Cumulative Toxicity Research Articles

Interactive Effects of Dichlorvos, Dimethoate, And Cypermethrin On Growth and Oxidative Homeostasis in Maize (Zea Mays)

This study investigates the effects of dichlorvos, dimethoate, and cypermethrin, individually and in combinations, on maize (Zea mays) growth and physiology. Maize seeds were grown in pesticide-treated soil, and growth parameters, oxidative stress markers, and enzymatic activities were evaluated. Growth was significantly inhibited by pesticide exposure, with Group H (triple pesticide combination) showing the most severe reduction in plant height (48% lower) and stem girth (40% lower) compared to the control (p < 0.05). Biochemical assays revealed significant declines in catalase (CAT) and superoxide dismutase (SOD) activities across all tissues, indicating compromised oxidative stress defenses. For instance, CAT activity in roots decreased by 65% in Group H compared to the control (p < 0.05). Concurrently, malondialdehyde (MDA) concentrations, a marker of lipid peroxidation, increased significantly, with Group H showing a 75% rise in leaves relative to the control (p < 0.05). Relative water content (RWC) also decreased substantially, with Group H recording the lowest hydration levels (37% reduction, p < 0.05). These findings suggest synergistic or cumulative toxicity from combined pesticide exposure, with the most pronounced effects observed in triple pesticide treatments. Statistical analyses (ANOVA, Tukey's test) confirmed significant differences across groups (p < 0.05), reinforcing the reliability of the results. This study highlights the adverse impacts of pesticide combinations on maize growth and physiological stability, emphasizing the need for sustainable pest management strategies, such as integrated pest management (IPM), to mitigate the ecological and agricultural risks of pesticide use.

Trifluridine/tipiracil regimen in combination with bevacizumab for metastatic colorectal cancer in the third line: an expert opinion

The prolongation of survival along with the preservation of quality of life, possibly avoiding harmful cumulative toxicities, is the primary therapeutic aim for patients with metastatic colorectal cancer (mCRC) in the third-line setting. Several therapeutic options are now available, although some differences across countries in drug approval and the optimal therapeutic sequencing associated with each peculiar patient subgroup represent a clinical challenge for oncologists. Among various options, the SUNLIGHT trial showed how the combination of trifluridine/tipiracil (FTD/TPI) with bevacizumab is effective with an easily manageable toxicity profile compared to FTD/TPI alone. Of note, the efficacy is confirmed independently from KRAS mutational status and also for patients who had breaks in anti-vascular endothelial growth factor (anti-VEGF) therapy. Herein, we describe the current state of the art in the landscape of treatments after the second progression in mCRC. Based on a critical review of the literature aimed to guide clinicians in their daily decision-making, we point out that the combination of FTD/TPI with bevacizumab produces a clinical benefit in unselected mCRC patients. Therefore, the FTD/TPI plus bevacizumab regimen can represent a new standard of care for the treatment of patients with refractory mCRC who have progressed after two lines of therapy.

Combination therapy involving azacitidine for acute myeloid leukemia patients ineligible for intensive chemotherapy.

Acute myeloid leukemia (AML) is a complex hematological malignancy predominantly affecting the elderly, with a median diagnosis age of 68 years. Despite advances in treatment, elderly AML patients face suboptimal survival outcomes, with an estimated 5-year survival rate below 20 %. Epigenetic dysregulation, notably DNA methylation, is a key factor in the progression of myelodysplastic syndromes (MDS) to AML. This review examines various combination regimens involving azacitidine (AZA), including those with lenalidomide, histone deacetylase inhibitors (HDACi), kinase inhibitors, metabolic enzyme inhibitors, monoclonal antibodies, immune checkpoint inhibitors, and anti-apoptotic protein inhibitors. Notable among these are the combinations with venetoclax, which has demonstrated remarkable efficacy in phase III trials, and the emerging IDH inhibitors ivosidenib and enasidenib, which have shown significant clinical benefits in patients with IDH mutations. While combination therapies with AZA hold great promise, challenges persist, including translating in vitro synergies to in vivo efficacy and identifying optimal regimens for specific patient populations. Cumulative toxicities may also offset clinical benefits, necessitating rigorous clinical trial design. Future research must focus on refining combination strategies, optimizing dosages and sequences, and thoroughly evaluating therapeutic efficacy and safety to advance the treatment of AML and improve patient outcomes.

Magnesium Imbalance before and during Concomitant Chemoradiation in Cervical Cancer Patients: A Prospective Interventional Study

Introduction: Cervical cancer is a major health concern, especially in developing countries. It is the second most common cancer among women in India, largely due to limited access to advanced screening and Human Papilloma Virus (HPV) vaccination. Despite significant advancements in cervical cancer prevention and treatment, the disease remains a major health burden, particularly in low-resource settings. Magnesium (Mg), an essential mineral involved in immune function, inflammation and Deoxyribonucleic Acid (DNA) repair, has been linked to various cancers, including colorectal and breast cancers, but its role in cervical carcinoma is underexplored. Aim: To investigate the association between magnesium levels and cervical carcinoma and to explore the association of hypomagnesemia with concomitant chemotherapy using cisplatin during chemoradiation. Materials and Methods: This was a hospital-based prospective interventional study, in which a total of 322 subjects were included in the study, of which 161 were healthy controls and 161 were diagnosed cases of cervical carcinoma. The magnesium levels were estimated before and after treatment using the Xylidyl blue complexing method on an autoanalyser. The data were compared between the two groups using appropriate statistical analysis with Statistical Package for the Social Sciences (SPSS) software version 20.0. Results: The mean magnesium levels were 2.08±0.24 mg/ dL in controls and 1.56±1.02 mg/dL in cancer patients (p-value<0.001). Mean serum levels decreased in cancer patients postchemoradiation to 0.74±0.39 mg/dL. During concomitant chemoradiation with cisplatin, hypomagnesemia was observed as grade I in 62 (38.5%), grade II in 25 (15.5%), grade III in 12 (7.5%) and grade IV in 36 (22.4%). A significant correlation was found between hypomagnesemia and hyponatremia, hypokalemia and cumulative cisplatin dose toxicity. Conclusion: The study demonstrated a high prevalence of hypomagnesemia in cervical cancer patients, especially those undergoing cisplatin-based chemotherapy, with levels declining further during treatment. Routine magnesium monitoring and proactive management are essential to prevent complications and improve outcomes.

A mathematical framework for comparison of intermittent versus continuous adaptive chemotherapy dosing in cancer

Chemotherapy resistance in cancer remains a barrier to curative therapy in advanced disease. Dosing of chemotherapy is often chosen based on the maximum tolerated dosing principle; drugs that are more toxic to normal tissue are typically given in on-off cycles, whereas those with little toxicity are dosed daily. When intratumoral cell-cell competition between sensitive and resistant cells drives chemotherapy resistance development, it has been proposed that adaptive chemotherapy dosing regimens, whereby a drug is given intermittently at a fixed-dose or continuously at a variable dose based on tumor size, may lengthen progression-free survival over traditional dosing. Indeed, in mathematical models using modified Lotka-Volterra systems to study dose timing, rapid competitive release of the resistant population and tumor outgrowth is apparent when cytotoxic chemotherapy is maximally dosed. This effect is ameliorated with continuous (dose modulation) or intermittent (dose skipping) adaptive therapy in mathematical models and experimentally, however, direct comparison between these two modalities has been limited. Here, we develop a mathematical framework to formally analyze intermittent adaptive therapy in the context of bang-bang control theory. We prove that continuous adaptive therapy is superior to intermittent adaptive therapy in its robustness to uncertainty in initial conditions, time to disease progression, and cumulative toxicity. We additionally show that under certain conditions, resistant population extinction is possible under adaptive therapy or fixed-dose continuous therapy. Here, continuous fixed-dose therapy is more robust to uncertainty in initial conditions than adaptive therapy, suggesting an advantage of traditional dosing paradigms.

Evaluation of ixabepilone efficacy and tolerability in metastatic breast cancer.

Although microtubule inhibitors are generally used in advanced stages, they provide the opportunity to prolong survival as an alternative when medical oncologists have difficulty finding options in their patients, who typically have a poor prognosis and most of whom are unresponsive to treatment. For this reason, we wanted to investigate the effect of ixabepilone treatment on survival in earlier metastatic lines. Our study also examined the frequency of side effects and survival differences in patients whose dose was reduced or whose treatment was discontinued. Our study includes patients diagnosed with metastatic breast cancer who received ixabepilone treatment between January 2011 and January 2021. Median overall survival (OS) in the group receiving ixabepilone on the 5th line and before was 22.0 months (95% CI: 21.0-22.9), in the group receiving ixabepilone after the 5th line was calculated as 10.0 months (95% CI: 8.9-11.0) (P < .001). Median OS (months) in the group receiving ixabepilone on the 4th line and before was 26.0 (95% CI: 23.6-28.3), in the group receiving ixabepilone after the 4th line was determined as 12.0 (95% CI: 10.5-13.4) (P < .001). Dose reduction or discontinuation of ixabepilone treatment in patients due to side effects did not affect OS and progression-free survival with ixabepilone statistically significantly. Ixabepilone treatment has side effects, similar to all other treatments used in metastatic breast cancer, however, these side effects are manageable. Additionally, since ixabepilone treatment is preferred in patients who have previously received many different chemotherapeutics and experienced cumulative toxicity, the side effects of ixabepilone may seem to be greater than they are. In our study, we showed that ixabepilone treatment has a statistically significant positive effect on survival if preferred in earlier metastatic lines. As similar studies increase in centers where ixabepilone treatment is generally given in advanced metastatic lines, treatment approaches may change in the coming years.

225Ac]Ac‐PSMA for the treatment of metastatic castration‐resistant prostate cancer: A systematic review and meta‐analysis

AbstractBackgroundApproximately 10%–20% of prostate cancers progress to metastatic and castration‐resistant forms (mCRPC). Radioligand (RLT) therapy with [177Lu]Lu‐prostate‐specific membrane antigen (PSMA) is an approved treatment for metastasized mCRPC. Moreover, Actinium‐225 (225Ac), an alpha‐emitter isotope, has also been used to label PSMA and, recently, to treat mCRPC patients with encouraging results. However, robust clinical data on [225Ac]Ac‐PSMA therapy and its comparison with [177Lu]Lu‐PSMA are still limited. Our aim was to evaluate the role of [225Ac]Ac‐PSMA in treating mCRPC and compare it with conventional [177Lu]Lu‐PSMA therapy.MethodsA systematic search was performed in PubMed, Web of Science, Scopus and the Cochrane Register of Controlled Trials from June 2023 to January 2024. This work was conducted in accordance with PRISMA guidelines.ResultsAfter screening and study selection according to PRISMA guidelines, 11 studies were included, 9 of which focused on [225Ac]Ac‐PSMA only and two on tandem therapy ([225Ac]Ac‐PSMA/[177Lu]Lu‐PSMA). Overall, the pooled proportion of PSA decline in patients was .85 (95% CI: .79–.91, p &lt; .001); patients pretreated with [177Lu]Lu‐PSMA achieved a pooled proportion of PSA decline of .90 (95% CI: .82–.97, p &lt; .001). In patients treated with tandem therapy, PSA decline was observed in approximately 90% of them, while PSA response rates above 50% ranged from 53.3% to 65%. Xerostomia was the most frequently reported side effect, along with anaemia, thrombocytopenia and nephrotoxicity.ConclusionsOverall, the main results of our study showed that [225Ac]Ac‐PSMA‐617 had a significant therapeutic effect on mCRPC with an acceptable toxicity level. The latter, however, appears greater than with [177Lu]Lu‐PSMA‐617. In future studies, an adequate analysis of the incidence of side effects associated with [225Ac]Ac‐PSMA should be performed to evaluate the role of cumulative toxicity of earlier treatments and the higher frailty of heavily pretreated patients.

CTNI-61. PRELIMINARY RESULTS OF A PHASE I/II TRIAL OF SELINEXOR AND TEMOZOLOMIDE IN RECURRENT GLIOBLASTOMA

Abstract BACKGROUND Selinexor (SEL) is a first-in-class XPO1 inhibitor with potent antitumor activity through the nuclear retention and reactivation of tumor suppressor proteins, reduced translation of oncogenes, and decreased expression of anti-apoptotic proteins. As a single agent, SEL has demonstrated brain penetration and clinically relevant responses in glioblastoma. We seek to enhance the effect and benefit of SEL by priming with temozolomide (TMZ). METHODS Through an NCI Project Team, we developed a multi-institutional phase I/II clinical trial which opened across the NCI Experimental Therapeutics Clinical Trial Network. Eligibility included histologically confirmed 1st recurrent MGMT promoter methylated glioblastoma. We evaluated safety, tolerability, and dose finding with an IQ 3 + 3 design of TMZ 150mg/m2 on days 1-5 of a 28-day cycle plus SEL on days 8 and 15. RESULTS From October 2022 to March 2024, we enrolled 12 patients (n=11 evaluable) into phase I of the study. Patient characteristics included 82% male, median age 62 (range 50-77), 64% white. The median number of cycles administered was 6 (range 1-12). Two dose levels (SEL 60mg and SEL 80mg) were evaluated. No dose-limiting toxicities (DLTs) were observed. The most common treatment related adverse events were nausea (58%), decreased platelet count (50%), fatigue (50%), constipation (42%), vomiting (25%), decreased lymphocyte count (25%), and decreased neutrophil count (25%). Grade 3+ treatment related adverse events included nausea, grade 3 (n=1); decreased lymphocyte count, grades 3-4 (n=2); and anorexia, grade 3 (n=1). Phase I has completed enrollment and the recommended phase II dose will be SEL 80mg. Additional results will be presented. CONCLUSION Results suggest that a sequential dosing regimen of SEL+TMZ is feasible, well-tolerated, and may minimize the cumulative toxicity of SEL. The phase II randomized portion of this trial is enrolling nationwide and will investigate efficacy and candidate molecular signatures of vulnerability (NCI #10505, NCT05432804).

Combined ecotoxicity of polystyrene microplastics and Di-(2-ethylhexyl) phthalate increase exposure risks to Mytilus coruscus based on the bioaccumulation, oxidative stress, metabolic profiles, and nutritional interferences

Di-(2-ethylhexyl) phthalate (DEHP) and microplastics (MPs) are emerging contaminants frequently detected in the marine environment. However, the influence of MPs on DEHP bioaccumulation and their combined effects on eco-environmental risks remain underexplored. Mytilus coruscus (M. coruscus) were exposed to DEHP (200.0 µg/L), polystyrene (PS) (0.050, 0.50, and 5.0 mg/L), and their combination at environmentally relevant concentrations for 15-day, followed by a 7-day depuration period. The amount of DEHP accumulation followed the order of digestive gland > gills > muscles > gonad, with PS dose-dependently amplifying DEHP bioaccumulation in digestive gland. The changes in antioxidant enzyme activity indicated disruptions in oxidative defense. Furthermore, metabolomic analysis revealed that PS and DEHP considerably altered the lipid, energy, and citric acid cycles in digestive gland and gonad. Post-depuration analysis showed combined exposure resulted in persistent effects. Compared with single exposures, combined exposure had a greater adverse effect on the metabolism of essential amino acids, fatty acids, and volatile compounds, potentially influencing edibility and nutritional value of M. coruscus. This study underscores cumulative eco-environmental toxicity of PS and DEHP toward M. coruscus and highlights the potential increased risks of co-pollution.

Visual colorimetric immunosensor for sensitive detection of 4-Chlorophenoxyacetic based on TMB2+-mediated etching of Au NRs

4-Chlorophenoxyacetic acid (4-CPA), a synthetic plant regulator, has been banned due to its cumulative toxicity to humans. However, unqualified sampling remains common in the market. To address the poor sensitivity of 4-CPA antibodies reported previously, a highly sensitive monoclonal antibody specific to 4-CPA was produced by redesigning and synthesizing a novel hapten in this study. Additionally, a visual colorimetric immunosensor based on TMB2+ mediated etching of gold nanorods (Au NRs) was developed. The ∆λ of the localized surface plasmon resonance (LSPR) peak exhibited a linear dependence on the 4-CPA concentration in the range of 0.2–6.25 ng mL−1, with a low limit of detection (LOD) of 0.2 ng mL−1. Recovery tests (85.0% to 108%) and HPLC validation demonstrated the immunosensor’s accuracy and precision. This visual colorimetric immunosensor illustrates significant potential for rapid detection of 4-CPA in biological environments.

Association of volatile organic compound exposure and metabolic syndrome

The cumulative toxicity of volatile organic compounds (VOCs) cause many medical diseases. We analyzed the evidence of association between VOCs and risk of metabolic syndrome in the Korean population using 1771 participants from the 2023 National Health and Nutrition Examination Survey. The creatinine-corrected urinary concentrations of BMA, 2-MHA, PGA, SPMA, 3-HPMA, BPMA and DHBMA were higher in the metabolic syndrome group than in the non-metabolic syndrome group. Urine N-Acetyl-S-(phenyl)-L-cysteine (SPMA) levels were significantly associated with metabolic syndrome after adjusting for confounders (odds ratio: 1.71). 2-MHA (OR 1.29, P=0.035) and SPMA (OR 2.84, P<0.001) were associated with the risk of elevated FBG impairment and SPMA (OR 1.57) was positively connected with the high blood pressure (P=0.016). In conclusion, the findings indicated significant association between the metabolic syndrome and a number of VOCs. Among them, there was a substantial positive correlation between the urinary SPMA levels and metabolic syndrome.

Allergy to aquatic biological resources as food

The review reveals the problem of allergies to fish and other highly allergenic foods. First of all, the products obtained from aquatic organisms are considered. The world production of fish of various species is discussed with the presentation of FAO statistics for recent years in this article. The role of aquaculture in the production of fish, shellfish and crustaceans is considered. In particular, the trends of fishing in the Black Sea and the growth of aquaculture production in Russia are analyzed. Generalized data indicate an increase in the importance of aquatic biological resources (ABR) in a balanced human diet. The study demonstrates the role of parvalbumin in the mechanism of development of allergies to products from ABR. Examples of other allergenic proteins that contain epitopes that trigger allergic reactions in the human body are given. The mechanism of these reactions is briefly described. Attention is drawn to cross-allergic reactions. Anthropogenic factors that can exacerbate allergies to fish products are discussed. These are pesticides, herbicides, antibiotics, detergent components, changes in chemical composition, and food storage conditions. Pseudoallergens with the ability to cause allergic reactions are also mentioned. Allergy symptoms can range from skin rashes and itching to respiratory problems and anaphylaxis. Treatment of fish allergy is similar to treatment for allergies to other foods. It includes the use of antihistamines, corticosteroids and sorbents. Heredity plays a major role in the development of allergic reactions. It is important to pay attention to the purity and quality of products, cooking methods, and also follow a diet. Due to the potentially higher cumulative toxicity of freshwater species, it is recommended that marine fish be preferred.

The Impact of Cobalt Species on the Hazardous Characteristics of Cobalt-Leaching Residue: A Case Study from Guangdong Province, China

Cobalt (Co) is a hazardous element of significant environmental concern, primarily due to its potential leaching toxicity. However, the current assessments of leached Co residues have focused solely on the total cobalt concentration, often overlooking the distinct Co species that contribute to its hazardous nature. This study attempts to determine the impact of cobalt speciation on the toxicity of cobalt and the related hazardous characteristics. The objective of this study is to enhance the understanding of how different Co species influence the environmental toxicity of leached residues. Cobalt speciation is studied by a multivariate analysis including ignitability, reactivity, corrosiveness, acute toxicity, leaching toxicity, and toxic substance concentration. The tested concentrations are compared with the identification standards and technical specifications in China. Co species, particularly cobalt oxide, are identified as the main contributors to the toxicity of the leached Co residue. It is also noted that Co occurrence significantly affects the calculation results of cumulative toxicity, thus impacting the hazard characteristics of leached cobalt residue. The findings benefit risk evaluators and decision makers by offering a new approach for managing leached Co residues and providing a scientific foundation for the development of relevant laws and regulations in China.

T Cell-Redirecting Bispecific Antibodies in Multiple Myeloma: Optimal Dosing Schedule and Duration of Treatment.

T cell-redirecting bispecific antibodies (BsAb) induce significant responses in heavily pretreated multiple myeloma. BsAbs are currently administered in a dose-dense manner until disease progression. However, continuous therapy is associated with safety concerns, including a high risk of infections and high costs. In addition, chronic exposure to BsAbs, and thus long-term T-cell stimulation, induces T-cell exhaustion, which may contribute to relapse. There is increasing evidence that the strategy of induction treatment followed by maintenance with longer intervals between BsAb doses, or limited treatment duration with cessation of therapy in patients who achieve deep remission, improves the balance between toxicity and efficacy. Significance: There is increasing evidence that after initial debulking, less-frequent BsAb administration mitigates T-cell exhaustion and minimizes the potential for chronic or cumulative toxicity while maintaining durable clinical responses. In addition, specific patient subsets may experience an extended treatment-free period following fixed-duration treatment. Fixed-duration treatment may, therefore, decrease cumulative toxicities and the burden on patients and healthcare systems.

Preparation irinotecan hydrochloride loaded PEGylated liposomes using novel method supercritical fluid and condition optimized by Box–Behnken design

A semi-synthetic camptothecin derivative known as irinotecan hydrochloride is frequently used to treat colorectal cancer, including colorectal adenocarcinoma and lung cancers involving small cells. Irinotecan has a very short half-life; therefore, continuous infusions are required to keep the drug’s blood levels at therapeutic levels, which could produce cumulative toxicities. Effective delivery techniques, including liposomes, have been developed to address these shortcomings. In this study, a continuous supercritical fluid approach dubbed Expansion Supercritical Fluid into an aqueous solution, in which the pressure decreases rapidly but remains over the critical pressure, is proposed to manufacture polyethylene glycolylated (PEGylated) liposomes carrying irinotecan hydrochloride. To accomplish this, PEGylated liposomes were created using a Box–Behnken design, and the operating parameters (flow rate, temperature, and pressure drop) were optimized. Encapsulation efficiency, mean size, and prepared liposome count were 94.6%, 55 nm, and 758 under ideal circumstances. Additionally, the stability of the PEGylated liposome was investigated during 8 weeks, and also PEGylated liposome-loaded irinotecan release profile was compared to conventional liposomes and free irinotecan, and a constant drug release was seen after the first burst release from liposomes.

Effects of Schisandrae Fructus alone or in combination in viral hepatitis treatment: A systematic review and meta-analysis of randomized controlled trials

Abstract Background Viral hepatitis causes annual deaths of 1.4 million people. Antiviral therapy rarely cures the disease, and patients are usually required to maintain lifelong medication, leading to cumulative drug toxicity. Schisandrae Fructus (SF) is efficacious in the treatment of viral hepatitis. Objective The systematic review and meta-analysis aim to examine the efficacy and safety of SF alone or in combination with specific and nonspecific treatments for treating viral hepatitis by analyzing the clinical trials performed up to date. Methods An extensive literature was searched in 7 databases from inception to May 2023. Final outcomes were divided into the primary outcomes containing the total effective rate and virological responses, as well as the secondary outcomes containing liver biochemical functions and frequencies of adverse events. RevMan 5.3 and GRADE pro 3.6 software were used for meta-analysis and assessment of evidence quality. Subgroup analysis was conducted to explore the source of the heterogeneity. Results Twenty-nine randomized controlled trials were included in the meta-analysis. SF treatment was comparable with western medicines or other traditional Chinese treatments in terms of primary and secondary outcomes. In combination with specific treatments with antiviral medicines, SF group reduced 18.45 U/L of alanine aminotransferase levels [weighted mean difference: 18.45, 95% confidence interval (CI): (16.12, 20.78), p &lt; 0.000 01] and 8.37 U/L of aspartate aminotransferase levels [weighted mean difference: 8.37, 95% CI: (1.25, 15.48), p = 0.02], and it decreased the levels of hyaluronic acid (HA) [standard mean difference (SMD): 0.92, 95% CI: (0.58, 1.27), p &lt; 0.000 01], laminin (LN) [SMD: 0.64, 95% CI: (0.38, 0.90), p &lt; 0.000 01], and procollagen type III [SMD: 0.48, 95% CI: (0.28, 0.67), p &lt; 0.000 01] while increasing the total effective rate by 24% [risk ratio: 1.24, 95% CI: (1.15, 1.32), p &lt; 0.000 01]. There were no severe adverse events during treatment. Conclusions SF was a potential adjuvant for antiviral therapy in restoring liver function. However, the poor quality of the included randomized controlled trials limited the recommendations. More long-term, randomized, and double-blind studies should be performed to assess the efficacy and safety of combination therapy.

Controlled electrocatalysis of the dechlorination and detoxification of chlorinated ethylenes to avoid production of highly toxic intermediates

In this study, electrochemical dechlorination and detoxification of a mixture of chlorinated ethylenes was investigated under various conditions using a double monoatomic synergistic metal catalytic cathode. Electrocatalytic degradation of mixed chlorinated with stepwise voltage and alternating current exhibited excellent dechlorination efficiency. The removal ratios of 1,2-dichloroethylene (1,2-DCE), trichloroethylene (TCE), and tetrachloroethylene (PCE) reached 78.79 %, 79.27 %, and 93.44 % in 10 min, and 98.14 %, 97.56 %, and 98.70 % in 30 min, respectively. The toxicity was evaluated using a quantitative structure–activity relationship model. The cumulative toxicity was reduced to 8.00 % of the initial cumulative toxicity in 30 min. An electrochemical dechlorination strategy for selective degradation and detoxification of mixtures of chlorinated pollutants is proposed. Controlled dechlorination and detoxification under low-voltage control avoided the accumulation of toxic intermediates. Cumulative toxicity was reduced by strategies of selective dechlorination, and segmented and alternating current decreased the energy consumption. The strategy provides a basis for alternating current electrocatalytic dechlorination associated with mixed chlorinated pollutants treatment.

Long-term evaluation of the safety of a rectal-prostate spacer, the ProSpace® balloon, in patients treated with radiotherapy for prostate cancer

BackgroundDue to the close proximity of the prostate and rectum, rectal toxicity remains a major problem in patient treated by radiotherapy for prostate adenocarcinoma. One method of increasing the distance between the prostate and the rectum is to use a spacer implanted into the rectoprostatic space. This report describes the long-term outcomes obtained with a new ballon spacer.MethodsPatients treated with curative radiotherapy for low- or intermediate-risk prostate adenocarcinoma, who underwent insertion of the ProSpace® (BioProtect Ltd, Tzur Yigal, Israel) rectal-prostate balloon spacer, were included. The main objective was to evaluate the dosimetric benefit of the spacer for OARs. The secondary objectives were to evaluate the feasibility and tolerability of ProSpace® balloon placement and to evaluate its long-term therapeutic efficacy and tolerance.ResultsBetween October 2013 and March 2015, 16 patients were enrolled in the Pasteur Clinic, Toulouse, France. The median follow-up was 85.5 months. From top to bottom, the space created was a mean of 16.3 mm (range: 11–20.5 mm) at the base of the prostate, 12.1 mm (range: 4–16 mm) at the middle and 8.9 mm at the apex (range: 5–15 mm). On average, rectal volumes receiving a dose of 70 Gy, 60 Gy and 50 Gy were significantly lower after balloon implantation: -4.81 cc (1.5 vs. 6.3; p < 0.0005), -8.08 cc (6.4 vs. 14.5; p = 0.002) and -9.06 cc (16.7 vs. 25.7; p = 0.003), respectively. There were significant differences in coverage after balloon implantation: Median V95% (p < 0.0005), median Dmin (p = 0.01) and median V98% (p < 0.001) were higher after balloon implantation. At 5 years, cumulative gastrointestinal toxicity was grade 1 in 6% (1/16 patients). No toxicity of grade 2 or higher was found. At 5 years, no urinary toxicity grade 3 or 4 toxicity was found. The QoL was not deteriorated.ConclusionsThe use of the ProSpace® balloon seems to be well accepted by patients, allowing a double dosimetric gain: a decrease in doses received by the rectum and an improvement in the coverage of the high-risk PTV. The long-term gastrointestinal toxicity remains low and QoL is preserved in all treated patients.

Factors contributing to pesticide contamination in riverine systems: The role of wastewater and landscape sources

Wastewater treatment plant (WWTP) discharges can be a source of organic contaminants, including pesticides, to rivers. An integrated model was developed for the Potomac River watershed (PRW) to determine the amount of accumulated wastewater percentage of streamflow (ACCWW) and calculate predicted environmental concentrations (PECs) for 14 pesticides in non-tidal National Hydrography Dataset Plus Version 2.1 stream segments. Predicted environmental concentrations were compared to measured environmental concentrations (MECs) from 32 stream sites that represented a range of ACCWW and land use to evaluate model performance and to assess possible non-WWTP loading sources. Statistical agreement between PECs and MECs was strongest for insecticides, followed by fungicides and herbicides. Principal component analysis utilizing optical fluorescence and ancillary water quality data identified wastewater and urban runoff sources. Pesticides that indicated relatively larger sources from WWTPs included dinotefuran, fipronil, carbendazim, thiabendazole, and prometon whereas imidacloprid, azoxystrobin, propiconazole, tebuconazole, and diuron were more related to urban runoff. In addition, PECs generally comprised a low proportion of MECs, which indicates possible dominant loading sources beyond WWTP discharges. Cumulative potential toxicity was higher for sites with greater ACCWW and/or located in developed areas. Imidacloprid, fipronil, and carbendazim accounted for the largest portion of predicted potential toxicity across sites. The chronic aquatic life toxicity benchmarks for freshwater invertebrates were exceeded for 82 % of the imidacloprid detections (n = 28) and 47 % of the fipronil detections (n = 19). These results highlight the ecological implications of pesticide contamination from WWTP discharges and also the potential legacy effects from accumulated soil and groundwater sources. Pesticide management strategies that mitigate both current and historical impacts may improve the health of aquatic ecosystems.

A Podcast on Practical Considerations in Patients with Advanced Urothelial Cancer Receiving First-Line Cisplatin- or Carboplatin-Based Chemotherapy Followed by Avelumab Maintenance in a Changing Therapeutic Landscape.

Platinum-based chemotherapy has been the cornerstone of first-line treatment for advanced urothelial carcinoma for decades, based on its proven efficacy and well-characterized safety profile. Although enfortumab vedotin (EV) plus pembrolizumab showed superior efficacy versus platinum-based chemotherapy in the EV-302 phase 3 trial, common and potentially cumulative toxicities associated with EV plus pembrolizumab may make this combination less suitable for some patients, such as those with pre-existing neuropathy, hyperglycemia, or hepatic impairment, or patients likely to have favorable outcomes with platinum-based chemotherapy. The availability of EV plus pembrolizumab in various countries may also be limited by financial considerations. Thus, platinum-based chemotherapy is likely to remain a valuable option for advanced urothelial carcinoma. Eligibility for cisplatin- or carboplatin-based regimens can be determined by assessing renal function, performance status, and specific comorbidities. In cisplatin-eligible and -ineligible patients without disease progression following platinum-based chemotherapy, avelumab first-line maintenance is standard of care based on findings from the JAVELIN Bladder 100 phase 3 trial, which showed that avelumab first-line maintenance plus best supportive care prolonged overall survival and progression-free survival compared with best supportive care alone across clinically relevant subgroups. Adverse events associated with avelumab were generally consistent with those observed with other immune checkpoint inhibitors, and long-term follow-up showed no new safety concerns with prolonged treatment. Efficacy benefits and safety profiles were similar in patients who received avelumab first-line maintenance after cisplatin- or carboplatin-based chemotherapy. The effectiveness and safety of avelumab first-line maintenance have been confirmed in several real-world studies. Overall, these data support the use of avelumab first-line maintenance for all platinum-treated patients without disease progression. In this podcast, we discuss the evolving role of platinum-based chemotherapy in this disease setting in the context of EV-302 trial results and describe practical considerations in patients receiving first-line cisplatin- or carboplatin-based chemotherapy followed by avelumab maintenance therapy.