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Amadori D.,IRCCS Scientific Institute of Romagna for the Study and Treatment of Cancer IRST IRCCS | Aglietta M.,Institute for Cancer Research and Treatment | Alessi B.,University of Udine | Gianni L.,Infermi Hospital | And 8 more authors.
The Lancet Oncology | Year: 2013

Background: Zoledronic acid reduces skeletal-related events in patients with breast cancer, but concerns have been raised about prolonged monthly administration. We assessed the efficacy and safety of a reduced dosing frequency of zoledronic acid in women treated previously with monthly zoledronic acid. Methods: We did this non-inferiority, phase 3 trial in 62 centres in Italy. We enrolled patients with breast cancer who had one or more bone metastases and had completed 12-15 months of monthly treatment with zoledronic acid. Patients were randomly assigned with a permutated block (size four to eight) random list stratified by centre in a 1:1 ratio to zoledronic acid 4 mg once every 12 weeks or once every 4 weeks, and followed up for at least 1 year. Neither patients nor investigators were masked to treatment allocation. The primary outcome was skeletal morbidity rate (skeletal-related events per patient per year) in the intention-to-treat population. We used a non-inferiority margin of 0·19. The trial is registered with EudraCT, number 2005-004942-15. Findings: We screened 430 patients and enrolled 425, of whom 209 were assigned to the 12-week group and 216 to the 4-week group. The skeletal morbidity rate was 0·26 (95% CI 0·15-0·37) in the 12-week group versus 0·22 (0·14-0·29) in the 4-week group. The between-group difference was 0·04 and the upper limit of one-tailed 97·5% CI was 0·17, which is lower than the non-inferiority margin. The most common grade 3-4 adverse events were bone pain (56 [27%] patients in the 12-week group vs 65 [30%] in the 4-week group), nausea (24 [11%] vs 33 [15%]), and asthenia (18 [9%] vs 33 [15%]). Renal adverse events occurred in one patient (<1%) in the 12-week group versus two (1%) in the 4-week group. One patient (<1%) in the 4-week group had grade 1 acute renal failure. Osteonecrosis of the jaw occurred in four patients in the 12-week group versus three in the 4-week group. No treatment-related deaths were reported. Median N-terminal telopeptide concentration changed from baseline more in the 12-week group than in the 4-week group after 12 months (12·2% vs 0·0%; p=0·011). Interpretation: Our results raise the possibility of decreasing administration of zoledronic acid to a 12-weekly regimen to reduce exposure during the second year, while maintaining its therapeutic effects. However, the effects on N-terminal telopeptide should be investigated further before changing current practice. Funding: Novartis Farma. © 2013 Elsevier Ltd.


Rubini A.,University of Padua | Del Monte D.,ULSS | Catena V.,ULSS
Annals of Thoracic Medicine | Year: 2012

Purpose: To describe the consequences of the cranial displacement of the diaphgram occurring during pneumoperitoneum (Pnp) and/or Trendelenburg (Tnd) position on respiratory mechanics. Possible addictive effects and the changes of the viscoelastic respiratory system resistance were studied, which were not extensively described before. Methods: The end-inflation occlusion method was applied on eight rats. It allows us to determine mechanical parameters such as respiratory system static elastance, the ohmic resistance due to frictional forces in the airways, and the additional viscoelastic impedance due to tissues deformation. Measurements during mechanical ventilation were taken in controls (supine position), after 20-25° head-down tilting (Tnd), after abdominal air insufflation up to 12 mmHg abdominal pressure in the supine position (Pnp), and combining Tnd + Pnp. Tnd and Pnp modalities were similar to those commonly applied during surgical procedures in humans. Results: We confirmed the previously described detrimental effects on respiratory mechanics due to the diaphgram displacement during both Pnp and Tnd. The increment in the total resistive pressure dissipation was found to depend primarily on the effects on the viscoelastic characteristics of the respiratory system. Data suggesting greater effects of Pnp compared to those of Tnd were obtained. Conclusion: The cranial displacement of the diaphgram occurring as a consequence of Pnp and/or Tnd, for example during laparoscopic surgical procedures, causes an increment of respiratory system elastance and viscoelastic resistance. The analysis of addictive effects show that these are more likely to occur when Pnp + Tnd are compared to isolated Tnd rather than to isolated Pnp.


Artioli G.,Haemato Oncology Unit | Wabersich J.,ULSS | Ludwig K.,University of Padua | Gardiman M.P.,University of Padua | And 2 more authors.
Critical Reviews in Oncology/Hematology | Year: 2015

Uterine carcinosarcoma (UCS) is an aggressive malignancy. With an incidence of 2/100,000 females and a 5 years Survival at stage IV of 0%, it is an uncommon type of cancer with a very poor prognosis. Histologically, UCS is a biphasic neoplasm consisting of a mixture of malignant epithelial and mesenchymal components but there is now enough clinical-pathological evidence to consider UCS as metaplastic carcinoma in which the mesenchymal part retains epithelial features. The principal treatment in early/locally-advanced UCS is surgery; because of its aggressiveness, it generally presents distant metastases at diagnosis. Adjuvant radiotherapy and chemotherapy have uncertain effect. Chemotherapy alone or associated with radiotherapy seems to improve disease free survival (DFS) and overall survival (OS) in stage III and IV UCS. No advantages in OS and DFS have been shown with radiotherapy alone. The present review summarizes and analyzes the most important news about this type of gynaecological cancer. © 2014 Elsevier Ireland Ltd.


Rubini A.,University of Padua | del Monte D.,ULSS | Catena V.,ULSS
Regulatory Peptides | Year: 2012

While some experimental data suggest that erythropoietin (EPO) influences respiratory mechanics, reports on scientific trials are lacking.In the present work, respiratory mechanics were measured using the end-inflation occlusion method in control and EPO treated anaesthetised and positive-pressure ventilated rats. Causing an abrupt inspiratory flow arrest, the end-inflation occlusion method makes it possible to measure the ohmic airway resistance and the respiratory system elastance.It was found that EPO induces a significant decrement in the ohmic airway resistance, not noted in control animals, 20 and 30. min after intraperitoneal EPO injection. The elastic characteristics of the respiratory system did not vary.Hypotheses about the mechanism (s) explaining these results were addressed. In particular, additional experiments have indicated that the decrement in airway resistance could be related to an increase in nitric oxide production induced by EPO.Spontaneous increments in plasmatic erythropoietin levels, such as those that take place in association with hypoxia and/or blood loss, appear to be related to the decrement in airway resistance, allowing pulmonary ventilation to increase without altering respiratory mechanics leading to deleterious increments in energy dissipation during breathing. © 2012 Elsevier B.V.


Casaluce F.,The Second University of Naples | Sgambato A.,The Second University of Naples | Maione P.,Sg Moscati Hospital | Rossi A.,Sg Moscati Hospital | And 5 more authors.
Targeted Oncology | Year: 2013

The anaplastic lymphoma kinase (ALK) fusion gene is a key oncogenic driver in a subset of patients with advanced non-small cell lung cancer (NSCLC). Oncogenic fusion genes, including echinoderm microtubule-associated protein-like 4 (EML4) and ALK, have been detected in approximately 2-7 % of NSCLC patients. Fluorescence in situ hybridization (FISH) is the recommended method for detecting ALK gene rearrangement. EML4-ALK fusion genes define a molecular subset of NSCLC with distinct clinical characteristic (lung adenocarcinoma, never or former smoker, usually mutually exclusive with EGFR mutations). Crizotinib (PF-02341066) is an orally bioavailable, ATP-competitive, small molecule inhibitor of both the receptor tyrosine kinases ALK and c-MET (hepatocyte growth factor receptor). Crizotinib has been shown to yield important clinical benefit such as objective response rate, progression-free survival (PFS), and anticipated improvements in quality of life when used in pretreated patients with advanced NSCLC harboring EML4-ALK gene rearrangement. Preliminary phase II data suggested that crizotinib is safe and well tolerated with rapid and robust antitumor activity. A phase III randomized trial in a second-line setting showed response rate and PFS (primary study endpoint) advantage for crizotinib as compared to second-line chemotherapy. Treatment-related adverse events, predominantly restricted to the gastrointestinal and visual systems, are generally self-limiting or easily managed. Crizotinib is a new standard of care for patients with advanced, ALK-positive, NSCLC. In this review, we will discuss the discovery of ALK rearrangements, the clinical epidemiology of lung cancer driven by ALK, the clinical data for ALK-targeted therapy in NSCLC, and ongoing ALK inhibitor-based clinical trials. © 2013 Springer-Verlag France.


Rossi A.,Sg Moscati Hospital | Maione P.,Sg Moscati Hospital | Sacco P.C.,Sg Moscati Hospital | Sgambato A.,The Second University of Naples | And 5 more authors.
International Journal of Oncology | Year: 2014

Treatment of unselected patients with advanced non-small cell lung cancer (NSCLC) receiving third-generation platinum-based chemotherapy has reached a plateau of effectiveness. Histology and molecular analyses are the cornerstone in the initial diagnosis of NSCLC and are key determinants to address the appropriate strategy of treatment. In non-squamous histology the combination of cisplatin plus pemetrexed or carboplatin plus paclitaxel plus bevacizumab are considered today the best regimens yielding better activity and efficacy. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib or afatinib are the standard-of-care for patients with advanced NSCLC harbouring activating EGFR mutations. The identification of anaplastic lymphoma kinase (ALK ) rearrangements in 2-5% of NSCLC patients led to the rapid clinical development of its oral TKI, crizotinib, also targeting the proto-oncogene MET and ROS1. The results reported from the first phase III trial showed superiority of crizotinib compared with standard chemotherapy in second-line treatment of ALK-positive NSCLC, which was recently approved in several countries in this setting. Unfortunately, after initial activity of crizotinib, patients will ultimately develop acquired resistances within 1 or 2 years of therapy. A second generation of ALK inhibitors, such as LDK378, alectinib and AP26113 may represent a promising treatment approach: they are under investigation with very promising early results. This review discusses ALK rearrangements, the clinical development and use of crizotinib, and other ALK-TKIs in advanced NSCLC.


A previous study of the corrections needed for output factor measurements with the CyberKnife system has been extended to include new diode detectors (IBA SFD and Exradin D1V), an air filled microchamber (Exradin CC01) and a scintillation detector (Exradin W1). The dependence of the corrections on detector orientation (detector long axis parallel versus perpendicular to the beam axis) and source to detector distance (SDD) was evaluated for these new detectors and for those in our previous study. The new diodes are found to over-respond at the smallest (5 mm) field size by 2.5% (D1V) and 3.3% (SFD) at 800 mm SDD, while the CC01 under-responds by 7.4% at the same distance when oriented parallel to the beam. Corrections for all detectors tend to unity as field size increases. The W1 corrections are <0.5% at all field sizes. Microchamber correction factors increase substantially if the detector is oriented perpendicular to the beam (by up to 23% for the PTW 31014). Corrections also vary with SDD, with the largest variations seen for microchambers in the perpendicular orientation (up to 13% change at 650 mm SDD versus 800 mm) and smallest for diodes (∼1% change at 650 mm versus 800 mm). The smallest and most stable corrections are found for diodes, liquid filled microchambers and scintillation detectors, therefore these should be preferred for small field output factor measurements. If air filled microchambers are used, then the parallel orientation should be preferred to the perpendicular, and care should be taken to use corrections appropriate to the measurement SDD. © 2014 Institute of Physics and Engineering in Medicine.


Francescon P.,ULSS | Kilby W.,Accuray Incorporated | Satariano N.,ULSS | Cora S.,ULSS
Physics in Medicine and Biology | Year: 2012

Monte Carlo (MC) simulation of dose to water and dose to detector has been used to calculate the correction factors needed for dose calibration and output factor measurements on the CyberKnife system. Reference field ionization chambers simulated were the PTW 30006, Exradin A12, and NE 2571 Farmer chambers, and small volume chambers PTW 31014 and 31010. Correction factors for Farmer chambers were found to be 0.7%0.9% larger than those determined from TRS-398 due mainly to the dose gradient across the chamber cavity. For one microchamber where comparison was possible, the factor was 0.5% lower than TRS-398 which is consistent with previous MC simulations of flattening filter free Linacs. Output factor detectors simulated were diode models PTW 60008, 60012, 60017, 60018, Sun Nuclear edge detector, air-filled microchambers Exradin A16 and PTW 31014, and liquid-filled microchamber PTW 31018 microLion. Factors were generated for both fixed and iris collimators. The resulting correction factors differ from unity by up to+11% for air-filled microchambers and6% for diodes at the smallest field size (5 mm), and tend towards unity with increasing field size (correction factor magnitude <1% for all detectors at field sizes >15 mm). Output factor measurements performed using these detectors with fixed and iris collimators on two different CyberKnife systems showed initial differences between detectors of >15% at 5 mm field size. After correction the measurements on each unit agreed within 1.5% at the smallest field size. This paper provides a complete set of correction factors needed to apply a new small field dosimetry formalism to both collimator types on the CyberKnife system using a range of commonly used detectors. © 2012 Institute of Physics and Engineering in Medicine.


Masi L.,Casa di Cura S. Chiara | Casamassima F.,Casa di Cura S. Chiara | Doro R.,Casa di Cura S. Chiara | Francescon P.,ULSS
Medical Physics | Year: 2011

Purpose: To compare and evaluate different dosimetric techniques and devices for the QA of VMAT plans created by two treatment planning systems (TPSs). Methods: A total of 50 VMAT plans were optimized for treatment of anatomical sites of various complexities by two TPSs which use rather different approaches to VMAT optimization. Dosimetric plan verifications were performed both as part of commissioning and as patient specific QA of clinical treatments. Absolute point doses were measured for all plans by a micro ion chamber inserted in a dedicated water-filled cylindrical phantom. Delivered dose distributions were verified by four techniques based on different detectors: radiographic and gafchromic films, two systems based on 2D diode arrays and an ion chamber array. Gamma index analysis with various tolerance levels (3%, 3 mm and 3%, 2 mm) was used to analyze differences between calculated and delivered doses. Sensitivity to possible delivery errors was also evaluated for three of the considered devices introducing ±3 mm shifts along the three directions and a 3° gantry offset. Results: Ion chamber measured point doses were within 3% of calculated ones for 48 out of 50 values. For delivered dose distribution, the average fraction of passed gamma values using 3% and 3 mm criteria was above 95% for both TPSs and all detectors except gafchromic film which yielded on average of 91.4%. For 49 out of 50 plans, a pass-rate above 94% was obtained by at least one of the four techniques. Shrinking the tolerance to 3% and 2 mm, the average pass-rate by all detectors (except film) was still above 95% for one of the two TPSs, but lower for the other one. The detector sensitivity to 3 mm shifts and to gantry angle offset was strongly plan and partially detector dependent: the obtained pass-rate reduction ranged from 2% to 30%. Conclusions: The presented results for VMAT plans QA assess the reliability of the delivered doses for both TPSs. The slightly lower pass-rate obtained for one of the considered TPS can be attributed to a higher level of complexity of the optimized plans. The results by different dosimetric techniques are coherent, apart from a few measurements by gafchromic films. The detector sensitivity to delivery errors, being strongly plan dependent, is not easy to evaluate. © 2011 American Association of Physicists in Medicine.


Purpose: The scope of this study was to determine a complete set of correction factors for several detectors in static small photon fields for two linear accelerators (linacs) and for several detectors. Methods: Measurements for Monte Carlo (MC) commissioning were performed for two linacs, Siemens Primus and Elekta Synergy. After having determined the source parameters that best fit the measurements of field specific output factors, profiles, and tissue-phantom ratio, the generalized version of the classical beam quality correction factor for static small fields, k Q clin, Q msr f clin, f msr, were determined for several types of detectors by using the egs chamber Monte Carlo user code which can accurately reproduce the geometry and the material composition of the detector. The influence of many parameters (energy and radial FWHM of the electron beam source, field dimensions, type of accelerator) on the value of k Q clin, Q msr f clin, f msr was evaluated. Moreover, a MC analysis of the parameters that influence the change of k Q clin, Q msr f clin, f msr as a function of field dimension was performed. A detailed analysis of uncertainties related to the measurements of the field specific output factor and to the Monte Carlo calculation of k Q clin, Q msr f clin, f msr was done. Results: The simulations demonstrated that the correction factor k Q clin, Q msr f clin, f msr can be considered independent from the quality beam factor Q in the range 0.68 0.01 for all the detectors analyzed. The k Q clin, Q msr f clin, f msr of PTW 60012 and EDGE diodes can be assumed dependent only on the field size, for fields down to 0.5 0.5 cm 2. The microLion, and the microchambers, instead, must be used with some caution because they exhibit a slight dependence on the radial FWHM of the electron source, and therefore, a correction factor only dependent on field size can be used for fields 0.75 0.75 and 1.0 1.0 cm 2, respectively. The analysis of uncertainties gave an estimate of uncertainty for the 0.5 0.5 cm 2 field of about 0.7 (1) for k Q clin, Q msr f clin, f msr factor and of about 1.0 (1) for the field output factor, Q clin, Q msr f clin, f msr, of diodes, microchambers, and microLion. Conclusions: Stereotactic diodes with the appropriate k Q clin, Q msr f clin, f msr are recommended for determining Q clin, Q msr f clin, f msr of small photon beams. © 2011 American Association of Physicists in Medicine.

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