Definitive radiotherapy consisting of external beam radiotherapy without central shielding and 3D image-guided brachytherapy for patients with cervical cancer: feasibility for Japanese patients and dose-response analyses for local control in the low-dose range.

OBJECTIVE: To assess the feasibility of external beam radiotherapy without central shielding in definitive radiotherapy for Japanese patients with cervical cancer. METHODS: We retrospectively analysed the data of cervical cancer patients treated with definitive radiotherapy consisting of external beam radiotherapy without central shielding and three-dimensional-image-guided brachytherapy. RESULTS: The study included 167 patients (T1 + 2 = 108, T3 + 4 = 59) from eight Japanese institutions. For three-dimensional-image-guided brachytherapy, intra-cavitary and interstitial brachytherapy was utilized in 33 patients (20%). The median follow-up was 26.6 months (interquartile range, 20-43.2). The maximum rectal D2 (75 Gy)/bladder D2 (90 Gy) constraints were deviated by 6%/10% and 10%/5% for T1 + 2 and T3 + 4, respectively. The 2-year incidence of ≥grade 3 proctitis/cystitis was 4%/1% for T1 + 2 and 10%/2% for T3 + 4. The 2-year local progression-free survival was 89% for T1 + 2 and 82% for T3 + 4. For T1 + 2, the 2-year local progression-free survival for the high-risk clinical target volume D90 ≥ 68 Gy (indicated by receiver operating characteristic analysis; area under the curve = 0.711) was 92% versus 67% for <68 Gy (log-rank; P = 0.019). Cox multivariate analysis indicated that the high-risk clinical target volume D90 was one of independent predictors of local failure (P = 0.0006). For T3 + 4, the 2-year local progression-free survival was 87% for the high-risk clinical target volume <82 cm3 (area under the curve = 0.67) and 43% for ≥82 cm3 (P = 0.0004). Only the high-risk clinical target volume was an independent predictor of local failure (P = 0.0024). CONCLUSIONS: Definitive radiotherapy consisting of external beam radiotherapy without central shielding and three-dimensional-image-guided brachytherapy was feasible for Japanese patients with cervical cancer. Dose de-escalation from the current global standards is suggested for patients with T1 + 2 disease.

Automated preparation of washed platelet concentrates through spinning-membrane filtration.

BACKGROUND: Washed platelet concentrates (WPC), prepared with an automated system cell processor (ACP), have recently been approved to be manufactured and marketed in Japan. From the perspective of risk management, it is preferable to secure alternative technologies for ACP. Here, we conducted a study to evaluate the quality of WPC prepared using an automated membrane filtration-based system, Lovo. STUDY DESIGN AND METHODS: Replaced PCs prepared from apheresis PCs were equally divided into control and test units, and subsequently washed using ACP and Lovo respectively. Work and operational efficiencies were evaluated by in vitro analyses, including total handling time, platelet recovery, and plasma protein removal rate. Product quality, including a set of biochemical and physiological indicators of platelets and supernatants, were assessed before and 3 days after washing. RESULTS: In vitro platelet recovery rates and plasma protein removal rates were >85% and >95%, respectively, in both groups. The pH values on day 0 were significantly high (6.97 vs. 6.86) due to low pCO2 in the test group, while no significant differences in glucose consumption and lactate production were observed between the two groups. The levels of hypotonic shock responses, aggregation response, platelet shape, CD62P expression, and sCD62P concentration were similar in both groups during the 3-day storage period. CONCLUSION: Platelet washing with Lovo provides platelet quality equivalent to, or better than, conventional washing with ACP. Thus, the new automated system, Lovo, can be considered as an alternative to ACP for WPC preparation.

Formation and evaluation of mechanism-based chemical categories for regulatory read-across assessment of repeated-dose toxicity: A case of hemolytic anemia.

The aim of this study is to define chemical categories that can be applied to regulatory read-across assessments for repeated-dose toxicity, by classifying toxic substances based on their structures and mechanism of actions (MoAs). Hemolytic anemia, which often appears primarily, was examined as an example. An integrated database was constructed by collecting publicly available datasets on repeated-dose toxicity, in which 423 out of a total of 1518 chemicals were identified as capable of inducing hemolytic anemia. Subsequently, by grouping these chemicals based on their chemical structures and plausible MoAs on hemolytic substances, we identified the following categories: (i) anilines, (ii) nitrobenzenes, (iii) nitroanilines, (iv) dinitroanilines, (v) ethylene glycol alkyl ethers, (vi) hydroquinones, (vii) oximes, and (viii) hydrazines. In these categories, the toxicant and the measurable key events leading to hematotoxicity were identified, thereby allowing us to justify the categories and to discriminate the category substances. Moreover, toxicokinetics seems to critically affect the hemolytic levels of the category substances. Overall, the categories were validated through a comprehensive analysis of the collected information, while the utility was demonstrated by conducting a case study on the selected category. Further endeavors with this approach would attain categories for other organ toxicity endpoints.

Evaluation of a silver-amplified immunochromatography kit for adenoviral conjunctivitis.

OBJECTIVE: To compare and evaluate the sensitivity of a newly developed silver-amplified immunochromatography (SAI) kit with various immunochromatography (IC) kits for adenoviruses based on the detection limit (copies/test). METHODS: An SAI kit and four ophthalmic IC kits were evaluated. The detection limits of the five kits were determined using the limiting dilution method for 15 conjunctivitis-associated adenoviruses (adenoviruses 1, 2, 3, 4, 5, 7, 8, 11, 37, 53, 54, 56, 64, 81, and 85). The detection limits were presented as numerical values as determined by real-time polymerase chain reaction (PCR). RESULTS: The detection limit of the SAI kit for the adenovirus types ranged from 1.0 × 103 -5.0 × 10 4 copies/test (geometric mean, 4.7 × 10 3 ). SAI had a 10-250-fold lower detection limit than the four IC kits for all adenoviruses studied. There were also differences in detection limits among the adenovirus types for each kit. DISCUSSION: The detection limit of the SAI kit was drastically reduced because the silver-amplification reaction increased the color development sensitivity. The results revealed the high sensitivity of SAI for detecting adenoviruses and suggested its usefulness for conjunctivitis examination.

In silico prediction of chromosome damage: comparison of three (Q)SAR models.

Two major endpoints for genotoxicity tests are gene mutation and chromosome damage (CD), which includes clastogenicity and aneugenicity detected by chromosomal aberration (CA) test or micronucleus (MN) test. Many in silico prediction systems for bacterial mutagenicity (i.e. Ames test results) have been developed and marketed. They show good performance for prediction of Ames mutagenicity. On the other hand, it seems that in silico prediction of CD does not progress as much as Ames prediction. Reasons for this include different mechanisms and detection methods, many false positives and conflicting test results. However, some (quantitative) structure-activity relationship ((Q)SAR) models (e.g. Derek Nexus [Derek], ADMEWorks [AWorks] and CASE Ultra [MCase]) can predict CA test results. Therefore, performances of the three (Q)SAR models were compared using the expanded Carcinogenicity Genotoxicity eXperience (CGX) dataset for understanding current situations and future development. The constructed dataset contained 440 chemicals (325 carcinogens and 115 non-carcinogens). Sensitivity, specificity, accuracy or applicability of each model were 56.0, 86.9, 68.6 or 89.1% in Derek, 67.7, 61.5, 65.2 or 99.3% in AWorks, and 91.0, 64.9, 80.5 or 97.7% in MCase, respectively. The performances (sensitivity and accuracy) of MCase were higher than those of Derek or AWorks. Analysis of predictivity of (Q)SAR models of certain chemical classes revealed no remarkable differences among the models. The tendency of positive prediction by (Q)SAR models was observed in alkylating agents, aromatic amines or amides, aromatic nitro compounds, epoxides, halides and N-nitro or N-nitroso compounds. In an additional investigation, high sensitivity but low specificity was noted in in vivo MN prediction by MCase. Refinement of test data to be used for in silico system (e.g. consideration of cytotoxicity or re-evaluation of conflicting test results) will be needed to improve performance of CD prediction.

Evaluation of adenovirus amplified detection of immunochromatographic test using tears including conjunctival exudate in patients with adenoviral keratoconjunctivitis.

BACKGROUND: We evaluated a novel silver amplification immunochromatography test for rapid detection of adenovirus (AdV) antigen equipped with an automated reader system using tears including conjunctival exudate in patients with adenoviral keratoconjunctivitis. METHODS: Two kinds of immunochromatographic (IC) kits, a conventional IC kit for conjunctival scrapings (control kit) and an IC kit using tears including conjunctival exudate collected by pressing a filter paper strip on the conjunctiva (test kit), were tested on 90 patients who attended Migita Eye Clinic with suspected adenoviral conjunctivitis. The results of the test kits were automatically obtained by a specific reader, which was based on silver amplification immunochromatography system, in 15 min. The detection of AdV was confirmed by real-time polymerase chain reaction (PCR) method, and typing was performed by direct sequencing. Comparative dilution assay was carried out with the two kits, using AdV type 3 and type 54 strains. RESULTS: The sensitivity of the control kit and test kit was 89.8% and 98.3%, respectively. The specificity of both kits was 100%. A significant difference in the sensitivities of the two IC kits against PCR positivity was observed (P < 0.01). A significant correlation was found between AdV DNA copy numbers on a logarithmic scale obtained with the two tests (P < 0.01). The sensitivity of the test kit was 32-64-fold higher than that of the control kit without silver amplification for both AdV types. CONCLUSIONS: These results suggest that this novel amplified AdV detection kit using tears including conjunctival exudate is useful, because it decreases patients' discomfort from specimen collection and its sensitivity is significantly higher than that of the conventional IC kit.

Initial hazard assessment of benzyl salicylate: In vitro genotoxicity test and combined repeated-dose and reproductive/developmental toxicity screening test in rats.

Benzyl salicylate is used as a fragrance ingredient and an ultraviolet light absorber, but its toxicity is unknown. Therefore, toxicity tests and hazard classification were conducted for screening assessment under the Japanese Chemical Substances Control Law. Benzyl salicylate was found to be non-genotoxic in vitro based on the chromosomal aberration test using Chinese hamster lung cells. However, the combined repeated-dose and reproductive/developmental screening toxicity test, in which male and female rats were administered benzyl salicylate by gavage at 0, 30, 100, or 300 mg/kg/day for 42 and 41-46 days, respectively, from 14 days before mating until postnatal Day 4, showed that repeated doses had major effects on the thymus, liver, epididymis, and femur at 100 and/or 300 mg/kg/day. Furthermore, although benzyl salicylate had no effect on the estrus cycle, fertility, corpus lutea, or implantation rate, embryonic resorption, offspring mortality, and neural tube defects were observed at 300 mg/kg/day, and the offspring had lower body weights at 30 and 100 mg/kg/day, suggesting teratogenicity similar to other salicylates. Based on the developmental toxicity, this chemical was classified as hazard class 2, with a lowest observed adverse effect level (LOAEL) of 30 mg/kg/day and a D-value of 0.003 mg/kg/day.

Initial hazard assessment of 4-benzylphenol, a structural analog of bisphenol F: Genotoxicity tests in vitro and a 28-day repeated-dose toxicity study in rats.

4-Benzylphenol (CAS No. 101-53-1), a structural analog of bisphenol F, has estrogenic activity in vitro and in vivo, as is the case with bisphenol F. 4-Benzylphenol is used in plastics and during organic synthesis. Since its safety is largely unknown, we conducted toxicity tests as part of screening risk assessment in an existing chemical safety survey program. Based on results of the Ames test and the chromosomal aberration test using Chinese hamster lung cells (OECD TG 471 and 473), 4-benzylphenol was determined to be non-genotoxic in vitro. In a 28-day repeated-dose toxicity study, Crl:CD (SD) rats were administrated 4-benzylphenol by gavage at 0, 30, 150, or 750 mg/kg/day (OECD TG 407). Consequently, body weight was lower in males at 750 mg/kg/day. In the liver, relative organ weights were increased in both sexes at 750 mg/kg/day, and centrilobular hepatocellular hypertrophy was observed in males at 150 and 750 mg/kg/day. In the forestomach, hyperkeratosis and hyperplasia of squamous cells were observed in males at 150 and 750 mg/kg/day, and in females at 750 mg/kg/day. Based on these results, we identified the NOAEL for 4-benzylphenol as 30 mg/kg/day, with a hazard assessment value (D-value) of 0.05 mg/kg/day corresponding to hazard class 3.

Evaluation of anti-adenoviral effects of the polyvinyl alcohol iodine ophthalmic solution.

PURPOSE: To investigate the virucidal effects of a polyvinyl alcohol iodine, Saniode, against 16 types of human mastadenovirus (HAdV) causing ophthalmic, respiratory, gastrointestinal, urinary, and systemic infections. STUDY DESIGN: Laboratory investigation METHODS: Fifty microliters of Saniode were exposed to 10 µL each containing HAdV virus stock solution of 1 × 106 copies/µL of HAdV-1, -2, -3, -4, 5, -6, -7, -8, -11, -37, -53, -54, -56, -64, -81, and -85 for 10 s, 30 s, 1 min, and 3 min. After neutralization with 0.5% sodium thiosulfate, the mixture was diluted by ten-fold serial dilution and inoculated into 24 wells containing confluent A549 cell monolayers. Virucidal effects were calculated relative to the positive control on days 7-10 and observed until 30 days post-infection. RESULTS: Saniode satisfied the EN-14476 criterion for virucidal effects (>99.99%) for all HAdV types at all exposure times, including at 10 s on days 7 to 10 post-infection. All types of HAdVs that reacted for > 1 min achieved 99.99% reduction, including after 30 days. CONCLUSION: Saniode displayed virucidal effects against all tested HAdV types. Currently, with no specific medication available for HAdVs in ocular infection, this could be an option to prevent the spread of keratoconjunctivitis.

Finite Element Analysis of Changes in Deformation of Intraocular Segments by Airbag Impact in Eyes of Various Axial Lengths.

Background: We studied the kinetic phenomenon of an airbag impact on eyes with different axial lengths using finite element analysis (FEA) to sequentially determine the physical and mechanical responses of intraocular segments at various airbag deployment velocities. Methods: The human eye model we created was used in simulations with the FEA program PAM-GENERISTM. The airbag was set to impact eyes with axial lengths of 21.85 mm (hyperopia), 23.85 mm (emmetropia) and 25.85 mm (myopia), at initial velocities of 20, 30, 40, 50 and 60 m/s. The deformation rate was calculated as the ratio of the length of three segments, anterior chamber, lens and vitreous, to that at the baseline from 0.2 ms to 2.0 ms after the airbag impact. Results: Deformation rate of the anterior chamber was greater than that of other segments, especially in the early phase, 0.2-0.4 ms after the impact (P < 0.001), and it reached its peak, 80%, at 0.8 ms. A higher deformation rate in the anterior chamber was found in hyperopia compared with other axial length eyes in the first half period, 0.2-0.8 ms, followed by the rate in emmetropia (P < 0.001). The lens deformation rate was low, its peak ranging from 40% to 75%, and exceeded that of the anterior chamber at 1.4 ms and 1.6 ms after the impact (P < 0.01). The vitreous deformation rate was lower throughout the simulation period than that of the other segments and ranged from a negative value (elongation) in the later phase. Conclusion: Airbag impact on the eyeball causes evident deformation, especially in the anterior chamber. The results obtained in this study, such as the time lag of the peak deformation between the anterior chamber and lens, suggest a clue to the pathophysiological mechanism of airbag ocular injury.

Familial Exudative Vitreoretinopathy With and Without Pathogenic Variants of Norrin/ß-Catenin Signaling Genes.

Purpose: To determine the clinical characteristics of familial exudative vitreoretinopathy (FEVR) associated with or without pathogenic variants of the Norrin/ß-catenin genes. Design: This was a multicenter, cross-sectional, observational, and genetic study. Subjects: Two-hundred eighty-one probands with FEVR were studied. Methods: Whole-exome sequence and/or Sanger sequence was performed for the Norrin/ß-catenin genes, the FZD4, LRP5, TSPAN12, and NDP genes on blood collected from the probands. The clinical symptoms of the probands with or without the pathogenic variants were assessed as well as differences in the inter Norrin/ß-catenin genes. Main Outcome Measures: The phenotype associated with or without pathogenic variants of the Norrin/ß-catenin genes. Results: One-hundred eight probands (38.4%) had 88 different pathogenic or likely pathogenic variants in the genes: 24 with the FZD4, 42 with the LRP5, 10 with the TSPAN12, and 12 with the NDP gene. Compared with the 173 probands without pathogenic variants, the 108 variant-positive probands had characteristics of familial predisposition (63.9% vs. 37.6%, P < 0.0001), progression during infancy (75.0% vs. 53.8%, P = 0.0004), asymmetrical severity between the 2 eyes (50.0% vs. 37.6%, P = 0.0472), and nonsyndromic characteristics (10.2% vs. 17.3%, P = 0.1185). The most frequent stage at which the more severe eye conditions was present was at stage 4 in both groups (40.7% vs. 34.7%). However, the advanced stages of 3 to 5 in the more severe eye were found more frequently in probands with variants than in those without variants (83.3% vs. 58.4%, P < 0.0001). Patients with rhegmatogenous retinal detachments progressed from stage 1 or 2 were found less frequently in the variant-positive probands (8.3% vs. 17.3%, P = 0.0346). Nine probands with NDP variants had features different from probands with typical Norrin/ß-catenin gene variants including the sporadic, symmetrical, and systemic characteristics consistent with Norrie disease. Conclusions: The results showed that the clinical characteristics of FEVR of patients with variants in the Norrin/ß-catenin genes are different from those with other etiologies. We recommend that clinicians who diagnose a child with FEVR perform genetic testing so that the parents can be informed on the prognosis of the vision and general health in the child. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Simulation of Changes in Tensile Strain by Airbag Impact on Eyes After Trabeculectomy by Using Finite Element Analysis.

Purpose: We studied the kinetic phenomenon of an airbag impact on eyes after trabeculectomy using finite element analysis (FEA), a computerized method for predicting how an object reacts to real-world physical effects and showing whether an object will break, to sequentially determine the responses at various airbag deployment velocities. Methods: A human eye model was used in the simulations using the FEA program PAM-GENERISTM (Nihon ESI, Tokyo, Japan). A half-thickness incised scleral flap was created on the limbus and the strength of its adhesion to the outer sclera was set at 30%, 50%, and 100%. The airbag was set to hit the surface of the post-trabeculectomy eye at various velocities in two directions: perpendicular to the corneal center or perpendicular to the scleral flap (30° gaze-down position), at initial velocities of 20, 30, 40, 50, and 60 m/s. Results: When the airbag impacted at 20 m/s or 30 m/s, the strain on the cornea and sclera did not reach the mechanical threshold and globe rupture was not observed. Scleral flap lacerations were observed at 40 m/s or more in any eye position, and scleral rupture extending posteriorly from the scleral flap edge and rupture of the scleral flap resulting from extension of the corneal laceration through limbal damage were observed. Even in the case of 100% scleral flap adhesion strength, scleral flap rupture occurred at 50 m/s impact velocity in the 30° gaze-down position, whereas in eyes with 30% or 50% scleral flap adhesion strength, scleral rupture was observed at an impact velocity of 40 m/s or more in both eye positions. Conclusion: An airbag impact of ≥40 m/s might induce scleral flap rupture, indicating that current airbags may induce globe rupture in the eyes after trabeculectomy. The considerable damage caused by an airbag on the eyes of short-stature patients with glaucoma who have undergone trabeculectomy might indicate the necessity of ocular protection to avoid permanent eye damage.

Application of fused-grid-based CYP-Template systems for genotoxic substances to understand the metabolisms.

Understanding of metabolic processes is a key factor to evaluate biological effects of carcinogen and mutagens. Applicability of fused-grid Template* systems of CYP enzymes (Drug Metab Pharmacokinet 2019, 2020, 2021, and 2022) was tested for three phenomena. (1) Possible causal relationships between CYP-mediated metabolisms of ß-naphthoflavone and 3-methylcholanthrene and the high inducibility of CYP enzymes were examined. Selective involvement of non-constitutive CYP1A1, but not constitutive CYP1A2, was suggested on the oxidative metabolisms of efficient inducers, ß-naphthoflavone and 3-methylcholanthrene. These results supported the view of the causal link of their high inducibility with their inefficient metabolisms due to the lack of CYP1A1 in livers at early periods after the administration of both inducers. (2) Clear differences exist between human and rodent CYP1A1 enzymes on their catalyses with heterocyclic amines, dioxins and polyaromatic hydrocarbons (PAHs). Reciprocal comparison of simulation results with experimental data suggested the rodent specific site and distinct sitting-preferences of ligands on Template for human and rodent CYP1A1 enzymes. (3) Enhancement of metabolic activation and co-mutagenicity have been known as phenomena associated with Salmonella mutagenesis assay. Both the phenomena were examined on CYP-Templates in ways of simultaneous bi-molecule bindings of distinct ligands as trigger and pro-metabolized molecules. α-Naphthoflavone and norharman served consistently as trigger-molecules to support the oxidations of PAHs and arylamines sitting simultaneously as pro-metabolized molecules on Templates of CYP1A1, CYP1A2 and CYP3A4. These CYP-Template simulation systems with deciphering capabilities are promising tools to understand the mechanism basis of metabolic activations and to support confident judgements in safety assessments.

Hemodynamic Variability During Drainage of Large Volumes of Malignant Ascites in Patients With Cancer.

This study compared the variability in mean arterial pressure (MAP) during drainage of ascites in patients with cancer who underwent drainage of a large (5-10 L) or small (<5 L) volume of ascites. We prospectively enrolled 50 patients scheduled for cell-free and concentrated ascites reinfusion therapy. Equivalence was considered to be established if the 95% confidence interval (95% CI) for the highest variability rate of MAP was within ±20%. The median volume of ascites removed was 3.30 L (95% CI [2.84, 4.40]) in the small-drainage-volume group (n = 15) and 6.75 L (95% CI [6.40, 7.30]) in the large-drainage-volume group (n = 34). The 95% CIs for the highest variability rates in MAP ranged from -19.60 to -6.23 and from -19.16 to -12.95 (p = .594), respectively, indicating equivalence. These findings indicate that variability in MAP during drainage of ascites is not dependent on drainage volume.

Classification of Subtypes of Vernal Keratoconjunctivitis by Cluster Analysis Based on Clinical Features.

Background: Vernal keratoconjunctivitis (VKC) is a refractory ocular allergic disorder that mainly affects boys. A few studies have attempted to develop a classification of subtypes of VKC. In this study, we investigated a computational approach called cluster analysis to separate VKC cases into groups based on clinically relevant characteristics. Methods: In total, 41 consecutive patients clinically diagnosed with VKC at the Department of Ophthalmology of Fukuoka University Hospital were included. Patients were treated with immunosuppressive eye drops without simultaneous corticosteroid eye drops, except for the occurrence of exacerbations. Collated variables were age at onset, clinical score of ocular lesions at baseline, clinical score of ocular lesions at final visit, clinical score of atopic dermatitis (AD) at baseline, frequency of exacerbations of VKC, serum total IgE level and peripheral blood eosinophil count. Results: VKC patients were grouped into three clusters by cluster analysis, and cluster 1, 2, and 3 comprised 25, 9 and 7 cases, respectively. There were differences in the incidence of complications of AD and age at onset among the clusters; therefore, we named the three clusters for better understanding as traditional VKC (cluster 1), early-onset atopic keratoconjunctivitis (AKC)/VKC (cluster 2) and puberty-onset AKC (cluster 3). Conclusion: We found in this study that VKC in childhood has three phenotypes which were previously unknown. Our findings may help to establish precision medicine by focusing on the phenotype of each case to develop individualized medicine to prevent exacerbations.

[Toxicity effects of phthalate substitute plasticizers used in toys].

Phthalate esters are widely used as plasticizers in polyvinyl chloride products. Because of human health concerns, regulatory authorities in Japan, US, Europe and other countries control the use of di(2-ethylhexyl) phthalate, diisononyl phthalate, di-n-butyl phthalate, butylbenzyl phthalate, diisodecyl phthalate and di-n-octyl phthalate for the toys that can be put directly in infants' mouths. While these regulatory actions will likely reduce the usage of phthalate esters, there is concern that other plasticizers that have not been sufficiently evaluated for safety will be used more frequently. We therefore collected and evaluated the toxicological information on di(2-ethylhexyl) terephthalate (DEHT), 1,2-cyclohexanedicarboxylic acid, diisononyl ester (DINCH), diisononyl adipate (DINA), 2,2,4-trimetyl-1,3-pentanediol diisobutyrate (TXIB), tri-n-butyl citrate (TBC) and acetyl tri-n-butyl citrate (ATBC) which were detected at a relatively high frequency in toys. The collected data have shown that chronic exposure to DEHT affects the eye and nasal turbinate, and DINCH exerts effects on the thyroid and kidney in rats. DINA and TXIB have been reported to have hepatic and renal effects in dogs or rats, and ATBC slightly affected the liver in rats. The NOAELs for repeated dose toxicity are relatively low for DINCH (40 mg/kg bw/day) and TXIB (30 mg/kg bw/day) compared with DEHT, DINA and ATBC. DEHT, TXIB and ATBC have been reported to have reproductive/developmental effects at relatively high doses in rats. For DINA and TBC, available data are insufficient for assessing the hazards, and therefore, adequate toxicity studies should be conducted. In the present review, the toxicity information on 6 alternatives to phthalate plasticizers is summarized, focusing on the effects after oral exposure, which is the route of most concern.

Intra-arterial chemoradiotherapy for locally advanced buccal mucosal cancer in an elderly patient with multiple comorbidities: A case report.

BACKGROUND: The management of locally advanced oral cavity squamous cell carcinoma (LA-OCScc) in elderly patients with multiple comorbidities is difficult. CASE: We report the case of an elderly patient with buccal mucosal squamous cell carcinoma as well as chronic renal dysfunction, hepatic cirrhosis, rheumatoid arthritis, and metachronous diffuse large B-cell lymphoma. We performed radiation therapy (a total dose of 70 Gy in 35 fractions) and six cycles of intra-arterial chemotherapy with 40 mg/m2 cisplatin per week. After treatment, the tumor completely disappeared, and there was no recurrence or deterioration of comorbidities during the 12-month follow-up period. CONCLUSION: Intra-arterial chemoradiotherapy may be a good treatment option for LA-OCScc in elderly patients with multiple comorbidities.

Combined Risk Assessment of Food-derived Coumarin with in Silico Approaches.

Hepatotoxicity associated with food-derived coumarin occurs occasionally in humans. We have, herein, assessed the data of existing clinical and nonclinical studies as well as those of in silico models for humans in order to shed more light on this association. The average intakes of food-derived coumarin are estimated to be 1-3 mg/day, while a ten-times higher level is expected in the worst-case scenarios. These levels are close to or above the tolerable daily intake suggested by a chronic study in dogs. The human internal exposure levels were estimated by a physiologically-based pharmacokinetic model with the use of virtual doses of coumarin in the amounts expected to derive from foods. Our results suggest that: (i) coumarin can be cleared rapidly via 7-hydroxylation in humans, and (ii) the plasma levels of coumarin and of its metabolite, o-hydroxyphenylacetic acid associated with hepatotoxicity, are considerably lower than those yielding hepatotoxicity in rats. Pharmacokinetic data suggest a low or negligible concern regarding a coumarin-induced hepatotoxicity in humans exposed to an average intake from foods. Detoxification of coumarin through the 7-hydroxylation, however, might vary among individuals due to genetic polymorphisms in CYP2A6 enzyme. In addition, the CYP1A2- and CYP2E1-mediated activation of coumarin can fluctuate as a result of induction caused by environmental factors. Furthermore, the daily consumption of food-contained coumarin was implicated in the potential risk of hepatotoxicity by the drug-induced liver injury score model developed by the US Food and Drug Administration. These results support the idea of the existence of human subpopulations that are highly sensitive to coumarin; therefore, a more precise risk assessment is needed. The present study also highlights the usefulness of in silico approaches of pharmacokinetics with the liver injury score model as battery components of a risk assessment.

Preliminary results of reduced myocardial blood flow in the subacute phase after radiation therapy for thoracic esophageal cancer: A quantitative analysis with stress dynamic myocardial computed tomography perfusion imaging.

BACKGROUND AND PURPOSE: Late adverse cardiac events after radiation therapy (RT) for thoracic malignancies are known, but the underlying mechanisms are poorly understood. This study aimed to determine the radiation dose that can cause MBF alterations in the subacute phase after RT for thoracic esophageal cancer using stress dynamic myocardial computed tomography perfusion imaging (CTP). MATERIALS AND METHODS: Twenty-five patients with esophageal cancer scheduled for RT were prospectively enrolled. The quantitative analysis of MBF by CTP was performed before and 3 months after RT. The mean radiation dose and hyperemic MBF in 15 segments of the left ventricular (LV) myocardium were determined. ΔMBF was calculated in each segment as MBFafter RT - MBFbeforeRT. The myocardial segments were classified into the following 5 groups according to the mean radiation dose: group A, <10 Gy; B1, 10-15 Gy; B2, 15-20 Gy; C, 20-30 Gy; and D, >30 Gy. RESULTS: The final cohort included 22 patients who completed pre- and post-RT CTP. A one-way analysis of variance revealed a significant difference (p=0.005) in ΔMBF among the five groups of LV segments classified by the mean radiation dose. ΔMBF was significantly lower in group C (-7.7 ± 28.9 mL/min/100 g, p=0.020) and group D (-8.4 ± 34.8 mL/min/100 g, p=0.004) in comparison to ΔMBF in group A (4.9 ± 26.1 mL/min/100 g). CONCLUSIONS: This study using CTP early after RT demonstrated a significant reduction of the MBF in the LV segments with ≥20 Gy of radiation. The results might provide important insights into preventing radiotherapy-induced cardiac events.

Constructing a developmental and reproductive toxicity database of chemicals (DART NIHS DB) for integrated approaches to testing and assessment.

Developmental and reproductive toxicity (DART) is an important endpoint, and databases (DBs) are essential for evaluating the risk of untested substances using alternative methods. We have constructed a reliable and transparent DART DB, which we named DART NIHS DB, using the publicly available datasets of DART studies of industrial chemicals conducted by Japanese government ministries in accordance with the corresponding OECD test guidelines (OECD TG421 and TG422). This DB is unique because its dataset chemicals have little overlap with those of ToxRefDB, which compiles large-scale DART data, and it is reliable because the included datasets were created after reviewing the individual study reports. In DART NIHS DB, 171 of 404 substances exhibited signs of DART, which occurred during fertility and early embryonic development (49 substances), organogenesis (59 substances), and the perinatal period (161 substances). When the lowest-observed-adverse-effect level (LOAEL) of DART was compared with that of repeated-dose toxicity (RDT), 15 substances (12%) had a lower LOAEL for DART than for RDT. Of these, five substances displayed significant DART at doses of ≤ 50 mg/kg bw/day. The chemical and toxicity information in this DB will be useful for the development of stage-specific adverse outcome pathways (AOPs) via integration with mechanistic information. The whole datasets of the DB can be implemented in read-across support tools such as the OECD QSAR Toolbox, which will further lead to future integrated approaches to testing and assessment based on AOPs.