Dosimetric and NTCP advantages of robust proton therapy over robust VMAT for Stage III NSCLC in the immunotherapy era.

AIMS: To assess the robustness and to define the dosimetric and NTCP advantages of pencil-beam-scanning proton therapy (PBSPT) compared with VMAT for unresectable Stage III non-small lung cancer (NSCLC) in the immunotherapy era. MATERIAL AND METHODS: 10 patients were re-planned with VMAT and PBSPT using: 1) ITV-based robust optimization with 0.5 cm setup uncertainties and (for PBSPT) 3.5 % range uncertainties on free-breathing CT 2) CTV-based RO including all 4DCTs anatomies. Target coverage (TC), organs at risk dose and TC robustness (TCR), set at V95%, were compared. The NTCP risk for radiation pneumonitis (RP), 24-month mortality (24MM), G2 + acute esophageal toxicity (ET), the dose to the immune system (EDIC) and the left anterior descending (LAD) coronary artery V15 < 10 % were registered. Wilcoxon test was used. RESULTS: Both PBSPT methods improved TC and TCR (p < 0.01). The mean lung dose and lung V20 were lower with PBSPT (p < 0.01). Median mean heart dose reduction with PBSPT was 8 Gy (p < 0.001). PT lowered median LAD V15 (p = 0.004). ΔNTCP > 5 % with PBSPT was observed for two patients for RP and for five patients for 24 MM. ΔNTCP for ≥ G2 ET was not in favor of PBSPT for all patients. PBSPT halved median EDIC (4.9/5.1 Gy for ITV/CTV-based VMAT vs 2.3 Gy for both ITV/CTV-based PBSPT, p < 0.01). CONCLUSIONS: PBSPT is a robust approach with significant dosimetric and NTCP advantages over VMAT; the EDIC reduction could allow for a better integration with immunotherapy. A clinical benefit for a subset of NSCLC patients is expected.

Experimental validation of an innovative approach in biokinetics study for personalised dosimetry of molecular radiation therapy treatments.

One of today's main challenges in molecular radiation therapy is to assess an individual dosimetry that allows treatment to be tailored to the specific patient, in accordance with the current paradigm of 'personalized medicine'. The evaluation of the absorbed doses for tumor and organs at risk in molecular radiotherapy is typically based on MIRD schema acquiring few experimental points for the assessement of biokinetic parameters. WIDMApp, the wearable individual dose monitoring apparatus, is an innovative approach for internal dosimetry based on a wearable radiation detecting system for individual biokinetics sampling, a Monte Carlo simulation for particle interaction, and an unfolding algorithm for data analysis and integrated activity determination at organ level. A prototype of a WIDMApp detector element was used to record the photon emissions in a body phantom containing 3 spheres with liquid sources (18F,64Cu and99mTc) to simulate organs having different washout. Modelling the phantom geometry on the basis of a CT scan imaging, the Monte Carlo simulation computed the contribution of each emitting sphere to the signal detected in 3 positions on the phantoms surface. Combining the simulated results with the data acquired for 120 h, the unfolding algorithm deconvolved the detected signal and assessed the decay half-life (T1/2) and initial activity values (A(0)) that best reproduces the observed exponential decays. A 3%-18% level of agreement is found between the actualA(0) andT1/2values and those obtained by means of the minimization procedure based on the Monte Carlo simulation. That resulted in an estimation of the cumulated activity <15%. Moreover, WIDMApp data redundancy has been used to mitigate some experimental occurrences that happened during data taking. A first experimental test of the WIDMApp approach to internal radiation dosimetry is presented. Studies with patients are foreseen to validate the technique in a real environment.

Fine tuning of the DNAM-1/TIGIT/ligand axis in mucosal T cells and its dysregulation in pediatric inflammatory bowel diseases (IBD).

De-regulated T-cell activation and functions are pivotal in the orchestration of immune-mediated tissue damage in IBD. We investigated the role of DNAM-1 (co-activating)/TIGIT (co-inhibitory)/ligand axis in the regulation of T-cell functions and its involvement in IBD pathogenesis. We show that DNAM-1 and TIGIT display a peculiar expression pattern on gut mucosa T-cell populations, in a microenvironment where their shared ligands (PVR and Nectin-2) are physiologically present. Moreover, DNAM-1 family receptor/ligand system is perturbed in IBD lesions, in a disease activity-dependent manner. The expression profile of CCR6 and CD103 mucosa addressins suggests that microenvironment-associated factors, rather than skewed recruitment of circulating T-cell populations, play a more relevant role in supporting the establishment of DNAM-1 and TIGIT expression pattern in mucosal T-cell populations, and may explain its alteration in IBD. Although both co-receptors mark functionally competent T cells, DNAM-1 and TIGIT segregate on T cells endowed with different proliferative potential. Moreover, their opposing role in regulating T-cell proliferation exquisitely depends on ligand availability. All together, our data propose a role for DNAM-1 and TIGIT in regulating mucosal T-cell activation and immune homeostasis, and highlight the involvement of an imbalance of this system in IBD.

THE TOP-IMPLART PROTON LINEAR ACCELERATOR: INTERIM CHARACTERISTICS OF THE 35 MEV BEAM.

In the framework of the Italian TOP-IMPLART project (Regione Lazio), ENEA-Frascati, ISS and IFO are developing and constructing the first proton linear accelerator based on an actively scanned beam for tumor radiotherapy with final energy of 150 MeV. An important feature of this accelerator is modularity: an exploitable beam can be delivered at any stage of its construction, which allows for immediate characterization and virtually continuous improvement of its performance. Currently, a sequence of 3 GHz accelerating modules combined with a commercial injector operating at 425 MHz delivers protons up to 35 MeV. Several dosimetry systems were used to obtain preliminary characteristics of the 35-MeV beam in terms of stability and homogeneity. Short-term stability and homogeneity better than 3% and 2.6%, respectively, were demonstrated; for stability an improvement with respect to the respective value obtained for the previous 27 MeV beam.

CHARACTERIZATION OF 27 MEV PROTON BEAM GENERATED BY TOP-IMPLART LINEAR ACCELERATOR.

The first proton linear accelerator for tumor therapy based on an actively scanned beam up to the energy of 150 MeV, is under development and construction by ENEA-Frascati, ISS and IFO, under the Italian TOP-IMPLART project. Protons up to the energy of 7 MeV are generated by a customized commercial injector operating at 425 MHz; currently three accelerating modules allow proton delivery with energy up to 27 MeV. Beam homogeneity and reproducibility were studied using a 2D ionizing chamber, EBT3 films, a silicon diode, MOSFETs, LiF crystals and alanine dosimetry systems. Measurements were taken in air with the detectors at ~1 m from the beam line exit window. The maximum energy impinging on the detectors surface was 24.1 MeV, an energy suitable for radiobiological studies. Results showed beam reproducibility within 5% and homogeneity within 4%, on a circular surface of 16 mm in diameter.

Intraoperative radiation therapy as adjuvant treatment in locally advanced stage tumours involving the middle ear: a hypothesis-generating retrospective study.

The objective of this study was to evaluate the safety, effectiveness and functional outcomes of intraoperative radiotherapy (IORT) followed by intensity-modulated radiation therapy (IMRT) in locally advanced stage tumours involving the middle ear. Data on 13 consecutive patients treated for malignant tumor of external auditory canal involving the middle ear were retrospectively reviewed. Median follow-up was 33 months (range 6-133). Five (38%) patients were stage III and 8 (62%) were Stage IV according to the University of Pittsburgh staging system. Lateral temporal bone resection (LTBR) was performed in all cases. LTBR was associated with parotidectomy in 5 (38%) cases, and with neck dissection and parotidectomy in 6 (46%) cases. No patients had gross residual tumour. Surgical treatment was followed by IORT (12 Gy) and IMRT (50 Gy). Adjuvant chemotherapy was used in 4 (30%) cases. Preoperative and postoperative audiometric tests were performed to assess hearing loss. 5-year local-control (LC), 5-year distant-metastasis (DM), 5-year disease-free-survival (DFS) and 5-year overall-survival (OS) were calculated with Kaplan-Meyer method. Significant changes in bone conduction were reported after treatment. Partial flap necrosis was the only early complication observed in three (23%) cases, while meningeal fistula was seen in one (7.6%) case as a late complication. The 5-year LC-rate was 68%. The 5-year DM-rate was 90%. The 5-year DFS-rate was 61%. The 5-year OS-rate was 69%. IORT followed by IMRT for the treatment of advanced external auditory canal and middle ear tumours seems to be safe. No intraoperative death was reported. IORT may reduce the postoperative irradiation of remnant tissue obtaining the same full dose on the tumour bed. No complications of the residual external ear were observed. Detriment of neurosensory hearing may be expected. Future studies are required to confirm the benefit of this procedure in the ear.

The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress.

The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex might be connected on a unique pathway essential for the safe expansion of neuronal cells. Here, we show that MYCN transcriptionally controls the expression of each component of the MRN complex. By genetic and pharmacological inhibition of the MRN complex in a MYCN overexpression model and in the more physiological context of the Hedgehog-dependent expansion of primary cerebellar granule progenitor cells, we also show that the MRN complex is required for MYCN-dependent proliferation. Indeed, its inhibition resulted in DNA damage, activation of a DNA damage response, and cell death in a MYCN- and replication-dependent manner. Our data indicate the MRN complex is essential to restrain MYCN-induced replication stress during neural cell proliferation and support the hypothesis that replication-born DNA damage is responsible for the neuronal defects associated with MRN dysfunctions.

Clinical evaluation of X-ray voxel Monte Carlo versus pencil beam-based dose calculation in stereotactic body radiotherapy of lung cancer under normal and deep inspiration breath hold.

The purpose of this study is to evaluate the differences between dose distributions calculated with the pencil beam (PB) and X-ray voxel Monte Carlo (MC) algorithms for patients with lung cancer using intensity-modulated radiotherapy (IMRT) or HybridArc techniques. The 2 algorithms were compared in terms of dose-volume histograms, under normal and deep inspiration breath hold, and in terms of the tumor control probability (TCP). The dependence of the differences in tumor volume and location was investigated. Dosimetric validation was performed using Gafchromic EBT3 (International Specialty Products, ISP, Wayne, NJ). Forty-five Computed Tomography (CT) data sets were used for this study; 40 Gy at 8 Gy/fraction was prescribed with 5 noncoplanar 6-MV IMRT beams or 3 to 4 dynamic conformal arcs with 3 to 5 IMRT beams distributed per arc. The plans were first calculated with PB and then recalculated with MC. The difference between the mean tumor doses was approximately 10% ± 4%; these differences were even larger under deep inspiration breath hold. Differences between the mean tumor dose correlated with tumor volume and path length of the beams. The TCP values changed from 99.87% ± 0.24% to 96.78% ± 4.81% for both PB- and MC-calculated plans (P = .009). When a fraction of hypoxic cells was considered, the mean TCP values changed from 76.01% ± 5.83% to 34.78% ± 18.06% for the differently calculated plans (P < .0001). When the plans were renormalized to the same mean dose at the tumor, the mean TCP for oxic cells was 99.05% ± 1.59% and for hypoxic cells was 60.20% ± 9.53%. This study confirms that the MC algorithm adequately accounts for inhomogeneities. The inclusion of the MC in the process of IMRT optimization could represent a further step in the complex problem of determining the optimal treatment plan.

Monte Carlo as a tool to evaluate the effect of different lung densities on radiotherapy dose distribution.

This study aims at evaluating the effects of different lung densities on dose distribution after irradiation at different field sizes, by comparing experimental measurements, GEANT4 Monte Carlo (MC) simulations and two TPS calculation algorithms on ad hoc phantoms. Irradiations were performed with a Varian Clinac 2100 C/D with a nominal energy of 6 MV. Dosimetric experimental measurements were obtained with radiochromic films. A model based on GEANT4 MC code was developed to simulate both the accelerator and the phantoms. Results of dose distribution show an acceptable agreement between MC simulations and experimental measurements, both in the tumour-equivalent region and in the normal tissue-equivalent ones. On the opposite, results vary among the TPS algorithms, especially in regions of lung-equivalent material at low density, but also at the interface between lung- and tumour-equivalent materials.

Physical and dosimetric optimization of laser equipment in dermatology: a preliminary study.

The aim of this preliminary study is to investigate the correlation between clinical set-up at present used in the treatment of specific skin conditions and laser beam absorbed power in the tissue. This study focused on the CO2 and Nd-Yag laser equipment used in the daily clinical practice in the Department of Dermatology of San Gallicano Institute in Rome. Different types of tissue-equivalent material with various water and haemoglobin concentrations were tested to evaluate laser beam attenuation power. In particular, thinly sliced pork loin, of uniform consistency and without fat, was selected for its high content of haemoglobin to mimic human tissues. An optical power meter was used to measure the power or energy of a laser beam. During measurements, the tissue equivalent phantoms were positioned on the detector head and the laser beam was orthogonally oriented. The results of two experimental set-ups are reported here. The dependence of residual power (W) as a function of ex vivo tissue thickness (mm) for different laser output powers was studied. Data were fitted by a parametric logistic equation. These preliminary data allow for more accurately determining the energy fraction released from lasers to the tissues in order to improve clinical outcomes.

Monte Carlo simulation of electron beams generated by a 12 MeV dedicated mobile IORT accelerator.

The aim of this study was to investigate the dosimetric characteristics of the electron beams generated by the light intraoperative accelerator, Liac® (SORDINA, Italy), using Monte Carlo (MC) calculations. Moreover we investigated the possibility of characterizing the Liac® dosimetry with a minimal set of dosimetric data. In fact accelerator commissioning requires measurements of both percentage depth doses (PDDs) and off-axis profiles for all the possible combinations of energy, applicator diameter and bevelled angle. The Liac® geometry and water phantom were simulated in a typical measurement setup, using the MC code EGSnrc/BEAMnrc. A simulated annealing optimization algorithm was used in order to find the optimal non-monoenergetic spectrum of the initial electron beam that minimizes the differences between calculated and measured PDDs. We have concluded that, for each investigated nominal energy beam, only the PDDs of applicators with diameters of 30, 70 and 100 mm and the PDD without an applicator were needed to find the optimal spectra. Finally, the output factors of the entire set of applicator diameters/bevelled angles were calculated. The differences between calculated and experimental output factors were better than 2%, with the exception of the smallest applicator which gave differences between 3% and 4% for all energies. The code turned out to be useful for checking the experimental data from various Liac® beams and will be the basis for developing a tool based on MC simulation to support the medical physicist in the commissioning phase.

Single fraction partial breast irradiation in prone position.

The purpose of this work is to introduce a new treatment approach and technique for partial breast irradiation in only one session to patients in prone position by using a dedicated positioning device. The patients were treated on a home-made treatment table top that allows the breast to hang down. A particular immobilization system was introduced in order to assure the reproducibility of patient positioning between the CT acquisition session and the treatment session. The clinical target volume (CTV) was outlined according to surgical clips position and/or tumor location on preoperative mammography. Because of negligible movement due to respiration, only an additional margin of 3 mm was added to obtain the planning target volume (PTV). Based on radiobiological calculations, a dose of 21 Gy was prescribed to PTV. The tumor bed was treated with 3D-CRT technique by using 5 fields and rotating the table while the gantry was approximately 90 or 270 degrees. Thirty patients were enrolled for this study chosen in conformity to an approved clinical protocol. The average percentage of PTV volume enclosed in the 90% and 95% of prescribed dose were 99.9 and 98.6% respectively, while only 3.4% of PTV volume received more than 105% of prescribed dose. Dose to 3% of skin volume was, on average, 15.2 Gy. In 97% of patients, less than 50% of the ipsilateral breast received a dose greater than half the prescribed dose. Mean doses to lungs, heart and contralateral breast were negligible. With a median follow-up of 9 months, no important early toxicity was observed both for skin and breast tissue. The treatment of breast tumor bed in prone position in only one session by using the 3D-CRT is technically feasible and seems to be a promising alternative to other accelerated partial breast irradiation techniques.

On measuring the output of an IORT mobile dedicated accelerator.

In the present work, dose-to-water values derived from Fricke (operated by the Italian Primary Standard Dosimetry Laboratory) and alanine (operated by the Istituto Superiore di Sanità, Italy) measurements in IORT electron beams characterised by a high dose per pulse were compared to show the extent of equivalence of the two dosimetry systems. This study demonstrates agreement (within 2%) of the two dosimetry systems for plane-base IORT applicators, but in the case of small diameter (40 mm) and bevelled (22.5 degrees ) applicators, Fricke dosemeters underestimated doses by 2.4%. For base bevelled IORT applicators (22.5 degrees or more) with small diameter ( approximately 40 mm or less) reduced dimensions of the dosemeter are needed. Under these measurement conditions, the alanine dosemeter gives better accuracy in beam output determination compared with the Fricke dosemeter used.

A role for PKCtheta in outside-in alpha(IIb)beta3 signaling.

Fibrinogen binding to platelets triggers alpha(IIb)beta3-dependent outside-in signals that promote actin rearrangements and cell spreading. Studies with chemical inhibitors or activators have implicated protein kinase C (PKC) in alpha(IIb)beta3 function. However, the role of individual PKC isoforms is poorly understood. Biochemical and genetic approaches were used to determine whether PKCtheta is involved in alpha(IIb)beta3 signaling. PKCtheta was constitutively associated with alpha(IIb)beta3 in human and murine platelets. Fibrinogen binding to alpha(IIb)beta3 stimulated the association of PKCtheta with tyrosine kinases Btk and Syk, and tyrosine phosphorylation of PKCtheta, Btk and the actin regulator, Wiskott-Aldrich syndrome protein (WASP). Mouse platelets deficient in PKCtheta or Btk failed to spread on fibrinogen. Furthermore, PKCtheta was required for phosphorylation of WASP-interacting protein on Ser-488, an event that has been linked to WASP activation of the Arp2/3 complex and actin polymerization in lymphocytes. Neither PKCtheta nor Btk were required for agonist-induced inside-out signaling and fibrinogen binding to alpha(IIb)beta3. Thus, PKCtheta is a newly identified, essential member of a dynamic outside-in signaling complex that includes Btk and that couples alpha(IIb)beta3 to the actin cytoskeleton.

Radiation exposure of personnel during intraoperative radiotherapy (IORT): radiation protection aspects.

Intraoperative radiotherapy (IORT) is a multidisciplinary procedure which combines two conventional methods of cancer treatment surgery and radiation therapy. The purpose is to deliver a large single dose to the surgically exposed tumor bed while minimizing doses to normal tissues. Intraoperative radiation therapy (IORT) is a technique which allows irradiating the patient directly after the surgical operation using a linear accelerator that can be situated in the operating room. For medical accelerators with energy over 10MeV the need to characterize the neutron spectra for this particular situation arises from the fact that, when neutron spectra is not fully known, it becomes necessary to be more cautious introducing a weight factor wR of 20 (maximum value). This leads to overesteem the equivalent dose due to neutrons and it indicates to introduce additional (mobile) shields for photon and neutrons radiation not easily achievable in an operating room.

Estudio de la IORT para la búsqueda de dosis tras la prostactetomía radical (PR) en el cáncer de próstata / A dose-finding study of IORT after radical prostatectomy (RP) in prostate cancer

No disponible

Epithelial ovarian cancer in female pseudohermaphroditism. A diagnosis by computed tomography and review of the literature.

We describe the case of a patient proven to be a female pseudohermaphrodite with a complete virilization syndrome who developed an epithelial tumor of the ovary of borderline malignancy. The tumor appeared as an abdominal mass with cystic features on ultrasonography. The diagnosis of the intersexual condition and adnexal cancer was made by computed tomography (CT).

The saturation loss for plane parallel ionization chambers at high dose per pulse values.

The use of plane parallel ionization chambers with electron beams with high dose per pulse entails dose uncertainties due to the overestimation of the ion recombination factor, k, up to 20% if conventional dosimetric protocols are used. In this work MD-55-2 radiochromic films have been used as reference dosimeters to obtain dose to water per pulse DGAF(w) values for three Novac7 (Hitesys) electron beams of E0 = 5.8 MeV. However, the beam calibration by MD-55-2 films is time consuming and the use of plane parallel chambers is fundamental for a periodic quality control procedure. Three plane parallel chambers have been used and the general formula for the k determination has been tested using the calibration doses, DGAF(w). In particular, consistent ion recombination factors ksat(V0) (with the ion chamber polarized at V0), that follow the Boag theory, have been estimated at different dose per pulse values for the three plane parallel ionization chambers. This means that at present any ion chamber needs a specific ksat (V0) determination by using a reference dosimeter for which the response is independent of the dose rate. An accurate determination of ksat(V0), using a reference quality beam, can be used to determine the dose to water per pulse for electron beams of different quality and geometrical configuration.

RAC1/P38 MAPK signaling pathway controls beta1 integrin-induced interleukin-8 production in human natural killer cells.

The MAP kinase (MAPK) p38 plays a key role in regulating inflammatory responses. Here, we demonstrate that beta1 integrin ligation on human NK cells results in the activation of the p38 MAPK signaling pathway, which is required for integrin-triggered IL-8 production. In addition, we identified some of the upstream events accompanying the beta1 integrin-mediated p38 MAPK activation, namely, the activation of the Rac guanine nucleotide exchange factor (GEF) p95 Vav, the small G protein Rac1, and the cytoplasmic kinases Pak1 and MKK3. Finally, we provide direct evidence that p95 Vav and Rac control the activation of p38 MAPK triggered by beta1 integrins.