Transcriptomic analyses of livers from mice exposed to 1,4-dioxane for up to 90 days to assess potential mode(s) of action underlying liver tumor development.

1,4-Dioxane is a volatile organic compound with industrial and commercial applications as a solvent and in the manufacture of other chemicals. 1,4-Dioxane has been demonstrated to induce liver tumors in chronic rodent bioassays conducted at very high doses. The available evidence for 1,4-dioxane-induced liver tumors in rodents aligns with a threshold-dependent mode of action (MOA), with the underlying mechanism being less clear in the mouse than in rats. To gain a better understanding of the underlying molecular mechanisms related to liver tumor development in mice orally exposed to 1,4-dioxane, transcriptomics analysis was conducted on liver tissue collected from a 90-day drinking water study in female B6D2F1/Crl mice (Lafranconi et al., 2020). Using tissue samples from female mice exposed to 1,4-dioxane in the drinking water at concentrations of 0, 40, 200, 600, 2,000 or 6,000 ppm for 7, 28, and 90 days, transcriptomic analyses demonstrate minimal treatment effects on global gene expression at concentrations below 600 ppm. At higher concentrations, genes involved in phase II metabolism and mitotic cell cycle checkpoints were significantly upregulated. There was an overall lack of enrichment of genes related to DNA damage response. The increase in mitotic signaling is most prevalent in the livers of mice exposed to 1,4-dioxane at the highest concentrations for 90 days. This finding aligns with phenotypic changes reported by Lafranconi et al. (2020) after 90-days of exposure to 6,000 ppm 1,4-dioxane in the same tissues. The transcriptomics analysis further supports overarching study findings demonstrating a non-mutagenic, threshold-based, mitogenic MOA for 1,4-dioxane-induced liver tumors.

Lack of potential carcinogenicity for steviol glycosides - Systematic evaluation and integration of mechanistic data into the totality of evidence.

Steviol glycosides are present in the leaves of the Stevia rebaudiana plant, have a sweet taste, and have been used as a sweetener for centuries. To build on previous authoritative safety assessments of steviol glycosides, a systematic assessment of mechanistic data related to key characteristics of carcinogens (KCCs) was conducted. Over 900 KCC-relevant endpoints from peer-reviewed literature and high-throughput screening data (ToxCast/Tox21) were identified across individual steviol glycosides and derivatives, metabolites, and whole leaf extracts. Most data (both in vivo and in vitro, including human cells), showed inactivity. Studies were weighted according to quality and relevance. Although data were available for eight of the ten KCC, genotoxicity, oxidative stress, inflammation, and cell proliferation/cell death represent the KCCs with the most data. The data for these KCC primarily show beneficial activity (anti-inflammatory, antioxidant, and anti-proliferative). Following integration across all data, and accounting for study quality and relevance, the totality of the evidence demonstrated an overall lack of genotoxic and carcinogenic activity for steviol glycosides. This is in agreement with previous regulatory decisions, and is consistent with the lack of tumor response in two-year rodent cancer bioassays. The findings support prior conclusions that steviol glycosides are unlikely to be carcinogenic in humans.

Fluorescence 125I eye applicator.

A new approach to optimize curative eye plaque brachytherapy is presented. The application of ophthalmic plaques is a common therapy modality for small and medium sized intraocular tumors. At Essen University Hospital eye applicators with photon emitting 125I seeds are used for the treatment of tumors with a thickness from 5 to 10 mm. Our clinical experiences indicate that the dose distributions of these applicators-used so far worldwide-are not optimal. A steeper dose falloff would meet the radiobiological requirements better, to provide the eradication of all tumor cells as well as sufficient occlusion of tumor supplying blood vessels. Our investigations for eye plaque optimization are based both on measurements and Monte Carlo simulation. For fast dosimetric measurements we have built a computer controlled device which allows reading out, directly and simultaneously, 16 1 mm3 scintillators. For the numerical simulations of the dose distribution of 125I eye plaques we have adapted a Monte Carlo program originally developed to calculate the synchrotron radiation in particle physics. We have investigated the influence of geometrical as well as physical eye plaque parameters on the dose distribution: Shielding of the primary radiation, penumbra modification, and energy conversion by exploiting fluorescence x-radiation have been considered. New types of fluorescence eye applicators have been designed which are more suitable for the prevention of radiopathic effects on structures at risk.

Direct reading measurement of absorbed dose with plastic scintillators--the general concept and applications to ophthalmic plaque dosimetry.

We have developed dosemeters based on plastic scintillators for a variety of applications in radiation therapy. The dosemeters consist basically of a tissue-substituting scintillator probe, an optical fiber light guide, and a photomultiplier tube. The background light generated in the light guide can be compensated by a simultaneous measurement of the light from a blind fiber. Plastic scintillator dosemeters combine several advantageous properties which render them superior to other dosemeter types for many applications: minimal disturbance of the radiation field because of the homogeneous detector volume and the approximate water equivalence; no dependence on temperature and pressure (under standard clinical conditions) and angle of radiation incidence; no high voltage in the probe; high spatial resolution due to small detector volumes; direct reading of absorbed doses; and a large dynamical range. The high spatial resolution together with direct reading make these detectors suitable for real-time 3-D dosimetry using multi-channel detector systems. Such a system has been developed for eye plaque dosimetry and successfully employed for dosimetric treatment optimization. The plaque optimization can be performed by dosimetric measurements for the individual patient ("dosimetric treatment planning"). The time consumption for this procedure is less than for a physically correct computer-based therapy planning, e.g., by means of a Monte Carlo simulation.

Surgery in ovarian cancer: the concept of cytoreductive surgery.

Critical analysis of the collected evidence on cytoreductive surgery suggests a median survival benefit of 9-12 months in combination with platinum-based chemotherapy. Recently, a randomized study on the value of secondary cytoreduction showed a median survival benefit of 6 months for those with small residual disease after the second operation. Primary cytoreduction is feasible in approximately 70% of patients, with an acceptable level of morbidity. The reported evidence justifies a serious attempt at cytoreductive surgery at the first operation by an experienced gynaecological oncologist.

Percutaneous transluminal angioplasty of anomalous right coronary artery.

Angioplasty of anomalous coronary arteries can be technically challenging because of difficulty in selectively cannulating the aberrant vessel. We present our experience with angioplasty of an anomalous right coronary artery. A Judkins-type left coronary catheter with an eccentric tip, the FL4-G type catheter was used to obtain stable position in the right coronary artery and angioplasty was performed.

Myocardial bridges: effect of propranolol on systolic compression.

Myocardial bridges may exert an ischemic effect on the myocardium and often warrant therapy including surgical correction in selected cases. Decrease in systolic compression after the administration of propranolol has not been reported. We report a patient who demonstrated angiographic systolic compression of the coronary artery with subsequent improvement on treatment with propranolol. The reduction in severity of systolic compression caused by propranolol may be due to the negative inotropic effect and perhaps from an increase in coronary artery vascular tone secondary to a beta-blocker with unopposed alpha effect. Further studies are needed to assess the efficacy of beta-blocker therapy in patients with myocardial bridging and the use of intravenous propranolol at the time of coronary angiography may have practical implications in selecting drug therapy for patients with symptomatic myocardial bridging.

[Antenatal diagnosis of the sex of the fetus by diagnostic ultrasound (echography) (author's transl)]. / Diagnostic échographique anténatal du sexe.

The authors present the results they obtained in diagnosing fetal sex in utero by the use of real-time echography. They also have reviewed the other different techniques for the diagnosis and their fallibility. The prediction of fetal sex is possible in 90 p. 100 of echographies carried out routinely. When a very careful well codified technique is used the method becomes highly reliable. In a successive series of 103 pregnancies fetal sex was diagnosed correctly in every case. The authors point out that they diagnose female sex through positive echographic finding and not by a process of exclusion of the male organs.