SRAP markers as an alternative tool for Alternaria classification.

Alternaria is one of the main fungal contaminants of cereal grains worldwide with the potential to produce mycotoxins hazardous to human and animal health. Many studies have been carried out to characterize Alternaria sp.-grp. using traditional morphology or polyphasic approach, but a good correlation between morphological sp.-grp., molecular, and chemotaxonomic groups has not always been achieved. For this reason, this study aimed to investigate the usefulness of a cheaper alternative tool, SRAP markers, in identifying Alternaria sp.-grps. obtained from Argentinean barley grains and to compare it with preliminary characterization using morphological traits, phylogeny, and metabolite profiles. Fifty-three Alternaria isolates from barley grains of the main producing regions of Argentina were analyzed with four combinations of SRAP markers. The UPGMA dendrogram, based on the Simple Matching similarity coefficient, revealed three distinct groups. SRAP markers allowed the separation of Alternaria from Infectoriae sections in agreement with the results of a polyphasic approach previously made. Besides, isolates of A. arborescens sp.-grp. were clustered in a separate group from isolates of A. tenuissima and A. alternata sp.-grp., which were grouped in the same cluster. SRAP markers are a recommended tool for classifying Alternaria isolates because of its simplicity, reliability, and cost-effectiveness compared to other molecular markers.

Ion recombination correction factors and detector comparison in a very-high dose rate proton scanning beam.

PURPOSE: Accurate dosimetry is paramount to study the FLASH biological effect since dose and dose rate are critical dosimetric parameters governing its underlying mechanisms. With the goal of assessing the suitability of standard clinical dosimeters in a very-high dose rate (VHDR) experimental setup, we evaluated the ion collection efficiency of several commercially available air-vented ionization chambers (IC) in conventional and VHDR proton irradiation conditions. METHODS: A cyclotron at the Orsay Proton Therapy Center was used to deliver VHDR pencil beam scanning irradiation. Ion recombination correction factors (ks) were determined for several detectors (Advanced Markus, PPC05, Nano Razor, CC01) at the entrance of the plateau and at the Bragg peak, using the Niatel model, the Two-voltage method and Boag's analytical formula for continuous beams. RESULTS: Mean dose rates ranged from 4 Gy/s to 385 Gy/s, and instantaneous dose rates up to 1000 Gy/s were obtained with the experimental set-up. Recombination correction factors below 2 % were obtained for all chambers, except for the Nano Razor, at VHDRs with variations among detectors, while ks values were significantly smaller (0.8 %) for conventional dose rates. CONCLUSIONS: While the collection efficiency of the probed ICs in scanned VHDR proton therapy is comparable to those in the conventional regime with recombination coefficiens smaller than 1 % for mean dose rates up to 177 Gy/s, the reduction in collection efficiency for higher dose rates cannot be ignored when measuring the absorbed dose in pre-clinical proton scanned FLASH experiments and clinical trials.

Perspectives in linear accelerator for FLASH VHEE: Study of a compact C-band system.

PURPOSE: In order to translate the FLASH effect in clinical use and to treat deep tumors, Very High Electron Energy irradiations could represent a valid technique. Here, we address the main issues in the design of a VHEE FLASH machine. We present preliminary results for a compact C-band system aiming to reach a high accelerating gradient and high current necessary to deliver a Ultra High Dose Rate with a beam pulse duration of 3µs. METHODS: The proposed system is composed by low energy high current injector linac followed by a high acceleration gradient structure able to reach 60-160 MeV energy range. To obtain the maximum energy, an energy pulse compressor options is considered. CST code was used to define the specifications RF parameters of the linac. To optimize the accelerated current and therefore the delivered dose, beam dynamics simulations was performed using TSTEP and ASTRA codes. RESULTS: The VHEE parameters Linac suitable to satisfy FLASH criteria were simulated. Preliminary results allow to obtain a maximum energy of 160 MeV, with a peak current of 200 mA, which corresponds to a charge of 600 nC. CONCLUSIONS: A promising preliminary design of VHEE linac for FLASH RT has been performed. Supplementary studies are on going to complete the characterization of the machine and to manufacture and test the RF prototypes.

Future technological developments in proton therapy - A predicted technological breakthrough.

In the current spectrum of cancer treatments, despite high costs, a lack of robust evidence based on clinical outcomes or technical and radiobiological uncertainties, particle therapy and in particular proton therapy (PT) is rapidly growing. Despite proton therapy being more than fifty years old (first proposed by Wilson in 1946) and more than 220,000 patients having been treated with in 2020, many technological challenges remain and numerous new technical developments that must be integrated into existing systems. This article presents an overview of on-going technical developments and innovations that we felt were most important today, as well as those that have the potential to significantly shape the future of proton therapy. Indeed, efforts have been done continuously to improve the efficiency of a PT system, in terms of cost, technology and delivery technics, and a number of different developments pursued in the accelerator field will first be presented. Significant developments are also underway in terms of transport and spatial resolution achievable with pencil beam scanning, or conformation of the dose to the target: we will therefore discuss beam focusing and collimation issues which are important parameters for the development of these techniques, as well as proton arc therapy. State of the art and alternative approaches to adaptive PT and the future of adaptive PT will finally be reviewed. Through these overviews, we will finally see how advances in these different areas will allow the potential for robust dose shaping in proton therapy to be maximised, probably foreshadowing a future era of maturity for the PT technique.

Exploiting the full potential of proton therapy: An update on the specifics and innovations towards spatial or temporal optimisation of dose delivery.

Prescription and delivery of protons are somewhat different compared to photons and may influence outcomes (tumour control and toxicity). These differences should be taken into account to fully exploit the clinical potential of proton therapy. Innovations in proton therapy treatment are also required to widen the therapeutic window and determine appropriate populations of patients that would benefit from new treatments. Therefore, strategies are now being developed to reduce side effects to critical normal tissues using alternative treatment configurations and new spatial or temporal-driven optimisation approaches. Indeed, spatiotemporal optimisation (based on flash, proton minibeam radiation therapy or hypofractionated delivery methods) has been gaining some attention in proton therapy as a mean of improving (biological and physical) dose distribution. In this short review, the main differences in planning and delivery between protons and photons, as well as some of the latest developments and methodological issues (in silico modelling) related to providing scientific evidence for these new techniques will be discussed.

First proton minibeam radiation therapy treatment plan evaluation.

Proton minibeam radiation therapy (pMBRT) is a novel dose delivery method based on spatial dose fractionation. pMBRT has been shown to be promising in terms of reduced side effects and superior tumour control in high-grade glioma-bearing rats compared to standard irradiation. These findings, together with the recent optimized implementation of pMBRT in a clinical pencil beam scanning system, have triggered reflection on the possible application to patient treatments. In this context, the present study was designed to conduct a first theoretical investigation of the clinical potential of this technique. For this purpose, a dedicated dose engine was developed and used to evaluate two clinically relevant patient treatment plans (high-grade glioma and meningioma). Treatment plans were compared with standard proton therapy plans assessed by means of a commercial treatment planning system (ECLIPSE-Varian Medical systems) and Monte Carlo simulations. A multislit brass collimator consisting of 0.4 mm wide slits separated by a centre-to-centre distance of 4 or 6 mm was placed between the nozzle and the patient to shape the planar minibeams. For each plan, spread-out Bragg peaks and homogeneous dose distributions (±7% dose variations) can be obtained in target volumes. The Peak-to-Valley Dose Ratios (PVDR) were evaluated between 9.2 and 12.8 at a depth of 20 mm for meningioma and glioma, respectively. Dose volume histograms (DVHs) for target volumes and organs at risk were quantitatively compared, resulting in a slightly better target homogeneity with standard PT than with pMBRT plans, but similar DVHs for deep-seated organs-at-risk and lower average dose for shallow organs. The proposed delivery method evaluated in this work opens the way to an effective treatment for radioresistant tumours and will support the design of future clinical research.

Experimental characterisation of a proton kernel model for pencil beam scanning techniques.

The aim of this work is to perform Monte Carlo simulations of a proton pencil beam scanning machine, characterise the low-dose envelope of scanned proton beams and assess the differences between various approximations for nozzle geometry. Measurements and Monte Carlo simulations were carried out in order to describe the dose distribution of a proton pencil beam in water for energies between 100 and 220 MeV. Dose distributions were simulated by using a Geant4 Monte Carlo platform (TOPAS), and were measured in water using a two-dimensional ion chamber array detector. The beam source in air was adjusted for each configuration. Double Gaussian parameterisation was proposed for definition of the beam source model in order to improve simulations starting at the nozzle exit. Absolute dose distributions and field size factors were measured and compared with simulations. The influence of the high-density components present in the treatment nozzle was also investigated by analysis of proton phase spaces at the nozzle exit. An excellent agreement was observed between experimental dose distributions and simulations for energies higher than 160 MeV. However, minor differences were observed between 100 and 160 MeV, suggesting poorer modelling of the beam when the full treatment head was not taken into account. We found that the first ionisation chamber was the main cause of the tail component observed for low proton beam energies. In this work, various parameterisations of proton sources were proposed, thereby allowing reproduction of the low-dose envelope of proton beams and excellent agreement with measured data.

Spatial fractionation of the dose in proton therapy: Proton minibeam radiation therapy.

In radiation therapy, a renewed interest is emerging for the study of spatially fractionated irradiation. In this article, a few applications using spatial fractionation of the dose will be discussed with a focus on proton minibeam radiation therapy. Examples of calculated dose (1D profiles and 2D dose distributions) and biological evidence obtained so far will be presented for various spatially fractionated techniques GRID, micro- and minibeam radiation therapy. Recent results demonstrating that proton minibeam radiation therapy leads to an increase in normal tissues sparing will be discussed, which opens the door to a dose escalation in the tumour and a possibly efficient treatment of very radioresistant tumours.

Dosimetric characteristics of four PTW microDiamond detectors in high-energy proton beams.

Small diamond detectors are useful for the dosimetry of high-energy proton beams. However, linear energy transfer (LET) dependence has been observed in the literature with such solid state detectors. A novel synthetic diamond detector has recently become commercially available from the manufacturer PTW-Freiburg (PTW microDiamond type 60019). This study was designed to thoroughly characterize four microDiamond detectors in clinical proton beams, in order to investigate their response and their reproducibility in high LET regions. Very good dosimetric characteristics were observed for two of them, with good stability of their response (deviation less than 0.4% after a pre-irradiation dose of approximately 12 Gy), good repeatability (coefficient of variation of 0.06%) and a sensitivity of approximately 0.85 nC Gy(-1). A negligible dose rate dependence was also observed for these two microDiamonds with a deviation of the sensitivity less than 0.7% with respect to the one measured at the reference dose rate of 2.17 Gy min(-1), in the investigated dose rate range from 1.01 Gy min(-1) to 5.52 Gy min(-1). Lateral dose profile measurements showed the high spatial resolution of the microDiamond oriented with its stem perpendicular to the beam axis and with its small sensitive thickness of about 1 µm in the scanning profile direction. Finally, no significant LET dependence was found with these two diamond dosimeters in comparison to a reference ionization chamber (model IBA PPC05). These good results were in accordance to the literature. However, this study showed also a non reproducibility between the devices in terms of stability, sensitivity and LET dependence, since the two other microDiamonds characterized in this work showed different dosimetric characteristics making them not suitable for proton beam dosimetry with a maximum difference of the peak-to-plateau ratio of 6.7% relative to the reference ionization chamber in a clinical 138 MeV proton beam.

Proton minibeam radiation therapy: Experimental dosimetry evaluation.

PURPOSE: Proton minibeam radiation therapy (pMBRT) is a new radiotherapy (RT) approach that allies the inherent physical advantages of protons with the normal tissue preservation observed when irradiated with submillimetric spatially fractionated beams. This dosimetry work aims at demonstrating the feasibility of the technical implementation of pMBRT. This has been performed at the Institut Curie - Proton Therapy Center in Orsay. METHODS: Proton minibeams (400 and 700 µm-width) were generated by means of a brass multislit collimator. Center-to-center distances between consecutive beams of 3200 and 3500 µm, respectively, were employed. The (passive scattered) beam energy was 100 MeV corresponding to a range of 7.7 cm water equivalent. Absolute dosimetry was performed with a thimble ionization chamber (IBA CC13) in a water tank. Relative dosimetry was carried out irradiating radiochromic films interspersed in a IBA RW3 slab phantom. Depth dose curves and lateral profiles at different depths were evaluated. Peak-to-valley dose ratios (PVDR), beam widths, and output factors were also assessed as a function of depth. RESULTS: A pattern of peaks and valleys was maintained in the transverse direction with PVDR values decreasing as a function of depth until 6.7 cm. From that depth, the transverse dose profiles became homogeneous due to multiple Coulomb scattering. Peak-to-valley dose ratio values extended from 8.2 ± 0.5 at the phantom surface to 1.08 ± 0.06 at the Bragg peak. This was the first time that dosimetry in such small proton field sizes was performed. Despite the challenge, a complete set of dosimetric data needed to guide the first biological experiments was achieved. CONCLUSIONS: pMBRT is a novel strategy in order to reduce the side effects of RT. This works provides the experimental proof of concept of this new RT method: clinical proton beams might allow depositing a (high) uniform dose in a brain tumor located in the center of the brain (7.5 cm depth, the worst scenario), while a spatial fractionation of the dose is retained in the normal tissues in the beam path, potentially leading to a gain in tissue sparing. This is the first complete experimental implementation of this promising technique. Biological experiments are needed in order to confirm the clinical potential of pMBRT.

Occurrence of alternariol, alternariol monomethyl ether and tenuazonic acid in Argentinean tomato puree.

The occurrence ofAlternaria mycotoxins was investigated in 80 samples of tomato puree processed and sold in Argentina. Alternariol (AOH), alternariol monomethyl ether (AME) and tenuazonic acid (TA) were searched for by liquid chromatography. Thirty-nine of the 80 samples showed mycotoxin contamination. TA was found in 23 samples (39-4021 µg/kg), AOH in 5 samples (187-8756 µg/kg), and AME in 21 samples (84-1734 µg/kg). Co-occurrence of two of these toxins was detected in 10 samples. This is the first report of natural occurrence of AOH, AME and TA in tomato products in Argentina.

Recurrent spontaneous abortion. Etiologic factors.

BACKGROUND: Spontaneous abortion is the most common complication of pregnancy. It may be unique, remaining random and having no consequences on the reproductive process, or it can repeat itself, starting a clinical picture known as recurrent spontaneous abortion or habitual abortion. The term of RSA syndrome is used to define the repetition of three or more consecutive abortions before the 24th week. METHODS: A population of 195 couples with recurrent spontaneous abortion were screened for genetic, metabolic, infective, morphological, endocrine and autoimmune factors. Eighty-five completed the investigation, 44 are being tested and 66 did not complete the diagnostic course. Causes of recurrent abortion were evaluated in relation to the period of abortion and number of embryo losses. RESULTS: Forty-six percent of patients who completed the investigation turned out to be sine causa, which is in accordance with the findings in literature. CONCLUSIONS: Couple with RSA require accurate counselling and it is fundamental to eliminate any pathologies that can be discovered so as to improve the likelihood of the pregnancy's reaching term.

Transvaginal sonographic tubal patency testing using air and saline solution as contrast media in a routine infertility clinic setting.

Tubal patency testing by transvaginal sonography has been implemented in our infertility clinic since 1991. We report our experience with this technique during the last year of routine outpatient activity. A total of 154 infertile patients, including three patients on two occasions, underwent tubal patency testing by transvaginal sonography; 36 also underwent laparoscopy or hysterosalpingography, with a further three undergoing both. A detailed account of the method used to visualize the passage of air and saline through the salpinx is described. The 'gold standard' for tubal patency was laparoscopy. In any cases that were doubtful or if there was tubal occlusion, laparoscopy was advised. The diagnoses by transvaginal sonography in the 154 patients consisted of: 106 with bilateral tubal patency (68.8%), 34 with unilateral tubal occlusions (22.1%), and 13 with bilateral occlusion (8.4%); one case was undiagnosed. Tubal disease was present in 25 out of the 36 (69.4%) patients undergoing laparoscopy or hysterosalpingography (69.4%). The sensitivity, specificity, accuracy, positive and negative predictive values were respectively 80, 85, 82.7, 85 and 80% for the 29 patients undergoing transvaginal sonography and laparoscopy. When the number of tubes examined was considered, these values were respectively 85, 91.6, 89.3, 85 and 91.6%. No discordance was observed in the ten patients undergoing hysterosalpingography. Demonstration of the tubal course relies on a positive contrast medium filling the tubal lumen. Air and saline were successful for this purpose. In our study, the results of tubal patency testing by transvaginal sonography were very similar to those of hysterosalpingography, but differed in about 10% of the cases from those of laparoscopy. The most difficult problem to rule out was distal tubal occlusion without hydrosalpinx. Tubal patency testing by transvaginal sonography can be used safely as a first-step examination of tubal patency. Easy tubal passage can allow medical treatment, while a doubtful or frankly occluded salpinx should be investigated by laparoscopy.

A new technique to test tubal patency under transvaginal sonographic control.

OBJECTIVE: Since 1990 we have undertaken a trial to evaluate if TVS, even without contrast media, could diagnose tubal patency. MATERIALS AND METHODS: A detailed description of the technique is given. Two hundred and seventy-three patients underwent sonosalpingography in our department in the period 1990-1993. The sonographic findings were matched in 43 cases to hysterosalpingography and in 55 cases to laparoscopy. RESULTS: Tubal patency was demonstrated in 218 patients (80.5%), monolateral patency in 41 (15.1%) patients and bilateral tubal occlusion in 12 (4.4%) patients. In the 43 patients undergoing hysterosalpingography, discordance between the two examinations was observed in five cases (11.6%). However, only six out of 86 salpinxes had different results (6.9%). In only one case was total discordance observed. In three out of four other cases the difference was due to patency diagnosed at SSG and occlusion at HSG. Of the 55 patients undergoing laparoscopy 12 cases (21.8%) had discordant results. Complete discordance was observed in two cases while in ten cases one salpinx had a different patency report. The discordance goes to 12.7% when we take into account all the salpinxes evaluated. CONCLUSION: Sonosalpingography gives very similar results to hysterosalpingography and may be used on clinical basis for tubal patency evaluation.

Transvaginal salpingo-sonography (TSSG) in the evaluation of tubal patency.

Transvaginal sonography was used in 78 patients to evaluate tubal patency as a control in infertility workup. The cervix was fitted with a Semm cervix-adapter (Wisap); air and saline were injected through it. Careful scanning of the uterine angles and of the tubes permitted to demonstrate bilateral passage of the contrast medium in 52 of the 55 patients and monolateral passage in 3. 21 patients had also other conventional evaluations of tubal patency. Two patients were excluded from protocol. Total agreement with hysterosalpingography (HSG) was found in 69.2% of the cases, partial agreement in 23%. Total agreement with laparoscopy (LPS) was found in 83.3% of the cases. In conclusion transvaginal sonosalpingography (TSSG) can be used as a first ambulatorial evaluation of tubal patency in infertility work-up.