Publications by authors named "Roberto Pacelli"

66 Publications

Mastectomy alone for pT1-2 pN0-1 breast cancer patients: when postmastectomy radiotherapy is indicated.

Breast Cancer Res Treat 2021 Apr 27. Epub 2021 Apr 27.

Division of Breast Surgery, IEO European Institute of Oncology, IRCCS, Milan, Italy.

Purpose: To assess outcome of breast cancer (BC) stages pT1-2 N0-1 after mastectomy alone and to identify prognostic factors calling for the need of postmastectomy radiotherapy.

Methods: Patients who were not eligible for breast conserving surgery (BCS) were operated on with mastectomy between 1998 and 2008. Locoregional (LRR), distant (DM) control and breast cancer specific survival (BCSS) were retrospectively evaluated. Cumulative incidence (CI) of events was estimated according to Kalbfleisch and Prentice while Gray's test tested difference. Kaplan-Meier method for survival and Cox proportional hazards model for univariable and multivariable analysis were used. A matched pair analysis between mastectomy alone and BCS plus whole breast irradiation (WBI), using the propensity score method, was performed.

Results: 1281 pT1-2 N0 and 1081 pT1-2 N1 were identified. Median follow-up was 8.2 years (9.2 years for survival). Overall, LRR rate was low for both N0 and N1 subgroups (10-year CI, 8.8% and 10.9%, respectively). Young age, lymphovascular invasion and Ki-67 ≥ 20% were proved to be statistically significant prognostic factors at multivariable analysis. The combination of ≥ 2 risk factors increased LRR rate to ≥ 15%. Risk factors combination weighed on LRR rate more than nodal status itself. DM rate doubled moving from negative to positive nodal status (10-year CI 10.5% versus 20.3%, respectively). BCSS remained high in both N0 and N1 subgroups (10-year CI 92.4% versus 84.5%, respectively). Remarkably, all the molecular subtypes except Luminal A significantly affected DM and BCSS both in the N0 and N1 subgroups. Nodes number significantly impacted on DM and BCSS but not on locoregional control. In the matched pair analysis, WBI decreased nodal recurrence rate and improved distant control, without affecting survival.

Conclusions: Selected patients, namely those with at least two additional risk factors, presented high enough LRR risk to support the use of postmastectomy radiotherapy in both N0 and N1 subgroups. Moreover, the observation that radiotherapy may provide benefits that go beyond local control deserves to be further investigated.
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http://dx.doi.org/10.1007/s10549-021-06227-2DOI Listing
April 2021

New CXCR4 Antagonist Peptide R (Pep R) Improves Standard Therapy in Colorectal Cancer.

Cancers (Basel) 2020 Jul 18;12(7). Epub 2020 Jul 18.

Research Department, Microenvironment Molecular Targets, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", 80131 Napoli, Italy.

The chemokine receptor CXCR4 is overexpressed and functional in colorectal cancer. To investigate the role of CXCR4 antagonism in potentiating colon cancer standard therapy, the new peptide CXCR4 antagonist Peptide R (Pep R) was employed. Human colon cancer HCT116 xenograft-bearing mice were treated with chemotherapeutic agents (CT) 5-Fluorouracil (5FU) and oxaliplatin (OX) or 5FU and radio chemotherapy (RT-CT) in the presence of Pep R. After two weeks, CT plus Pep R reduced by 4-fold the relative tumor volume (RTV) as compared to 2- and 1.6-fold reductions induced, respectively, by CT and Pep R. In vitro Pep R addition to CT/RT-CT impaired HCT116 cell growth and further reduced HCT116 and HT29 clonal capability. Thus, the hypothesis that Pep R could target the epithelial mesenchyme transition (EMT) process was evaluated. While CT decreased ECAD and increased ZEB-1 and CD90 expression, the addition of Pep R restored the pretreatment expression. In HCT116 and HT29 cells, CT/RT-CT induced a population of CD133+CXCR4+ cells, supposedly a stem-resistant cancer cell population, while Pep R reduced it. Taken together, the results showed that targeting CXCR4 ameliorates the effect of treatment in colon cancer through inhibition of cell growth and reversal of EMT treatment-induced markers, supporting further clinical studies.
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http://dx.doi.org/10.3390/cancers12071952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409147PMC
July 2020

Fighting the Host Reaction to SARS-COv-2 in Critically Ill Patients: The Possible Contribution of Off-Label Drugs.

Front Immunol 2020;11:1201. Epub 2020 May 27.

Department of Advanced Biomedical Sciences, School of Medicine, University Federico II, Naples, Italy.

The severe acute respiratory syndrome coronavirus 2 (SARS-COv-2) is the etiologic agent of the 2019 coronavirus disease (COVID19). The majority of infected people presents flu like symptoms and among them 15-20% develops a severe interstitial pneumonitis (IP) that may eventually evolve in acute respiratory distress syndrome (ARDS). IP is caused by the viral glycoprotein spike (S) binding to the angiotensin converting enzyme 2 (ACE2) expressed on the surface of alveolar pneumocytes. The virus is recognized by the "pattern recognition receptors" (PRR) of the immune cells that release cytokines activating more immune cells that produce a large number of pro-inflammatory cytokines, tissue factors and vasoactive peptides. Affected patients might develop the "cytokine storm syndrome," a fulminant and fatal hypercytokinaemia with multiorgan failure. In patients infected by SARS-COv-2 increase in T-helper 2 (TH2) cytokines (IL-4 and IL10) are reported in addition to the T-helper 1 (TH1) cytokines (IL1B, IFNγ, IP10, and MCP1) previously detected in other coronavirus infections. Cytokines and other molecules involved in immune response and inflammation are conceivable therapeutic targets for IP and ARDS, improving symptoms and decreasing intensive care unit admissions. To this aim off label drugs may be used taking into consideration the window timing for immunosuppressive drugs in virus infected patients. Some off label therapeutic options and preclinical evidence drugs are herein considered.
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http://dx.doi.org/10.3389/fimmu.2020.01201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267058PMC
July 2020

COVID-19 outbreak and cancer radiotherapy disruption in Italy: Survey endorsed by the Italian Association of Radiotherapy and Clinical Oncology (AIRO).

Radiother Oncol 2020 08 12;149:89-93. Epub 2020 May 12.

Radiation Oncology Division, Oncology and Speciality Medicine Department, San Camillo-Forlanini Hospital, Roma, Italy; President of AIRO (Italian Association of Radiotherapy and Clinical Oncology), Italy.

Italy experienced one of the world's deadliest COVID-19 outbreaks and healthcare systems had to instantly reorganise activity. The Italian Radiation Oncology Departments adapted numerous solutions to minimize the disruptions. Information technologies, treatment prioritization and implementation of hypofractionation and protection procedures allowed balancing between cancer patient care and patient/healthcare workers safety.
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http://dx.doi.org/10.1016/j.radonc.2020.04.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215158PMC
August 2020

N-Isopentenyladenosine Enhances the Radiosensitivity of Glioblastoma Cells by Inhibiting the Homologous Recombination Repair Protein RAD51 Expression.

Front Oncol 2019 14;9:1498. Epub 2020 Jan 14.

Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II," Naples, Italy.

Glioblastoma is among the most common malignant brain tumors and has a dismal prognosis due to the poor response to therapeutic regimens such as ionizing radiation and DNA-alkylating agents. In our study, we investigated the radiosensitizing activity of the N-isopentenyladenosine (iPA), an naturally modified adenosine harboring an isopenenyl moiety, which shows antiproliferative effects on glioblastoma cell lines. We observed that co-treatment with ionizing radiation and iPA at micromolar concentration inhibited colony formation and viability of glioblastoma cell lines but not of non-malignant human cells. The combined treatment significantly attenuated the repair of radiation-induced DNA damage by inhibiting both the expression and irradiation-induced foci formation of RAD51, a key player in the homologous recombination repair process, leading to persistent DNA damage, as reflected by an increase of γ-H2AX foci. The radiosensitizing effect relied also on the inhibition of STAT5a/b activation, which is crucial for RAD51 expression, suggesting that iPA modulates the STAT5a/b-RAD51 axis following exposure to ionizing radiation. Overall, these data suggest that iPA, by acting through RAD51 inhibition at the mechanistic level, could function as a promising radiosensitizing agent and warrants further evaluation in prospective clinical trials.
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http://dx.doi.org/10.3389/fonc.2019.01498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971108PMC
January 2020

CAF-1 Subunits Levels Suggest Combined Treatments with PARP-Inhibitors and Ionizing Radiation in Advanced HNSCC.

Cancers (Basel) 2019 Oct 17;11(10). Epub 2019 Oct 17.

Department of Advanced Biomedical Sciences, University "Federico II", Surgical Pathology Section, 80131 Naples, Italy.

Oral (OSCC) and oropharyngeal (OPSCC) squamous cell carcinomas show high morbidity and mortality rates. We aimed to investigate the role of the "Chromatin Assembly Factor-1" (CAF-1) p60 and p150 subunits, involved in DNA repair and replication, in OSCC and OPSCC progression and in response to Poly(ADP-ribose) polymerase (PARP)-inhibitors and exposure to ionizing radiation (IR). We immunostained tissue microarrays (TMAs), including 112 OSCC and 42 OPSCC, with anti-CAF-1/p60 and anti-CAF-1/p150 specific antibodies, correlating their expression with prognosis. Moreover, we assessed the sensitivity to PARP inhibitors and the double-strand breaks repair proficiency by cell viability and HR reporter assays, respectively, in HPV-positive and HPV-negative cell lines upon CAF-1/p60 and CAF-1/p150 depletion. The immunohistochemical analysis revealed a significant prognostic value of both tissue biomarkers combined expression in OSCC but not in OPSCC. In in vitro studies, the p60/150 CAF-1 subunits' depletion impaired the proficiency of Homologous Recombination DNA damage repair, inducing sensitivity to the PARP-inhibitors, able to sensitize both the cell lines to IR. These results indicate that regardless of the prognostic meaning of p60/p150 tissue expression, the pharmacological depletion of CAF-1 complex's function, combined to PARP-inhibitors and/or IR treatment, could represent a valid therapeutic strategy for squamous cell carcinomas of head and neck region.
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http://dx.doi.org/10.3390/cancers11101582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827109PMC
October 2019

Normal tissue complication probability (NTCP) models for modern radiation therapy.

Semin Oncol 2019 06 13;46(3):210-218. Epub 2019 Aug 13.

National Research Council, Institute of Biostructures and Bioimaging, Napoli, Italy. Electronic address:

Mathematical models of normal tissue complication probability (NTCP) able to robustly predict radiation-induced morbidities (RIM) play an essential role in the identification of a personalized optimal plan, and represent the key to maximizing the benefits of technological advances in radiation therapy (RT). Most modern RT techniques pose, however, new challenges in estimating the risk of RIM. The aim of this report is to schematically review NTCP models in the framework of advanced radiation therapy techniques. Issues relevant to hypofractionated stereotactic body RT and ion beam therapy are critically reviewed. Reirradiation scenarios for new or recurrent malignances and NTCP are also illustrated. A new phenomenological approach to predict RIM is suggested.
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http://dx.doi.org/10.1053/j.seminoncol.2019.07.006DOI Listing
June 2019

What Is the Cardiac Impact of Chemotherapy and Subsequent Radiotherapy in Lymphoma Patients?

Antioxid Redox Signal 2019 11 23;31(15):1166-1174. Epub 2019 Sep 23.

Department of Translational Medical Sciences, Federico II University, Naples, Italy.

Anthracyclines are widely used in anticancer protocols, but can induce cardiotoxicity by mechanisms that mainly involve oxidative damage and mitochondrial dysfunction. Radiotherapy (RT) can also impair cardiac function by promoting myocardial fibrosis, microvascular damage, and decreased density of myocardial capillaries. Hence, we aim at investigating prospectively whether RT impacts heart function in lymphoma patients who had been already treated with anthracyclines. Twenty-nine consecutive patients with Hodgkin or non-Hodgkin lymphomas underwent echocardiography at baseline (before antineoplastic treatments), and then every 2 months, until 6 months after treatment completion. Echo evaluation included standard two-dimensional and speckle tracking. Twenty-two patients treated with anthracycline-based regimens were eligible. Out of the 22 patients, 8 received chemotherapy (CT) only (subgroup 1), while 14 underwent RT after CT [subgroup 2 (S2)]. At the end of CT, ejection fraction was significantly reduced in the whole population. At 6 months after completion of therapies, E/E' increased and global longitudinal strain was compromised in S2, suggesting additional damage induced by RT after CT. On the basis of the data from our small prospective study, we can hypothesize that in lymphoma patients, anthracyclines can worsen cardiac function, and RT may have an additional unfavorable myocardial impact.
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http://dx.doi.org/10.1089/ars.2019.7842DOI Listing
November 2019

Technological evolution of radiation treatment: Implications for clinical applications.

Semin Oncol 2019 06 30;46(3):193-201. Epub 2019 Jul 30.

Department of Advanced Biomedical Sciences, University "Federico II", Napoli, Italy.

The contemporary approach to the management of a cancer patient requires an "ab initio" involvement of different medical domains in order to correctly design an individual patient's pathway toward cure. With new therapeutic tools in every medical field developing faster than ever before the patient care outcomes can be achieved if all surgical, drug, and radiation options are considered in the design of the appropriate therapeutic strategy for a given patient. Radiation therapy (RT) is a clinical discipline in which experts from different fields continuously interact in order to manage the multistep process of the radiation treatment. RT is found to be an appropriate intervention for diverse indications in about 50% of cancer patients during the course of their disease. Technologies are essential in dealing with the complexity of RT treatments and for driving the increasingly sophisticated RT approaches becoming available for the treatment of Cancer. High conformal techniques, namely intensity modulated or volumetric modulated arc techniques, ablative techniques (Stereotactic Radiotherapy and Stereotactic Radiosurgery), particle therapy (proton or carbon ion therapy) allow for success in treating irregularly shaped or critically located targets and for the sharpness of the dose fall-off outside the target. The advanced on-board imaging, including real-time position management systems, makes possible image-guided radiation treatment that results in substantial margin reduction and, in select cases, implementation of an adaptive approach. The therapeutic gains of modern RT are also due in part to the enhanced anticancer activity obtained by coadministering RT with chemotherapy, targeted molecules, and currently immune checkpoints inhibitors. These main clinically relevant steps forward in Radiation Oncology represent a change of gear in the field that may have a profound impact on the management of cancer patients.
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http://dx.doi.org/10.1053/j.seminoncol.2019.07.004DOI Listing
June 2019

CXCL12 loaded-dermal filler captures CXCR4 expressing melanoma circulating tumor cells.

Cell Death Dis 2019 07 22;10(8):562. Epub 2019 Jul 22.

Functional Genomics, Istituto Nazionale Tumori - IRCCS - Fondazione "G. Pascale", Napoli, Italy.

Development of distant metastasis relies on interactions between cancer and stromal cells. CXCL12, also known as stromal-derived factor 1α (SDF-1α), is a major chemokine constitutively secreted in bone marrow, lymph nodes, liver and lung, playing a critical role in the migration and seeding of neoplastic cells. CXCL12 activates the CXCR4 receptor that is overexpressed in several human cancer cells. Recent evidence reveals that tumors induce pre-metastatic niches in target organ producing tumor-derived factors. Pre-metastatic niches represent a tumor growth-favoring microenvironment in absence of cancer cells. A commercially available dermal filler, hyaluronic acid (HA) -based gel, loaded with CXCL12 (CLG) reproduced a "fake" pre-metastatic niche. In vitro, B16-hCXCR4-GFP, human cxcr4 expressing murine melanoma cells efficiently migrated toward CLG. In vivo, CLGs and empty gels (EGs) were subcutaneously injected into C57BL/6 mice and 5 days later B16-hCXCR4-GFP cells were intravenously inoculated. CLGs were able to recruit a significantly higher number of B16-hCXCR4-GFP cells as compared to EGs, with reduced lung metastasis in mice carrying CLG. CLG were infiltrated by higher number of CD45-positive leukocytes, mainly neutrophils CD11b+Ly6G+ cells, myeloid CD11b+Ly6G- and macrophages F4/80. CLG recovered cells recapitulated the features of B16-hCXCR4-GFP (epithelial, melanin rich, MELAN A/ S100/ c-Kit/CXCR4 pos; α-SMA neg). Thus a HA-based dermal filler loaded with CXCL12 can attract and trap CXCR4+tumor cells. The CLG trapped cells can be recovered and biologically characterized. As a corollary, a reduction in CXCR4 dependent lung metastasis was detected.
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http://dx.doi.org/10.1038/s41419-019-1796-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646345PMC
July 2019

PACE: A Probabilistic Atlas for Normal Tissue Complication Estimation in Radiation Oncology.

Front Oncol 2019 13;9:130. Epub 2019 Mar 13.

Institute of Biostructures and Bioimaging, National Research Council, Naples, Italy.

In radiation oncology, the need for a modern Normal Tissue Complication Probability (NTCP) philosophy to include voxel-based evidence on organ radio-sensitivity (RS) has been acknowledged. Here a new formalism (Probabilistic Atlas for Complication Estimation, PACE) to predict radiation-induced morbidity (RIM) is presented. The adopted strategy basically consists in keeping the structure of a classical, phenomenological NTCP model, such as the Lyman-Kutcher-Burman (LKB), and replacing the dose distribution with a collection of RIM odds, including also significant non-dosimetric covariates, as input of the model framework. The theory was first demonstrated on synthetic dose maps, classified according to synthetic outcomes. PACE was then applied to a clinical dataset of thoracic cancer patients classified for lung fibrosis. LKB models were trained for comparison. Overall, the obtained learning curves showed that the PACE model outperformed the LKB and predicted synthetic outcomes with an accuracy >0.8. On the real patients, PACE performance, evaluated by both discrimination and calibration, was significantly higher than LKB. This trend was confirmed by cross-validation. Furthermore, the capability to infer the spatial pattern of underlying RS map for the analyzed RIM was successfully demonstrated, thus paving the way to new perspectives of NTCP models as learning tools.
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http://dx.doi.org/10.3389/fonc.2019.00130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424876PMC
March 2019

A Novel Small Peptide Inhibitor of NFB, RH10, Blocks Oxidative Stress-Dependent Phenotypes in Cancer.

Oxid Med Cell Longev 2018 4;2018:5801807. Epub 2018 Nov 4.

Department of Advanced Biomedical Sciences, Federico II University, Via Pansini 5, 80131 Naples, Italy.

Background: The RH domain of GRK5 is an effective modulator of cancer growth through the inhibition of NFB activity. The aim of this study was to identify the minimum effective sequence of RH that is still able to inhibit tumor growth and could be used as a peptide-based drug for therapy.

Methods: Starting from the RH sequence, small peptides were cloned and tested in KAT-4 cells. The effects on NFB signaling and its dependent phenotypes were evaluated by Western blot, TUNEL assay, proliferation assay, and angiogenesis . experiments were performed in KAT-4 xenografts in Balb/c nude mice.

Results: A minimum RH ten amino acids long sequence (RH10) was able to interact with IB, to increase IB levels, to induce apoptosis, to inhibit KAT4-cell proliferation, NFB activation, ROS production, and angiogenesis . , the peptide inhibited tumor growth in a dose-dependent manner. We also tested its effects in combination with chemotherapeutic drugs and radiotherapy. RH10 ameliorated the antitumor responses to cisplatin, doxorubicin, and ionizing radiation.

Conclusion: Our data propose RH10 as a potential peptide-based drug to use for cancer treatment both alone or in combination with anticancer therapies.
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http://dx.doi.org/10.1155/2018/5801807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247396PMC
January 2019

Auto- versus human-driven plan in mediastinal Hodgkin lymphoma radiation treatment.

Radiat Oncol 2018 Oct 19;13(1):202. Epub 2018 Oct 19.

National Research Council, Institute of Biostructures and Bioimaging, Naples, Italy.

Background: Technological advances in Hodgkin lymphoma (HL) radiation therapy (RT) by high conformal treatments potentially increase control over organs-at-risk (OARs) dose distribution. However, plan optimization remains a time-consuming task with great operator dependent variability. Purpose of the present study was to devise a fully automated pipeline based on the Pinnacle Auto-Planning (AP) algorithm for treating female supradiaphragmatic HL (SHL) patients.

Methods: CT-scans of 10 female patients with SHL were considered. A "butterfly" (BF) volumetric modulated arc therapy was optimized using SmartArc module integrated in Pinnacle v. 9.10 using Collapsed Cone Convolution Superposition algorithm (30 Gy in 20 fractions). Human-driven (Manual-BF) and AP-BF optimization plans were generated. For AP, an optimization objective list of Planning Target Volume (PTV)/OAR clinical goals was first implemented, starting from a subset of 5 patients used for algorithm training. This list was then tested on the remaining 5 patients (validation set). In addition to the BF technique, the AP engine was applied to a 2 coplanar disjointed arc (AP-ARC) technique using the same objective list. For plan evaluation, dose-volume-histograms of PTVs and OARs were extracted; homogeneity and conformity indices (HI and CI), OARs dose-volume metrics and odds for different toxicity endpoints were computed. Non-parametric Friedman and Dunn tests were used to identify significant differences between groups.

Results: A single AP objective list for SHL was obtained. Compared to the manual plan, both AP-plans offer comparable CIs while AP-ARC also achieved comparable HIs. All plans fulfilled the clinical dose criteria set for OARs: both AP solutions performed at least as good as Manual-BF plan. In particular, AP-ARC outperformed AP-BF in terms of heart sparing involving a lower risk of coronary events and radiation-induced lung fibrosis. Hands-on planning time decreased by a factor of 10 using AP on average.

Conclusions: Despite the high interpatient PTV (size and position) variability, it was possible to set a standard SHL AP optimization list with a high level of generalizability. Using the implemented list, the AP module was able to limit OAR doses, producing clinically acceptable plans with stable quality without additional user input. Overall, the AP engine associated to the arc technique represents the best option for SHL.
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http://dx.doi.org/10.1186/s13014-018-1146-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194601PMC
October 2018

Predictors of Hypothyroidism in Hodgkin Lymphoma Survivors After Intensity Modulated Versus 3-Dimensional Radiation Therapy.

Int J Radiat Oncol Biol Phys 2018 07 14;101(3):530-540. Epub 2018 Mar 14.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: To identify predictors of hypothyroidism after chemoradiation therapy for Hodgkin lymphoma (HL) and to compare outcomes after intensity modulated radiation therapy (IMRT) with those after 3-dimensional (3D) conformal radiation therapy (CRT).

Methods And Materials: Ninety patients who underwent involved-site IMRT in 2009 through 2014 were evaluated for treatment-induced hypothyroidism, defined as elevated thyroid-stimulating hormone or decreased free thyroxine levels (or both). Receiver operating characteristic curve analysis identified individuals at low versus high risk based on dosimetric variables. Dosimetric cutoff points were verified with an external data set of 50 patients who underwent 3D-CRT.

Results: In the IMRT group, most patients (75 [83%]) had stage II HL, and the median prescribed dose was 30.6 Gy; in the 3D-CRT group, 32 patients (64%) had stage II HL, and the median prescribed dose was 32.0 Gy. No differences were found in the proportions of patients with bilateral (P = .982) or unilateral (P = .074) neck involvement between the 2 groups. Hypothyroidism rates were marginally higher in the IMRT group, with estimated 3-year rates of freedom from hypothyroidism of 56.1% in the 3D-CRT group and 40% in the IMRT group (P = .057). Univariate analysis showed that smaller thyroid volume and higher thyroid dose were associated with hypothyroidism in both groups (P < .05). In the IMRT group, the percentage of the thyroid gland volume receiving ≥25 Gy (V25) and the absolute volume of the thyroid gland spared from 25 Gy (VS25Gy) were the strongest predictors of hypothyroidism (P = .001 and P < .001, respectively). Cutoff points of 63.5% (V25) and 2.2 mL (VS25Gy) classified patients as high risk (80%-82%) or low risk (37%-44%) (P < .001). Use of a thyroid avoidance structure reduced the incidence of hypothyroidism (P < .05) in the IMRT group.

Conclusions: The percentage of the thyroid receiving 25 Gy and the volume of the thyroid spared from 25 Gy predicted the risk of hypothyroidism after either IMRT or 3D-CRT for HL. IMRT may confer a higher risk than 3D-CRT unless a treatment avoidance structure is used during planning.
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http://dx.doi.org/10.1016/j.ijrobp.2018.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189963PMC
July 2018

Engineering of thermoresponsive gels as a fake metastatic niche.

Carbohydr Polym 2018 Jul 10;191:112-118. Epub 2018 Mar 10.

Department of Pharmacy, Università di Napoli Federico II, Via D. Montesano 49, 80131, Naples, Italy. Electronic address:

Chemoattraction through the CXCR4-CXCL12 axis has been shown to be an important mechanism to direct circulating tumor cells toward distant sites. The objective of this work was to prepare a fake metastatic niche made up of a gel loaded with CXCL12. The gel is designed to create a steep concentration gradient of the chemokine in the proximity of the site of administration/injection, aimed to divert and capture circulating CXCR4 tumor cells. To this aim, different thermoresponsive gels based on methylcellulose (MC) or poloxamers, loaded with CXCL12, with or without hyaluronic acid (HA) were designed and their mechanical properties correlated with the ability to attract and capture in vitro CXCR4 cells. Results of in vitro cell studies showed that all prepared gels induced CEM tumor cell migration whereas only gels based on MC embedded with CXCL12 are able to capture them.
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http://dx.doi.org/10.1016/j.carbpol.2018.03.016DOI Listing
July 2018

Inter-patient image registration algorithms to disentangle regional dose bioeffects.

Sci Rep 2018 03 20;8(1):4915. Epub 2018 Mar 20.

Institute of Biostructures and Bioimaging, National Research Council, Napoli, Italy.

Radiation therapy (RT) technological advances call for a comprehensive reconsideration of the definition of dose features leading to radiation induced morbidity (RIM). In this context, the voxel-based approach (VBA) to dose distribution analysis in RT offers a radically new philosophy to evaluate local dose response patterns, as an alternative to dose-volume-histograms for identifying dose sensitive regions of normal tissue. The VBA relies on mapping patient dose distributions into a single reference case anatomy which serves as anchor for local dosimetric evaluations. The inter-patient elastic image registrations (EIRs) of the planning CTs provide the deformation fields necessary for the actual warp of dose distributions. In this study we assessed the impact of EIR on the VBA results in thoracic patients by identifying two state-of-the-art EIR algorithms (Demons and B-Spline). Our analysis demonstrated that both the EIR algorithms may be successfully used to highlight subregions with dose differences associated with RIM that substantially overlap. Furthermore, the inclusion for the first time of covariates within a dosimetric statistical model that faces the multiple comparison problem expands the potential of VBA, thus paving the way to a reliable voxel-based analysis of RIM in datasets with strong correlation of the outcome with non-dosimetric variables.
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http://dx.doi.org/10.1038/s41598-018-23327-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861107PMC
March 2018

GRK2 moderates the acute mitochondrial damage to ionizing radiation exposure by promoting mitochondrial fission/fusion.

Cell Death Discov 2018 Dec 14;4:25. Epub 2018 Feb 14.

3Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy.

The modern understanding of the G protein-coupled receptor kinase 2 has grown towards the definition of a stress protein, for its ability to rapidly compartmentalize within the cell in response to acute stimulation. Also, mitochondria can be regulated by GRK2 localization. We show that Ionizing Radiation (IR) exposure acutely damages mitochondria regarding mass, morphology, and respiration, with recovery in a framework of hours. This phenomenon is actively regulated by GRK2, whose overexpression results to be protective, and reciprocally, deletion accelerates degenerative processes. The regulatory effects of the kinase involve a new interactome that includes binding HSP90 and binding and phosphorylation of the key molecules involved in the process of mitochondrial fusion and recovery: MFN-1 and 2.
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http://dx.doi.org/10.1038/s41420-018-0028-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841414PMC
December 2018

Predictive immune biomarkers: an unattainable chimera?

Cell Mol Immunol 2018 08 5;15(8):740-742. Epub 2018 Feb 5.

Functional Genomics, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione 'G. Pascale' Via Semmola, Naples, Italy.

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http://dx.doi.org/10.1038/cmi.2017.162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141568PMC
August 2018

Ionizing Radiation Deregulates the MicroRNA Expression Profile in Differentiated Thyroid Cells.

Thyroid 2018 03;28(3):407-421

1 Istituto di Endocrinologia ed Oncologia Sperimentale-CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II," Naples, Italy .

Background: Ionizing radiation (IR) is a well-known risk factor for papillary thyroid cancer, and it has been reported to deregulate microRNA expression, which is important to thyroid carcinogenesis. Therefore, this study investigated the impact of IR on microRNA expression profile of the normal thyroid cell line (FRTL-5 CL2), as well as its effect on radiosensitivity of thyroid cancer cell lines, especially the human anaplastic thyroid carcinoma cell line (8505c).

Methods: The global microRNA expression profile of irradiated FRTL-5 CL2 cells (5 Gy X-ray) was characterized, and data were confirmed by quantitative real-time polymerase chain reaction evaluating the expression of rno-miR-10b-5p, rno-miR-33-5p, rno-miR-128-1-5p, rno-miR-199a-3p, rno-miR-296-5p, rno-miR-328a-3p, and rno-miR-541-5p in irradiated cells. The miR-199a-3p and miR-10b-5p targets were validated by quantitative real-time polymerase chain reaction, Western blot, and luciferase target assays. The effects of miR-199a-3p and miR-10b-5p on DNA repair were determined by evaluating the activation of the protein kinases ataxia-telangiectasia mutated, ataxia telangiectasia, and Rad3-related and the serine 39 phosphorylation of variant histone H2AX as an indirect measure of double-strand DNA breaks in irradiated FRTL-5 CL2 cells. The impact of miR-10b-5p on radiosensitivity was analyzed by cell counting and MTT assays in FRTL-5 CL2, Kras-transformed FRTL-5 CL2 (FRTL KiKi), and 8505c cell lines.

Results: The results reveal that miR-10b-5p and miR-199a-3p display the most pronounced alterations in expression in irradiated FRTL-5 CL2 cells. Dicer1 and Lin28b were validated as targets of miR-10b-5p and miR-199a-3p, respectively. Functional studies demonstrate that miR-10b-5p increases the growth rate of FRTL-5 CL2 cells, while miR-199a-3p inhibits their proliferation. Moreover, both of these microRNAs negatively affect homologous recombination repair, reducing activated ataxia-telangiectasia mutated and Rad3-related protein levels, consequently leading to an accumulation of the serine 39 phosphorylation of variant histone H2AX. Interestingly, the overexpression of miR-10b-5p decreases the viability of the irradiated FRTL5-CL2 and 8505c cell lines. Consistent with this observation, its inhibition in FRTL KiKi cells, which display high basal expression levels of miR-10b-5p, leads to the opposite effect.

Conclusions: These results demonstrate that IR deregulates microRNA expression, affecting the double-strand DNA breaks repair efficiency of irradiated thyroid cells, and suggest that miR-10b-5p overexpression may be an innovative approach for anaplastic thyroid cancer therapy by increasing cancer cell radiosensitivity.
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http://dx.doi.org/10.1089/thy.2017.0458DOI Listing
March 2018

A regulatory role for the co-chaperone FKBP51s in PD-L1 expression in glioma.

Oncotarget 2017 Sep 17;8(40):68291-68304. Epub 2017 Jul 17.

Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Naples, Italy.

Background: FKBP51 is a co-chaperone with isomerase activity, abundantly expressed in glioma. We previously identified a spliced isoform (FKBP51s) and highlighted a role for this protein in the upregulation of Programmed Death Ligand 1 (PD-L1) expression in melanoma. Because gliomas can express PD-L1 causing a defective host anti-tumoral immunity, we investigated whether FKBP51s was expressed in glioma and played a role in PD-L1 regulation in this tumour.

Methods: We used D54 and U251 glioblastoma cell lines that constitutively expressed PD-L1. FKBP51s was measured by immunoblot, flow cytometry and microscopy. In patient tumours, IHC and qPCR were used to measure protein and mRNA levels respectively. FKBP51s depletion was achieved by siRNAs, and its enzymatic function was inhibited using selective inhibitors (SAFit). We investigated protein maturation using N-glycosidase and cell fractionation approaches.

Results: FKBP51s was expressed at high levels in glioma cells. Glycosylated-PD-L1 was increased and reduced by FKBP51s overexpression or silencing, respectively. Naïve PD-L1 was found in the endoplasmic reticulum (ER) of glioma cells complexed with FKBP51s, whereas the glycosylated form was measured in the Golgi apparatus. SAFit reduced PD-L1 levels (constitutively expressed and ionizing radiation-induced). SAFit reduced cell death of PBMC co-cultured with glioma.

Conclusions: Here we addressed the mechanism of post-translational regulation of PD-L1 protein in glioma. FKBP51s upregulated PD-L1 expression on the plasma membrane by catalysing the protein folding required for subsequent glycosylation. Inhibition of FKBP51s isomerase activity by SAFit decreased PD-L1 levels. These findings suggest that FKBP51s is a potential target of immunomodulatory strategies for glioblastoma treatment.
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http://dx.doi.org/10.18632/oncotarget.19309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620257PMC
September 2017

Voxel-based analysis unveils regional dose differences associated with radiation-induced morbidity in head and neck cancer patients.

Sci Rep 2017 08 3;7(1):7220. Epub 2017 Aug 3.

Institute of Biostructures and Bioimaging, National Research Council (CNR), Naples, Italy.

The risk of radiation-induced toxicity in patients treated for head and neck (HN) cancer with radiation therapy (RT) is traditionally estimated by condensing the 3D dose distribution into a monodimensional cumulative dose-volume histogram which disregards information on dose localization. We hypothesized that a voxel-based approach would identify correlations between radiation-induced morbidity and local dose release, thus providing a new insight into spatial signature of radiation sensitivity in composite regions like the HN district. This methodology was applied to a cohort of HN cancer patients treated with RT at risk of radiation-induced acute dysphagia (RIAD). We implemented an inter-patient elastic image registration framework that proved robust enough to match even the most elusive HN structures and to provide accurate dose warping. A voxel-based statistical analysis was then performed to test regional dosimetric differences between patients with and without RIAD. We identified a significantly higher dose delivered to RIAD patients in two voxel clusters in correspondence of the cricopharyngeus muscle and cervical esophagus. Our study goes beyond the well-established organ-based philosophy exploring the relationship between radiation-induced morbidity and local dose differences in the HN region. This approach is generally applicable to different HN toxicity endpoints and is not specific to RIAD.
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http://dx.doi.org/10.1038/s41598-017-07586-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543173PMC
August 2017

Locally advanced paranasal sinus carcinoma: A study of 30 patients.

Oncol Lett 2017 Mar 11;13(3):1338-1342. Epub 2017 Jan 11.

Institute of Biostructure and Bioimaging, National Council of Research, I-80128 Naples, Italy.

Sinonasal carcinomas (SNcs) are rare neoplasms arising from the paranasal sinuses and nasal cavity. Although these tumours have a heterogeneous histology, they are commonly diagnosed as a locally advanced disease and are associated with a poor prognosis. The present retrospective study reviewed 30 patients with locally advanced SNc, who were treated with surgery followed by chemoradiotherapy or radiotherapy, or radiotherapy with or without concomitant chemotherapy between January 1999 and January 2013 at the Department of Radiation Therapy, University of Naples 'Federico II' (Naples, Italy). A total of 19 patients were treated with upfront surgery followed by adjuvant radio- or chemoradiotherapy (group A), while the remaining 11 patients received exclusive radiotherapy with or without concomitant chemotherapy (group B). Concurrent cisplatin-based chemotherapy (100 mg/m, days 1, 22 and 43 for 3 cycles) was administered to 34% of patients in group A and 55% of patients in group B. At a median follow-up of 31 months, 33.3% of patients were alive. Cause-specific survival (CSS) and progression-free survival (PFS) times were 32 and 12 months, respectively. No difference in CSS rate was observed between the two treatment groups. Univariate analysis determined that disease stage was the only factor that significantly affected CSS (P=0.002) and PFS (P=0.0001) rates. Acute and chronic toxicities were mild, with only 23.3% of patients reporting G1-2 side effects and no treatment-related blindness. The present study reported moderate activity and efficacy of surgery followed by adjuvant radio- or chemoradiotherapy, and exclusive radiotherapy with or without chemotherapy in this poor prognosis category of patients.
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http://dx.doi.org/10.3892/ol.2017.5598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403341PMC
March 2017

Model-based approach for quantitative estimates of skin, heart, and lung toxicity risk for left-side photon and proton irradiation after breast-conserving surgery.

Acta Oncol 2017 May 10;56(5):730-736. Epub 2017 Mar 10.

e Department of Advanced Biomedical Sciences , Federico II University School of Medicine , Naples , Italy.

Background: Proton beam therapy represents a promising modality for left-side breast cancer (BC) treatment, but concerns have been raised about skin toxicity and poor cosmesis. The aim of this study is to apply skin normal tissue complication probability (NTCP) model for intensity modulated proton therapy (IMPT) optimization in left-side BC.

Material And Methods: Ten left-side BC patients undergoing photon irradiation after breast-conserving surgery were randomly selected from our clinical database. Intensity modulated photon (IMRT) and IMPT plans were calculated with iso-tumor-coverage criteria and according to RTOG 1005 guidelines. Proton plans were computed with and without skin optimization. Published NTCP models were employed to estimate the risk of different toxicity endpoints for skin, lung, heart and its substructures.

Results: Acute skin NTCP evaluation suggests a lower toxicity level with IMPT compared to IMRT when the skin is included in proton optimization strategy (0.1% versus 1.7%, p < 0.001). Dosimetric results show that, with the same level of tumor coverage, IMPT attains significant heart and lung dose sparing compared with IMRT. By NTCP model-based analysis, an overall reduction in the cardiopulmonary toxicity risk prediction can be observed for all IMPT compared to IMRT plans: the relative risk reduction from protons varies between 0.1 and 0.7 depending on the considered toxicity endpoint.

Conclusions: Our analysis suggests that IMPT might be safely applied without increasing the risk of severe acute radiation induced skin toxicity. The quantitative risk estimates also support the potential clinical benefits of IMPT for left-side BC irradiation due to lower risk of cardiac and pulmonary morbidity. The applied approach might be relevant on the long term for the setup of cost-effectiveness evaluation strategies based on NTCP predictions.
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http://dx.doi.org/10.1080/0284186X.2017.1299218DOI Listing
May 2017

CXCR4-CXCL12-CXCR7, TLR2-TLR4, and PD-1/PD-L1 in colorectal cancer liver metastases from neoadjuvant-treated patients.

Oncoimmunology 2016;5(12):e1254313. Epub 2016 Nov 29.

Functional Genomics Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy.

A neoadjuvant clinical trial was previously conducted in patients with resectable colorectal cancer liver metastases (CRLM). At a median follow up of 28 months, 20/33 patients were dead of disease, 8 were alive with disease and 5 were alive with no evidence of disease. To shed further insight into biological features accounting for different outcomes, the expression of CXCR4-CXCL12-CXCR7, TLR2-TLR4, and the programmed death receptor-1 (PD-1)/programmed death-1 ligand (PD-L1) was evaluated in excised liver metastases. Expression profiles were assessed through qPCR in metastatic and unaffected liver tissue of 33 CRLM neoadjuvant-treated patients. CXCR4 and CXCR7, TLR2/TLR4, and PD-1/PD-L1 mRNA were significantly overexpressed in metastatic compared to unaffected liver tissues. CXCR4 protein was negative/low in 10/31, and high in 21/31, CXCR7 was negative/low in 16/31 and high in 15/31, CXCL12 was negative/low in 14/31 and high in 17/31 CRLM. PD-1 was negative in 19/30 and positive in 11/30, PD-L1 was negative/low in 24/30 and high in 6/30 CRLM. Stromal PD-L1 expression, affected the progression-free survival (PFS) in the CRLM population. Patients overexpressing CXCR4 experienced a worse PFS and cancer specific survival (CSS) ( = 0.001 and = 0.0008); in these patients, KRAS mutation identified a subgroup with a significantly worse CSS ( < 0.01). Thus, CXCR4 and PD-L1 expression discriminate patients with the worse PFS within the CRLM evaluated patients. Within the CXCR4 high expressing patients carrying Mut-KRAS in CRLM identifies the worst prognostic group. Thus, CXCR4 targeting plus anti-PD-1 therapy should be explored to improve the prognosis of Mut-KRAS-high CXCR4-CRLMs.
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http://dx.doi.org/10.1080/2162402X.2016.1254313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5214751PMC
November 2016

A Voxel-Based Approach to Explore Local Dose Differences Associated With Radiation-Induced Lung Damage.

Int J Radiat Oncol Biol Phys 2016 09 7;96(1):127-33. Epub 2016 May 7.

Institute of Biostructure and Bioimaging, National Research Council, Naples, Italy. Electronic address:

Purpose: To apply a voxel-based (VB) approach aimed at exploring local dose differences associated with late radiation-induced lung damage (RILD).

Methods And Materials: An interinstitutional database of 98 patients who were Hodgkin lymphoma (HL) survivors treated with postchemotherapy supradiaphragmatic radiation therapy was analyzed in the study. Eighteen patients experienced late RILD, classified according to the Radiation Therapy Oncology Group scoring system. Each patient's computed tomographic (CT) scan was normalized to a single reference case anatomy (common coordinate system, CCS) through a log-diffeomorphic approach. The obtained deformation fields were used to map the dose of each patient into the CCS. The coregistration robustness and the dose mapping accuracy were evaluated by geometric and dose scores. Two different statistical mapping schemes for nonparametric multiple permutation inference on dose maps were applied, and the corresponding P<.05 significance lung subregions were generated. A receiver operating characteristic (ROC)-based test was performed on the mean dose extracted from each subregion.

Results: The coregistration process resulted in a geometrically robust and accurate dose warping. A significantly higher dose was consistently delivered to RILD patients in voxel clusters near the peripheral medial-basal portion of the lungs. The area under the ROC curves (AUC) from the mean dose of the voxel clusters was higher than the corresponding AUC derived from the total lung mean dose.

Conclusions: We implemented a framework including a robust registration process and a VB approach accounting for the multiple comparison problem in dose-response modeling, and applied it to a cohort of HL survivors to explore a local dose-RILD relationship in the lungs. Patients with RILD received a significantly greater dose in parenchymal regions where low doses (∼6 Gy) were delivered. Interestingly, the relation between differences in the high-dose range and RILD seems to lack a clear spatial signature.
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http://dx.doi.org/10.1016/j.ijrobp.2016.04.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533285PMC
September 2016

Dose-surface analysis for prediction of severe acute radio-induced skin toxicity in breast cancer patients.

Acta Oncol 2016 1;55(4):466-73. Epub 2015 Dec 1.

a Department of Advanced Biomedical Sciences , Federico II University School of Medicine , Naples , Italy ;

Background: Severe acute radiation-induced skin toxicity (RIST) after breast irradiation is a side effect impacting the quality of life in breast cancer (BC) patients. The aim of the present study was to develop normal tissue complication probability (NTCP) models of severe acute RIST in BC patients.

Patients And Methods: We evaluated 140 consecutive BC patients undergoing conventional three-dimensional conformal radiotherapy (3D-CRT) after breast conserving surgery in a prospective study assessing acute RIST. The acute RIST was classified according to the RTOG scoring system. Dose-surface histograms (DSHs) of the body structure in the breast region were extracted as representative of skin irradiation. Patient, disease, and treatment-related characteristics were analyzed along with DSHs. NTCP modeling by Lyman-Kutcher-Burman (LKB) and by multivariate logistic regression using bootstrap resampling techniques was performed. Models were evaluated by Spearman's Rs coefficient and ROC area.

Results: By the end of radiotherapy, 139 (99%) patients developed any degree of acute RIST. G3 RIST was found in 11 of 140 (8%) patients. Mild-moderate (G1-G2) RIST was still present at 40 days after treatment in six (4%) patients. Using DSHs for LKB modeling of acute RIST severity (RTOG G3 vs. G0-2), parameter estimates were TD50=39 Gy, n=0.38 and m=0.14 [Rs = 0.25, area under the curve (AUC) = 0.77, p = 0.003]. On multivariate analysis, the most predictive model of acute RIST severity was a two-variable model including the skin receiving ≥30 Gy (S30) and psoriasis [Rs = 0.32, AUC = 0.84, p < 0.001].

Conclusions: Using body DSH as representative of skin dose, the LKB n parameter was consistent with a surface effect for the skin. A good prediction performance was obtained using a data-driven multivariate model including S30 and a pre-existing skin disease (psoriasis) as a clinical factor.
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http://dx.doi.org/10.3109/0284186X.2015.1110253DOI Listing
December 2016

Modeling the risk of radiation-induced lung fibrosis: Irradiated heart tissue is as important as irradiated lung.

Radiother Oncol 2015 Oct 12;117(1):36-43. Epub 2015 Aug 12.

Institute of Biostructure and Bioimaging, National Research Council (CNR), Naples, Italy; Department of Advanced Biomedical Sciences, Federico II University School of Medicine, Naples, Italy.

Purpose: We used normal tissue complication probability (NTCP) modeling to explore the impact of heart irradiation on radiation-induced lung fibrosis (RILF).

Materials And Methods: We retrospectively reviewed for RILF 148 consecutive Hodgkin lymphoma (HL) patients treated with sequential chemo-radiotherapy (CHT-RT). Left, right, total lung and heart dose-volume and dose-mass parameters along with clinical, disease and treatment-related characteristics were analyzed. NTCP modeling by multivariate logistic regression analysis using bootstrapping was performed. Models were evaluated by Spearman Rs coefficient and ROC area.

Results: At a median time of 13months, 18 out of 115 analyzable patients (15.6%) developed RILF after treatment. A three-variable predictive model resulted to be optimal for RILF. The two models most frequently selected by bootstrap included increasing age and mass of heart receiving >30Gy as common predictors, in combination with left lung V5 (Rs=0.35, AUC=0.78), or alternatively, the lungs near maximum dose D2% (Rs=0.38, AUC=0.80).

Conclusion: CHT-RT may cause lung injury in a small, but significant fraction of HL patients. Our results suggest that aging along with both heart and lung irradiation plays a fundamental role in the risk of developing RILF.
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http://dx.doi.org/10.1016/j.radonc.2015.07.051DOI Listing
October 2015

Adjuvant treatment in patients at high risk of recurrence of thymoma: efficacy and safety of a three-dimensional conformal radiation therapy regimen.

Onco Targets Ther 2015 8;8:1345-9. Epub 2015 Jun 8.

Department of Radiotherapy, Istituto Nazionale per la Cura dei Tumori-Fondazione G. Pascale. IRCCS di Napoli, Naples, Italy.

Background: The clinical benefits of postoperative radiation therapy (PORT) for patients with thymoma are still controversial. In the absence of defined guidelines, prognostic factors such as stage, status of surgical margins, and histology are often considered to guide the choice of adjuvant treatment (radiotherapy and/or chemotherapy). In this study, we describe our single-institution experience of three-dimensional conformal PORT administered as adjuvant treatment to patients with thymoma.

Methods: Twenty-two consecutive thymoma patients (eleven male and eleven female) with a median age of 52 years and treated at our institution by PORT were analyzed. The patients were considered at high risk of recurrence, having at least one of the following features: stage IIB or III, involved resection margins, or thymic carcinoma histology. Three-dimensional conformal PORT with a median total dose on clinical target volume of 50 (range 44-60) Gy was delivered to the tumor bed by 6-20 MV X-ray of the linear accelerator. Follow-up after radiotherapy was done by computed tomography scan every 6 months for 2 years and yearly thereafter.

Results: Two of the 22 patients developed local recurrence and four developed distant metastases. Median overall survival was 100 months, and the 3-year and 5-year survival rates were 83% and 74%, respectively. Median disease-free survival was 90 months, and the 5-year recurrence rate was 32%. On univariate analysis, pathologic stage III and presence of positive surgical margins had a significant impact on patient prognosis. Radiation toxicity was mild in most patients and no severe toxicity was registered.

Conclusion: Adjuvant radiotherapy achieved good local control and showed an acceptable toxicity profile in patients with high-risk thymoma.
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http://dx.doi.org/10.2147/OTT.S75232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467740PMC
June 2015

Prediction of gastrointestinal toxicity after external beam radiotherapy for localized prostate cancer.

Radiat Oncol 2015 Apr 8;10:80. Epub 2015 Apr 8.

Institute of Biostructure and Bioimaging, National Council of Research (CNR), Naples, Italy.

Background: Gastrointestinal (GI) toxicity is a common effect following radiation therapy (RT) for prostate cancer. Purpose of the present work is to compare two Normal Tissue Complication Probability (NTCP) modelling approaches for prediction of late radio-induced GI toxicity after prostate external beam radiotherapy.

Methods: The study includes 84 prostate cancer patients evaluated for late rectal toxicity after 3D conformal radiotherapy. Median age was 72 years (range 53-85). All patients received a total dose of 76 Gy to the prostate gland with daily fractions of 2 Gy. The acute and late radio-induced GI complications were classified according to the RTOG/EORTC scoring system. Rectum dose-volume histograms were extracted for Lyman-Kutcher-Burman (LKB) NTCP model fitting using Maximum Likelihood Estimation. The bootstrap method was employed to test the fit robustness. The area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive power of the LKB and to compare it with a multivariate logistic NTCP model previously determined.

Results: At a median follow-up of 36 months, 42% (35/84) of patients experienced grade 1-2 (G1-2) acute GI events while 25% (21/84) of patients developed G1-2 late GI events. The best-estimate of fitting parameters for LKB NTCP model for mild\moderate GI toxicity resulted to be: D 50  = 87.3 Gy, m = 0.37 and n = 0.10. Bootstrap result showed that the parameter fit was robust. The AUC values for the LKB and for the multivariate logistic models were 0.60 and 0.75, respectively.

Conclusions: We derived the parameters of the LKB model for mild\moderate GI toxicity prediction and we compared its performance with that of a data-driven multivariate model. Compared to LKB, the multivariate model confirmed a higher predictive power as showed by the AUC values.
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http://dx.doi.org/10.1186/s13014-015-0389-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404272PMC
April 2015