Integrazione della riduzione della mobilità respiratoria nel trattamento radiante esterno conformazionale

Several methods to reduce respiratory-induced motion have been described in literature, with the goal of increasing accuracy of treatment to minimize normal tissue toxicity or increase dose to the target volume. We analyzed two different techniques of respiratory gating: the deep inspiration breath hold technique and the respiratory gating using the Real-time Position Management (RPM) system. The first method is a self-gating technique in which radiation treatment take place during a phase of breath-holding. The second technique use a reflective marker placed on the patient’s anterior surface. The motion of the marker is tracked using a camera interfaced to a computer. The gating thresholds are set when the tumor is in the desired portion of the respiratory cycle. These thresholds determine when the gating system turns the treatment beam on and off. We compared both techniques with a standard external radiation treatment. The dosimetric analysis has led to considerable advantage of these methods compared to the external radiation treatment, particularly in reducing the dose to the lung.

L'associazione Tipifarnib-Bortezomib nel trattamento delle leucemie acute mieloidi: risultati di uno studio multicentrico di fase I/II e validazione di un profilo genico predittivo di risposta

Background. Outcome of elderly acute myeloid leukemia (AML) patients is dismal. Targeted-therapies might improve current results by overcoming drug-resistance and reducing toxicity. Aim. We conduced a phase II study aiming to assess efficacy and toxicity of Tipifarnib (Zarnestra®) and Bortezomib (Velcade®) association in AML patients >18 years, unfit for conventional therapy, or >60 years, in relapse. Furthermore, we aimed to evaluated the predictive value of the RASGRP1/APTX ratio, which was previously found to be associated to treatment sensitivity in patients receiving Zarnestra alone. Methods. Velcade (1.0 mg/m2) was administered as weekly infusion for 3 weeks (days 1, 8, 15). Zarnestra was administered at dose of 300-600 mg BID for 21 consecutive days. Real-time quantitative-PCR (q-PCR) was used for RASGRP1/APTX quantification. Results. 50 patients were enrolled. Median age was 71 years (56-89). 3 patients achieved complete remission (CR) and 1 partial response (PR). 2 patients obtained an hematological improvement (HI), and 3 died during marrow aplasia. 10 had progressive disease (PD) and the remaining showed stable disease (SD). RASGRP1/APTX was evaluated before treatment initiation on bone marrow (BM) and/or peripheral blood (PB). The median RASGRP/APTX value on BM was higher in responder (R) patients than in non responders (NR) ones, respectively (p=0.006). Interestingly, no marrow responses were recorded in patients with BM RASGRP1/APTX ratio <12, while the response rate was 50% in patients with ratio >12. Toxicity was overall mild, the most common being febrile neutropenia. Conclusion. We conclude that the clinical efficacy of the combination Zarnestra-Velcade was similar to what reported for Zarnestra alone. However we could confirm that the RASGPR1/APTX level is an effective predictor of response. Though higher RASGRP1/APTX is relatively rare (~10% of cases), Zarnestra (±Velcade) may represent an important option in a subset of high risk/frail AML patients.

Sintesi e caratterizzazione di sistemi nanostrutturati per il trattamento del Glioblastoma multiforme

Nanomedicine is a science based on the preparation of nanosystems for biomedical application. The drugs can be entrapped inside the nanocarriers to improve the drug concentration in the diseased issue through a drug delivery approach; polimeric materials as PLGA-b-PEG has been revealed good properties for this purpose. To improve the nanosystem efficiency it is possible to bind a targeting agent on the carrier surface. In this thesis work silver nanoparticles or drugs as Temsirolimus and Alisertib have been entrapped in PLGA-b-PEG carriers. Chlorotoxin has been linked on the carrier surface as a specific targeting agent for brain tumors. Citotoxicity in vitro of the nanosystems on Glioblastoma cells has been studied.

Questioni di vita o di morte? Riflessioni sulle dichiarazioni anticipate di trattamento

Fino a non molto tempo fa vi erano linee di riflessione che tendevano a considerare la bioetica come una disciplina sostanzialmente attinente alla sfera privata della coscienza individuale degli operatori direttamente coinvolti e perciò non direttamente connessa a questioni di organizzazione complessiva della società pubblica. Nel corso del tempo la prospettiva si è progressivamente evoluta, dal momento che le questioni bioetiche sollevano molti interrogativi di carattere etico, deontologico e giuridico, divenendo così oggetto di riflessione anche sul versante sociale e politico: potremmo parlare, in altri termini, di biopolitica e biodiritto. Infatti il legislatore è spesso chiamato ad esprimersi su questioni sollevate da “casi” bioeticamente significativi e dovrebbe poterlo fare con cognizione di causa. Il dibattito sulle “Dichiarazioni Anticipate di Trattamento” rappresenta una di tali questioni. Molte e diverse sono le denominazioni utilizzate per indicare lo strumento atto a manifestare le scelte di fine vita. Tutte, però, fanno riferimento ad un documento scritto, contenente le indicazioni espresse da una persona sana e capace di intendere e di volere, avente per oggetto i trattamenti sanitari e assistenziali che si vogliono o non si vogliono ricevere nell’ipotesi in cui, a causa di una malattia grave, inguaribile o di un evento traumatico, tale persona si venisse a trovare in uno stato di incapacità di intendere e di volere. Dietro la diversa terminologia utilizzata, si evidenziano difficoltà di diversa natura: il riferimento alla libertà del singolo e al suo diritto di autodeterminazione, l’ampio concetto di salute, il principio dell’uguaglianza, la nozione di dignità, la questione dell’obiezione di coscienza. L'idea di affrontare questo tema nasce dal desiderio di approfondire uno degli aspetti maggiormente discussi nel settore delle scelte di fine vita; di riflettere sulla legittimità e sulla reale utilità di uno strumento come le DAT; di indagare la reale situazione intorno alle tematiche di fine vita.

Tecniche avanzate per l'analisi di sensitività globale: applicazione alla contaminazione delle acque sotterranee.

The thesis is framed within the field of the stochastic approach to flow and transport themes of solutes in natural porous materials. The methodology used to characterise the uncertainty associated with the modular predictions is completely general and can be reproduced in various contexts. The theme of the research includes the following among its main objectives: (a) the development of a Global Sensitivity Analysis on contaminant transport models in the subsoil to research the effects of the uncertainty of the most important parameters; (b) the application of advanced techniques, such as Polynomial Chaos Expansion (PCE), for obtaining surrogate models starting from those which conduct traditionally developed analyses in the context of Monte Carlo simulations, characterised by an often not negligible computational burden; (c) the analyses and the understanding of the key processes at the basis of the transport of solutes in natural porous materials using the aforementioned technical and analysis resources. In the complete picture, the thesis looks at the application of a Continuous Injection transport model of contaminants, of the PCE technique which has already been developed and applied by the thesis supervisors, by way of numerical code, to a Slug Injection model. The methodology was applied to the aforementioned model with original contribution deriving from surrogate models with various degrees of approximation and developing a Global Sensitivity Analysis aimed at the determination of Sobol’ indices.

Predittori precoci di outcome neurologico nei neonati affetti da Encefalopatia Ipossico-Ischemica sottoposti a trattamento ipotermico. Studio combinato Elettroencefalogramma ad integrazione di ampiezza e Spettroscopia nel vicino infrarosso

Background: Brain cooling (BC) represents the elective treatment in asphyxiated newborns. Amplitude Integrated Electroencephalography (aEEG) and Near Infrared Spectroscopy (NIRS) monitoring may help to evaluate changes in cerebral electrical activity and cerebral hemodynamics during hypothermia. Objectives: To evaluate the prognostic value of aEEG time course and NIRS data in asphyxiated cooled infants. Methods: 12 term neonates admitted to our NICU with moderate-severe Hypoxic-Ischemic Encephalopathy (HIE) underwent selective BC. aEEG and NIRS monitoring were started as soon as possible and maintained during the whole hypothermic treatment. Follow-up was scheduled at regular intervals; adverse outcome was defined as death, cerebral palsy (CP) or global quotient < 88.7 at Griffiths’ Scale. Results: 2/12 infants died, 2 developed CP, 1 was normal at 6 months of age and then lost at follow-up and 7 showed a normal outcome at least at 1 year of age. The aEEG background pattern at 24 hours of life was abnormal in 10 newborns; only 4 of them developed an adverse outcome, whereas the 2 infants with a normal aEEG developed normally. In infants with adverse outcome NIRS showed a higher Tissue Oxygenation Index (TOI) than those with normal outcome (80.0±10.5% vs 66.9±7.0%, p=0.057; 79.7±9.4% vs 67.1±7.9%, p=0.034; 80.2±8.8% vs 71.6±5.9%, p=0.069 at 6, 12 and 24 hours of life, respectively). Conclusions: The aEEG background pattern at 24 hours of life loses its positive predictive value after BC implementation; TOI could be useful to predict early on infants that may benefit from other innovative therapies.