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Deep learning models based on medical images play an increasingly important role for cancer outcome prediction. The standard approach involves usage of convolutional neural networks (CNNs) to automatically extract relevant features from the patient's image and perform a binary classification of the occurrence of a given clinical endpoint. In this work, a 2D-CNN and a 3D-CNN for the binary classification of distant metastasis (DM) occurrence in head and neck cancer patients were extended to perform time-to-event analysis. The newly built CNNs incorporate censoring information and output DM-free probability curves as a function of time for every patient. In total, 1037 patients were used to build and assess the performance of the time-to-event model. Training and validation was based on 294 patients also used in a previous benchmark classification study while for testing 743 patients from three independent cohorts were used. The best network could reproduce the good results from 3-fold cross validation [Harrell's concordance indices (HCIs) of 0.78, 0.74 and 0.80] in two out of three testing cohorts (HCIs of 0.88, 0.67 and 0.77). Additionally, the capability of the models for patient stratification into high and low-risk groups was investigated, the CNNs being able to significantly stratify all three testing cohorts. Results suggest that image-based deep learning models show good reliability for DM time-to-event analysis and could be used for treatment personalisation.

Many different therapeutic options are available for locally recurrent prostate cancer (PCa). However, standard treatment has not yet been established. We conducted a partial prostate re-irradiation (PPR) program for the treatment of isolated and limited-size intraprostatic recurrences, in patients who previously underwent external beam radiation therapy (EBRT) as primary treatment for prostatic cancer (PCa). The analysis of this experience in terms of feasibility, toxicity, and efficacy is reported. The inclusion criteria of this retrospective analysis were: previous definitive EBRT, evidence of biochemical recurrence, radiological detection of isolated local relapse, and PPR as local salvage therapy. Gastrointestinal (GI) and genitourinary (GU) toxicities were registered according to the RTOG/EORTC criteria. Between July 2012 and May 2019, 44 patients were treated with PPR. All patients completed the planned treatment. The median follow-up was 25.4 months. Tumor progression was observed in 18 patients (40.9%). Two-year local control, biochemical failure-, and clinical relapse-free survival rates were 90.1%, 58.3%, and 67.9%, respectively. The occurrence of biochemical failure after PPR is lower for patients with the time interval between the primary EBRT and first biochemical failure >4 years; local control results strongly associated with a biologically effective dose (BED) at first EBRT >177 Gy. No acute grade 3 or greater toxic events were observed. Two late grade 3 GU toxicities were reported. Although retrospective in design, our study indicates that PPR appears as a feasible, well-tolerated, and effective salvage treatment for isolated local PCa recurrence. Long term data are required in order to confirm these results.

Bone involvement in Hodgkin lymphoma (HL) is rare. The differential diagnosis between HL bone localization and other malignant or benign skeletal diseases is challenging. We report the case of a girl affected by classic HL, initially staged IVA because of supradiaphragmatic lymph nodes and skeletal involvement. After 6 ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) cycles, positron emission tomography (PET) showed a complete metabolic response of the nodal localizations and a persistent, high metabolic activity of bone lesions. Salvage treatment followed by autologous stem cell transplant was carried out. After the transplant, the bone lesions maintained a high metabolic activity at PET. A targeted bone biopsy led to the diagnosis of a fibrous dysplasia excluding the presence of HL. To our knowledge, the concomitant presence of HL and fibrous dysplasia has not been previously reported. An in-depth evaluation of disease response to frontline treatment with a biopsy of the PET-hypercaptant bone lesions could have avoided overtreatment in this patient., (© 2020 S. Karger AG, Basel.)

Lung malignancies have been extensively characterized through radiomics and deep learning. By providing a three-dimensional characterization of the lesion, models based on radiomic features from computed tomography (CT) and positron-emission tomography (PET) have been developed to detect nodules, distinguish malignant from benign lesions, characterize their histology, stage, and genotype. Deep learning models have been applied to automatically segment organs at risk in lung cancer radiotherapy, stratify patients according to the risk for local and distant recurrence, and identify patients candidate for molecular targeted therapy and immunotherapy. Moreover, radiomics has also been applied successfully to predict side effects such as radiation- and immunotherapy-induced pneumonitis and differentiate lung injury from recurrence. Radiomics could also untap the potential for further use of the cone beam CT acquired for treatment image guidance, four-dimensional CT, and dose-volume data from radiotherapy treatment plans. Radiomics is expected to increasingly affect the clinical practice of treatment of lung tumors, optimizing the end-to-end diagnosis-treatment-follow-up chain. The main goal of this article is to provide an update on the current status of lung cancer radiomics.

Radiomics is an emerging area in quantitative image analysis that aims to relate large-scale extracted imaging information to clinical and biological endpoints. The development of quantitative imaging methods along with machine learning has enabled the opportunity to move data science research towards translation for more personalized cancer treatments. Accumulating evidence has indeed demonstrated that noninvasive advanced imaging analytics, that is, radiomics, can reveal key components of tumor phenotype for multiple three-dimensional lesions at multiple time points over and beyond the course of treatment. These developments in the use of CT, PET, US, and MR imaging could augment patient stratification and prognostication buttressing emerging targeted therapeutic approaches. In recent years, deep learning architectures have demonstrated their tremendous potential for image segmentation, reconstruction, recognition, and classification. Many powerful open-source and commercial platforms are currently available to embark in new research areas of radiomics. Quantitative imaging research, however, is complex and key statistical principles should be followed to realize its full potential. The field of radiomics, in particular, requires a renewed focus on optimal study design/reporting practices and standardization of image acquisition, feature calculation, and rigorous statistical analysis for the field to move forward. In this article, the role of machine and deep learning as a major computational vehicle for advanced model building of radiomics-based signatures or classifiers, and diverse clinical applications, working principles, research opportunities, and available computational platforms for radiomics will be reviewed with examples drawn primarily from oncology. We also address issues related to common applications in medical physics, such as standardization, feature extraction, model building, and validation., (© 2019 American Association of Physicists in Medicine.)

Purpose: to predict the occurrence of late subcutaneous radiation induced fibrosis (RIF) after partial breast irradiation (PBI) for breast carcinoma by using machine learning (ML) models and radiomic features from 3D Biologically Effective Dose (3D-BED) and Relative Electron Density (3D-RED). Methods: 165 patients underwent external PBI following a hypo-fractionation protocol consisting of 40 Gy/10 fractions, 35 Gy/7 fractions, and 28 Gy/4 fractions, for 73, 60, and 32 patients, respectively. Physicians evaluated toxicity at regular intervals by the Common Terminology Adverse Events (CTAE) version 4.0. RIF was assessed every 3 months after the completion of radiation course and scored prospectively. RIF was experienced by 41 (24.8%) patients after average 5 years of follow up. The Hounsfield Units (HU) of the CT-images were converted into relative electron density (3D-RED) and Dose maps into Biologically Effective Dose (3D-BED), respectively. Shape, first-order and textural features of 3D-RED and 3D-BED were calculated in the planning target volume (PTV) and breast. Clinical and demographic variables were also considered (954 features in total). Imbalance of the dataset was addressed by data augmentation using ADASYN technique. A subset of non-redundant features that best predict the data was identified by sequential feature selection. Support Vector Machines (SVM), ensemble machine learning (EML) using various aggregation algorithms and Naive Bayes (NB) classifiers were trained on patient dataset to predict RIF occurrence. Models were assessed using sensitivity and specificity of the ML classifiers and the area under the receiver operator characteristic curve (AUC) of the score functions in repeated 5-fold cross validation on the augmented dataset. Results: The SVM model with seven features was preferred for RIF prediction and scored sensitivity 0.83 (95% CI 0.80-0.86), specificity 0.75 (95% CI 0.71-0.77) and AUC of the score function 0.86 (0.85-0.88) on cross-validation. The selected features included cluster shade and Run Length Non-uniformity of breast 3D-BED, kurtosis and cluster shade from PTV 3D-RED, and 10th percentile of PTV 3D-BED. Conclusion: Textures extracted from 3D-BED and 3D-RED in the breast and PTV can predict late RIF and may help better select patient candidates to exclusive PBI., (Copyright © 2020 Avanzo, Pirrone, Vinante, Caroli, Stancanello, Drigo, Massarut, Mileto, Urbani, Trovo, el Naqa, De Paoli and Sartor.)

Purpose: The purpose of study is to investigate the dosimetry of electron intraoperative radiotherapy (IOERT) of the Intraop Mobetron 2000 mobile LINAC in treatments outside of the breast. After commissioning and external validation of dosimetry, we report in vivo results of measurements for treatments outside the breast in a large patient cohort, and investigate if the presence of inhomogeneities can affect in vivo measurements., Methods and Materials: Applicator factors and profile curves were measured with a stereotactic diode. The applicators factors of the 6 cm flat and beveled applicators were also confirmed with radiochromic films, parallel-plate ion chamber and by an external audit performed with ThermoLuminescent Dosimeters (TLDs). The influence of bone on dose was investigated by using radiochromic films attached to an insert equivalent to cortical bone, immersed in the water phantom. In vivo dosimetry was performed on 126 patients treated with IOERT using metal oxide-silicon semiconductor field effect transistors (MOSFETs) placed on the tumor bed., Results: Relatively small differences were found among different detectors for measurements of applicator factors. In the external audit, the agreement with the TLD was mostly within ±0.2%. The largest increase of dose due to the presence of cortical bone insert was +6.0% with energy 12 MeV and 3 cm applicator. On average, in vivo dose was significantly (+3.1%) larger than prescribed dose., Conclusion: IOERT in applications outside the breast results in low discrepancies between in vivo and prescribed doses, which can be also explained with the presence of tissue inhomogeneity., (Copyright © 2019 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Introduction: The quantitative imaging features (radiomics) that can be obtained from the different modalities of current-generation hybrid imaging can give complementary information with regard to the tumour environment, as they measure different morphologic and functional imaging properties. These multi-parametric image descriptors can be combined with artificial intelligence applications into predictive models. It is now the time for hybrid PET/CT and PET/MRI to take the advantage offered by radiomics to assess the added clinical benefit of using multi-parametric models for the personalized diagnosis and prognosis of different disease phenotypes., Objective: The aim of the paper is to provide an overview of current challenges and available solutions to translate radiomics into hybrid PET-CT and PET-MRI imaging for a smart and truly multi-parametric decision model.

Background: There is growing evidence that non-alcoholic fatty liver disease (NAFLD) is a disease affecting not only the liver but also extrahepatic organs., Aim: To investigate whether in youths NAFLD is associated with extrahepatic complications such as subclinical atherosclerosis, cardiac abnormalities, hypertension, type 2 diabetes, decreased bone mineral density, renal dysfunction, obstructive sleep apnea, and polycystic ovary syndrome., Methods: We systematically reviewed PubMed; Scopus; Embase; and the Cochrane Library databases up to 28 February 2019 and assessed the quality of studies using the Newcastle-Ottawa Scale., Results: Thirty-five articles were selected for this systematic review: fifteen (4627 participants) evaluated the association of NAFLD with subclinical atherosclerosis; four (969 participants) with cardiac abnormalities; two (550 participants) with hypertension; four (1328 participants) with diabetes; six (523 participants) with low bone mineral density; two (865 participants) with renal dysfunction; one with obstructive sleep apnea; and one with polycystic ovary syndrome. Most studies found that youths with NAFLD have increased features of subclinical atherosclerosis; as well as of cardiac alterations. Limited data were available to endorse a solid estimate of the prevalence of diabetes; low mineral density and renal dysfunction in the pediatric NAFLD population., Conclusion: NAFLD-related intermediate CVD outcomes can occur and be detected early in young populations., Competing Interests: The authors declare no conflicts of interest.

Purpose: The purpose of this study was to implement a machine learning model to predict skin dose from targeted intraoperative (TARGIT) treatment resulting in timely adoption of strategies to limit excessive skin dose., Methods: A total of 283 patients affected by invasive breast carcinoma underwent TARGIT with a prescribed dose of 6 Gy at 1 cm, after lumpectomy. Radiochromic films were used to measure the dose to the skin for each patient. Univariate statistical analysis was performed to identify correlation of physical and patient variables with measured dose. After feature selection of predictors of in vivo skin dose, machine learning models stepwise linear regression (SLR), support vector regression (SVR), ensemble with bagging or boosting, and feed forward neural networks were trained on results of in vivo dosimetry to derive models to predict skin dose. Models were evaluated by tenfold cross validation and ranked according to root mean square error (RMSE) and adjusted correlation coefficient of true vs predicted values (adj-R 2 )., Results: The predictors correlated with in vivo dosimetry were the distance of skin from source, depth-dose in water at depth of the applicator in the breast, use of a replacement source, and irradiation time. The best performing model was SVR, which scored RMSE and adj-R 2 , equal to 0.746 [95% confidence intervals (CI), 95% CI 0.737,0.756] and 0.481 (95% CI 0.468,0.494), respectively, on the tenfold cross validation., Conclusion: The model trained on results of in vivo dosimetry can be used to predict skin dose during setup of patient for TARGIT and this allows for timely adoption of strategies to prevent of excessive skin dose., (© 2019 American Association of Physicists in Medicine.)

Partial breast irradiation (PBI) is an effective adjuvant treatment after breast conservative surgery for selected early-stage breast cancer patients. However, the best fractionation scheme is not well defined. Hereby, we report the 5-year clinical outcome and toxicity of a phase II prospective study of a novel regimen to deliver PBI, which consists in 40 Gy delivered in 10 daily fractions. Patients with early-stage (pT1-pT2, pN0-pN1a, M0) invasive breast cancer were enrolled after conservative surgery. The minimum age at diagnosis was 60 years old. PBI was delivered with 3D-conformal radiotherapy technique with a total dose of 40 Gy, fractionated in 10 daily fractions (4 Gy/fraction). Eighty patients were enrolled. The median follow-up was 67 months. Five-year local control (LC), disease-free survival (DFS), and overall survival (OS) were 95%, 91%, and 96%, respectively. Grade I and II subcutaneous fibrosis were documented in 23% and 5% of cases. No grade III late toxicity was observed. PBI delivered in 40 Gy in 10 daily fractions provided good clinical results and was a valid radiotherapy option for early-stage breast cancer patients., (© 2019 Wiley Periodicals, Inc.)

Purpose: To assess the contribution of Italian radiation oncologists in the current management of recurrent high-grade gliomas (HGG), focusing on a reirradiation (reRT) approach., Methods: In 2015, the Reirradiation and the Central Nervous System Study Groups on behalf of the Italian Association of Radiation Oncology (AIRO) proposed a survey. All Italian radiation oncologists were individually invited to complete an online questionnaire regarding their clinical management of recurrent HGG, focusing on a reRT approach., Results: A total of 37 of 210 questionnaires were returned (18% of all centers): 16 (43%) from nonacademic hospitals, 14 (38%) from academic hospitals, 5 (13%) from private institutions, and 2 (6%) from hadron therapy centers. The majority of responding centers (59%) treated ≤5 cases per year. Performance status at the time of recurrence, along with a target diameter <5 cm and an interval from primary radiation ≥6 months, were the prevalent predictive factors considered for reRT. Sixty percent of reirradiated patients had already received a salvage therapy, either chemotherapy (40%) or reoperation (20%). The most common approach for reRT was fractionated stereotactic radiotherapy to a mean (photon) dose of 41.6 Gy., Conclusions: Although there were wide variations in the clinical practice of reRT across the 37 centers, the core activities were reasonably consistent. These findings provide a basis for encouraging a national collaborative study to develop, implement, and monitor the use of reRT in this challenging clinical setting.

Local irradiation of cancer through radiotherapy can induce spontaneous regression of non-directly irradiated lesions, suggesting the involvement of systemic antitumor immune responses. In oligometastatic breast cancer (BC) patients, the use of stereotactic body radiotherapy (SBRT) favors the local control of treated lesions and may contribute to break local tolerance and release tumor-associated antigens (TAAs), improving host antitumor immunity. We performed a detailed immunomonitoring of BC patients undergoing SBRT to verify its ability to "switch on" the anti-tumor immunity both systemically, in peripheral blood, and locally, employing in vitro BC models. Twenty-one BC patients with ≤6 metastases were treated with 3 daily doses of 10 Gy with SBRT. Blood samples for immune profiling were collected before and after treatment. One month after treatment a third of patients displayed the boosting or even the de novo appearance of polyfunctional CD4 + and CD8 + T cell responses against known BC TAAs (survivin, mammaglobin-A, HER2), through intracellular staining in flow cytometry. Half of patients showed increased numbers of activated natural killer (NK) cells, measured with multispectral flow cytometry, immediately after the first dose of SBRT. Interestingly, high levels of activated NK cells at diagnosis correlated with a longer progression-free survival. BC in vitro models, treated with the same SBRT modality, showed enhanced expression of MHC class-I and class-II, major histocompatibility complex class I-related chain A/B, and Fas molecules, and increased release of pro-inflammatory cytokines, such as IL-1β and TNF-α. Consistently, we noticed enhanced production of perforin by CD4 + T cells when patients' lymphocytes were cultured in the presence of irradiated BC cell line, compared to untreated targets. Besides immunogenic effects, SBRT also enhanced the percentages of circulating regulatory T cells, and increased indoleamine 2,3 dioxygenase and PD-L1 expression in BC in vitro models. These results suggest that SBRT may boost host antitumor immune responses also in an advanced disease setting such as oligometastatic BC, by inducing immunomodulating effects both locally and systemically. However, the concomitant induction of immunosuppressive pathways suggests that a combination with immunotherapy could further enhance the in situ vaccination ability of radiotherapy, possibly further improving the curative potential of SBRT in this subset of patients.

Purpose: To correlate radiation dose to the risk of severe radiologically-evident radiation-induced lung injury (RRLI) using voxel-by-voxel analysis of the follow-up computed tomography (CT) of patients treated for lung cancer with hypofractionated helical Tomotherapy., Methods and Materials: The follow-up CT scans from 32 lung cancer patients treated with various regimens (5, 8, and 25 fractions) were registered to pre-treatment CT using deformable image registration (DIR). The change in density was calculated for each voxel within the combined lungs minus the planning target volume (PTV). Parameters of a Probit formula were derived by fitting the occurrences of changes of density in voxels greater than 0.361gcm -3 to the radiation dose. The model's predictive capability was assessed using the area under receiver operating characteristic curve (AUC), the Kolmogorov-Smirnov test for goodness-of-fit, and the permutation test (P test )., Results: The best-fit parameters for prediction of RRLI 6months post RT were D 50 of 73.0 (95% CI 59.2.4-85.3.7)Gy, and m of 0.41 (0.39-0.46) for hypofractionated (5 and 8 fractions) and D 50 of 96.8 (76.9-123.9)Gy, and m of 0.36 (0.34-0.39) for 25 fractions RT. According to the goodness-of-fit test the null hypothesis of modeled and observed occurrence of RRLI coming from the same distribution could not be rejected. The AUC was 0.581 (0.575-0.583) for fractionated and 0.579 (0.577-0.581) for hypofractionated patients. The predictive models had AUC>upper 95% band of the P test ., Conclusions: The correlation of voxel-by-voxel density increase with dose can be used as a support tool for differential diagnosis of tumor from benign changes in the follow-up of lung IMRT patients., (Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

The domain of investigation of radiomics consists of large-scale radiological image analysis and association with biological or clinical endpoints. The purpose of the present study is to provide a recent update on the status of this rapidly emerging field by performing a systematic review of the literature on radiomics, with a primary focus on oncologic applications. The systematic literature search, performed in Pubmed using the keywords: "radiomics OR radiomic" provided 97 research papers. Based on the results of this search, we describe the methods used for building a model of prognostic value from quantitative analysis of patient images. Then, we provide an up-to-date overview of the results achieved in this field, and discuss the current challenges and future developments of radiomics for oncology., (Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Purpose: To assess toxicity and clinical outcome, in breast cancer patients treated with external beam partial breast irradiation (PBI) consisting of 35 Gy in 7 daily fractions (5 Gy/fraction)., Materials and Methods: Patients affected by early-stage breast cancer were enrolled in this phase II trial. Patients had to be 60 years old or over and treated with breast conservative surgery for early stage invasive carcinoma., Results: Seventy-three patients were analyzed. Median follow-up was 40 months. The proposed schedule was well tolerated. No Grade 3 toxicity was documented. Late toxicity was assessable for all the treated patients. Two patients (2.7%) developed Grade 2 pain 6 months after PBI. Four patients (5%) developed asymptomatic fat necrosis. Grade 2 fibrosis was observed in 5 patients (6.7%). No correlation was found between early and late toxicity and the type of adjuvant systemic therapy (no therapy vs. hormonal therapy vs. chemotherapy). No statistical correlation between dosimetric parameters and toxicity was found. Patients who developed Grade 2 radiation fibrosis had not higher radiation volumes to the untreated normal breast than those without fibrosis. Cosmesis was judged good/excellent in the majority of the cases (93%). One patient relapsed locally, and one developed distant metastases, corresponding to a 5-year local control and distant metastases-free survival of 98% and 96.7%, respectively., Conclusions: 35 Gy in 7 daily fractions is an effective and well-tolerated regimen to deliver PBI.

Genomic instability represents a typical feature of aggressive cancers. Normal cells have evolved intricate responses to preserve genomic integrity in response to stress, such as DNA damage induced by γ-irradiation. Cyclin-dependent kinases (CDKs) take crucial part to these safeguard mechanisms, but involvement of CDK-inhibitors, such as p27 Kip1 , is less clear. We generated immortalized fibroblasts from p27 kip1 knock-out (KO) mouse embryos and re-expressed p27 kip1 WT, or its mutant forms, to identify the function of different domains. We γ-irradiated fibroblasts and observed that loss of p27 Kip1 was associated to accumulation of residual DNA damage, increased number of mitotic aberration and, eventually, to survival advantage. Nuclear localization and cyclin/CDK-binding of p27 Kip1 were critical to mediate proper response to DNA damage. In human luminal breast cancer (LBC) p27 kip1 is frequently down-modulated and CDKN1B, p27 Kip1 gene, sporadically mutated. We recapitulated results obtained in mouse fibroblasts in a LBC cell line genetically manipulated to be KO for CDKN1B gene. Following γ-irradiation, we confirmed that p27 kip1 expression was necessary to preserve genomic integrity and to recognize and clear-out aberrant cells. Our study provides important insights into mechanisms underlying radio-resistance and unveils the possibility for novel treatment options exploiting DNA repair defects in LBC.

The internal carotid artery agenesis is a rare malformation disorder. We report the case of a 12-year-old boy suffering migraine, who had presented an episode featuring amaurosis fugax, spontaneously regressed. CT angiography images show hypoplasia of the left common carotid artery with loss of opacification of the left internal carotid artery consistent to agenesis. Moreover CT scans through the skull base demonstrate absence of left petrous carotid canal and an hypertrophic left middle cerebral artery originating from an aberrant artery arising from the right cavernous carotid. All diagnostic examinations confirmed the presence of the internal carotid artery agenesis, as Lie's type IV. We started an annual follow up that over the next 7 years did not reveal any change in magnetic resonance angiography images.

Purpose: The aim of this study was to investigate the possible correlation between epicardial adipose tissue (EAT) thickness and predictive parameters for metabolic syndrome (MS) in overweight/obese prepubertal children., Methods: 73 prepubertal children, average age of 8.22 years, with no endocrine or syndromic causes of obesity or under drug therapy for chronic disease were enrolled. Weight, height, body circumferences and skinfolds' thickness were measured. BMI, BMI z score (z-BMI) and waist-to-height ratio (WtHR) were calculated. Standard MS-related laboratory parameters were assessed. Finally, all children underwent echocardiographic measurement of EAT., Results: A positive correlation between EAT and z-BMI was found only among overweight/obese children (r = 0.43, p = 0.001). In particular, data showed that 89 % of our sample had a waist (W) >90th percentile. Statistical differences in diastolic blood pressure (DBP; p < 0.01) and EAT (p = 0.02) were observed on comparing W <90th percentile vs W >90th percentile patients. Besides, in patients with W >90th percentile and family history of risk factors for MS, the value of EAT correlated positively with z-BMI, W, WtHR, triglycerides (Tg), insulin and homeostatic model assessment of insulin resistance and negatively with HDL., Conclusions: The EAT and the markers of MS probably share the same pathogenetic factors. Further studies might elucidate whether EAT deserves to be included among the diagnostic factors of MS.

Purpose: To report on single-fraction stereotactic body radiotherapy (RT) (SBRT) with flattening filter (FF)-free (FFF) volumetric modulated arc therapy (VMAT) for lung cancer and to compare dosimetric results with VMAT with FF., Methods and Materials: Overall, 25 patients were treated with 6-MV FFF VMAT (Varian TrueBeam STx LINAC) to a prescribed dose of 24Gy in a single fraction. Treatment plans were recreated using FF VMAT. Dose-volume indices, monitor units (MU), and treatment times were compared between FFF and FF VMAT techniques., Results: Dose constraints to PTV, spinal cord, and lungs were reached in FFF and FF plans. In FFF plans, average conformity index was 1.13 (95% CI: 1.07 to1.38). Maximum doses to spinal cord, heart, esophagus, and trachea were 2.9Gy (95% CI: 0.4 to 6.7Gy), 0.8Gy (95% CI: 0 to 3.6Gy), 3.3Gy (95% CI: 0.02 to 13.9Gy), and 1.5Gy (95% CI: 0 to 4.9Gy), respectively. Average V7Gy, V7.4Gy, and mean dose to the healthy lung were 126.5cc (95% CI: 41.3 to 248.9cc), 107.3cc (95% CI: 18.7 to 232.8cc), and 1.1Gy (95% CI: 0.3 to 2.2Gy), respectively. No statistically significant differences were found in dosimetric results and MU between FF and FFF treatments. Treatment time was reduced by an average factor of 2.31 (95% CI: 2.15 to 2.43) from FF treatments to FFF, and the difference was statistically significant., Conclusions: FFF VMAT for lung SBRT provides equivalent dosimetric results to the target and organs at risk as FF VMAT while significantly reducing treatment time., (Copyright © 2016 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

Purpose: To introduce volumetric modulated arc therapy treatments (VMAT) with simultaneous integrated boost (SIB) for pancreatic cancer and describe dosimetric results on a large patient series., Methods and Materials: 45 patients with pancreatic malignancies were treated with 18 MV single-arc VMAT. Image guidance was performed with daily online kilo-volt cone-beam computed tomography (CBCT). The conformity index (CI) and homogeneity index (HI) to the target volumes, PTV45Gy and PTV54Gy, and dose-volume indices to OARs from the QUANTEC task group were reported. The risk of clinical nephritis was evaluated using normal tissue complication probability (NTCP). Treatments were verified in-phantom with the Delta4 system., Results: Average CI was 1.06 with 95% confidence intervals (95% CI) of 0.97-1.22 for PTV45Gy and 1.17 (0.66-1.61) for PTV54Gy. HI of PTV54Gy was 1.06 (1.04-1.10). OAR constraints were achieved in all patients, except for kidneys V12Gy of 48 (35.4-72.3)%. NTCP of the kidneys was 0.98 (0.6-1.7)%. Kidneys V12Gy and V20Gy were inversely related to PTV54Gy CI and maximum dose. All in-phantom tests had gamma pass rates exceeding 95% with global 3% dose difference and 3 mm distance to agreement. Patient shifts measured with CBCT had 95% CI of -0.8, +0.8 in the RL, -0.7, +0.8 in the SI, and -0.8, +0.7 cm in the AP directions., Conclusions: Dosimetric results of VMAT were excellent on PTVs and organs at risk. The kidneys represent the dose-limiting organ at risk for this technique. NTCP indicates that this technique is safe from radiation-induced side effects to the kidneys., (Copyright © 2015 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Purpose: To reduce the fraction number in Partial Breast Irradiation (PBI) with initial prescription of 40 Gy in 10 fractions using radiobiological models with specific focus on risk of moderate/severe radiation-induced fibrosis (RIF) and report clinical results., Methods and Materials: 68 patients (patient group A) were treated with 40 Gy in 10 fractions delivered by field-in-field, forward-planned IMRT. Isotoxic regimens with decreasing number of fractions were calculated using Biological Effective Dose (BED) to the breast. Risk for RIF in hypofractionated treatment was predicted by calculating NTCP from DVHs of group A rescaled to fractions and dose of novel regimens. Moderate/severe RIF was prospectively scored during follow-up. Various NTCP models, with and without incomplete repair correction, were assessed from difference to observed incidence of RIF. In order to verify the value for α/β of 3 Gy assumed for breast, we fitted α/β to observed incidences of moderate/severe RIF., Results: Treatments with 35 Gy/7f and 28 Gy/4f were selected for the fraction reduction protocol. 75 patients (group B) were treated in 35 Gy/7f. Incidence of moderate/severe RIF was 5.9% in group A, 5.3% in group B. The NTCP model with correction for incomplete repair had lowest difference from observed RIF. The α/β obtained from fitting was 2.8 (95%CIs 1.1-10.7) Gy., Conclusions: The hypofractionated regimen was well tolerated. The model for NTCP corrected for incomplete repair was the most accurate and an assumed α/β value of 3 Gy is consistent with our patient data. The hypofractionation protocol is continuing with patients treated with 28 Gy/4f., (Copyright © 2015 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Aims and Background: To present the Italian state-of-the-art contribution to radiobiology of external beam radiotherapy, brachytherapy, and radionuclide radiotherapy., Methods and Study Design: A survey of the literature was carried out, using PubMed, by some independent researchers of the Italian group of radiobiology. Each paper was reviewed by researchers of centers not comprising its authors. The survey was limited to papers in English published over the last 20 years, written by Italian investigators or in Italian institutions, excluding review articles., Results: A total of 135 papers have been published in journals with an impact factor, with an increase in the number of published papers over time, for external beam radiotherapy rather than radionuclide radiotherapy. The quantity and quality of the papers researched constitutes a proof of the enduring interest in clinical radiobiology among Italian investigators., Conclusions: The survey could be useful to individuate expert partners for an Italian network on clinical radiobiology, addressing future collaborative investigations.

Purpose: To retrospectively assess toxicity and outcome of re-irradiation with stereotactic body radiation therapy (SBRT) in patients with recurrent or persistent non-small cell lung cancer (NSCLC), who were previously treated with radical radiation therapy (50-60 Gy). The secondary endpoint was to investigate whether there are dosimetric parameter predictors of severe radiation toxicity., Methods and Materials: The analysis was conducted in 17 patients with "in-field" recurrent/persistent centrally located NSCLC, who underwent re-irradiation with SBRT. SBRT consisted of 30 Gy in 5 to 6 fractions; these prescriptions would be equivalent for the tumor to 37.5 to 40 Gy, bringing the total 2-Gy-per-fraction cumulative dose to 87 to 100 Gy, considering the primary radiation therapy treatment. Actuarial analyses and survival were calculated by the Kaplan-Meier method, and P values were estimated by the log-rank test, starting from the date of completion of SBRT. Dosimetric parameters from the subgroups with and without grade ≥3 pulmonary toxicity were compared using a 2-tailed Student t test., Results: The median follow-up was 18 months (range, 4-57 months). Only 2 patients had local failure, corresponding to a local control rate of 86% at 1 year. The Kaplan-Meier estimates of overall survival (OS) rates at 1 and 2 years were 59% and 29%, respectively; the median OS was 19 months. Four patients (23%) experienced grade 3 radiation pneumonitis, and 1 patient developed fatal pneumonitis. One patient died of fatal hemoptysis 2 months after the completion of SBRT. Unexpectedly, heart maximum dose, D5 (minimum dose to at least 5% of the heart volume), and D10 were correlated with risk of radiation pneumonitis (P<.05)., Conclusions: Re-irradiation with SBRT for recurrent/persistent centrally located NSCLC achieves excellent results in terms of local control. However, the high rate of severe toxicity reported in our study is of concern., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study is to report results of measurements of dose to the skin in vivo with radiochromic EBT films in treatments with helical tomotherapy., Methods and Materials: In vivo measurements were performed by applying pieces of radiochromic films to the skin or to the inner side of thermoplastic mask before the treatment. The sites of treatment included scalp, brain, head and neck, cranio-spinal axis and lower limbs. Skin dosimetry was performed in a patient who experienced grade 3-4 acute side effects to the skin shortly after the first treatment sessions. For each patient we measured the setup errors using the daily MVCT acquired for image guidance of the treatment. EBT films were read with a flatbed Epson Expression scanner and images were processed with an in-house written routine., Results: A total of 96 measurements of dose to the skin performed on 14 patients. The mean difference and standard error of the mean difference between measured and TPS-calculated dose was -9.2% ± 2.6% for all treatments, -6.6% ± 2.6% for head and neck treatments. These differences were statistically significant at the 0.05 significance level (t-Student test). Planned dose and dose range in the region of measurements were not correlated with dose discrepancy., Conclusions: Radiochromic EBT films are suitable detectors for surface dose measurements in tomotherapy treatments. Results show that TPS overestimates dose to the skin measured with EBT radiochromic films. In vivo skin measurements with EBT films are a useful tool for quality assurance of tomotherapy treatments, as the treatment planning system may not give accurate dose values at the surface., (Copyright © 2012 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Purpose: To extend the application of current radiation therapy (RT) based normal tissue complication probability (NTCP) models of radiation-induced fibrosis (RIF) of the breast to include the effects of fractionation, inhomogeneous dose, incomplete recovery, and time after the end of radiotherapy in partial breast irradiation (PBI)., Materials and Methods: An NTCP Lyman model with biologically effective uniform dose (BEUD) with and without a correction for the effect of incomplete repair was used. The time to occurrence of RIF was also taken into account. The radiobiological parameters were determined by fitting incidences of moderate/severe RIF in published randomized studies on RT of the breast. The NTCP model was used to calculate the risk of toxicity in 35 patients treated with intensity modulated, non-accelerated PBI and the result was compared with observed incidence of RIF., Results: With α/β fixed at 3Gy the parameters of the model without correction for incomplete repair extracted from fitting were: 50% complication probability biologically effective dose BEUD(50) = 107.2 Gy (95%CI = 95.9-118.6 Gy), volume parameter n = 0.06 (95%CI = 0-0.23), and slope of dose response m = 0.22, (95%CI = 0.20-0.23). After including the correction for incomplete repair with repair halftime for subcutaneous tissue of τ = 4.4 h we obtained BEUD(50) = 105.8 Gy (95%CI = 96.9-114.6Gy), n = 0.15 (95%CI = 0-0.33), m = 0.22 (95%CI = 0.20-0.23). Average NTCP predicted by these models, 4.3% and 2.0% respectively, offered a good agreement with RIF incidence in our patients, 5.7%, after an average follow-up of 12 months., Conclusion: The NTCP models of RIF, incorporating the effects of fractionation, volume effect, and latency of toxicity look promising to model PBI. Clinical validation from a prospective PBI treatment study is under development and will help test this preliminary result., (Copyright © 2011 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the role of complex alleles, with two or more mutations in cis position, of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in the definition of the genotype-phenotype relationship in cystic fibrosis (CF), and to evaluate the functional significance of the highly controversial L997F CFTR mutation., Methods: We evaluated the diagnosis of CF or CFTR-related disorders in 12 unrelated subjects with highly variable phenotypes. According to a first CFTR mutational analysis, subjects appeared to be compound heterozygotes for a classic mutation and the L997F mutation. A further CFTR mutational analysis was conducted by means of a protocol of extended sequencing, particularly suited to the detection of complex alleles., Results: We detected a new [R117L; L997F] CFTR complex allele in the four subjects with the highest sweat test values and CF. The eight subjects without the complex allele showed the most varied biochemical and clinical outcome and were diagnosed as having mild CF, CFTR-related disorders, or even no disease., Conclusions: The new complex allele partially explains the variable phenotype in CF subjects with the L997F mutation. CFTR complex alleles are likely to have a role in the definition of the genotype-phenotype relationship in CF. Whenever apparently identical CFTR-mutated genotypes are found in subjects with divergent phenotypes, an extensive mutational search is mandatory.

We discuss the anatomic and pathophysiological patterns of preterm and term newborn. Particular attention is directed to technical artefacts relating to the interpretation of chest radiography. We analyze the reading of chest X-Ray of preterm with low birth weight and poor lung maturation. Are also taken into account X-Ray features relating to alveolar "recruitment" and radiographic changes after surfactant's administration. We highlight the most important paintings of bruncopulmonary dysplasia and its evolution. The most frequent neonatal pulmonary inflammation and thoraco-pulmonary malformation, that may affect more the neonatologist, are mentioned. We discuss the new diagnostic approach with non invasive techniques (ultrasound) in the neonatal distress. Some easily recognizable congenital heart disease are finally describes.

Purpose: To extend the application of current radiation therapy (RT) based tumor control probability (TCP) models of nasopharyngeal carcinoma (NPC) to include the effects of hypoxia and chemoradiotherapy (CRT)., Methods: A TCP model is described based on the linear-quadratic model modified to account for repopulation, chemotherapy, heterogeneity of dose to the tumor, and hypoxia. Sensitivity analysis was performed to determine which parameters exert the greatest influence on the uncertainty of modeled TCP. On the basis of the sensitivity analysis, the values of specific radiobiological parameters were set to nominal values reported in the literature for NPC or head and neck tumors. The remaining radiobiological parameters were determined by fitting TCP to clinical local control data from published randomized studies using both RT and CRT. Validation of the model was performed by comparison of estimated TCP and average overall local control rate (LCR) for 45 patients treated at the institution with conventional linear-accelerator-based or helical tomotherapy based intensity-modulated RT and neoadjuvant chemotherapy., Results: Sensitivity analysis demonstrates that the model is most sensitive to the radiosensitivity term alpha and the dose per fraction. The estimated values of alpha and OER from data fitting were 0.396 Gy(-1) and 1.417. The model estimate of TCP (average 90.9%, range 26.9%-99.2%) showed good correlation with the LCR (86.7%)., Conclusions: The model implemented in this work provides clinicians with a useful tool to predict the success rate of treatment, optimize treatment plans, and compare the effects of multimodality therapy.

The development of computer-based image guidance has allowed stereotactic radiosurgery and radiotherapy to be freed from the constraints imposed by the stereotactic frames once required for intracranial radiosurgery. This freedom has led to the application of radiosurgery to targets outside the brain. In this paper, we briefly review the technologies, treatment parameters, and clinical outcomes of radiosurgical treatment for spinal pathology, including metastatic tumors and rare but challenging lesions such as arteriovenous malformations and benign tumors. A special emphasis is put on the newest development, fiducial-less robotic radiosurgery. Spinal radiosurgery is associated with excellent rates of tumor control and pain relief with a good dose sparing of the highly sensitive spinal cord. Further research is required to optimize treatment strategies and to assess clinical benefits and toxicity in the long term.

Functional magnetic resonance imaging (fMRI) is used to distinguish areas of the brain responsible for different tasks and functions. It is possible, for example, by using fMRI images, to identify particular regions in the brain which can be considered as "functional organs at risk" (fOARs), i.e., regions which would cause significant patient morbidity if compromised. The aim of this study is to propose and validate a method to exploit functional information for the identification of fOARs in CyberKnife (Accuray, Inc., Sunnyvale, CA) radiosurgery treatment planning; in particular, given the high spatial accuracy offered by the CyberKnife system, local nonrigid registration is used to reach accurate image matching. Five patients affected by arteriovenous malformations (AVMs) and scheduled to undergo radiosurgery were scanned prior to treatment using computed tomography (CT), three-dimensional (3D) rotational angiography (3DRA), T2 weighted and blood oxygenation level dependent echo planar imaging MRI. Tasks were chosen on the basis of lesion location by considering those areas which could be potentially close to treatment targets. Functional data were superimposed on 3DRA and CT used for treatment planning. The procedure for the localization of fMRI areas was validated by direct cortical stimulation on 38 AVM and tumor patients undergoing conventional surgery. Treatment plans studied with and without considering fOARs were significantly different, in particular with respect to both maximum dose and dose volume histograms; consideration of the fOARs allowed quality indices of treatment plans to remain almost constant or to improve in four out of five cases compared to plans with no consideration of fOARs. In conclusion, the presented method provides an accurate tool for the integration of functional information into AVM radiosurgery, which might help to minimize undesirable side effects and to make radiosurgery less invasive.

Spatial accuracy in extracranial radiosurgery is affected by organ motion. Motion tracking systems may be able to avoid PTV enlargement while preserving treatment times, however special attention is needed when fiducial markers are used to identify the target can move with respect to organs at risk (OARs). Ten patients treated by means of the Synchrony system were taken into account. Sparing of irradiated volume and of complication probability were estimated by calculating treatment plans with a motion tracking system (Cyberknife Synchrony, Sunnyvale, CA, USA) and a PTV-enlargement strategy for ten patients. Six patients were also evaluated for possible inaccuracy of estimation of dose to OARs due to relative movement between PTV and OAR during respiration. Dose volume histograms (DVH) and Equivalent Uniform Dose (EUD) were calculated for the organs at risk. In the cases for which the target moved closer to the OAR (three cases of six), a small but significant increase was detected in the DVH and EUD of the OAR. In three other cases no significant variation was detected. Mean reduction in PTV volume was 38% for liver cases, 44% for lung cases and 8.5% for pancreas cases. NTCP for liver reduced from 23.1 to 14.5% on average, for lung it reduced from 2.5 to 0.1% on average. Significant uncertainty may arise from the use of a motion-tracking device in determination of dose to organs at risk due to the relative motion between PTV and OAR. However, it is possible to limit this uncertainty. The breathing phase in which the OAR is closer to the PTV should be selected for planning. A full understanding of the dose distribution would only be possible by means of a complete 4D-CT representation.

FG syndrome (FGS, MIM 305450) is a rare X-linked recessive disorder comprising mental retardation and multiple malformations. Various families have been described to date, increasing our knowledge of the phenotype variability and making the clinical diagnosis complex, especially in sporadic patients. The first locus for FG syndrome (FGS1) was linked to chromosome region Xq12-q21.31, but other families have been excluded from this locus. The genetic heterogeneity of FG syndrome has been confirmed by analysis of an X chromosome inversion [inv(X)(q11q28)] in an affected boy and in his mentally retarded maternal uncle, suggesting that an additional locus for FG syndrome (FGS2, MIM 300321) is located at either Xq11 or Xq28. Recently, a third locus (FGS3) has been mapped to Xp22.3. We have identified and clinically characterized an Italian FG family, including 31 members with three affected males in two generations and two obligate carriers. We have excluded linkage to known FGS loci, whereas an extensive study of the whole X chromosome has yielded a maximum LOD score (Z(max)) of 2.66 (recombination fraction=0) for markers between DXS8113 and sWXD805. This new locus for FG syndrome corresponds to a region of approximately 4.6 Mb on the X chromosome.

Diamond-Blackfan anaemia (DBA) is a congenital disease characterized by defective erythroid progenitor maturation: 30% of patients have congenital malformations. The link between these malformations and defective erythropoiesis is unclear: a defect in a molecule acting both on embryo development and haemopoiesis has been proposed. Inheritance is autosomal dominant in most familial cases, but recessive families have also been reported. Many cases are sporadic. A DBA locus has been mapped on chromosome 19q13.2 (Gustavsson et al, 1997), but several families unlinked to this locus have also been reported (Gustavsson et al, 1998). This paper presents clinical, epidemiological and molecular data for DBA in the Italian population. Segregation analysis of 19q markers in patients with DBA showed exclusion of this locus in 5/12 families with inherited DBA. There was evidently locus heterogeneity for DBA in this population. A new microdeletion was identified in one patient. Other families, in which DBA segregates concordantly with the 19q critical region, suggest incomplete penetrance and expressivity of the DBA gene.

Thrombocytopenia with absent radii (TAR) is a rare autosomal recessive disease characterized by hypomegakaryocytic thrombocytopenia and bilateral radial aplasia. We performed mutational screening of coding and promoter regions of the c-mpl gene, encoding thrombopoietin (TPO) receptor, by sequence analysis in four unrelated patients affected by TAR syndrome. Our results indicate that c-mpl gene mutations are not a common cause of thrombocytopenia in TAR syndrome.

Objective: To describe a mother and her 2 sons affected by idiopathic intracranial hypertension (IIH), associated in the sons with root irritation symptom. Unlike the other 4 families reported previously, obesity was not present in our patients., Design: Case reports., Setting: Department of pediatrics in a university school of Medicine, Naples, Italy., Patients: A mother (aged 36 years) and her 2 sons (aged 14 and 9 years) developed IIH at different times. Neuroimaging showed an empty sella in the mother, while IIH was associated with spinal and radicular pain in her 2 sons. The mother and the younger son developed permanent visual loss., Conclusions: Ophthalmologic follow-up in our patients indicates that IIH is a chronic disease. Surgical treatment should be considered an option.

A 4.5-year-old boy was admitted to three different hospitals because of a tendency towards dehydration and polyuria, along with normal blood pressure, hypochloraemia, hypokalaemia, metabolic alkalosis and an impaired urinary concentrating ability. A renal biopsy failed to reveal juxtaglomerular hyperplasia. The clinical and laboratory findings failed to improve despite supplementation with potassium chloride and treatment with indomethacin. The urine was found to contain frusemide. The parents denied any drug administration to the boy. The child is now doing well more than 1 year after separation from his mother. Since ingestion of diuretic cannot be differentiated from true Bartter syndrome by blood and urinary electrolyte measurements alone, a diuretic screen is warranted in children with findings consistent with Bartter syndrome.

We report an 18-year-old boy with common variable immunodeficiency who presented with splenomegaly as well as left axillary and lateral cervical lymphadenopathy. Main laboratory investigations showed severe thrombocytopenia. Epstein-Barr virus (EBV) DNA was detected in the patient's throat-washing specimens and lymph node biopsy. Lymphocytes from the lymph node biopsy were also positive for EBV nuclear antigen. Serology for EBV and cytomegalovirus was negative. A therapeutic attempt with acyclovir did not influence the course of infection. Six months' treatment with human lymphoblastoid interferon-alpha (IFN alfa) brought about the normalization of clinical and hematologic conditions. Detection on throat-washing specimens carried out 1 year after therapy was negative. Our preliminary experience suggests that human lymphoblastoid IFN-alpha is a valid alternative in therapy of immunodeficient EB virus-infected patients.

Here we report two children with Aase-Smith syndrome (triphalangeal thumbs and congenital red cell plasia). In vitro growth of erythroid colonies was normal in the first patient and totally absent in the other. In both patients, treatment with glucocorticoids induced remission of anemia. Our results suggest that the different growth patterns of erythroid colonies observed in the two patients could reflect the defect of erythroid differentiation occurring at discrete maturational levels.

The authors report a case of an infant affected by isolated thrombosis of splenic vein. They stress the necessity of a precious diagnosis in order to prevent the haemorragic consequences of distrectual portal hypertension. Splenectomy, the only therapeutic mean considered in these patients, has been followed, in our patient, by reimplantation of splenic tissue, in order to prevent the septic complicances (mainly due to pneumococcus) frequently occurring in splenectomized patients.