Publications by authors named "Valeria Masiello"

23 Publications

  • Page 1 of 1

Personalization in Modern Radiation Oncology: Methods, Results and Pitfalls. Personalized Interventions and Breast Cancer.

Front Oncol 2021 18;11:616042. Epub 2021 Mar 18.

Radiation Oncology Section, University of Perugia and Perugia General Hospital, Perugia, Italy.

Breast cancer, the most frequent malignancy in women worldwide, is a heterogeneous group of diseases, characterized by distinct molecular aberrations. In precision medicine, radiation oncology for breast cancer aims at tailoring treatment according to tumor biology and each patient's clinical features and genetics. Although systemic therapies are personalized according to molecular sub-type [i.e. endocrine therapy for receptor-positive disease and anti-human epidermal growth factor receptor 2 (HER2) therapy for HER2-positive disease] and multi-gene assays, personalized radiation therapy has yet to be adopted in the clinical setting. Currently, attempts are being made to identify prognostic and/or predictive factors, biomarkers, signatures that could lead to personalized treatment in order to select appropriate patients who might, or might not, benefit from radiation therapy or whose radiation therapy might be escalated or de-escalated in dosages and volumes. This overview focuses on what has been achieved to date in personalized post-operative radiation therapy and individual patient radiosensitivity assessments by means of tumor sub-types and genetics.
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http://dx.doi.org/10.3389/fonc.2021.616042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012886PMC
March 2021

The Assisi Think Tank Meeting Breast Large Database for Standardized Data Collection in Breast Cancer-ATTM.BLADE.

J Pers Med 2021 Feb 19;11(2). Epub 2021 Feb 19.

Radiation Oncology Section, University of Perugia and Perugia General Hospital, 06123 Perugia, Italy.

During the 2016 Assisi Think Tank Meeting (ATTM) on breast cancer, the panel of experts proposed developing a validated system, based on rapid learning health care (RLHC) principles, to standardize inter-center data collection and promote personalized treatments for breast cancer. The seven-step project included data collection, analysis, application, and evaluation on a data-sharing platform. The multidisciplinary team developed a consensus-based ontology of validated variables with over 80% agreement. This English-language ontology constituted a breast cancer library with seven knowledge domains: baseline, primary systemic therapy, surgery, adjuvant systemic therapies, radiation therapy, follow-up, and toxicity. The library was uploaded to the domain. The safety of data encryption and preservation was tested according to General Data Protection Regulation (GDPR) guidelines on data from 15 clinical charts. The system was validated on 64 patients who had undergone post-mastectomy radiation therapy. In October 2018, the system was approved by the Ethical Committee of Fondazione Policlinico Gemelli IRCCS, Rome, Italy (Protocol No. 0043996/18). From June 2016 to July 2019, the multidisciplinary team completed the work plan. An ontology of 218 validated variables was uploaded to the domain. The GDPR safety test confirmed encryption and data preservation (on 5000 random cases). All validation benchmarks were met. is a support system for follow-up and assessment of breast cancer care. To successfully develop and validate it as the first standardized data collection system, multidisciplinary collaboration was crucial in selecting its ontology and knowledge domains. is suitable for multi-center uploading of retrospective and prospective clinical data, as it ensures anonymity and data privacy.
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http://dx.doi.org/10.3390/jpm11020143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926376PMC
February 2021

GENERATOR Breast DataMart-The Novel Breast Cancer Data Discovery System for Research and Monitoring: Preliminary Results and Future Perspectives.

J Pers Med 2021 Jan 22;11(2). Epub 2021 Jan 22.

Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, UOC di Radioterapia Oncologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, 00186 Rome, Italy.

Background: Artificial Intelligence (AI) is increasingly used for process management in daily life. In the medical field AI is becoming part of computerized systems to manage information and encourage the generation of evidence. Here we present the development of the application of AI to IT systems present in the hospital, for the creation of a DataMart for the management of clinical and research processes in the field of breast cancer.

Materials And Methods: A multidisciplinary team of radiation oncologists, epidemiologists, medical oncologists, breast surgeons, data scientists, and data management experts worked together to identify relevant data and sources located inside the hospital system. Combinations of open-source data science packages and industry solutions were used to design the target framework. To validate the DataMart directly on real-life cases, the working team defined tumoral pathology and clinical purposes of proof of concepts (PoCs).

Results: Data were classified into "Not organized, not 'ontologized' data", "Organized, not 'ontologized' data", and "Organized and 'ontologized' data". Archives of real-world data (RWD) identified were platform based on ontology, hospital data warehouse, PDF documents, and electronic reports. Data extraction was performed by direct connection with structured data or text-mining technology. Two PoCs were performed, by which waiting time interval for radiotherapy and performance index of breast unit were tested and resulted available.

Conclusions: GENERATOR Breast DataMart was created for supporting breast cancer pathways of care. An AI-based process automatically extracts data from different sources and uses them for generating trend studies and clinical evidence. Further studies and more proof of concepts are needed to exploit all the potentials of this system.
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http://dx.doi.org/10.3390/jpm11020065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911086PMC
January 2021

Evaluation of a generalized knowledge-based planning performance for VMAT irradiation of breast and locoregional lymph nodes-Internal mammary and/or supraclavicular regions.

PLoS One 2021 15;16(1):e0245305. Epub 2021 Jan 15.

Università Cattolica del Sacro Cuore, Rome, Italy.

Purpose: To evaluate the performance of eleven Knowledge-Based (KB) models for planning optimization (RapidPlantm (RP), Varian) of Volumetric Modulated Arc Therapy (VMAT) applied to whole breast comprehensive of nodal stations, internal mammary and/or supraclavicular regions.

Methods And Materials: Six RP models have been generated and trained based on 120 VMAT plans data set with different criteria. Two extra-structures were delineated: a PTV for the optimization and a ring structure. Five more models, twins of the previous models, have been created without the need of these structures.

Results: All models were successfully validated on an independent cohort of 40 patients, 30 from the same institute that provided the training patients and 10 from an additional institute, with the resulting plans being of equal or better quality compared with the clinical plans. The internal validation shows that the models reduce the heart maximum dose of about 2 Gy, the mean dose of about 1 Gy and the V20Gy of 1.5 Gy on average. Model R and L together with model B without optimization structures ensured the best outcomes in the 20% of the values compared to other models. The external validation observed an average improvement of at least 16% for the V5Gy of lungs in RP plans. The mean heart dose and for the V20Gy for lung IPSI were almost halved. The models reduce the maximum dose for the spinal canal of more than 2 Gy on average.

Conclusions: All KB models allow a homogeneous plan quality and some dosimetric gains, as we saw in both internal and external validation. Sub-KB models, developed by splitting right and left breast cases or including only whole breast with locoregional lymph nodes, have shown good performances, comparable but slightly worse than the general model. Finally, models generated without the optimization structures, performed better than the original ones.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245305PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810311PMC
January 2021

Diagnosis and Treatment of Bone Metastases in Breast Cancer: Radiotherapy, Local Approach and Systemic Therapy in a Guide for Clinicians.

Cancers (Basel) 2020 Aug 24;12(9). Epub 2020 Aug 24.

"A. Gemelli" IRCCS, UOC di Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario, 00168 Roma, Italy.

The standard care for metastatic breast cancer (MBC) is systemic therapies with imbrication of focal treatment for symptoms. Recently, thanks to implementation of radiological and metabolic exams and development of new target therapies, oligometastatic and oligoprogressive settings are even more common-paving the way to a paradigm change of focal treatments role. In fact, according to immunophenotype, radiotherapy can be considered with radical intent in these settings of patients. The aim of this literature review is to analyze available clinical data on prognosis of bone metastases from breast cancer and benefits of available treatments for developing a practical guide for clinicians.
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http://dx.doi.org/10.3390/cancers12092390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563945PMC
August 2020

C-PK11195 PET-based molecular study of microglia activation in SOD1 amyotrophic lateral sclerosis.

Ann Clin Transl Neurol 2020 09 6;7(9):1513-1523. Epub 2020 Aug 6.

School of Psychology, Vita-Salute San Raffaele University, Milan, Italy.

Objective: Neuroinflammation is considered a key driver for neurodegeneration in several neurological diseases, including amyotrophic lateral sclerosis (ALS). SOD1 mutations cause about 20% of familial ALS, and related pathology might generate microglial activation triggering neurodegeneration. C-PK11195 is the prototypical and most validated PET radiotracer, targeting the 18-kDa translocator protein which is overexpressed in activated microglia. In this study, we investigated microglia activation in asymptomatic (ASYM) and symptomatic (SYM) SOD1 mutated carriers, by using C-PK11195 and PET imaging.

Methods: We included 20 subjects: 4 ASYM-carriers, neurologically normal, 6 SYM-carriers with probable ALS, and 10 healthy controls. A receptor parametric mapping procedure estimated C-PK11195 binding potentials and voxel-wise statistical comparisons were performed at group and single-subject levels.

Results: Both the SYM- and ASYM-carriers showed significant microglia activation in cortical and subcortical structures, with variable patterns at individual level. Clusters of activation were present in occipital and temporal regions, cerebellum, thalamus, and medulla oblongata. Notably, SYM-carriers showed microglia activation also in supplementary and primary motor cortices and in the somatosensory regions.

Interpretation: In vivo neuroinflammation occurred in all SOD1 mutated cases since the presymptomatic stages, as shown by a significant cortical and subcortical microglia activation. The involvement of sensorimotor cortex became evident at the symptomatic disease stage. Although our data indicate the role of in vivo PET imaging for assessing resident microglia in the investigation of SOD1-ALS pathophysiology, further studies are needed to clarify the temporal and spatial dynamics of microglia activation and its relationship with neurodegeneration.
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http://dx.doi.org/10.1002/acn3.51112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480909PMC
September 2020

Oncotype DX Predictive Nomogram for Recurrence Score Output: The Novel System ADAPTED01 Based on Quantitative Immunochemistry Analysis.

Clin Breast Cancer 2020 10 5;20(5):e600-e611. Epub 2020 May 5.

UOC di Radioterapia Oncologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Dipartimento di Scienze della Salute della Donna e del Bambino e di Sanità Pubblica, Rome, Italy; Università Cattolica del Sacro Cuore, Istituto di Radiologia, Rome, Italy.

Purpose: Oncotype DX (ODX) predicts breast cancer recurrence risk, guiding the choice of adjuvant treatment. In many countries, access to the test is not always available. We used correlation between phenotypical tumor characteristics, quantitative classical immunohistochemistry (IHC), and recurrence score (RS) assessed by ODX to develop a decision supporting system for clinical use.

Patients And Methods: Breast cancer patients who underwent ODX testing between 2014 and 2018 were retrospectively included in the study. The data selected for analysis were age, menopausal status, and pathologic and IHC features. IHC was performed with standardized quantitative methods. The data set was split into two subsets: 70% for the training set and 30% for the internal validation set. Statistically significant features were included in logistic models to predict RS ≤ 25 or ≤ 20. Another set was used for external validation to test reproducibility of prediction models.

Results: The internal set included 407 patients. Mean (range) age was 53.7 (31-80) years, and 222 patients (54.55%) were > 50 years old. ODX results showed 67 patients (16.6%) had RS between 0 and 10, 272 patients between 11 and 25 (66.8%), and 68 patients > 26 (16.6%). Logistic regression analysis showed that RS score (for threshold ≤ 25) was significantly associated with estrogen receptor (P = .004), progesterone receptor (P < .0001), and Ki-67 (P < .0001). Generalized linear regression resulted in a model that had an area under the receiver operating characteristic curve (AUC) of 92.2 (sensitivity 84.2%, specificity 80.1%) and that was well calibrated. The external validation set (183 patients) analysis confirmed the model performance, with an AUC of 82.3 and a positive predictive value of 91%. A nomogram was generated for further prospective evaluation to predict RS ≤ 25.

Conclusion: RS was related to quantitative IHC in patients with RS ≤ 25, with a good performance of the statistical model in both internal and external validation. A nomogram for enhancing clinical approach in a cost-effective manner was developed. Prospective studies must test this application in clinical practice.
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http://dx.doi.org/10.1016/j.clbc.2020.04.012DOI Listing
October 2020

Adult Onset Still's Disease and Radiotherapy treatment for breast cancer: Case report about management of this rare association and literature review.

Rep Pract Oncol Radiother 2020 Jul-Aug;25(4):527-532. Epub 2020 May 22.

Fondazione Policlinico Universitario "A. Gemelli" IRCCS, UOC di Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Roma, Italy.

Aim: This manuscript focuses on the first experience in literature of a patient with a complicated Adult Onset Still's Disease-related heart failure who thereafter underwent adjuvant radiotherapy for left breast cancer.

Background: AOSD is a rare autoimmune inflammation-related disease, in which life-threatening pulmonary and cardiac complications can occur. In literature, AOSD is often associated with cancer, as paraneoplastic syndrome, but there are few data about primary AOSD and management of oncological therapies.

Materials And Methods: A patient who needed adjuvant breast cancer radiotherapy underwent tumour board evaluation to define feasibility of an RT in a patient with of a history of a heart life-threatening complication 2 years before AOSD. Results of the review were discussed by a multidisciplinary panel of experts that chose the type of surgery, radiotherapy and monitoring of patient.

Results: Literature review confirmed association of AOSD with BC in some pts and uniqueness of this treatment management experience. Patient underwent RT according to schedule of 40.05/2.67 Gy/fx on residual left breast and 10/2 Gy/fx on tumour bed with the gating technique. The panel chose to keep immunosuppressive therapy with anakinra. No complications were observed at clinical, ECG and laboratory examinations. Maximum toxicity was G2 skin. At first follow up AOSD signs of flare were negative.

Conclusion: In conclusion, when oncological treatments, especially radiotherapy, are mandatory for AOSD pts, multidisciplinary management and tailored monitoring are necessary to avoid acute adverse effects and allow pts to complete therapies.
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http://dx.doi.org/10.1016/j.rpor.2020.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251537PMC
May 2020

The 2018 assisi think tank meeting on breast cancer: International expert panel white paper.

Crit Rev Oncol Hematol 2020 Jul 22;151:102967. Epub 2020 Apr 22.

Radiation Oncology, University of Perugia and Perugia General Hospital, Perugia, Italy. Electronic address:

We report on the second Assisi Think Tank Meeting (ATTM) on breast cancer which was held under the auspices of the European Society for RadioTherapy & Oncology (ESTRO). In discussing in-depth current evidence and practice it was designed to identify grey areas in diverse forms of the disease. It aimed at addressing uncertainties and proposing future trials to improve patient care. Before the meeting, three key topics were selected: 1) primary systemic therapy, mastectomy, breast reconstruction and post-mastectomy radiation therapy, 2) therapeutic options in ductal carcinoma in situ, and 3) therapy de-escalation in early stage breast cancer. Clinical practice in these areas was investigated by means of an online questionnaire. The time lapse period between the survey and the meeting was used to review the literature and on-going clinical trials. At the ATTM both were discussed in depth and research protocols were proposed.
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http://dx.doi.org/10.1016/j.critrevonc.2020.102967DOI Listing
July 2020

Could a Personalized Strategy Using Accelerated Partial Breast Irradiation be an Advantage for Elderly Patients? A Systematic Review of the Literature and Multidisciplinary Opinion.

J Oncol 2020 28;2020:3928976. Epub 2020 Feb 28.

UOC Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

. Elderly patients are underrepresented from a majority of clinical trials and the choice of the best treatment becomes a challenge. The optimal treatment should be personalized and based on a multidisciplinary approach that includes radiation oncologists, surgeons, geriatricians, medical oncologists, social workers, and support services. The global evaluation of the patients and the creation of nomograms may facilitate the definition of long-term treatment benefits minimizing the use of unnecessary therapy. . A systematic research using PubMed, Scopus, and Cochrane library was performed to identify full articles analyzing the efficacy of APBI in elderly patients with breast cancer. ClinicalTrials.gov was searched for ongoing or recently completed trials, and PROSPERO was searched for ongoing or recently completed systematic reviews.

Results: Seven papers fulfilled the eligibility criteria. The number of evaluated patients was 405 and the median age was 77.7 years. The disease-free survival (DFS) range was 96.1%-100%, the grade 3-4 toxicity range was 0%-6.6%, the cancer-specific survival (CSS) range was 97.9%-100%, and the overall survival (OS) range was 87%-100%. All studies reported excellent/good cosmetic results in a range of 74% to 99%.

Conclusion: Accelerated partial breast irradiation (APBI) results in a safe and effective substitute for the adjuvant external beam radiotherapy in selected elderly early-stage breast cancer patients. Based on the relatively low toxicity, APBI should be advised in selected patients with life expectancies larger than 5-10 years.
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http://dx.doi.org/10.1155/2020/3928976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064828PMC
February 2020

Age and Sex Influence the Neuro-inflammatory Response to a Peripheral Acute LPS Challenge.

Front Aging Neurosci 2019 5;11:299. Epub 2019 Nov 5.

PET and Nuclear Medicine Unit, San Raffaele Scientific Institute, Milan, Italy.

Aging is associated with an exaggerated response to peripheral inflammatory challenges together with behavioral and cognitive deficits. Studies considering both age and sex remain limited, despite sex dimorphism of astrocytes and microglial cells is largely recognized. To fill this knowledge gap, we investigated the effect of a single intraperitoneal lipopolysaccharide (LPS) administration in adult and aged mice. We assessed the expression of different inflammatory mediators, and the microglial response through binding of [F]-VC701 tracer to translocator protein (TSPO) receptors in the male and female brain. Aged female brain showed a higher pro-inflammatory response to LPS compared to adult female and to aged male, as revealed by binding to TSPO receptors and pro-inflammatory mediator transcript levels. The highest astroglial reaction was observed in the brain of aged females. Differently to the other groups of animals, in aged males LPS challenge did not affect transcription of triggering receptor expressed on myeloid cells 2 (TREM2). In conclusion, our study shows that in the mouse's brain the neuro-inflammatory response to an acute peripheral insult is sex- and age-dependent. Moreover, our results might set the basis for further studies aimed at identifying sex-related targets involved in the modulation of the aberrant neuro-inflammatory response that characterizes aging. This knowledge could be relevant for the treatment of conditions such as delirium and dementia.
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http://dx.doi.org/10.3389/fnagi.2019.00299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848890PMC
November 2019

The prognostic role of FDG PET/CT before combined radio-chemotherapy in anal cancer patients.

Ann Nucl Med 2020 Jan 14;34(1):65-73. Epub 2019 Nov 14.

Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, UOC di Medicina Nucleare, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Objective: We assessed the prognostic value of several FDG PET/CT parameters, measured within the primary tumor and the involved lymph nodes, before definitive radio-chemotherapy (RCT) in anal cancer patients.

Methods: Anal cancer patients with positive baseline FDG PET/CT who underwent definitive RCT from May 2011 to February 2018 were retrospectively assessed. Primary tumour (T)-SUVmax, T-SUVpeak, T-SUVmean, T-MTV, T-TLG, whole-body (WB) MTV, and WB-TLG were measured. Kaplan-Meier curves, Cox-regression analysis, and logistic regression machine-learning technique were used to test for associations between clinical data, metabolic parameters, and outcomes as overall survival (OS), disease-specific survival (DSS), metastatic-free survival (MFS), disease-free survival (DFS), local relapse-free survival (LRFS), and colostomy-free survival (CFS).

Results: Fifty-nine patients were included in the study. Median follow-up was 28 months. Higher pre-treatment WB-MTV, T-TLG, and WB-TLG were associated with worse OS (p = 0.025, 0.021, and 0.02, respectively). PET parameters resulted also statistically significant for DSS, DFS, and CFS (p = 0.032, 0.043, 9 × 10 for WB-TLG). Cox analysis showed that PET parameters are significant predictors of OS, DSS, DFS, CFS, and LRFS. On multivariate analysis, age, stage, T-SUVpeak, WB-MTV, and T-TLG resulted significantly related to OS. A further stratification for patients with advanced stage (cT3-4 any N or any cT, N + ) showed that MTV and TLG, measured within the primary tumor and the involved nodes, are significantly higher in patients with a worse prognosis. In this subgroup, cut-off values of T- and WB-TLG as well as T- and WB-MTV showed a statistically significant correlation with clinical outcomes.

Conclusions: Pre-treatment metabolic parameters measured within the primary tumor and the involved nodes may represent additional new biomarkers for estimating prognosis in anal cancer patients, especially in advanced stage patients.
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http://dx.doi.org/10.1007/s12149-019-01416-yDOI Listing
January 2020

Pain REduction with bone metastases STereotactic radiotherapy (PREST): A phase III randomized multicentric trial.

Trials 2019 Oct 28;20(1):609. Epub 2019 Oct 28.

Fondazione Policlinico Universitario "A. Gemelli" IRCCS, UOC di Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Rome, Italy.

Background: Palliative antalgic treatments represent an issue for clinical management and a challenge for scientific research. Radiotherapy (RT) plays a central role. Techniques such as stereotactic body radiotherapy (SBRT) were largely investigated in several phase 2 studies with good symptom response, becoming widely adopted. However, evidence from randomized, direct comparison of RT and SBRT is still lacking.

Methods/design: The PREST trial was designed as an interventional study without medicinal treatment. It is a phase 3, open-label, multicentric trial randomized 1:1. Inclusion criteria include painful spinal bone metastases presenting with a pain level > 4 (or > 1 if being treated with an analgesic) on the Numeric Rating Scale (NRS); expected intermediate/high prognosis (greater than 6 months) according to the Mizumoto prognostic score; low spine instability neoplastic score (SINS) sores (< 7); magnetic resonance imaging (MRI) assessment of the bulky lesion. Patients will be assigned to either standard conventional radiotherapy involving 4 Gy × 5 fractions (fx) to the whole involved vertebra or SBRT by intensity modulated radiotherapy with simultaneous integrated boost (IMRT-SIB) involving 7 Gy × 3 fx to the whole involved vertebra + 10 Gy × 3 fx on the macroscopic lesion (gross tumor volume (GTV)). In the experimental arm, the GTV will be contoured by registration with baseline MRI.

Discussion: The primary endpoint is overall pain reduction, defined in terms of variation between baseline and 3-month evaluation; pain will be measured using the NRS. Secondary endpoints include pain control duration; retreatment rates (after a minimum interval of 1 month); local control assessed with RECIST criteria; symptom progression free survival; progression-free survival; overall survival; and quality of life (at 0, 30, and 90 days). Accrual of 330 lesions is planned. The experimental arm is expected to have an improvement in overall pain response rates of 15% with respect to the standard arm (60% according to Chow et al. (Int J Radiat Oncol Biol Phys. 82(5):1730-7, 2012)).

Trial Registration: ClinicalTrials.gov, NCT03597984 . Registered on July 2018.
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http://dx.doi.org/10.1186/s13063-019-3676-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816218PMC
October 2019

Shoulder girdle impairment in breast cancer survivors: the role of range of motion as predictive factor for dose distribution and clinical outcome.

Tumori 2019 Aug 1;105(4):319-330. Epub 2019 Apr 1.

1 Fondazione Policlinico Universitario "A. Gemelli" IRCCS, UOC di Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Roma, Italia.

Background: Pain and functional impairment of the ipsilateral shoulder girdle in patients who underwent surgery and radiotherapy for breast cancer (BC) is a late complication reported in the literature. We analyze a correlation with dosimetric parameters and propose an algorithm for sparing strategies.

Methods: A total of 111 patients treated for BC were included in this observational analysis during follow-up protocol visits. Exclusion criteria were the presence of moderate or severe arthrosis history and/or rheumatologic diseases. All the patients had complete physical and multidimensional examinations during joint (physiatrist and radiotherapy oncology) follow-up visits. A scapula-humeral articulation (SHA) standardized contouring was performed retrospectively on Eclipse® treatment plans. A possible correlation between patients' characteristics, radiotherapy, and dosimetry analysis and functional impairment was investigated at statistical analysis. Results of analysis were summarized into a proposal of algorithm for sparing SHA.

Results: A total of 111 patients were selected during follow-up visits. Mean age of patients was 60 years (range 41-85 years). A total of 103 patients (93%) underwent conservative surgery, with 110 patients (99%) undergoing axilla surgery as well. Fifty-two patients (46.8%) presented a reduction of range of motion (ROM) abduction on the treated side at the observational analysis. Mean ROM abduction reduction was 13°06' (range 0°-100°). Disability of the Arm, Shoulder and Hand questionnaire (DASH) score results were excellent in 79 patients (71.2%), discrete in 15 patients (13.5%), good in 15 patients (13.5%), and sufficient in 2 patients (1.8%). Median EQD D at SHA was 18 Gy (range 0.22-51.9 Gy) and median EQD mean dose at SHA was 2 Gy (range 0.04-24.32 Gy). Univariate analysis showed a linear correlation between DASH score and ROM of abduction of treated side (ρ=-0.7), ROM of abduction and ROM of flexion in ipsilateral arm (ρ=0.8), or ROM of abduction and ROM of flexion in contralateral arm (ρ=0.8). A statistically significant difference in ROM abduction between the 2 arms was found at χ test (<0.05 at χ confidence interval = 95%). Cox linear regression analysis showed ROM abduction on treated arm as a predictive factor of DASH score (<0.0001). Age (<0.05), DASH score (=0.006), and ROM abduction on treated arm (=0.005) were found as independent predictive factors of mean dose at multivariate analysis. A mean dose higher than 7 Gy and ROM abduction reduction more than 30° were related to DASH score level reduction.

Conclusions: This hypothesis-generating study introduces an algorithm to be validated for management of sparing SHA and improving quality of survivorship. ROM evaluation after surgery, early physiotherapy, standard contouring, and planning adaptation represent possible indications to preserve shoulder impairment. Further prospective studies are needed to discriminate impairment of surgery and radiotherapy in order to personalized therapeutic plan programs.
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http://dx.doi.org/10.1177/0300891619839287DOI Listing
August 2019

Response evaluation with F-FDG PET/CT in metastatic breast cancer patients treated with Palbociclib: first experience in clinical practice.

Ann Nucl Med 2019 Mar 19;33(3):193-200. Epub 2018 Dec 19.

Nuclear Medicine Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Francesco Vito, 1, 00168, Rome, Italy.

Objective: Palbociclib is a cyclin-dependent kinase 4/6 inhibitor recently approved for treatment in advanced or metastatic breast cancer (BC) patients. The use of F-FDG PET/CT for chemo/endocrine therapy response assessment in BC patients is well reported in the literature, but no studies have evaluated its role for assessing Palbociclib efficacy in clinical practice. Our study aimed to evaluate the potential role of F-FDG PET/CT in this setting.

Methods: In 12 metastatic BC patients (mean age = 62 ± 10 years) treated with Palbociclib plus endocrine therapy and who underwent a baseline and post-therapy F-FDG PET/CT, we retrospectively compared the Metabolic Response Evaluation (MRE, based on PET/CT) to the Standard Response Evaluation (SRE, based on clinico-laboratory and morphological data); we also assessed the influence of additional PET/CT information on the patients' management.

Results: Compared to SRE, MRE increased the proportion of patients classified with progressive disease from 25 to 50% and differed from SRE in 8/12 patients: 3/8 shifted from stable disease or undetermined response to metabolic progression (more unfavorable category), 4/8 from stable disease to partial or complete metabolic response, and 1/8 from partial response to complete metabolic response (more favorable category). Additional PET/CT information led to a change in patients' management in 3/12 (25%) patients.

Conclusion: In BC patients treated with Palbociclib, additional F-FDG PET/CT information seems clinically useful, with respect to personalized management, to early intercept patients who should discontinue Palbociclib because of progressive disease and to select patients requiring a strict monitoring of additional metabolic findings. Further studies are needed to confirm these preliminary results.
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http://dx.doi.org/10.1007/s12149-018-01323-8DOI Listing
March 2019

F-VC701-PET and MRI in the in vivo neuroinflammation assessment of a mouse model of multiple sclerosis.

J Neuroinflammation 2018 Feb 5;15(1):33. Epub 2018 Feb 5.

IBFM-CNR, Segrate, Italy.

Background: Positron emission tomography (PET) using translocator protein (TSPO) ligands has been used to detect neuroinflammatory processes in neurological disorders, including multiple sclerosis (MS). The aim of this study was to evaluate neuroinflammation in a mouse MS model (EAE) using TSPO-PET with F-VC701, in combination with magnetic resonance imaging (MRI).

Methods: MOG/CFA and pertussis toxin protocol was used to induce EAE in C57BL/6 mice. Disease progression was monitored daily, whereas MRI evaluation was performed at 1, 2, and 4 weeks post-induction. Microglia activation was assessed in vivo by F-VC701 PET at the time of maximum disease score and validated by radioligand ex vivo distribution and immunohistochemistry at 2 and 4 weeks post-immunization.

Results: In vivo and ex vivo analyses show that F-VC701 significantly accumulates within the central nervous system (CNS), particularly in the cortex, striatum, hippocampus, cerebellum, and cervical spinal cord of EAE compared to control mice, at 2 weeks post-immunization. MRI confirmed the presence of focal brain lesions at 2 weeks post-immunization in both T1-weighted and T2 images. Of note, MRI abnormalities attenuated in later post-immunization phase. Neuropathological analysis confirmed the presence of microglial activation in EAE mice, consistent with the in vivo increase of F-VC701 uptake.

Conclusion: Increase of F-VC701 uptake in EAE mice is strongly associated with the presence of microglia activation in the acute phase of the disease. The combined use of TSPO-PET and MRI provided complementary evidence on the ongoing disease process, thus representing an attractive new tool to investigate neuronal damage and neuroinflammation at preclinical levels.
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http://dx.doi.org/10.1186/s12974-017-1044-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800080PMC
February 2018

Concomitant Lung Cancer and Gastrointestinal Stromal Tumor: First Report of Hypoxia Imaging With 18F-FAZA PET/CT.

Clin Nucl Med 2017 Jul;42(7):e349-e351

From the Departments of *Nuclear Medicine, and †Pathology, IRCCS San Raffaele Scientific Institute, Milan; ‡Vita-Salute San Raffaele University, Milan; and §Department of Thoracic Surgery, IRCCS San Raffaele Scientific Institute, Milan, Italy.

A 76-year-old man underwent F-FDG PET/CT to complete staging and characterize a suspicious lung mass. Images showed intense uptake in the lung lesion and faint uptake in correspondence of a gastric mass, which was subsequently biopsied revealing a gastrointestinal stromal tumor. A F-FAZA PET/CT was also performed because of patient's enrollment in a prospective clinical trial (trial registration no. EudraCT 2011-002647-98), showing heterogeneous uptake of F-FAZA in the pulmonary lesion and faint uptake in correspondence of the gastrointestinal stromal tumor.
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http://dx.doi.org/10.1097/RLU.0000000000001704DOI Listing
July 2017

MITHRA - multiparametric MR/CT image adapted brachytherapy (MR/CT-IABT) in anal canal cancer: a feasibility study.

J Contemp Brachytherapy 2015 Oct 19;7(5):336-45. Epub 2015 Oct 19.

Radiation Oncology Department, Gemelli-ART, Università Cattolica del Sacro Cuore, Rome, Italy.

Purpose: The aim of this study is to test a novel multiparametric imaging guided procedure for high-dose-rate brachytherapy in anal canal cancer, in order to evaluate the feasibility and safety.

Material And Methods: For this analysis, we considered all consecutive patients who underwent magnetic resonance/computed tomography image adapted brachytherapy (MR/CT-IABT) treated from February 2012 to July 2014. To conduct this project, we formed a working group that established the procedure and identified the indicators and benchmarks to evaluate the feasibility and safety. We considered the procedure acceptable if 90% of the indicators were consistent with the benchmarks. Magnetic resonance imaging with contrast and diffusion weighted imaging were performed with an MRI-compatible dummy applicator in the anus to define the position of the clinical target volume disease and biological information. A pre-implantation treatment planning was created in order to get information on the optimal position of the needles. Afterwards, the patient underwent a simulation CT and the definite post-implantation treatment planning was created.

Results: We treated 11 patients (4 men and 7 women) with MR/CT-IABT and we performed a total of 13 procedures. The analysis of indicators for procedure evaluation showed that all indicators were in agreement with the benchmark. The dosimetric analysis resulted in a median of V200, V150, V100, V90, V85, respectively of 24.6%, 53.4%, 93.5%, 97.6%, and 98.7%. The median coverage index (CI) was 0.94, the median dose homogeneity index (DHI) was 0.43, the median dose non-uniformity ratio (DNR) resulted 0.56, the median overdose volume index (ODI) was 0.27. We observed no episodes of common severe acute toxicities.

Conclusions: Brachytherapy is a possible option in anal cancer radiotherapy to perform the boost to complete external beam radiotherapy (EBRT). Magnetic resonance can also have biological advantages compared to the US. Our results suggest that the multiparametric MR/CT-IABT for anal cancer is feasible and safe. This new approach paves the way to prospective comparison studies between MRI and ultrasound-guided brachytherapy (USBT) in anal canal cancer.
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http://dx.doi.org/10.5114/jcb.2015.55118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663214PMC
October 2015

Radiosynthesis and Preliminary Biological Evaluation of [18F]VC701, a Radioligand for Translocator Protein.

Mol Imaging 2015 ;14

Positron emission tomography (PET) can be used to monitor in vivo translocator protein (TSPO) expression by using specific radioligands. Recently, several [11C]PK11195 analogues have been synthesized to improve binding stability and brain availability. [18F]VC701 was synthesized and validated in CD healthy rats by biodistribution and inhibition analysis. Imaging studies were also conducted on animals injected unilaterally in the striatum with quinolinic acid (QA) to evaluate the TSPO ligand uptake in a neuroinflammation/neurodegenerative model. [18F]VC701 was synthesized with a good chemical and radiochemical purity and specific activity higher than 37 GBq/μmol. Kinetic studies performed on healthy animals showed the highest tracer biodistribution in TSPO-rich organs, and preadministration of cold PK11195 caused an overall radioactivity reduction. Metabolism studies showed the absence of radiometabolites in the rat brain of QA lesioned rats, and biodistribution analysis revealed a progressive increase in radioactivity ratios (lesioned to nonlesioned striatum) during time, reaching an approximate value of 5 4 hours after tracer injection. These results encourage further evaluation of this TSPO radioligand in other models of central and peripheral diseases.
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http://dx.doi.org/10.2310/7290.2015.00007DOI Listing
March 2016

Comparison of 18F-fluoroazomycin-arabinofuranoside and 64Cu-diacetyl-bis(N4-methylthiosemicarbazone) in preclinical models of cancer.

J Nucl Med 2013 Jul 22;54(7):1106-12. Epub 2013 May 22.

IBFM-CNR, Segrate, Milan, Italy.

Unlabelled: Hypoxic regions are present in different types of cancer and are a negative prognostic factor for disease progression and response to therapy. (18)F-fluoroazomycin-arabinofuranoside ((18)F-FAZA) and (64)Cu-diacetyl-bis(N4-methylthiosemicarbazone) ((64)Cu-ATSM) have been widely used to visualize hypoxic regions in preclinical and clinical studies. Although both these radioligands have high signal-to-noise ratios, (64)Cu-ATSM may be suitable for use in in vivo imaging and as a radiotherapeutic agent. Despite encouraging results suggesting that it may have a role as a prognostic tracer, (64)Cu-ATSM was recently shown to display cell line-dependent kinetics of oxygen-dependent uptake. We set out to evaluate the kinetics of (64)Cu-ATSM distribution in different cancer models, using (18)F-FAZA as the gold standard.

Methods: (18)F-FAZA and (64)Cu-ATSM uptake were compared ex vivo using dual-tracer autoradiography and in vivo using PET in different xenograft mouse models (FaDu, EMT-6, and PC-3). (18)F-FAZA uptake was compared with (64)Cu-ATSM uptake in PET studies acquired at early (2 h after injection) and delayed time points (24 h after injection). To evaluate the presence of hypoxia and copper pumps, the tumors from animals submitted to PET were harvested and analyzed by an immunohistochemical technique, using antibodies against carbonic anhydrase IX (CAIX) and copper pumps (Ctr1 and ATP7B).

Results: (64)Cu-ATSM showed a higher tumor-to-muscle ratio than did (18)F-FAZA. In the FaDu mouse model, radioactivity distribution profiles were overlapping irrespective of the hypoxic agent injected or the time of (64)Cu acquisition. Conversely, in the EMT-6 and PC-3 models there was little similarity between the early and delayed (64)Cu-ATSM images, and both the radiotracers showed a heterogeneous distribution. The microscopic analysis revealed that (18)F-FAZA-positive areas were also positive for CAIX immunostaining whereas immunolocalization for copper pumps in the 3 models was not related to radioactivity distribution.

Conclusion: The results of this study confirm the cell-dependent distribution and retention kinetics of (64)Cu-ATSM and underline the need for proper validation of animal models and PET acquisition protocols before exploration of any new clinical applications.
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http://dx.doi.org/10.2967/jnumed.112.111120DOI Listing
July 2013

Non-peptide NK1 receptor ligands based on the 4-phenylpyridine moiety.

Bioorg Med Chem 2011 Apr 24;19(7):2242-51. Epub 2011 Feb 24.

Dipartimento Farmaco Chimico Tecnologico and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy.

The quinoline nucleus of the previously described 4-phenylquinoline-3-carboxamides NK(1) receptor ligands 7 has been transformed into either substituted or azole-(i.e., triazole or tetrazole) fused pyridine moieties of compounds 9 and 10, respectively, in order to obtain NK(1) receptor ligands showing lower molecular weight or higher hydrophilicity. The program of molecular manipulations produced NK(1) receptor ligands showing affinity in the nanomolar range. In particular, 4-methyl-1-piperazinyl derivative 9j showed an IC(50) value of 4.8 nM and was proved to behave as a NK(1) antagonist blocking Sar(9)-SP-sulfone induced proliferation and migration of microvascular endothelial cells. Therefore, compound 9j has been labeled with [(11)C]CH(3)I (t(1/2)=20.4 min, β(+)=99.8%) starting from the corresponding des-methyl precursor 9i using with a radiochemical yield of about 10% (not decay corrected) and a specific radioactivity>1 Ci/μmol in order to be used as a radiotracer in next PET studies.
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http://dx.doi.org/10.1016/j.bmc.2011.02.031DOI Listing
April 2011

Automated production of copper radioisotopes and preparation of high specific activity [(64)Cu]Cu-ATSM for PET studies.

Appl Radiat Isot 2010 Jan 25;68(1):5-13. Epub 2009 Aug 25.

Institute of Molecular Bioimaging and Physiology-CNR, University of Milano-Bicocca, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy.

(60)Cu and (64)Cu are useful radioisotopes for positron emission tomography (PET) radiopharmaceuticals and may be used for the preparation of promising agents for diagnosis and radiotherapy. In this study, the production and purification of (60/64)Cu starting from (60/64)Ni using a new automated system, namely Alceo, is described. A dynamic process for electrodeposition and dissolution of (60/64)Ni/(60/64)Cu was developed. Preliminary production yields of (60)Cu and (64)Cu were 400 and 300mCi, respectively. (64)Cu was used to radiolabel the hypoxia detection tracer ATSM with a specific activity of 2.2+/-1.3Ci/micromol.
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http://dx.doi.org/10.1016/j.apradiso.2009.08.010DOI Listing
January 2010

Synthesis and carbon-11 labeling of (R)- and (S)-thionisoxetine, norepinephrine reuptake inhibitors, potential radioligands for positron emission tomography.

Appl Radiat Isot 2007 Nov 26;65(11):1232-9. Epub 2007 Jun 26.

Institute of Molecular Bioimaging and Physiology, CNR, University of Milano-Bicocca, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy.

Standards and des-methyl precursors of (R)- and (S)-thionisoxetine, potent and selective norepinephrine reuptake inhibitors, were synthesized and radiolabeled with carbon-11. Both enantiomers of the N-methyl-3-(2-thiomethylphenoxy)-3-phenylpropanamine and the 3-(2-thiomethylphenoxy)-3-phenylpropylamine were obtained via multi-step syntheses, while the radiosyntheses were carried out using [11C]CH3I. The radiochemical yields were 26%, decay corrected and the specific radioactivity ranging from 2 to 3 Ci/micromol. The HPLC analyses were performed using a chiral column: during the radiolabeling, no racemization occurred and the isomers were synthesized with high enantiomeric purity.
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http://dx.doi.org/10.1016/j.apradiso.2007.06.004DOI Listing
November 2007