Comparison of different calculation techniques for absorbed dose assessment in patient specific peptide receptor radionuclide therapy

Aim: The present work concerns the comparison of the performances of three systems for dosimetry in RPT that use different techniques for absorbed dose calculation (organ-level dosimetry, voxel-level dose kernel convolution and Monte Carlo simulations). The aim was to assess the importance of the choice of the most adequate calculation modality, providing recommendations about the choice of the computation tool. Methods: The performances were evaluated both on phantoms and patients in a multi-level approach. Different phantoms filled with a 177Lu-radioactive solution were used: a homogeneous cylindrical phantom, a phantom with organ-shaped inserts and two cylindrical phantoms with inserts different for shape and volume. A total of 70 patients with NETs treated by PRRT with 177Lu-DOTATOC were retrospectively analysed. Results: The comparisons were performed mainly between the mean values of the absorbed dose in the regions of interest. A general better agreement was obtained between Dose kernel convolution and Monte Carlo simulations results rather than between either of these two and organ-level dosimetry, both for phantoms and patients. Phantoms measurements also showed the discrepancies mainly depend on the geometry of the inserts (e.g. shape and volume). For patients, differences were more pronounced than phantoms and higher inter/intra patient variability was observed. Conclusion: This study suggests that voxel-level techniques for dosimetry calculation are potentially more accurate and personalized than organ-level methods. In particular, a voxel-convolution method provides good results in a short time of calculation, while Monte Carlo based computation should be conducted with very fast calculation systems for a possible use in clinics, despite its intrinsic higher accuracy. Attention to the calculation modality is recommended in case of clinical regions of interest with irregular shape and far from spherical geometry, in which Monte Carlo seems to be more accurate than voxel-convolution methods

DNA damage in lens epithelial cells exposed to occupationally-relevant X-ray doses and role in cataract formation

The current framework of radiological protection of occupational exposed medical workers reduced the eye-lens equivalent dose limit from 150 to 20 mSv per year requiring an accurate dosimetric evaluation and an increase understanding of radiation induced effects on Lens cells considering the typical scenario of occupational exposed medical operators. Indeed, it is widely accepted that genomic damage of Lens epithelial cells (LEC) is a key mechanism of cataractogenesis. However, the relationship between apoptosis and cataractogenesis is still controversial. In this study biological and physical data are combined to improve the understanding of radiation induced effects on LEC. To characterize the occupational exposure of medical workers during angiographic procedures an INNOVA 4100 (General Electric Healthcare) equipment was used (scenario A). Additional experiments were conducted using a research tube (scenario B). For both scenarios, the frequencies of binucleated cells, micronuclei, p21-positive cells were assessed with different doses and dose rates. A Monte-Carlo study was conducted using a model for the photon generation with the X-ray tubes and with the Petri dishes considering the two different scenarios (A and B) to reproduce the experimental conditions and validate the irradiation setups to the cells. The simulation results have been tallied using the Monte Carlo code MCNP6. The spectral characteristics of the different X-ray beams have been estimated. All irradiated samples showed frequencies of micronuclei and p21-positive cells higher than the unirradiated controls. Differences in frequencies increased with the delivered dose measured with Gafchromic films XR-RV3. The spectrum incident on eye lens and Petri, as estimated with MCNP6, was in good agreement in the scenario A (confirming the experimental setup), while the mean energy spectrum was higher in the scenario B. Nevertheless, the response of LEC seemed mainly related to the measured absorbed dose. No effects on viability were detected. Our results support the hypothesis that apoptosis is not responsible for cataract induced by low doses of X-ray (i.e. 25 mGy) while the induction of transient p21 may interfere with the disassembly of the nuclear envelop in differentiating LEC, leading to cataract formation. Further studies are needed to better clarify the relationship we suggested between DNA damage, transient p21 induction and the inability of LEC enucleation

Impact of Tributyltin and Triphenyltin on Ivory Shell (Babylonia japonica) Populations

We histopathologically examined gonads and chemically determined organotin compounds in tissues of the ivory shell, Babylonia japonica. Imposex (a superimposition of male-type genital organs on females) occurred in approximately 80–90% of B. japonica specimens that we examined, with the penis and vas deferens both well developed. No oviduct blockage by vas deferens formation was observed. Ovarian spermatogenesis and suppressed ovarian maturation were observed in the females that exhibited imposex, although no histopathological abnormalities were found in males. Tissue distributions of organotin compounds [tributyltin (TBT), triphenyltin (TPhT), and their metabolites] were different for butyltins and phenyltins; a remarkably high accumulation of TBT was observed in the ctenidium, osphradium, and heart, whereas high concentrations of TPhT were detected in the ovary and digestive gland. More than one-third of TBT accumulated in the digestive glands of both males and females, followed by the testis, ctenidium, muscle, and heart tissues in males and in the muscle, ovary, ctenidium, and head tissues (including the central nervous system ganglia) in females. In both males and females, more than half of total TPhT accumulated in the digestive glands, followed by the gonads. The next highest values were in the muscle, ctenidium, and heart tissues in males and in the muscle, oviduct, and head tissues in females. Both TBT and TPhT concentrations in the gonads were positively correlated with penis length in females. Our findings strongly suggest that reproductive failure in adult females accompanied by imposex, possibly induced by TBT and TPhT from antifouling paints, may have caused the marked decline of B. japonica populations in Japan

An Adaptive Thresholding Method for BTV Estimation Incorporating PET Reconstruction Parameters: A Multicenter Study of the Robustness and the Reliability

Objective. The aim of this work was to assess robustness and reliability of an adaptive thresholding algorithm for the biological target volume estimation incorporating reconstruction parameters. Method. In a multicenter study, a phantom with spheres of different diameters (6.5–57.4 mm) was filled with 18F-FDG at different target-to-background ratios (TBR: 2.5–70) and scanned for different acquisition periods (2–5 min). Image reconstruction algorithms were used varying number of iterations and postreconstruction transaxial smoothing. Optimal thresholds (TS) for volume estimation were determined as percentage of the maximum intensity in the cross section area of the spheres. Multiple regression techniques were used to identify relevant predictors of TS. Results. The goodness of the model fit was high (R2: 0.74–0.92). TBR was the most significant predictor of TS. For all scanners, except the Gemini scanners, FWHM was an independent predictor of TS. Significant differences were observed between scanners of different models, but not between different scanners of the same model. The shrinkage on cross validation was small and indicative of excellent reliability of model estimation. Conclusions. Incorporation of postreconstruction filtering FWHM in an adaptive thresholding algorithm for the BTV estimation allows obtaining a robust and reliable method to be applied to a variety of different scanners, without scanner-specific individual calibration

A regional audit system for stillbirth: A way to better understand the phenomenon

Background: Implementation of high-quality national audits for perinatal mortality are needed to improve the registration of all perinatal deaths and the identification of the causes of death. This study aims to evaluate the implementation of a Regional Audit System for Stillbirth in Emilia-Romagna Region, Italy. Methods: For each stillbirth ( 65 22 weeks of gestation, 65 500 g) occurred between January 1, 2014 to December 1, 2016 (n = 332), the same diagnostic workup was performed and a clinical record with data about mother and stillborn was completed. Every case was discussed in a multidisciplinary local audit to assess both the cause of death (ReCoDe classification) and the quality of care. Data were reviewed by the Regional Audit Group. Stillbirth rates, causes of death and the quality of care were established for each case. Results: Total stillbirth rate was 3.09 per 1000 births (332/107,528). Late stillbirth rate was 2.3 per 1000 (251/107,087). Sixteen stillbirths were not registered by the Regional Birth Register. The most prevalent cause of death was placental disorder (33.3%), followed by fetal (17.6%), cord (14.2%) and maternal disorders (7.6%). Unexplained cases were 14%. Compared to local audits, the regional group attributed different causes of death in 17% of cases. At multivariate analysis, infections were associated with early stillbirths (OR 3.38, CI95% 1.62-7.03) and intrapartum cases (OR 6.64, CI95% 2.61-17.02). Placental disorders were related to growth restriction (OR 1.89, CI95% 1.06-3.36) and were more frequent before term (OR 1.86, CI95% 1.11-3.15). Stillbirths judged possibly/probably preventable with a different management (10.9%) occurred more frequently in non-Italian women and were mainly related to maternal disorders (OR 6.64, CI95% 2.61-17.02). Conclusions: Regional Audit System for Stillbirth improves the registration of stillbirth and allows to define the causes of death. Moreover, sub-optimal care was recognized, allowing to identify populations which could benefit from preventive measures

The effect of membrane curvature on the conformation of antimicrobial peptides: implications for binding and the mechanism of action

Short cationic antimicrobial peptides (AMPs) are believed to act either by inducing transmembrane pores or disrupting membranes in a detergent-like manner. For example, the antimicrobial peptides aurein 1.2, citropin 1.1, maculatin 1.1 and caerin 1.1, despite being closely related, appear to act by fundamentally different mechanisms depending on their length. Using molecular dynamics simulations, the structural properties of these four peptides have been examined in solution as well as in a variety of membrane environments. It is shown that each of the peptides has a strong preference for binding to regions of high membrane curvature and that the structure of the peptides is dependent on the degree of local curvature. This suggests that the shorter peptides aurein 1.2 and citropin 1.1 act via a detergent-like mechanism because they can induce high local, but not long-range curvature, whereas the longer peptides maculatin 1.1 and caerin 1.1 require longer range curvature to fold and thus bind to and stabilize transmembrane pores

An overlooked connection: serotonergic mediation of estrogen-related physiology and pathology

BACKGROUND: In humans, serotonin has typically been investigated as a neurotransmitter. However, serotonin also functions as a hormone across animal phyla, including those lacking an organized central nervous system. This hormonal action allows serotonin to have physiological consequences in systems outside the central nervous system. Fluctuations in estrogen levels over the lifespan and during ovarian cycles cause predictable changes in serotonin systems in female mammals. DISCUSSION: We hypothesize that some of the physiological effects attributed to estrogen may be a consequence of estrogen-related changes in serotonin efficacy and receptor distribution. Here, we integrate data from endocrinology, molecular biology, neuroscience, and epidemiology to propose that serotonin may mediate the effects of estrogen. In the central nervous system, estrogen influences pain transmission, headache, dizziness, nausea, and depression, all of which are known to be a consequence of serotonergic signaling. Outside of the central nervous system, estrogen produces changes in bone density, vascular function, and immune cell self-recognition and activation that are consistent with serotonin's effects. For breast cancer risk, our hypothesis predicts heretofore unexplained observations of the opposing effects of obesity pre- and post-menopause and the increase following treatment with hormone replacement therapy using medroxyprogesterone. SUMMARY: Serotonergic mediation of estrogen has important clinical implications and warrants further evaluation