Toxicological evaluation of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylaminocarbonyl)hydrazine (VNP40101M), a novel alkylating agent with potential antitumor activity, with intravenous administration in rats and dogs

These studies investigated the toxicological effects of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylaminocarbonyl) hydrazine, VNP40101M, a novel alkylating antitumor agent, in animals. Sprague-Dawley rats (2-10/sex/time point at each dose) and Beagle dogs (1-3/sex/time point at each dose) were treated with VNP40101M (0 [vehicle], 1, 3, 10, and 20 mg/kg in rats and 0, 0.3, 1, and 3 mg/kg in dogs), given intravenously (IV, bolus via the tail or slow push via the cephalic or saphenous vein, respectively) once daily for 5 consecutive days. Clinical signs, mortality, body weight, clinical pathology, gross necropsy, organ weights, and histopathology were evaluated for as long as 43 days in rats and 50 days in dogs. In rats, the toxic doses were found to be at 10 and 20 mg/kg, which induced mainly pulmonary toxicity and mortality. The pulmonary toxicity was reflected by an increase in lung weight; clear, pink or red fluid within the thoracic cavity observed at necropsy; and histopathological evidence of alveolar edema, vascular congestion, alveolar histiocytosis, and vascular thrombi. Although some of these effects were observed in rats treated with 3 mg/kg, the incidence was low (approximately 7%-30%) and may be reversible (based on the time-dependent reduction in the magnitude of lung weight increases). Therefore, the maximum tolerated dose (MTD, or the maximum dose that did not induce significant toxicity or induced reversible toxicity) was > or = 3 mg/kg. VNP40101M at 1 mg/kg did not induce any toxicity, other than low incidence of alveolar edema (2/30 rats), and increased incidences of capillary ectasis/congestion and alveolar histocytosis (2-6/30 rats vs. 1/30-36 in control rats). Therefore, the low effect level (LOEL) is considered to be 1 mg/kg in rats when given IV for 5 days. In dogs, LOEL, MTD, and toxic dose levels were comparable (based on a body weight/surface area conversion) to those in rats, except for some gastrointestinal (GI) effects (i.e., red lesion in the ileum) observed at 0.3 mg/kg (equivalent to 1 mg/kg, or similar to the LOEL in rats) and the associated effects (slight body weight loss and inappetence). For dogs treated with 1 mg/kg (equivalent to approximately 3 mg/kg, or MTD, in rats), VNP40101M induced the same GI effects seen in dogs treated with 0.3 mg/kg of VNP40101M. Additionally, a transient reduction in white blood cell counts was also observed. Three mg/kg (equivalent to approximately 10 mg/kg, or toxic dose level, in rats) was toxic to dogs, as reflected by the poor clinical condition of these dogs, which subsequently required euthanasia. In conclusion, VNP40101M, when given IV once daily for 5 consecutive days, has a LOEL of 1 mg/kg, a MTD of 3 mg/kg, and toxic doses at > or = 10 mg/kg in rats. The primary toxicity of VNP40101M was pulmonary toxicity and mortality. Based on an interspecies body weight/surface area conversion, VNP40101M had comparable LOEL (0.3 mg/kg), MTD (1 mg/kg), and toxic doses (> or = 3 mg/kg) in dogs, except that dogs appeared to be more sensitive to the GI effects of VNP40101M.     

Intrahepatic biliary anatomy of living adult liver donors: correlation of mangafodipir trisodium-enhanced MR cholangiography and intraoperative cholangiography

OBJECTIVE: The purpose of our study was to assess the usefulness of mangafodipir trisodium-enhanced MR cholangiography for evaluating intrahepatic biliary anatomy of adult living liver donors and to correlate the results with intraoperative cholangiography. CONCLUSION: Mangafodipir trisodium-enhanced MR cholangiography accurately shows the biliary anatomy in the livers of donors. Noninvasive preoperative evaluation of the biliary anatomy in donor candidates is important for the detection of common anatomic variants that may require alternative graft-harvesting surgery.     

Hydro-jet-assisted pneumonectomy: a new technique in a porcine model

BACKGROUND AND OBJECTIVES: Hydro-jet technology has long been used to cut various materials, such as metal and wood, in the industrial field. In the medical field, this technology has been applied successfully in selective cutting of the parenchyma of the liver. However, to our knowledge, no data are available on the use of the hydro-jet technique for pneumonectomy. The purpose of this study was to evaluate a new dissection technique in which a high-pressure water stream (hydro-jet) and a new dissection probe for pulmonary resection are used. METHODS: Thirty pigs underwent right pneumonectomy. Pigs were randomized to either the conventional or hydro-jet-assisted dissection technique. The feasibility of this technique and the features of surgical dissection were evaluated and compared between the two groups. RESULTS: Pneumonectomy was successful in all animals. The mean operative times were 55 and 65 minutes and the mean volumes of blood loss were 37 and 65 mL for the hydro-jet and conventional dissection techniques, respectively. Complications included vascular injury in 6% and 20% of cases with the hydro-jet and conventional techniques, respectively. The use of hydro-jet for pneumonectomy had clear technical advantages over the conventional dissection. Hydro-jet resulted in a selective dissection of fibrous and connective tissue, preserving blood vessels for later ligation. Therefore, the dissection was performed in a relatively bloodless field. The ease of dissection with the bent-tip dissector represents another advantage. The continuous water flow allows a clear view for the operator. CONCLUSIONS: This study shows that hydro-jet dissection represents an excellent alternative to the conventional technique for pulmonary resection. The improved anatomic dissection combined with an almost bloodless operating field secondary to continuous water flow may decrease dissection-related complications.     

Influence of compensator thickness,field size,and off-axis distance on the effective attenuation coefficient of a cerrobend compensator for intensity-modulated radiation therapy

Intensity-modulated radiation therapy (IMRT) can be performed by using compensators. To make a compensator for an IMRT practice, it is required to calculate the effective attenuation coefficient (μ_eff) of its material, which is affected by various factors. We studied the effect of the variation of the most important factors on the calculation of the μ_eff of the cerrobend compensator for 6-MV photon beams, including the field size, compensator thickness, and off-axis distance. Experimental measurements were carried out at 100 cm source-to-surface distance and 10 cm depth for the 6-MV photon beams of an Elekta linac using various field size, compensator thickness, and off-axis settings. The field sizes investigated ranged from 4 × 4 to 25 × 25 cm² and the cerrobend compensator thicknesses from 0.5–6 cm. For a fixed compensator thickness, variation of the μ_eff with the field size ranged from 3.7–6.8%, with the highest value attributed to the largest compensator thickness. At the reference field size of 10 × 10 cm², the μ_eff varied by 16.5% when the compensator thickness was increased from 0.5–6 cm. However, the variation of the μ_eff with the off-axis distance was only 0.99% at this field size, whereas for the largest field size, it was more significant. Our results indicated that the compensator thickness and field size have the most significant effect on the calculation of the compensator μ_eff for the 6-MV photon beam. Therefore, it is recommended to consider these parameters when calculating the compensator thickness for an IMRT practice designed for these beams. The off-axis distance had a significant effect on the calculation of the μ_eff only for the largest field size. Hence, it is recommended to consider the effect of this parameter only for field sizes larger than 25 × 25 cm².     

Association between human leucocyte antigen alleles and risk of stroke in Iranian population

Previous studies have demonstrated associations between human leucocyte antigen (HLA) and some types of ischaemic stroke. In the present study, we genotyped HLA‐A,‐B and ‐DRB1 alleles in 140 Iranian patients with history of ischaemic stroke and 140 age‐/sex‐matched healthy subjects. No significant difference has been found in the distribution of HLA‐A and B alleles between cases and controls. The DRB1*16 allele was significantly over‐represented in patient group compared with control group (Adjusted p value = 0.048). Other HLA‐DRB1 alleles were not associated with stroke risk. The HLA‐B*35,B*52 genotype was significantly more prevalent among patients compared with controls (Adjusted p value = 0.03, OR [95% CI] = 9.3 [1.3, 407.2]). Several HLA haplotypes were associated with risk of stroke in the assessed population. The current study provides further evidences for participation of HLA in conferring risk of ischaemic stroke.     

KIR2DS1, 2DS5, 3DS1 and KIR2DL5 are associated with the risk of head and neck squamous cell carcinoma in Iranians

Background

Activating and inhibitory KIR receptors (aKIR, iKIR) control the development and function of NK cells whose function alterations adjust the tumor microenvironment immunity. This research was conducted to determine the KIRs gene impact on genetic predisposition to Head and Neck Squamous Cell Carcinoma (HNSCC) in Iranians.

Improved,ACMG‐compliant,in silico prediction of pathogenicity for missense substitutions encoded by TP53 variants

Clinical interpretation of germline missense variants represents a major challenge, including those in the TP53 Li–Fraumeni syndrome gene. Bioinformatic prediction is a key part of variant classification strategies. We aimed to optimize the performance of the Align‐GVGD tool used for p53 missense variant prediction, and compare its performance to other bioinformatic tools (SIFT, PolyPhen‐2) and ensemble methods (REVEL, BayesDel). Reference sets of assumed pathogenic and assumed benign variants were defined using functional and/or clinical data. Area under the curve and Matthews correlation coefficient (MCC) values were used as objective functions to select an optimized protein multisequence alignment with best performance for Align‐GVGD. MCC comparison of tools using binary categories showed optimized Align‐GVGD (C15 cut‐off) combined with BayesDel (0.16 cut‐off), or with REVEL (0.5 cut‐off), to have the best overall performance. Further, a semi‐quantitative approach using multiple tiers of bioinformatic prediction, validated using an independent set of nonfunctional and functional variants, supported use of Align‐GVGD and BayesDel prediction for different strength of evidence levels in ACMG/AMP rules. We provide rationale for bioinformatic tool selection for TP53 variant classification, and have also computed relevant bioinformatic predictions for every possible p53 missense variant to facilitate their use by the scientific and medical community.     

Estimation of cell response in fractionation radiotherapy using different methods derived from linear quadratic model

Background

The aim of this study was to use various theoretical methods derived from the Linear Quadratic (LQ) model to calculate the effects of number of subfractions, time intervals between subfractions, dose per subfraction, and overall fraction time on the cells’ survival. Comparison of the results with experimental outcomes of melanoma and breast adenocarcinoma cells was also performed. Finally, the best matched method with experimental outcomes is introduced as the most accurate method in predicting the cell response.

Materials and methods.

The most widely used theoretical methods in the literature, presented by Keall et al., Brenner, and Mu et al., were used to calculate the cells’ survival following radiotherapy with different treatment schemes. The overall treatment times were ranged from 15 to 240 minutes. To investigate the effects of number of subfractions and dose per subfraction, the cells’ survival after different treatment delivery scenarios were calculated through fixed overall treatment times of 30, 60 and 240 minutes. The experimental tests were done for dose of 4 Gy. The results were compared with those of the theoretical outcomes.

Results

The most affective parameter on the cells’ survival was the overall treatment time. However, the number of subfractions per fractions was another effecting parameter in the theoretical models. This parameter showed no significant effect on the cells’ survival in experimental schemes. The variations in number of subfractions per each fraction showed different results on the cells’ survival, calculated by Keall et al. and Brenner methods (P<0.05).

Conclusions

Mu et al. method can predict the cells’ survival following fractionation radiotherapy more accurately than the other models. Using Mu et al. method, as an accurate and simple method to predict the cell response after fractionation radiotherapy, is suggested for clinical applications.