Radiomic- and dosiomic-based clustering development for radio-induced neurotoxicity in pediatric medulloblastoma.

BACKGROUND: Texture analysis extracts many quantitative image features, offering a valuable, cost-effective, and non-invasive approach for individual medicine. Furthermore, multimodal machine learning could have a large impact for precision medicine, as texture biomarkers can underlie tissue microstructure. This study aims to investigate imaging-based biomarkers of radio-induced neurotoxicity in pediatric patients with metastatic medulloblastoma, using radiomic and dosiomic analysis. METHODS: This single-center study retrospectively enrolled children diagnosed with metastatic medulloblastoma (MB) and treated with hyperfractionated craniospinal irradiation (CSI). Histological confirmation of medulloblastoma and baseline follow-up magnetic resonance imaging (MRI) were mandatory. Treatment involved helical tomotherapy (HT) delivering a dose of 39 Gray (Gy) to brain and spinal axis and a posterior fossa boost up to 60 Gy. Clinical outcomes, such as local and distant brain control and neurotoxicity, were recorded. Radiomic and dosiomic features were extracted from tumor regions on T1, T2, FLAIR (fluid-attenuated inversion recovery) MRI-maps, and radiotherapy dose distribution. Different machine learning feature selection and reduction approaches were performed for supervised and unsupervised clustering. RESULTS: Forty-eight metastatic medulloblastoma patients (29 males and 19 females) with a mean age of 12 ± 6 years were enrolled. For each patient, 332 features were extracted. Greater level of abstraction of input data by combining selection of most performing features and dimensionality reduction returns the best performance. The resulting one-component radiomic signature yielded an accuracy of 0.73 with sensitivity, specificity, and precision of 0.83, 0.64, and 0.68, respectively. CONCLUSIONS: Machine learning radiomic-dosiomic approach effectively stratified pediatric medulloblastoma patients who experienced radio-induced neurotoxicity. Strategy needs further validation in external dataset for its potential clinical use in ab initio management paradigms of medulloblastoma.

PSMA guided approach for bIoCHEmical relapse after prostatectomy- (PSICHE) trial (NCT05022914). Detection rate and treatment decision after 68Ga-PSMA PET/CT within a prospective study.

BACKGROUND: Ultrasensitive imaging has been demonstrated to influence biochemical relapse treatment. PSICHE is a multicentric prospective study, aimed at exploring detection rate with 68Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) and outcomes with a predefined treatment algorithm tailored to the imaging. METHODS: Patients affected by biochemical recurrence after surgery (prostate specific antigen [PSA] > 0.2 < 1 ng/mL) underwent staging with 68Ga-PSMA PET/CT. Management followed this treatment algorithm accordingly with PSMA results: prostate bed salvage radiotherapy (SRT) if negative or positive within prostate bed, stereotactic body radiotherapy (SBRT) if pelvic nodal recurrences or oligometastatic disease, androgen deprivation therapy (ADT) if nonoligometastatic disease. Chi-square test was used to evaluate the relationship between baseline features and rate of positive PSMA PET/CT. RESULTS: One hundred patients were enrolled. PSMA results were negative/positive in the prostate bed in 72 patients, pelvic nodal or extrapelvic metastatic disease were detected in 23 and 5 patients. Twenty-one patients underwent observation because of prior postoperative radiotherapy (RT)/treatment refusal. Fifty patients were treated with prostate bed SRT, 23 patients underwent SBRT to pelvic nodal disease, five patients were treated with SBRT to oligometastatic disease. One patient underwent ADT. NCCN high-risk features, stage > pT3 and ISUP score >3 reported a significantly higher rate of positive PSMA PET/CT after restaging (p = 0.01, p = 0.02, and p = 0.002). By quartiles of PSA, rate of positive PSMA PET/CT was 26.9% (>0.2; <0.29 ng/mL), 24% (>0.3; <0.37 ng/mL), 26.9% (>0.38; <0.51 ng/mL), and 34.7% (>0. 52; <0.98 ng/mL). CONCLUSIONS: PSICHE trial constitute a useful platform to collect data within a clinical framework where modern imaging and metastasis-directed therapy are integrated.

Pattern of recurrence after stereotactic body radiotherapy for para-aortic oligo-recurrent prostate cancer, a multicentric analysis.

BACKGROUND: M1a disease represents an intermediate status between loco-regional relapse and bone metastatic disease. Metastasis directed therapy (MDT), through stereotactic body RT (SBRT) may be offered to patients, aiming to exclusively treat sites of macroscopic relapse and avoiding wide prophylactic treatment volumes. This appears as a viable treatment, especially after the rise of PSMA tailored treatment approaches. MATERIALS AND METHODS: Data about patients treated in two different institutions were retrieved from a prospectively collected dataset. All included patients were affected by oligo-recurrent M1a disease after definitive RT or radical prostatectomy, defined as ≤ 3 nodal lesions situated above aortic bifurcation and below renal arteries. Both castration resistant PCa (CRPC) and castration sensitive (CSPC) PCa patients were included. All imaging methods were allowed to detect recurrence (CT scan, Choline or PSMA PET/CT).All sites of recurrences were treated with SBRT. RESULTS: Median PFS was 10 months (95% CI 8-17). Twelve patients died, with a median OS of 114 months (95% CI 85-114). Out of the 83 recurrences, 2 (2.4%), 11 (13.25%), 36 (43.37%) and 15 (18%) patients had respectively prostate bed only, pelvic nodal, para-aortic or distant relapse. Furthermore, 19 (22.9%) patients experienced a biochemical only relapse with negative imaging at re-staging. DISCUSSION: MDT conferred a remarkable PFS outcome in a mixed cohort of CSPC and CRPC patients with m1a disease, with an optimal safety profile. Prospective trials are needed in order to compare MDT and ENRT for these patients, allowing to select the best treatment option.

Stereotactic reirradiation with CyberknifeR for locally recurrent prostate cancer, long-term toxicity and clinical outcomes from a monocentric cohort.

PURPOSE: Up to 47% of patients with localized prostate cancer (PCa) treated with radiotherapy (EBRT) eventually develop local recurrence. To date, no clear consensus exists on optimal management. A growing body of interest supports the use of stereotaxic re-irradiation (rSBRT), with promising oncological outcomes and low toxicity profile. We collected a single-center case series of locally recurrent PCa who underwent re-irradiation after a previous course of postoperative or definitive radiotherapy. METHODS AND MATERIALS: Data from 101 patients treated at our institution for locally recurrent PCa from June 2012 to June 2021 were retrospectively collected. Patients underwent rSBRT with CyberKnife system (Accuray Inc., Sunnyvale, CA, USA), delivered to intraprostatic or macroscopic recurrences within the prostate bed, for a total dose of 30 Gy in 5 fractions. RESULTS: All patients received prior EBRT. The median EQD2 total dose was 75.0 Gy (range, 60-80 Gy). Thirty-two (32%) patients were receiving androgen deprivation therapy (ADT) after prior biochemical recurrence. After a median follow-up of 57.8 months, BR occurred in 55 patients (54.5%), with a median BR-free survival (BRFS) of 40.4 months (95% C.I. 34.3-58.3). Thirty-two patients (31.7%) developed metastatic disease, with a median metastasis-free survival (MFS) not reached. PSA ≥ 2.5 ng/ml and ADT were associated with worst BRFS (26.06 vs. 39.3 months, p = 0.03 and 22.7 vs. 27 months, p = 0.01, respectively). Castration-resistant status and ADT were found to be predictive of worst MFS (34.1 vs. 50.5 months, p = 0.02 and 33.5 vs. 53.1 months, p = 0.002, respectively). Concomitant ADT was confirmed as an independent factor for MFS (HR 4.8, 95% CI 1.5-10.6, p = 0.007). No grade > /2 adverse were recorded. CONCLUSIONS: After almost 5 years of follow-up, with a median BRFS of 40.4 months and no grade ≥ 2 AEs, CyberknifeR rSBRT proved effective and safe in a cohort of 101 patients affected by locally recurrent PCa.

Clinical validation of an automatic atlas-based segmentation tool for male pelvis CT images.

PURPOSE: This retrospective work aims to evaluate the possible impact on intra- and inter-observer variability, contouring time, and contour accuracy of introducing a pelvis computed tomography (CT) auto-segmentation tool in radiotherapy planning workflow. METHODS: Tests were carried out on five structures (bladder, rectum, pelvic lymph-nodes, and femoral heads) of six previously treated subjects, enrolling five radiation oncologists (ROs) to manually re-contour and edit auto-contours generated with a male pelvis CT atlas created with the commercial software MIM MAESTRO. The ROs first delineated manual contours (M). Then they modified the auto-contours, producing automatic-modified (AM) contours. The procedure was repeated to evaluate intra-observer variability, producing M1, M2, AM1, and AM2 contour sets (each comprising 5 structures × 6 test patients × 5 ROs = 150 contours), for a total of 600 contours. Potential time savings was evaluated by comparing contouring and editing times. Structure contours were compared to a reference standard by means of Dice similarity coefficient (DSC) and mean distance to agreement (MDA), to assess intra- and inter-observer variability. To exclude any automation bias, ROs evaluated both M and AM sets as "clinically acceptable" or "to be corrected" in a blind test. RESULTS: Comparing AM to M sets, a significant reduction of both inter-observer variability (p < 0.001) and contouring time (-45% whole pelvis, p < 0.001) was obtained. Intra-observer variability reduction was significant only for bladder and femoral heads (p < 0.001). The statistical test showed no significant bias. CONCLUSION: Our atlas-based workflow proved to be effective for clinical practice as it can improve contour reproducibility and generate time savings. Based on these findings, institutions are encouraged to implement their auto-segmentation method.

Pleomorphic Xanthoastrocytoma: a single institution retrospective analysis and a review of the literature.

BACKGROUND:  Pleomorphic xanthoastrocytoma (PXA) is a rare low-grade brain tumor. To date, limited studies have analyzed factors affecting survival outcomes and defined the therapeutic strategy. The aim of this retrospective analysis was to investigate the clinicopathologic characteristics of PXA and identify factors associated with outcomes. METHODS:  We retrospectively analyzed a cohort of 16 adult and children patients with PXA who underwent primary resection from 1997 to 2019, referred to our Radiation Oncology Unit and to Meyer's Paediatric Hospital. We also reviewed the relevant literature. RESULTS:  All patients underwent primary surgical resection; 10 patients received adjuvant radiation treatment course, ranging from DTF 54 to 64 Gy; 8 of them received, in addition, concurrent adjuvant chemotherapy; 6 patients underwent only radiological follow-up. After a median follow up was 60 months: median OS was 34.9 months (95% CI 30-218), 1-year OS 87%, 5-years OS 50%, 10-years OS 50%; median PFS 24.4 months (95% CI 13-156), 1-year PFS 80%, 5-years PFS 33%, 10-years PFS 33%. A chi-square test showed a significant association between OS and recurrent disease (p = 0.002) and with chemotherapy adjuvant treatment (p = 0.049). A borderline statistical significant association was instead recognized with BRAF mutation (p = 0.058). CONCLUSIONS: Despite our analysis did not reveal a strong prognostic or predictive factor able to address pleomorphic xanthoastrocytoma management; however, in selected patients could be considered the addition of adjuvant radiation chemotherapy treatment after adequate neurosurgical primary resection. Furthermore, recurrent disease evidenced a detrimental impact on survival.

Radiosensitizing Effect of Trabectedin on Human Soft Tissue Sarcoma Cells.

Trabectedin is used for the treatment of advanced soft tissue sarcomas (STSs). In this study, we evaluated if trabectedin could enhance the efficacy of irradiation (IR) by increasing the intrinsic cell radiosensitivity and modulating tumor micro-environment in fibrosarcoma (HS 93.T), leiomyosarcoma (HS5.T), liposarcoma (SW872), and rhabdomyosarcoma (RD) cell lines. A significant reduction in cell surviving fraction (SF) following trabectedin + IR compared to IR alone was observed in liposarcoma and leiomyosarcoma (enhancement ratio at 50%, ER50: 1.45 and 2.35, respectively), whereas an additive effect was shown in rhabdomyosarcoma and fibrosarcoma. Invasive cells' fraction significantly decreased following trabectedin ± IR compared to IR alone. Differences in cell cycle distribution were observed in leiomyosarcoma and rhabdomyosarcoma treated with trabectedin + IR. In all STS lines, trabectedin + IR resulted in a significantly higher number of γ-H2AX (histone H2AX) foci 30 min compared to the control, trabectedin, or IR alone. Expression of ATM, RAD50, Ang-2, VEGF, and PD-L1 was not significantly altered following trabectedin + IR. In conclusion, trabectedin radiosensitizes STS cells by affecting SF (particularly in leiomyosarcoma and liposarcoma), invasiveness, cell cycle distribution, and γ-H2AX foci formation. Conversely, no synergistic effect was observed on DNA damage repair, neoangiogenesis, and immune system.

Bevacizumab in recurrent high-grade glioma: a single institution retrospective analysis on 92 patients.

BACKGROUND: High-grade gliomas are among the most aggressive central nervous system primary tumors, with a high risk of recurrence and a poor prognosis. Re-operation, re-irradiation, chemotherapy are options in this setting. No-best therapy has been established. Bevacizumab was approved on the basis of two Phase 2 trials that evaluated its efficacy in patients with recurrent glioblastoma. MATERIALS AND METHODS: We have retrospectively review data of patients with high-grade glioma treated at our institution that undergone radiological or histological progression after at least one systemic treatment for recurrent disease. Bevacizumab was administered alone or in combination with chemotherapy until disease progression or unacceptable toxicity. Bevacizumab regimen was analyzed to assess PFS and OS. Histological, molecular and clinical features of the entire cohort were collected. RESULTS: We reviewed data from 92 patients, treated from April 2009 to November 2019, with histologically confirmed diagnosis of high-grade gliomas and recurrent disease. A PFS of 55.2%, 22.9% and 9.6% was observed at 6, 12 and 24 months, respectively. Performance status, age at diagnosis (< 65 or > 65 ys.) and use of corticosteroids during bevacizumab therapy were strongly associated with PFS. The OS was 74.9% at 6 months, 31.7% at 12 months, 10.1% at 24 months. In our cohort, 51.1% were long-term responders (PFS > 6 months). Globally, bevacizumab treatment was well tolerated. CONCLUSION: Our analysis confirms the efficacy of bevacizumab in recurrent high-grade glioma patients with an acceptable toxicity profile, in keeping with its known safety in the literature.

Impact of COVID-19 on workload burden of a complex radiotherapy facility.

BACKGROUND AND PURPOSE: COVID-19 constitutes a worldwide threat, prompting Italian Government to implement specific measures on March 8, 2020, to protect patients and health workers from disease transmission. The impact of preventive measures on daily activity of a radiotherapy facility may hamper the ability to fulfill normal workload burden. Thus, we assessed the number of delivered treatments in a specific observation period after the adoption of preventive measures (since March 11 to April 24, 2020) and compared it with the corresponding period of the year 2019. MATERIALS AND METHODS: Overall number of delivered fractions was related to actual time of platform daily activity and reported as a ratio between number of delivered fractions and activity hours (Fr/Hrs). Fr/Hrs were calculated and compared for two different periods of time, March 11-April 24, 2019 (Fr/Hrs1), and March 11-April 24, 2020 (Fr/Hrs2). RESULTS: Fr/Hrs1 and Fr/Hrs2 were 2.66 and 2.54 for year 2019 and 2020, respectively, for a Fr/Hrsratio of 1.07 (95% CI 1.03-1.12, p = 0.0005). Fr/Hrs1 was significantly higher than Fr/Hrs2 for SliR and PreciseR, with Fr/Hrsratio of 1.92 (95% CI 1.66-2.23, p < 0.0001) and 1.11 (95% CI 1.03-1.2, p = 0.003), respectively. No significant difference was reported for SynergyR and CyberknifeR with Fr/Hrsratio of 0.99 (95% CI 0.91-1.08, p = 0.8) and 0.9 (95% CI 0.77-1.06, p = 0.2), respectively. Fr/Hrs1 was significantly lower than Fr/Hrs2 for TomotherapyR, with Fr/Hrsratio of 0.88 (95% CI 0.8-0.96, p = 0.007). CONCLUSION: Preventive measures did not influence workload burden performed. Automation in treatment delivery seems to compensate effectively for health workers number reduction.

Ewing family tumors of the appendicular skeleton: a retrospective analysis of prognostic factors.

PURPOSE: Authors retrospectively analyzed possible prognostic factors in a series of patients affected by Ewing sarcoma of extremities (eEWS) and treated over a 20-year period at a single institution. METHODS: Between 1997 and 2017, 88 bone eEWS were treated at our institution. Staging, age, gender, tumoral volume, local treatment, surgical margins, post-ChT necrosis were investigated for prognostic correlation with overall survival (OS) and event-free survival (EFS). Median follow-up was 74 months (1-236). RESULTS: Staging of disease correlated with OS (81% vs 59%, p = 0.01) and not with EFS (68% vs 57%, p = 0.28) in localized vs metastatic eEWS at presentation. Age ≥ 14 years (p = 0.002) and volume ≥ 100 cm3 (p = 0.04) were significant negative prognostic factors. No difference was found in local treatment: OS was 76% vs 63% (p = 0.33), while EFS was 68% vs 49% (p = 0.06) after surgery alone or surgery + radiotherapy, respectively. Regarding surgical margins, OS was 76% vs 38% (p = 0.14), and EFS was 65% vs 33% (p = 0.14) in adequate vs not adequate, respectively. OS was 86% and 68% in good and poor responders, respectively (p = 0.13). CONCLUSION: In eEWS, metastatic disease at presentation, age > 14 years and tumoral volume > 100 cm3 are negative prognostic factors. Intensified adjuvant ChT can improve prognosis in poor responders and metastatic patients.

Methodological approach to create an atlas using a commercial auto-contouring software.

PURPOSE: The aim of this work was to establish a methodological approach for creation and optimization of an atlas for auto-contouring, using the commercial software MIM MAESTRO (MIM Software Inc. Cleveland OH). METHODS: A computed tomography (CT) male pelvis atlas was created and optimized to evaluate how different tools and options impact on the accuracy of automatic segmentation. Pelvic lymph nodes (PLN), rectum, bladder, and femurs of 55 subjects were reviewed for consistency by a senior consultant radiation oncologist with 15 yr of experience. Several atlas and workflow options were tuned to optimize the accuracy of auto-contours. The deformable image registration (DIR), the finalization method, the k number of atlas best matching subjects, and several post-processing options were studied. To test our atlas performances, automatic and reference manual contours of 20 test subjects were statistically compared based on dice similarity coefficient (DSC) and mean distance to agreement (MDA) indices. The effect of field of view (FOV) reduction on auto-contouring time was also investigated. RESULTS: With the optimized atlas and workflow, DSC and MDA median values of bladder, rectum, PLN, and femurs were 0.91 and 1.6 mm, 0.85 and 1.6 mm, 0.85 and 1.8 mm, and 0.96 and 0.5 mm, respectively. Auto-contouring time was more than halved by strictly cropping the FOV of the subject to be contoured to the pelvic region. CONCLUSION: A statistically significant improvement of auto-contours accuracy was obtained using our atlas and optimized workflow instead of the MIM Software pelvic atlas.

PAIDEIA: pacemaker and implanted cardioverter defibrillator management in radiation therapy-a survey by the Young Group of the Italian Association of Radiotherapy and Clinical Oncology (AIRO).

INTRODUCTION: The management of patients bearing a cardiac implantable electronic device and needing a radiotherapy treatment is an important clinical scenario. The aim of this survey was to evaluate the level of awareness within the Italian Radiation Oncologist community on this topic. MATERIALS AND METHODS: A survey was promoted by the Young Group of Italian Association of Radiotherapy and Clinical Oncology (AIRO) with a questionnaire made up of 22 questions allowing for multiple answers, which was administered, both online and on paper version. It was addressed to Radiation Oncologists, AIRO members, participating in the National Congress held in 2015. RESULTS: A total of 113 questionnaires were collected back and analyzed (survey online: 50 respondents; paper version: 63). The answers showed a good level of awareness on the issue, but with a nonhomogeneous adherence to the different published guidelines (GL). There is a general low rate of referral for a preliminary cardiological evaluation in patients bearing PM/ICDs, in line with some published surveys; nevertheless, a focused attention to certain specific treatment factors and patient-centered point of view emerged. CONCLUSIONS: A generally good awareness of this topic was shown but homogeneous application of GL was not observed, possibly due to the multiplicity of available GL. A prospective data collection could help to better clarify the shadows on this topics.

Assessment of a guideline-based heart substructures delineation in left-sided breast cancer patients undergoing adjuvant radiotherapy : Quality assessment within a randomized phase III trial testing a cardioprotective treatment strategy (SAFE-2014).

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.

Management of severe bio-radiation dermatitis induced by radiotherapy and cetuximab in patients with head and neck cancer: emphasizing the role of calcium alginate dressings.

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.

Robotic stereotactic radiotherapy for liver oligometastases from colorectal cancer: a single-center experience.

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 (maxBED10) 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 maxBED10. 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.

Evaluation of Italian radiotherapy research from 1985 to 2005: preliminary analysis.

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.

Soft tissue sarcomas: new opportunity of treatment with PARP inhibitors?

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 matched cohort study of radio-chemotherapy versus radiotherapy alone in soft tissue sarcoma patients.

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.

Influence of age and subtype in outcome of operable liposarcoma.

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.

BRCA mutation in breast cancer patients: Prognostic impact and implications on clinical management.

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.