowel function, psychological distress (PD), anxiety, and depression., Results: Several significant differences among the three groups of treatment were found regarding the total score of the functional questionnaires. Regarding PD, cases submitted to radical prostatectomy showed stable scores during all the 12 months of follow-up whereas cases submitted to radiotherapy showed a rapid significant worsening of scores at 1-month interval and persistent also at 6- and 12-month interval. Cases submitted to active surveillance showed a slight and slow worsening of scores only at 12-month interval. PD and depression resulted to be more associated with urinary symptoms than sexual function worsening whereas anxiety resulted to be associated either with urinary symptoms or sexual function worsening., Conclusions: The results of our comparative and prospective analysis could be used to better inform treatment decision-making. Patients and their teams might wish to know how functional and psychological aspects may differently be influenced by treatment choice., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Thyroid angiosarcoma (TAS) is rare and represents a very aggressive malignancy. Its rarity is principally linked to two major pitfalls. Firstly, TAS histopathology diagnosis can be difficult; second, the limited clinical experience with this condition can make its management complex. We conducted a detailed systematic review, focusing on the knowledge available regarding TAS etiopathogenesis, treatment options and prognosis. The aim is to present the main TAS characteristics and to summarize the clinical experiences described worldwide, in order to provide a useful clinical tool., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: The use of dose-dense weekly chemotherapy in the management of advanced ovarian cancer (OC) remains controversial. The aim of this meta-analysis was to evaluate the efficacy of dose-dense regimen to improve clinical outcomes in OC patients with the inclusion of new trials., Methods: For this updated meta-analysis, PubMed Medline and Scopus databases and meeting proceedings were searched for eligible studies with the limitation of randomized controlled trials, comparing dose-dense chemotherapy versus standard treatment. Trials were grouped in two types of dose-dense chemotherapy: weekly dose-dense (both paclitaxel and carboplatin weekly administration) and semi-weekly dose-dense (weekly paclitaxel and three weekly carboplatin administration). Data were extracted independently and were analyzed using RevMan statistical software version 5.3 (http://www.cochrane.org). Primary end-point was progression-free survival (PFS)., Results: Four randomized controlled trials comprising 3698 patients were identified as eligible. Dose-dense chemotherapy had not a significant benefit on PFS (HR 0.92, 95% CI 0.81-1.04, p = 0.20). When the analysis was restricted to both weekly and semi-weekly dose-dense data, a no significant interaction between dose-dense and standard regimen was confirmed (HR 1.01, 95% CI 0.93-1.10 and HR 0.82, 95% CI 0.63-1.08, respectively)., Conclusions: In the absence of PFS superiority of dose-dense schedule, three weekly schedule should remain the standard of care for advanced OC., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Treatment of ovarian cancer (OC) is a challenge and its poor prognosis still remains a problem of major importance. Due to the lack of early and specific symptoms, the vast majority of women are diagnosed with an advanced stage disease. The aim of this meta-analysis is to evaluate the impact of OC screening program in asymptomatic women on clinical outcomes., Methods and Material: A systematic literature electronic search was conducted in Pubmed, Medline, Scopus, and ClinicalTrials.gov databases. Articles were selected with a systematic approach. Clinical trials concerning screening strategy compared with usual care in asymptomatic OC women were considered, without any restrictions on the publication date. Trials were eligible if participants were asymptomatic and postmenopausal women. Outcomes included OC diagnosis and disease specific mortality. The pooled relative risk (RR) was calculated using a fixed-effects model., Results: Overall, 3 randomized controlled trials met inclusion criteria, totaling 353,590 asymptomatic women. In total 177,188 women were assigned to screening program, and 176,402 women were assigned to usual care. The risk of OC diagnosis, both overall and at an early stage, was higher in screening group (RR = 1.07, 95% CI: 0.98-1.18; and RR = 1.30, 95% CI: 1.14-1.49, respectively). The RR for disease specific mortality was 0.96 (95% CI: 0.85-1.10)., Conclusion: Our results suggest the possible benefit of OC screening program in term of early stage diagnosis and reduced specific OC mortality. Further studies of environmental or constitutional factors may lead to the identification of patient populations that could benefit from a screening program., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background/aim: To evaluate outcomes in patients with low-risk prostate cancer treated with hypofractionated radiotherapy (HyRT)., Patients and Methods: Between April 2004 and December 2015, 175 patients with low-risk prostate cancer were treated with HyRT 60 Gy in 20 fractions with or without image guidance and reduction of margin from clinical target volume to planning target volume., Results: The median follow-up was 66 months. The 8-year overall survival for the whole patient cohort was 88.9%. The 8-year biochemical no evidence of disease was higher in patients treated with image-guided HyRT (98.8% vs. 88%, p=0.023). During treatment, patients treated with image-guided HyRT presented a lower rate of grade 1-2 gastrointestinal toxicity (25.3% vs. 42.2%, p=0.001). At the last follow-up, the grade 1 Gastro-intestinal toxicity rate was 4.0% and the grade 1-2 genito-urinary toxicity rate was 25.1%., Conclusion: Our study demonstrated the efficacy of the schedule used with a low rate of acute and late toxicities. Therefore, reduction of margins with image-guided HyRT is safe., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: We report the treatment compliance, toxicity rates, and long-term clinical outcomes of elderly patients who received intensified neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC)., Patients and Methods: We identified a retrospective cohort of patients aged ≥ 70 years with LARC who received intensified neoadjuvant CRT, followed by surgery and adjuvant chemotherapy, from 2007 to 2014. Intensified neoadjuvant CRT consisted of radiotherapy (total dose, 50.4/54 Gy) with concomitant oxaliplatin (50 mg/m 2 /wk) and 5-fluorouracil (200 mg/m 2 in 5 daily continuous infusion)., Results: A total of 26 patients were included. All patients completed the programmed CRT. Severe acute toxicity was recorded in 19.2% of cases. Conservative surgery was performed in 16 patients, and a pathologic complete response was achieved in 19.2%. Overall, 26.9% of the patients died. The 5-year overall survival and disease-free survival rates were 70.6% and 65.5%, respectively., Conclusions: Intensified neoadjuvant CRT is an efficacious and safe treatment option for LARC in elderly patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In treating head and neck cancer (HNC), the objectives are provided for best functional results and minimal risk of serious complications. The choice of appropriate management depends primarily on specific site and stage of primary tumor at diagnosis. Radiation therapy (RT) with or without concomitant chemotherapy represents a classical treatment option. In this review, we provide an update of recent research strategies to counteract the existing damage caused by RT and highlight clinical trials currently in progress. We discuss the challenges in the evaluation of new stage system and RT-related toxicity onset. We mainly address the deficiencies and the advantages noted in the current treatment era., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The use of alkylating agents such as temozolomide in association with radiotherapy (RT) is the therapeutic standard of glioblastoma (GBM). This regimen modestly prolongs overall survival, also if, in light of the still dismal prognosis, further improvements are desperately needed, especially in the patients with O6-methylguanine-DNA-methyltransferase (MGMT) unmethylated tumors, in which the benefit of standard treatment is less. Tinostamustine (EDO-S101) is a first-in-class alkylating deacetylase inhibitor (AK-DACi) molecule that fuses the DNA damaging effect of bendamustine with the fully functional pan-histone deacetylase (HDAC) inhibitor, vorinostat, in a completely new chemical entity., Methods: Tinostamustine has been tested in models of GBM by using 13 GBM cell lines and seven patient-derived GBM proliferating/stem cell lines in vitro. U87MG and U251MG (MGMT negative), as well as T98G (MGMT positive), were subcutaneously injected in nude mice, whereas luciferase positive U251MG cells and patient-derived GBM stem cell line (CSCs-5) were evaluated the orthotopic intra-brain in vivo experiments., Results: We demonstrated that tinostamustine possesses stronger antiproliferative and pro-apoptotic effects than those observed for vorinostat and bendamustine alone and similar to their combination and irrespective of MGMT expression. In addition, we observed a stronger radio-sensitization of single treatment and temozolomide used as control due to reduced expression and increased time of disappearance of γH2AX indicative of reduced signal and DNA repair. This was associated with higher caspase-3 activation and reduction of RT-mediated autophagy. In vivo, tinostamustine increased time-to-progression (TTP) and this was additive/synergistic to RT. Tinostamustine had significant therapeutic activity with suppression of tumor growth and prolongation of DFS (disease-free survival) and OS (overall survival) in orthotopic intra-brain models that was superior to bendamustine, RT and temozolomide and showing stronger radio sensitivity., Conclusions: Our data suggest that tinostamustine deserves further investigation in patients with glioblastoma.

Due to substantial improvement in the diagnosis and treatment of gynaecologic cancers, a better understanding of patient care needs to be revised. We reviewed the literature related to fertility preservation strategies in gynaecological cancer and discussed current general management approaches. New technical modalities and patients' own desire for motherhood should be integral and paramount in the clinical evaluation to significantly contribute to preserving fertility in those women diagnosed with gynaecologic cancers during the reproductive years.

Purpose: Bone metastases are a common cause of cancer-related pain. The aim of this study is to determine the optimal radiotherapy schedule for the treatment of painful bone metastases and verify if could cause different biological effects on bone. This has been achieved using functional Magnetic Resonance Imaging (MRI) with diffusion-weighted imaging (DWI)., Patients and Methods: Fifteen patients received Multiple Fractions Radiation Therapy (MFRT) with a total dose of 30Gy in 10 daily fractions of 3Gy given over 2 weeks and 15 patients received a Single Fraction Radiation Therapy (SFRT) with a dose of 8Gy. Quantitative Apparent Diffusion Coefficient (ADC) values after SFRT or MFRT were compared with response to treatment (pain relief), assessed by Visual Analogue Scale (VAS) before radiotherapy and at 1 and 3 months after the completion of treatment., Results: The two schedules had equal efficacy in terms of pain control, without any difference at 1 and 3 months post radiotherapy. In both treatments, pain reduction was related to an increase in the ADC. However, the median ADC value had an increase of 575 points between the baseline and 3 months (from 1010 to 1585, p=0.02) in the 30Gy group, while it was only 178 points (from 1417 to 1595) in the 8Gy group., Conclusions: The increase in the ADC values after radiotherapy corresponds to increased cell death. Despite an equal pain control, MFRT treatment seems to be more effective to achieve cancer cells kill. Our preliminary data could also explain the higher retreatment rates in SFRT vs MFRT in long survivors., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aim: To report the long-term results after definitive chemoradiotherapy (CRT) for anal carcinoma, using consistent time-to-event endpoints., Methods and Materials: Anal carcinoma patient charts were reviewed. All patients received definitive CRT. Overall survival (OS), local failure-free survival (LFFS), locoregional failure-free survival (LRFFS), distant metastasis-free survival (DMFS), and anal dysfunction-free survival (ADFS) were estimated., Results: In total, 65 patients were included. CRT was well tolerated, with only 24.6% grade ≥3 acute toxicity. Overall, the 5-year OS, LFFS, LRFFS, and DMFS were 75.3, 60.2, 74.2, and 66.2%, respectively. Early complete clinical response and tumor stage at diagnosis were the strongest predictors of OS (p = 0.04) and local failure (p = 0.03), respectively., Conclusions: In the treatment of anal cancers, excellent ADFS and OS, and valid LFFS, LRFFS, and DMFS can be achieved with definitive CRT. Adequacy of time-to-event endpoints is paramount., (© 2017 S. Karger AG, Basel.)

This review is focused on the ovarian cancer risk reduction management in BRCA mutation carriers and is intended to assist with clinical decision-making. Obviously, treatment decisions must be based on the available evidence. Despite risk-reducing salpingo-oophorectomy is firmly recommended, several separate questions can be raised to address the variety of intense controversy of this approach. A special emphasis lies in the effective preventive surgical measure against ovarian cancer risk, in an attempt to detect the optimal timing and mitigate the impact on patients. The long term implications of risk-reducing salpingo-oophorectomy as well as hormone replacement therapy are also actively debated. This is expected to represent an opportunity for improved management modelling of BRCA mutated patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Salivary gland malignant tumor (SGMT) is a malignant disease requiring multidisciplinary approach. The rare incidence and the consequent lack of robust evidence-based medicine has called for a comprehensive update to draw recommendations for clinical practice. This paper is a summary of the XXX Head and Neck Unit guidelines regarding the management of SGMT. Recommendations include the indications for exclusive and adjuvant therapy, as well as metastatic management, for both major and minor SGMT., (Copyright © 2017 Elsevier B.V. All rights reserved.)