Comparative Toxicity Research Articles

Comparative toxicity of polyhexamethylene guanidine phosphate in three strains of rats

Comparative toxicity of polyhexamethylene guanidine phosphate in three strains of rats

Trifluridine/Tipiracil in Metastatic Colorectal Cancer: A UK Multicenter Real-world Analysis on Efficacy, Safety, Predictive and Prognostic Factors

BackgroundThe orally administered combination trifluridine/tipiracil has been approved as third line treatment in mCRC, demonstrating survival benefit and acceptable toxicity profile in the phase III RECOURSE study. Patient and methodsWe performed a multicenter retrospective real-world analysis of patients with mCRC receiving trifluridine/tipiracil between 2016 and 2019 in eight cancer centers across the United Kingdom. ResultsA total of 236 patients were included with median age of 69 years. All patients had received at least 2 lines of fluoropyrimidine-based chemotherapy doublet with oxaliplatin or irinotecan. About 10% of patients had ECOG ≥ 2. Median duration of trifluridine/tipiracil treatment was 3 months with an ORR of 2.1% and disease control rate of 21.6%. Median OS was 7.6 and median PFS 3.3 months. A dose reduction was required in 27% of patients, while 7.6% discontinued treatment due to toxicity. The most common grade 3 toxicities were neutropenia (34%), fatigue (10%), anemia (9%) and febrile neutropenia (5%). Baseline NLR <5 and CEA <200 had favorable prognostic (HR: 0.52 and 0.39, P≤ .001) and predictive value (OR: 4.1 and 6.7, P< .05). Development of grade 3 neutropenia predicted treatment response (OR: 0.32, P< .001). Following treatment with trifluridine/tipiracil 41% were referred for phase I trial or rechallenged with chemotherapy. ConclusionTrifluridine/tipiracil is well tolerated in refractory mCRC patients with comparable efficacy and toxicity profile to that of the phase III RECOURSE. Pretreatment NLR and CEA could serve as potential markers for patient selection, while treatment-induced grade 3 neutropenia predicted response. Prospective validation is needed.

OdTx12/GNA, a chimeric variant of a β excitatory toxin from Odontobuthus doriae, reveals oral toxicity towards Locusta migratoria and Tenebrio molitor

OdTx12, a beta excitatory toxin from Odontobothus doriae had previously been identified and characterized. It had been shown that OdTx12 causes significant lethal effects on insects by injection but does not show any toxicity on mice. Due to the natural ineffectiveness of scorpion toxins to act as oral toxins, OdTx12 was fused to Galanthus nivalis agglutinin (GNA), a protein with the potential to cross the insect gut. The sequence of OdTx12/GNA gene was chemically synthesized, cloned in Escherichia coli, and expressed. The effect of the purified fusion protein (OdTx12/GNA) was assessed on the insect and mammalian cell lines, insect larvae and mice. Toxicity assay on insect cell culture (SF9 cell line) showed comparable toxicity between OdTx12 and OdTx12/GNA (LD50 of 0.0030 and 0.0048 μM, respectively). Also very similar mortality rates were observed by injecting OdTx12 and OdTx12/GNA to Locusta migratoria and Tenebrio molitor. Oral administration of OdTx12/GNA, after five days of feeding, resulted in 96.6% and 98.3% mortality of L. migratoria and T. molitor larvae with an LC50 of 0.69 and 0.43 nmol/g of insect food, respectively, while OdTx12 alone did not cause any toxic effects on the larvae orally, suggesting the role of GNA in delivering the toxin to the insect's haemolymph. No toxicity or mortality was observed after toxicity testing of OdTx12/GNA on a mammalian cell line (HEP-2) or any mortality in vivo, by testing the protein in the laboratory mouse.Herein, we demonstrated that the fusion protein OdTx12/GNA could be considered an effective toxin for the biological control of insects.

Pro-inflammatory response and genotoxicity caused by clay and graphene nanomaterials in A549 and THP-1 cells

Nanoclays and graphene oxide nanomaterials represent a class of materials sharing similar shapes constituted of high aspect ratio platelets. The increased production of these materials for various industrial applications increases the risk of occupational exposure, consequently with elevated risk of adverse reactions and development of pulmonary diseases, including lung cancer. In this study, pro-inflammatory responses and genotoxicity were assessed in alveolar epithelial cells (A549) and activated THP-1 macrophages (THP-1a) after exposure to three nanoclays; a pristine (Bentonite) and two surface modified (benzalkonium chloride-coated Nanofil9, and dialkyldimethyl-ammonium-coated NanofilSE3000); graphene oxide (GO) and reduced graphene oxide (r-GO) nanomaterials. The pro-inflammatory response in terms of IL-8 expression was strongest in cells exposed to Bentonite, whereas surface modification resulted in decreased toxicity in both cell lines when exposed to Nanofil9 and NanofilSE3000. GO and r-GO induced a pro-inflammatory response in A549 cells, while no effect was detected with the two nanomaterials on THP-1a cells. The pro-inflammatory response was strongly correlated with in vivo inflammation in mice after intra-tracheal instillation when doses were normalized against surface area. Genotoxicity was assessed as DNA strand breaks, using the alkaline comet assay. In A549 cells, an increase in DNA strand breaks was detected only in cells exposed to Bentonite, whereas Bentonite, NanofilSE3000 and GO caused an increased level of genotoxicity in THP-1a cells. Genotoxicity in THP-1a cells was concordant with the DNA damage in bronchoalveolar lavage fluid cells following 1 and 3 days after intra-tracheal instillation in mice. In conclusion, this study shows that surface modification of pristine nanoclays reduces the inflammatory and genotoxic response in A549 and THP-1a cells, and these in vitro models show comparable toxicity to what seen in previous mouse studies with the same materials.

Carvacrol Attenuates Disrupted Lipid Profile Induced by Organophosphates in Male Wistar Rat: a Comparative Toxicity

Many people in agricultural industry are nowadays struggling with protecting their products utilizing pesticides. Pesticides, such as organophosphate (OPE) insecticides, may remain on agricultural products as pesticide residues. Malathion (MTN) is an OPE widely used around the world. Some OPEs, such as parathion (PTN), are more toxic pesticides and have been restricted. Carvacrol (CRL) is a major component of Satureja khuzestanica essential oil, which exerted protective effects against toxicity of chemicals. OPEs can alter lipid profile. In addition, lipid profile may alter due to certain disorders, such as nephrotic syndrome. The present study aimed to investigate the effects of coadministration of CRL and the effect of these two pesticides on serum acetylcholinesterase (AchE) activity and lipid profile in male wistar rat. Coadministration of CRL and PTN, but not MTN, significantly decreased serum AchE activity in comparison with the group receiving OPES. Serum levels of cholesterol and triglyceride were analyzed after 10 days of administration of the chemicals. Malathion and PTN significantly increased cholesterol and triglyceride. However, administration of CRL modified lipid profile (P < 0.05). It was concluded that CRL could be considered as a drug to treat lipid profile alteration and owing to the beneficial effects as well as inhibition of acetylcholine, it could be considered as a component of OPE pesticide. © 2021, Islamic Azad University. All rights reserved

Comparative Toxicity, Biodistribution and Excretion of Ultra-Small Gold Nanoclusters with Different Emission Wavelengths.

The exponentially increased use of gold nanoclusters in diagnosis and treatment has raised serious concern about their potential threat to living organisms. However, the mechanisms of toxicity of gold nanoclusters in vitro and in vivo remain poorly understood. In this work, comparative toxicity studies, including biodistribution and excretion, were carried out with mildly and chemically synthesized ultra-small L-histidine-protected and bovine serum albumin (BSA)-protected gold nanoclusters in an all-aqueous process. These nanoclusters did not induce a remarkable impact on cell viability, even at relatively high concentrations (100 μg/mL). The haemolytic assay demonstrated that the gold nanoclusters could not destroy blood cell at 600 μg/mL. After intravenous injection with mice, the biocompatibility, biodistribution, and excretion were determined. Quantitative analysis results showed that accumulation varied in the liver, spleen, kidney, and lung, though primarily in the liver and spleen. They were excreted in urine and faeces, but mainly excreted through urine. In our study, no obvious abnormalities were found in body weight, behavioral changes, blood and serum biochemical indicators, and histopathology. These findings suggested that both gold nanoclusters showed similar effects in vivo and were safe and biocompatible, laying the foundation for safe biomedical application in the future.

Comparative Toxicity of Nitenpyrem and Neem Oil Against Amrasca biguttula biguttula in Okra

The Jassid, Amarasca bigutulla bigutullaa is an important sucking pest of the okra crop. An experimental study was conducted during 2018 to check the comparative toxicity of nitenpyrem and neem oil against jassid under okra field conditions. The study revealed that 24 hours after treatment, nitenpyrem was found more toxic and effective with maximum reduction of jassid population (72.15%). Whereas, 120 hours after treatment with 4% neem oil, 15.05% jassid reduction was observed. The mortality rate of the jassid was increased with increasing in time after application of chemical insecticides. The study concluded that insecticide was most toxic and gives higher mortality of jassid as compared to neem oil. Keywords: Abelmoschus esculentus, Malvaceae, Amarasca bigutulla bigutullaa, botanicals, insecticides, Pakistan

Comparative toxicities of BPA, BPS, BPF, and TMBPF in the nematode Caenorhabditis elegans and mammalian fibroblast cells

Bisphenol A (BPA) is a chemical compound commonly used in the production of plastics for daily lives and industry. As BPA is well known for its adverse health effects, several alternative materials have been developed. This study comprehensively analyzed the toxicity of BPA and its three substitutes including bisphenol S (BPS), bisphenol F (BPF), and tetramethyl bisphenol F (TMBPF) on aging, healthspan, and mitochondria using an in vivo Caenorhabditis elegans (C. elegans) model animal and cultured mammalian fibroblast cells. C. elegans treated with 1 mM BPA exhibited abnormalities in the four tested parameters related to development and growth, including delayed development, decreased body growth, reduced reproduction, and abnormal tissue morphology. Exposure to the same concentration of each alternative including TMBPF, which has been proposed as a relatively safe BPA alternative, detrimentally affected at least three of these events. Moreover, all bisphenols (except BPS) remarkably shortened the organismal lifespan and increased age-related changes in neurons. Exposure to BPA and BPF resulted in mitochondrial abnormalities, such as reduced oxygen consumption and mitochondrial membrane potential. In contrast, the ATP levels were noticeably higher after treatment with all bisphenols. In mammalian fibroblast cells, exposure to increasing concentrations of all bisphenols (ranging from 50 μM to 500 μM) caused a severe decrease in cell viability in a dose-dependent manner. BPA increased ATP levels and decreased ROS but did not affect mitochondrial permeability transition pores (mPTP). Notably, TMBPF was the only bisphenol that caused a significant increase in mitochondrial ROS and mPTP opening. These results suggest that the potentially harmful physiological effects of BPA alternatives should be considered.

The impact of differential lignin S/G ratios on mutagenicity and chicken embryonic toxicity.

Lignin and lignin-based materials have received considerable attention in various fields due to their promise as sustainable feedstocks. Guaiacol (G) and syringol (S) are two primary monolignols that occur in different ratios for different plant species. As methoxyphenols, G and S have been targeted as atmospheric pollutants and their acute toxicity examined. However, there is a rare understanding of the toxicological properties on other endpoints and mixture effects of these monolignols. To fill this knowledge gap, our study investigated the impact of different S/G ratios (0.5, 1, and 2) and three lignin depolymerization samples from poplar, pine, and miscanthus species on mutagenicity and developmental toxicity. A multitiered method consisted of in silico simulation, in vitro Ames test, and in vivo chicken embryonic assay was employed. In the Ames test, syringol showed a sign of mutagenicity, whereas guaiacol did not, which agreed with the T.E.S.T. simulation. For three S and G mixture and lignin monomers, mutagenic activity was related to the proportion of syringol. In addition, both S and G showed developmental toxicity in the chicken embryonic assay and T.E.S.T. simulation, and guaiacol had a severe effect on lipid peroxidation. A similar trend and comparable developmental toxicity levels were detected for S and G mixtures and the three lignin depolymerized monomers. This study provides data and insights on the differential toxicity of varying S/G ratios for some important building blocks for bio-based materials.

Applicability of Enchytraeus bulbosus as a model species in ecotoxicology and risk assessment

Enchytraeus bulbosus is listed in the ISO and OECD standard guidelines as a possible test species of enchytraeid. However, in contrast to other listed species, its applicability in ecotoxicological studies as well as its sensitivity is widely unknown. Therefore, copper, pentachlorophenol(PCP), carbendazim, and chloroacetamide have been investigated by performing two-generation studies with multiple endpoints. Comparable toxicity trends to the existing studies were shown for copper and PCP in the two-generation studies of E. bulbosus. Dose-related abnormal swelling of clitella were found for the first time with PCP and chloroacetamide treatments. Sensitivity comparisons of E. bulbosus to other terrestrial test species were also conducted. E. bulbosus showed high sensitivity, it has comparable sensitivity as other sensitive species of genus Enchytraeus ( E. albidus or E. luxuriosus)to different chemicals, and was more sensitive than E. crypticus and earthworm species ( Eisenia fetida or Eisenia andrei). Combined with the phylogenetic and biological characterization, the results lead to the conclusion that E.bulbosus is a suitable model species in ecotoxicology and the chemical risk assessment (especially in multi-generation) because it has a short generation time, comparatively moderate fecundity, ideal and reasonable sensitivity.

A Comparative Study of Cytotoxicity of PPG and PEG Surface-Modified 2-D Ti3C2 MXene Flakes on Human Cancer Cells and Their Photothermal Response.

The MXenes are a novel family of 2-D materials with promising biomedical activity, however, their anticancer potential is still largely unexplored. In this study, a comparative cytotoxicity investigation of Ti3C2 MXenes with polypropylene glycol (PPG), and polyethylene glycol (PEG) surface-modified 2-D Ti3C2 MXene flakes has been conducted towards normal and cancerous human cell lines. The wet chemical etching method was used to synthesize MXene followed by a simple chemical mixing method for surface modification of Ti3C2 MXene with PPG and PEG molecules. SEM and XRD analyses were performed to examine surface morphology and elemental composition, respectively. FTIR and UV-vis spectroscopy were used to confirm surface modification and light absorption, respectively. The cell lines used to study the cytotoxicity of MXene and surface-modified MXenes in this study were normal (HaCaT and MCF-10A) and cancerous (MCF-7 and A375) cells. These cell lines were also used as controls (without exposure to study material and irradiation) to measure their baseline cell viability under the same lab environment. The surface-modified MXenes exhibited a sharp reduction in cell viability towards both normal (HaCaT and MCF-10A) and cancerous (MCF-7 and A375) cells but cytotoxicity was more pronounced towards cancerous cell lines. This may be due to the difference in cell metabolism and the occurrence of high pre-existing levels of reactive oxygen species (ROS) within cancerous cells. The highest toxicity towards both normal and cancerous cell lines was observed with PEGylated MXenes followed by PPGylated and bare MXenes. The normal cell’s viability was barely above 70% threshold with 250 mg/L PEGylated MXene concentration whereas PPGylated and bare MXene were less toxic towards normal cells, even at 500 mg/L concentration. Moreover, the toxicity was found to be directly related to the type of cell lines. In general, the HaCaT cell line exhibited the lowest toxicity while toxicity was highest in the case of the A375 cell line. The photothermal studies revealed high photo response for PEGylated MXene followed by PPGylated and bare MXenes. However, the PPGylated MXene’s lower cytotoxicity towards normal cells while comparable toxicity towards malignant cells as compared to PEGylated MXenes makes the former a relatively safe and effective anticancer agent.

Comparative toxicity of potential leachates from perovskite and silicon solar cells in aquatic ecosystems.

Globally, perovskite solar cells (PSCs) represent a third-generation photovoltaic technology that is being increasingly implemented and commercialized. However, the biological impacts of leachates from PSCs are poorly understood. Therefore, the aim of this study was to investigate the ecotoxicity of PSC leachates compared with that of commercial Si-based solar cell (SBSC) leachates. We performed leaching assessments and aquatic bioassays using internationally recommended test species and measured and compared the ecotoxicity of PSC and SBSC leachates. As a result of the leaching analyses, Si, Pb, and Al were found to be the most leached elements from broken PSCs and SBSCs. The bioassays indicated that polycrystalline SBSC (p-Si) and monocrystalline SBSC (m-Si) leachates were more toxic to fish embryos than the PSC leachates and that water fleas were sensitive to m-Si leachates, but less sensitive to PSC and p-Si leachates. In addition, principle component analyses indicated that the ecotoxicity of solar cell leachates was related to either the Pb or Si content. This is the first comparative study of the potential ecotoxicity of PSC and SBSC leachates in aquatic ecosystems, and the results of which can be used in the environmentally safe commercialization of solar cells.

Toxicity and antitumor activity of novel agents in elderly patients with cancer included in phase 1 studies.

IntroductionThe number of cancer cases among the elderly continue to increase as the worldwide population ages. This patient subset is underrepresented in clinical trials, partly because of unresolved uncertainties about age-associated tolerabilities and antitumor activities. We reviewed phase 1 trial data to study tolerance and efficacy of novel agents used for treatment of elderly patients with cancer.MethodsData from 773 consecutive evaluable patients in 85 phase 1 clinical trials (2008-2016) at START Madrid-CIOCC were analyzed according to age, with respect to objective response, survival, and toxicity.ResultsThe mean age was 58.7 (range: 18-87) years; 260 (33.6%) patients were >65 y (elderly group). One hundred thirty-seven (17.8%) patients received immunotherapy drugs, 308 (39.8%) received targeted agents, and 328 (42.4%) received chemotherapy. No statistically significant differences in overall survival, objective response, or severe toxicity rates were found according to treatment type. Similar toxicities and clinical activities were found between the two age subgroups; 18.8% of the elderly and 20.7% of the younger patients experienced severe hematological toxicity (p=0.5), and 30.2% and 32.7%, respectively, experienced severe non-hematological toxicity (p=0.4). Regarding antitumor activity, 12.4% of the elderly and 15% of the younger patients achieved objective responses (p=0.41). There were no significant between-group differences in overall survival (9.7 versus 11.5 months, respectively, p=0.1) or progression-free survival (2.3 versus 2.2 months, respectively, p=0.7).ConclusionsThis retrospective study found that elderly and younger populations had comparable antitumor activities and toxicity profiles. These results support including elderly patients with cancer in early-phase trials.

Synthesis and evaluation of novel arylisoxazoles linked to tacrine moiety: in vitro and in vivo biological activities against Alzheimer's disease.

Alzheimer's disease (AD) is now ranked as the third leading cause of death after heart disease and cancer. There is no definite cure for AD due to the multi-factorial nature of the disease, hence, multi-target-directed ligands (MTDLs) have attracted lots of attention. In this work, focusing on the efficient cholinesterase inhibitory activity of tacrine, design and synthesis of novel arylisoxazole-tacrine analogues was developed. In vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition assay confirmed high potency of the title compounds. Among them, compounds 7l and 7b demonstrated high activity toward AChE and BChE with IC50 values of 0.050 and 0.039μM, respectively. Both compounds showed very good self-induced Aβ aggregation and AChE-induced inhibitory activity (79.4 and 71.4% for compound 7l and 61.8 and 58.6% for compound 7b, respectively). Also, 7l showed good anti-BACE1 activity with IC50 value of 1.65µM. The metal chelation test indicated the ability of compounds 7l and 7b to chelate biometals (Zn2+, Cu2+, and Fe2+). However, they showed no significant neuroprotectivity against Aβ-induced damage in PC12 cells. Evaluation of in vitro hepatotoxicity revealed comparable toxicity of compounds 7l and 7b with tacrine. In vivo studies by Morris water maze (MWM) task demonstrated that compound 7l significantly reversed scopolamine-induced memory deficit in rats. Finally, molecular docking studies of compounds 7l and 7b confirmed establishment of desired interactions with the AChE, BChE, and BACE1 active sites.

TOXICITY OF Piper guineense SCHUM AND THONN AND Chlorpyrifos POWDERS FOR THE CONTROL OF Callosobruchus subinnotatus (Pic.) ON STORED Vigna subterranea (L.) Verdcourt IN GOMBE STATE, NIGERIA

A study was conducted with aim of determining toxicity effects of Piper guineense and chlorpyrifos powders on adult mortality of Callosobruchus subinnotatus, progeny emergence (F1), damage and weight loss, germination of Bambara nuts. Study was carried out at Botany laboratory, Gombe State University, Gombe State, Nigeria. P. guineense and chlorpyrifos were mixed at 0.0g and 0.8g concentration with 20g Bambara nuts inside 1000ml plastic containers. Experiment was conducted in randomized complete block design in three replicates. Ten pairs of adult C. subinnotatus unsexed were introduced into treatments nuts and stored for 7days. Bruchid mortality, progeny emergence, nut damage and weight loss, and germination were assessed. Data obtained were subjected to analyses of variance, significant differences of treatment mean were separated using New Duncan’s multiple range test at 5% probability level. Piper guineense and chlorpyrifos powders had comparable toxicity effects, causing 100% C. subinnotatus adult mortality between 5-7 days of treatment. P. guineense and chlorpyrifos powders proved effective as lower C. subinnotatus progeny emergence was observed compared with control. Progeny emergence under control was 93.42% and 100% higher than nuts treated with P. guineense and chlorpyrifos, respectively. P. guineense and chlorpyrifos did not cause significant reduction in seed germination. Study recommends P. guineense is a reliable organic material that could offer protection to Bambara nuts against C. subinnotatus

Oxaliplatin/capecitabine or carboplatin/paclitaxel-based preoperative chemoradiation for resectable oesophageal adenocarcinoma (NeoSCOPE): Long-term results of a randomised controlled trial

AimThis is the first randomised study to evaluate toxicity and survival outcomes of two neoadjuvant chemoradiotherapy (CRT) regimens for patients with localised oesophageal adenocarcinoma (OAC) or gastro-oesophageal junction (GOJ) adenocarcinoma. The initial results showed comparable toxicity between regimens and pathological complete response (pCR) rate favouring CarPacRT. Herein, we report survival, progression patterns, and long-term toxicity after a median follow-up of 40.7 months. MethodsNeoSCOPE was an open-label, UK multicentre, randomised, phase II trial. Eighty-five patients with resectable OAC or GOJ adenocarcinoma, ≥cT3 and/or ≥cN1 (TNM v7), suitable for neoadjuvant CRT, were recruited between October 2013 and February 2015.Patients were randomised to OxCapRT (oxaliplatin 85 mg/m2 on Days 1, 15, and 29; capecitabine 625 mg/m2 orally twice daily on days of radiotherapy [RT]) or CarPacRT (carboplatin AUC2; paclitaxel 50 mg/m2 on Days 1, 8, 15, 22, and 29). RT dose was 45 Gy/25 fractions/5 weeks. Both arms received induction chemotherapy (two cycles oxaliplatin 130 mg/m2 on Day 1, capecitabine 625 mg/m2 orally twice daily on Days 1–21) before CRT. Surgery was performed 6–8 weeks after CRT.The primary end-point was pCR. Secondary end-points were toxicity, progression-free survival (PFS), overall survival (OS), and patterns of progression. ResultsEighty-five patients were recruited from 17 UK centres. The median OS was 41.7 months (95% confidence interval [CI] 19.6 to not reached) in the OxCapRT arm and was not reached in the CarPacRT arm (multivariable hazard ratio [HR] = 0.48, 95% CIs: 0.24–0.95, P = 0.035). The median PFS was 32.6 months (95% CIs: 17.1 to not reached) in the OxCapRT arm and was not reached in the CarPacRT arm (multivariable HR = 0.54, 95% CIs: 0.29–1.01, P = 0.053). In both arms, the distant progression was twice as common as locoregional progression. ConclusionsOS and PFS favoured neoadjuvant CarPacRT over OxCapRT. Distant was more common than locoregional progression; therefore, priority should be given to optimising the systemic treatment component. Clinical trial informationEudraCT Number: 2012-000640-10; ClinicalTrials.gov: NCT01843829.

Selenium (Se) as well as mercury (Hg) may influence the methylation and toxicity of inorganic arsenic, but further research is needed with combination of Inorg-arsenic, Se, and Hg

Selenium (Se) as well as mercury (Hg) may influence the methylation and toxicity of inorganic arsenic, but further research is needed with combination of Inorg-arsenic, Se, and Hg

Intravesical gemcitabine for non-muscle invasive bladder cancer.

It remains unclear whether people with non-muscle invasive bladder cancer (NMIBC) benefit from intravesical gemcitabine compared to other agents in the primary or recurrent setting following transurethral resection of a bladder tumor. This is an update of a Cochrane Review first published in 2012. Since that time, several randomized controlled trials (RCTs) have been reported, making this update relevant. OBJECTIVES: To assess the comparative effectiveness and toxicity of intravesical gemcitabine instillation for NMIBC. We performed a comprehensive literature search of the Cochrane Library, MEDLINE, Embase, four other databases, trial registries, and conference proceedings to 11 September 2020, with no restrictions on the language or status of publication. We included RCTs in which participants received intravesical gemcitabine for primary or recurrent NMIBC. Two review authors independently assessed the included studies and extracted data for the primary outcomes: time to recurrence, time to progression, grade III to V adverse events determined by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0), and the secondary outcomes: time to death from bladder cancer, time to death from any cause, grade I or II adverse events determined by the CTCAE v5.0 and disease-specific quality of life. We performed statistical analyses using a random-effects model and rated the certainty of the evidence using GRADE. We included seven studies with 1222 participants with NMIBC across five comparisons. This abstract focuses on the primary outcomes of the three most clinically relevant comparisons. 1. Gemcitabine versus saline: based on two years' to four years' follow-up, gemcitabine may reduce the risk of recurrence over time compared to saline (39% versus 47% recurrence rate, hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.54 to 1.09; studies = 2, participants = 734; I2 = 49%; low-certainty evidence), but the CI included the possibility of no effect. Gemcitabine may result in little to no difference in the risk of progression over time compared to saline (4.6% versus 4.8% progression rate, HR 0.96, 95% CI 0.19 to 4.71; studies = 2, participants = 654; I2 = 53%; low-certainty evidence). Gemcitabine may result in little to no difference in the CTCAE grade III to V adverse events compared to saline (5.9% versus 4.7% adverse events rate, risk ratio [RR] 1.26, 95% CI 0.58 to 2.75; studies = 2, participants = 668; I2 = 24%; low-certainty evidence). 2. Gemcitabine versus mitomycin: based on three years' follow-up (studies = 1, participants = 109), gemcitabine may reducethe risk of recurrence over time compared to mitomycin (17% versus 40% recurrence rate, HR 0.36, 95% CI 0.19 to 0.69; low-certainty evidence). Gemcitabine may reduce the risk of progression over time compared to mitomycin (11% versus 18% progression rate, HR 0.57, 95% CI 0.32 to 1.01; low-certainty evidence), but the CI included the possibility of no effect. We are very uncertain about the effect of gemcitabine on the CTCAE grade III to V adverse events compared to mitomycin (RR 0.51, 95% CI 0.13 to 1.93; very low-certainty evidence).The analysis was only based on recurrent NMIBC. 3.Gemcitabine versus Bacillus Calmette-Guérin (BCG) for recurrent (one-course BCG failure) high-risk NMIBC: based on 6 months' to 22 months' follow-up (studies = 1, participants = 80), gemcitabine may reducethe risk of recurrence compared to BCG (41% versus 97% recurrence rate, HR 0.15, 95% CI 0.09 to 0.26; low-certainty evidence) and progression over time (16% versus 33% progression rate, HR 0.45, 95% CI 0.27 to 0.76; low-certainty evidence).We are very uncertain about the effect of gemcitabine on the CTCAE grade III to V adverse events compared to BCG (RR 1.00, 95% CI 0.21 to 4.66; very low-certainty evidence). In addition, the review provides information on the comparison of gemcitabine versus BCGandgemcitabine versusone-third dose BCG. AUTHORS' CONCLUSIONS: Based on findings of this review, gemcitabine may have a more favorableimpacton recurrence and progression-free survival than mitomycin but we are very uncertain as to how major adverse events compare. The same is true when comparing gemcitabineto BCG in individuals with high risk disease who have previously failed BCG.The underlying low- to very low-certainty evidence indicates that our confidence in these results is limited; the true effects may be substantially different from these findings; therefore, better quality studies are needed.

Implementation of Single-Fraction Lung Stereotactic Ablative Radiotherapy in a Multicenter Provincial Cancer Program During the COVID-19 Pandemic.

BackgroundDuring the novel coronavirus disease 2019 (COVID-19) pandemic, cancer centers considered shortened courses of radiotherapy to minimize the risk of infectious exposure of patients and staff members. Amidst a pandemic, the process of implementing new treatment approaches can be particularly challenging in larger institutions with multiple treatment centers. We describe the implementation of single-fraction (SF) lung stereotactic ablative radiotherapy (SABR) in a multicenter provincial cancer program.Materials and MethodsBritish Columbia, Canada has a provincial cancer program with six geographically distributed radiotherapy centers serving a population of 5.1 million, over 944,735 square kilometers. In March 2020, provincial mitigation strategies were developed in case of reduced access to radiotherapy due to the COVID-19 pandemic. SF lung SABR was identified by the provincial lung radiation oncology group as a mitigation measure supported by high-quality randomized evidence that could provide comparable outcomes and toxicity to existing fractionated SABR protocols. A working group consisting of radiation oncologists and medical physicists reviewed the medical literature and drafted consensus guidelines that were reviewed by a group of center representatives as a component of provincial lung radiotherapy mitigation strategic planning. Individual centers were encouraged to implement SF lung SABR as their resources and staffing would allow. Centers were then surveyed about barriers to implementation.ResultsOn March 24, 2020, a working group was created and consensus guidelines for SF lung SABR were drafted. The final version was approved and distributed by the working group on March 26, 2020. The provincial lung radiotherapy mitigation strategy group adopted the guidelines for implementation on April 1, 2020. Implementation was completed at the first center on April 27, 2020. Barriers to implementation were identified at five of six centers. Two centers in regions with disproportionately high COVID-19 cases described inadequate staffing as a barrier to implementation. One center encountered delays due to pre-scheduled commissioning of new treatment techniques. Three centers cited competing priorities as reasons for delay. As of May 2021, two centers had active SF lung SABR programs in place, three centers were in the process of implementation, and one center had no immediate plans for implementation due to ongoing resource issues.ConclusionSF lung SABR was adopted by a provincial cancer program within weeks of conception through rapid communication during the development of COVID-19 pandemic mitigation strategies for radiotherapy. Although consensus guidelines were written and approved in an expedited timeframe, the completion of implementation by individual centers was variable due to differences in resource allocation and staffing among the centers. Strong organizational structures and early identification of potential barriers may improve the efficiency of implementing new treatment initiatives in large multicenter radiotherapy programs.

Comparative physicochemical properties and toxicity of organic UV filters and their photocatalytic transformation products

Transformation products (TPs) of micropollutants contaminating our water resources have become an emerging issue due to the potential threats they pose to environmental and human health. This study investigated the transformation chemistry, toxicity, physicochemical properties and environmental behavior resulting from photocatalytic transformation of organic UV filters as model micropollutants. 3-Benzylidene camphor (3-BC), 4-hydroxybenzophenone (4-HB) and octocrylene (OC) were effectively degraded by UV-A/TiO2 treatment, with TPs identified and characterized with high resolution mass spectrometry. Nitrated-TPs were observed to be formed in the presence of nitrite and nitrate for 3-BC and 4-HB, suggesting that the transformation process could be altered by components in the water matrix. Vibrio fischeri bioluminescence inhibition assay revealed an increase in toxicity of TPs derived from photocatalytic treatment, with quantitative structure-activity relationship model (ECOSAR) predicted an enhanced toxicity of individual TPs' after transformation. Assessment of physicochemical properties and environmental behavior suggested that TPs as compared to parent organic UV filters, may represent even greater hazards due to their increased water solubility, persistence and mobility – in addition to retaining the parent organic UV filter's toxicity. The results provide important information relevant to the potential risks for the selected organic UV filters, and their corresponding transformation products.