FLASH ultra-high dose rates in radiotherapy: preclinical and radiobiological evidence.

PURPOSE: Flash radiotherapy (FLASH-RT) is currently being regarded as the next breakthrough in radiation treatment of cancer, delivering ultrahigh radiation doses in a very short time, and sparing normal tissues from detrimental injury. Here we review the current evidence on the preclinical findings as well as the radiobiological mechanisms underlying the FLASH effect. We also briefly examine the scenario of available technologies for delivering FLASH dose-rates for research and their implications for future clinical use. CONCLUSIONS: Preclinical studies report that the FLASH-RT reduces radiation-induced toxicity whilst maintaining an equivalent tumor response across different animal models. However, the molecular radiobiology underlying FLASH effect is not fully understood and further experiments are necessary to understand the biological response. Future studies also includes the design of a FLASH delivery system able to produce beams appropriate for treatment of tumors with ultra-high dose rates. All these research activities will greatly benefit from a multidisciplinary collaboration across biology, physics and clinical oncology, increasing the potential of a rapid clinical translation of FLASH-RT.

Enhanced laser-driven proton acceleration via improved fast electron heating in a controlled pre-plasma.

The interaction of ultraintense laser pulses with solids is largely affected by the plasma gradient at the vacuum-solid interface, which modifies the absorption and ultimately, controls the energy distribution function of heated electrons. A micrometer scale-length plasma has been predicted to yield a significant enhancement of the energy and weight of the fast electron population and to play a major role in laser-driven proton acceleration with thin foils. We report on recent experimental results on proton acceleration from laser interaction with foil targets at ultra-relativistic intensities. We show a threefold increase of the proton cut-off energy when a micrometer scale-length pre-plasma is introduced by irradiation with a low energy femtosecond pre-pulse. Our realistic numerical simulations agree with the observed gain of the proton cut-off energy and confirm the role of stochastic heating of fast electrons in the enhancement of the accelerating sheath field.

Toward an effective use of laser-driven very high energy electrons for radiotherapy: Feasibility assessment of multi-field and intensity modulation irradiation schemes.

Radiotherapy with very high energy electrons has been investigated for a couple of decades as an effective approach to improve dose distribution compared to conventional photon-based radiotherapy, with the recent intriguing potential of high dose-rate irradiation. Its practical application to treatment has been hindered by the lack of hospital-scale accelerators. High-gradient laser-plasma accelerators (LPA) have been proposed as a possible platform, but no experiments so far have explored the feasibility of a clinical use of this concept. We show the results of an experimental study aimed at assessing dose deposition for deep seated tumours using advanced irradiation schemes with an existing LPA source. Measurements show control of localized dose deposition and modulation, suitable to target a volume at depths in the range from 5 to 10 cm with mm resolution. The dose delivered to the target was up to 1.6 Gy, delivered with few hundreds of shots, limited by secondary components of the LPA accelerator. Measurements suggest that therapeutic doses within localized volumes can already be obtained with existing LPA technology, calling for dedicated pre-clinical studies.

Intra and extra oral clinical manifestations of Rendu-Osler-Weber syndrome: case report and literature review.

Hereditary Hemorrhagic Telangiectasia or Rendu-Osler-Weber syndrome is an incomplete penetrance dominant autosomal transmission disease which determines microcirculatory beds alterations (capillary and venules), caused by the loss of the support tissues that usually enclose blood vessels, and hemorrhage potentially in every organ. The syndrome clinical manifestations are multiple telangiectasia of small proportions on the skin or on the mucous membranes (e.g. of the gastrointestinal tract or other organs), in association with recurring bleedings of the affected areas and external and internal melena. The treatment is a supportive one so to prevent complications. This study reports a case of a patient affected by this syndrome in need of a dental implant following the fracture of a tooth. Furthermore, a bibliographical review of etiopathogenesis, clinical manifestations and therapy options has been made.

Low-level laser therapy protocols in dental movement acceleration and in pain management during orthodontic treatment.

In recent years various studies about the biostimulatory effects of the laser therapy in orthodontics have been carried out. This study investigates the potential advantages obtainable using the Low-level Laser Therapy during orthodontic treatment and the most efficient clinical protocols. Recently published randomized controlled trials (RCTs) have been obtained through a search on electronic databases (Cochrane Library and Pubmed). Clinical studies in humans in which Low-level Laser Therapy was applied during orthodontic treatment were included. In conclusion, 14 relevant clinical studies were identified. This study shows the possibility to obtain an increase in tooth movement between 31% and 100% depending on the laser therapy considered and the time interval for measuring the value. In addition, there is a potential impact in reducing orthodontic pain limited to the day following the application of laser therapy when orthodontic therapy includes canine retraction, and during a period not exceeding five days from the placement of fixed orthodontic appliances in the others clinical cases.Low-level Laser Therapy is considered effective both to increase the movement of the dental elements and to reduce pain during orthodontic therapy. Different clinical protocols have been identified depending on the orthodontic cases considered. Both an LED device and an AlGaAs diode device can be used. In the future paying more attention to the therapeutic possibilities offered by laser devices with greater power is recommended. A greater energy density directed to the target tissues has been proven to provoke more significant therapeutic effects.

Role of mesenchymal stem cells in osteotomy sinus graft healing: a case report and a literature review.

Prosthetic rehabilitation of the edentulous posterior maxilla with implant-supported prostheses frequently presents a challenge for the oral surgeon because of the lack of bone due to alveolar ridge resorption or maxillary sinus pneumatization. To overcome these problems, different solutions were proposed over the years. Maxillary sinus membrane elevation is a common surgical technique for increasing bone height in the posterior maxilla prior to dental implant placement. However, the biological nature of bone regeneration in maxillary sinus membrane remains largely unidentified. The authors present a clinical case and literature review to understand the fundamental of bone formation in osteotomy sinus floor elevation.

The use of a new collagen matrix to support the regeneration of peri-implant soft tissue laser-assisted: case report.

Several factors compete for both the achievement and the long-term maintenance of osseointegration; among these, of importance is the width and integrity of the peri-implant soft tissue. Many authors already underlined the importance for implant-prosthesis procedures to maintain a good biological seal together with a low bacterial cell surface charge (this is also valid for a natural tooth with an undamaged periodontium). The aim of this work is to present, through a clinical case, a new technique that focuses on the regeneration of soft tissue around a post-extractive implant. For the case reported, a post-extractive implant surgery of an inferior molar of the fourth quadrant with a buccal bone resorption of 3mm in the mesial section of the root, three dimensional collagen matrices (Bioteck) and a blend of equine spongy bone granules (OX Bioteck) were used, combined with aPDT without dye (Rey Protocol). With an easy and not invasive surgery, this technique allows the recreation of new gingiva around the implant.

Evaluation of the degree of differentiation of human mesenchimal stem cells on different titanium superfaces: a pilot study.

The aim of our study was to evaluate the properties of a laser-modified titanium surface, specifically the promotion of a faster differentiation of human Mesenchymal Stem Cells (hMSCs) into osteoblasts and a more stable connection between differentiated cells and titanium, compared to machined and sand-blasted surfaces. Furthermore, we wanted to assess if the titanium alone could be a sufficient factor in the induction of the differentiation towards the osteogenic lineage. MATERIALS AND METHODS: we harvested stem cells from an individual (under his consensus) and cultivated them into dishes containing titanium disks presenting three different surfaces: machined (M), sand-blasted (S) and laser-modified (L). In the test group, cells were cultivated in an osteogenic medium, while in the control group, cells were seeded in a standard DMEM. Evaluations of the degree of differentiation were made with Alizarin coloration after 28, 38, 42, 49, 56 and 63 days from induction. RESULTS: no signs of differentiation were evident in the control group, while in the test group there was a statistically significant differentiation, evident since the fourth week. Laser-modified and sand-blasted surfaces showed similar values, higher than the machined surface. DISCUSSION: on the laser-modified surface the differentiation reached its peak on the sixth week, while on the seventh week for the other two surfaces. After the peak, the differentiation showed a slow decrease for the laser-modified surface and a rapid decrease for the other two. CONCLUSIONS: titanium alone can't be considered enough to induce differentiation of human Mesenchymal Stem Cells into osteoblasts. Still, the laser-modified once induced a faster differentiation of stem cells and a more stable connection between osteoblasts and titanium.

Numerical simulation of novel concept 4D cardiac microtomography for small rodents based on all-optical Thomson scattering X-ray sources.

Accurate dynamic three-dimensional (4D) imaging of the heart of small rodents is required for the preclinical study of cardiac biomechanics and their modification under pathological conditions, but technological challenges are met in laboratory practice due to the very small size and high pulse rate of the heart of mice and rats as compared to humans. In 4D X-ray microtomography (4D µCT), the achievable spatio-temporal resolution is hampered by limitations in conventional X-ray sources and detectors. Here, we propose a proof-of-principle 4D µCT platform, exploiting the unique spatial and temporal features of novel concept, all-optical X-ray sources based on Thomson scattering (TS). The main spatial and spectral properties of the photon source are investigated using a TS simulation code. The entire data acquisition workflow has been also simulated, using a novel 4D numerical phantom of a mouse chest with realistic intra- and inter-cycle motion. The image quality of a typical single 3D time frame has been studied using Monte Carlo simulations, taking into account the effects of the typical structure of the TS X-ray beam. Finally, we discuss the perspectives and shortcomings of the proposed platform.

Effects of small misalignments on the intensity and Strehl ratio for a laser beam focused by an off-axis parabola.

A general procedure is described to calculate the intensity and Strehl ratio, at a generic plane in the focal region, of a beam focused by an off-axis parabolic mirror in the presence of small misalignments. The general theoretical framework is first developed, which allows a full vector diffraction treatment in the case of general misalignments. Then, a parametric numerical study is reported, aimed at highlighting the tolerances of both the intensity and Strehl ratio for small misalignments, for different focusing and off-axis parabola parameters. A set of experimental measurements aimed at validating the theoretical model is also discussed.

Radiobiological Effectiveness of Ultrashort Laser-Driven Electron Bunches: Micronucleus Frequency, Telomere Shortening and Cell Viability.

Laser-driven electron accelerators are capable of producing high-energy electron bunches in shorter distances than conventional radiofrequency accelerators. To date, our knowledge of the radiobiological effects in cells exposed to electrons using a laser-plasma accelerator is still very limited. In this study, we compared the dose-response curves for micronucleus (MN) frequency and telomere length in peripheral blood lymphocytes exposed to laser-driven electron pulse and X-ray radiations. Additionally, we evaluated the effects on cell survival of in vitro tumor cells after exposure to laser-driven electron pulse compared to electron beams produced by a conventional radiofrequency accelerator used for intraoperative radiation therapy. Blood samples from two different donors were exposed to six radiation doses ranging from 0 to 2 Gy. Relative biological effectiveness (RBE) for micronucleus induction was calculated from the alpha coefficients for electrons compared to X rays (RBE = alpha laser/alpha X rays). Cell viability was monitored in the OVCAR-3 ovarian cancer cell line using trypan blue exclusion assay at day 3, 5 and 7 postirradiation (2, 4, 6, 8 and 10 Gy). The RBE values obtained by comparing the alpha values were 1.3 and 1.2 for the two donors. Mean telomere length was also found to be reduced in a significant dose-dependent manner after irradiation with both electrons and X rays in both donors studied. Our findings showed a radiobiological response as mirrored by the induction of micronuclei and shortening of telomere as well as by the reduction of cell survival in blood samples and cancer cells exposed in vitro to laser-generated electron bunches. Additional studies are needed to improve preclinical validation of the radiobiological characteristics and efficacy of laser-driven electron accelerators in the future.

Effects of low-level laser irradiation on proliferation and osteoblastic differentiation of human mesenchymal stem cells seeded on a three-dimensional biomatrix: in vitro pilot study.

Mesenchymal stem cells (MSCs) from bone marrow are a recent source for tissue engineering. Several studies have shown that low-level laser irradiation has numerous biostimulating effects. The purpose of this trial was to evaluate the effects of Nd:Yag laser irradiation on proliferation and differentiation of MSCs induced into the osteoblastic lineage. MSCs were collected from adult human bone marrow, isolated, and cultured in complete medium (α-MEM). Subsequently, they were treated with osteogenic medium, seeded in three-dimensional collagen scaffolds, and incubated. We used six scaffolds, equally divided into three groups: two of these were irradiated with Nd:Yag laser at different power levels (15 Hz, 100 mJ, 1.5 W, and one with a power level of 15 Hz, 150 mJ, 2.25 W), and one was left untreated (control group). Evaluations with specific staining were performed at 7 and 14 days. After 7 days, proliferation was significantly increased in scaffolds treated with laser, compared with the control scaffold. After 14 days, however, laser irradiation did not appear to have any further effect on cell proliferation. As concerns differentiation, an exponential increase was observed after 14 days of laser irradiation, with respect to the control group. However, this was a pilot study with very limited sample size, we conclude, that low-level laser irradiation might lead to a reduction in healing times and potentially reduces risks of failure.

Scleroderma and CREST syndrome: a case report in dentistry.

CREST syndrome is part of the heterogeneous scleroderma group of autoimmune diseases that cause thickening, hardening and tightening of the connective tissue in different parts of the body, and it may lead to complex disorders. CREST syndrome is characterized by the coexistence of calcinosis, Raynaud's phenomenon, esophageal hypomotility, sclerodactily and telangectasia. A 72-year-old caucasian woman is referred to the S. Gerardo Hospital of Monza, with a chief complaint of oral pain and difficulties in deglutition and eating, associated with denture instability and difficulties to fit it. She had been previously diagnosed with Raynaud's phenomenon, and afterwards with CREST syndrome. Extra-oral examination underlined taut, thickened and rigid skin, pallid-red irregular maculae all over the face, telangiectasias and acrocyanosis. Intra-oral examination showed no alteration of the mucosa, but we can observe tongue rigidity and some speckled red alternating with white spots on the hard palate and in the vestibule. We undermitted the patient the dental treatment of Sjogren's syndrome. The management of the Sjogren's syndrome is symptomatic and empirical, and involves the use of saliva secretion stimulators, salivary substitutes and coadjuvants. Dental treatment and prophylaxis are important to prevent the consequences of xerostomia, such as rampant caries, based on the administration of topical fluoride in toothpastes and rinses, and supplemented by fluoride gels and varnishes. Instruction and reinforcement of oral hygiene, along with frequent dental assessment and management by the dentist are essential measures to preserve the oral health of those affected with CREST syndrome in progression to SS, complicated with Sjogren's syndrome.