Terms Of Toxicity Research Articles

Abstract A020: Liposomal topotecan with low-intensity focused ultrasound utilization to improve drug penetration with brain parenchyma in pediatric brain tumors

Abstract The blood-brain barrier (BBB) remains a significant obstacle in delivering effective chemotherapeutics to treat pediatric brain tumors, limiting drug penetration and reducing therapeutic outcomes. To overcome this challenge, we investigated the use of liposomal topotecan (TPT), encapsulated in a sonosensitive formulation, designed for controlled release triggered by low-intensity focused ultrasound (LIFU). In this study, we evaluated the in vitro efficacy of a sonosensitive liposomal topotecan formulation. The liposomal topotecan was created using remote loading with an ammonium sulfate gradient. TPT was loaded at a drug-to-lipid ratio of 1:10. The liposome was composed of hydrogenated soy PC, cholesterol, and DSPE-PEG2000. IC50 assay comparing free topotecan to the liposomal topotecan indicated that the cytoxicity of free TPT is lower than liposomal TPT indicating a sustained release of drug which would decrease long term toxicity. In addition, pharmcokinetic fluorescent quantification of liposomal topotecan showed linear increase in free drug (ug/uL) as liposomal TPT concentration is increased in brain homogenates. We hypothesize that tumor growth inhibition and overall survival would be significantly improved in mice receiving LIFU-mediated liposomal topotecan delivery. Our future work includes additional pharmokinetics with survival analysis in vivo with and without low intensity focused ultrasound. These results highlight the potential of combining liposomal drug formulations with focused ultrasound to overcome the challenges of BBB permeability, offering a promising therapeutic strategy for improving drug accumulation and survival outcomes in pediatric brain tumor models. Citation Format: Avani Mangoli, Sarah Kim, Kathryn Blethen, Angela Everhart, Sasha Nikiforov, Gerry Grant, Luke Avigliano. Liposomal topotecan with low-intensity focused ultrasound utilization to improve drug penetration with brain parenchyma in pediatric brain tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A020.

Can TK-TD modelling bridge the gap between in vitro and in vivo mammalian toxicity data?

Repeated dietary dose testing is used to assess longer term toxicity of chemicals, such as pesticides, to mammals. However, the internal pesticide concentration varies significantly as feeding rate relative to body size fluctuates over time. Toxicokinetic-toxicodynamic (TK-TD) models can estimate internal toxicant concentration over time and link this directly to observed effects on endpoints such as the growth rate of laboratory rats. Using TK-TD models it is therefore possible to predict the effects that would result from a constant internal concentration of a pesticide. This presents the possibility of comparison with data from in vitro experiments, potentially facilitating quantitative in vitro to in vivo extrapolation (QIVIVE). We used in vivo TK-TD models to identify relevant internal concentrations and then estimated the experimental conditions required to replicate these in cultured cells, using in vitro TK models. Cell population growth was measured, with a view to extrapolating through time and comparing effect sizes with in vivo predictions. However, observed cell proliferation was not significantly affected by the tested concentrations of any of the five pesticides in this study and so extrapolation was not possible. In light of this negative result, we highlight areas for future work towards QIVIVE of graded sublethal effects in mammals. The most pressing objective is improving the accuracy of in vivo TK predictions, which could be achieved with dietary dosing in TK studies.

A double-blind, randomized control trial to investigate the therapeutic potential of garlic scapes for high apoprotein E levels in a high-Fat diet-induced hypercholesteremic rat model.

Hypercholesteremia is the main contributor to metabolic diseases, including obesity, hypertension, and diabetes, which are the primary global sources of morbidity and death rates. Garlic scapes, a member of the Allium sativum family and a rich source of antioxidants, are utilized in various cuisine preparations due to their unique flavors and tastes. The current study examined garlic scape powder's effect on apoprotein E and its ability to decrease cholesterol. In an invivo experiment, normal, healthy Wistar albino rats (weeks) were divided into a negative control group (NC, n = 10) and a high-fat diet-raised group (n = 50) until they achieved cholesterol ≥250 mg/dL. Hypercholesteremic rats were further divided randomly into five groups: positive control (PC), standard group (fenofibrate 20 mg/kg bwt), and treatment groups G1, G2, and G3 that were administered with garlic scape powder 400 mg, 800 mg, and 1200 mg/kg bwt orally, respectively, for 3 months. The blood samples were examined for cholesterol, triglycerides, high-density lipoproteins (HDLs), low-density lipoproteins, apoprotein E, albumin levels, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). The liver tissues of the rats were subjected to histopathology. The lipid profile was assessed using serum kit techniques, whereas an ELISA kit was used to evaluate apoprotein E, and a serum kit was used to estimate ALT and AST. In comparison to all other groups except NC, the highest dose of 1200 mg/kg bwt of garlic scapes significantly (p ≤ .05) increased serum insulin (13.66 ± 0.72 μU/mL), apoprotein E levels (6.08 ± 0.10 mg/dL), HDL (42.1 ± 1.81 mg/dL), and reduce TG (88.7 ± 1.64 mg/dL) and decreased overall cholesterol levels (67.9 ± 1.17 mg/dL). Except for NC, all treatment groups had significantly (p ≤ .05) lower ALT and AST values than PC. To sum up, powdered garlic scapes may be a great way to avoid hyperlipidemia, which raises the risk of cardiovascular illnesses. ALT and AST levels were significantly (p ≤ .05) reduced in all treatment groups compared to PC, except for NC. In conclusion, garlic scape powder may be an excellent source to prevent hyperlipidemia, a risk factor for cardiovascular diseases. In addition, powdered garlic scapes supplementation at high doses may be used as an alternative natural source in functional foods to halt hyperlipidemia without liver toxicity in the long term.

Nab-paclitaxel, cisplatin, and capecitabine versus cisplatin and gemcitabine as first line chemotherapy in patients with recurrent or metastatic nasopharyngeal carcinoma: randomised phase 3 clinical trial

ObjectiveTo compare the effectiveness and safety of nab-paclitaxel, cisplatin, and capecitabine (nab-TPC) with gemcitabine and cisplatin as an alternative first line treatment option for recurrent or metastatic nasopharyngeal carcinoma.DesignPhase 3,...

Impact of a proactive patient assistance program for diverse ambulatory oncology patients: A retrospective cohort study.

e13513 Background: Significant differences persist in cancer incidence, survival, morbidity, and mortality among populations in the U.S. Individuals of lower socioeconomic status (SES) suffer disproportionately from cancer and other disease burdens compared to individuals with higher SES. Financial hardship is increasingly common, with many cancer survivors reporting difficulty paying medical bills, high financial distress, and delaying or forgoing care because of cost. Cancer patients reporting financial hardship are more likely to have psychosocial distress. Financial distress has been linked with several clinically relevant patient outcomes including quality of life, symptom burden, compliance, and survival. An NCI-designated comprehensive cancer center (CCC) with a diverse racial, ethnic, and linguistic patient population utilizes My Wellness Check (MWC) program to identify patients experiencing emotional, physical, practical, and social concerns. Among 4,117 MWC patient responders representing 43.1% of eligible patients during October 2019 - February 2022, 801 patients (19.5%) with 976 supportive or practical needs alerts were triggered to social workers where only 68.4% of the alerts were acted upon within a 72-hour window. For patients identified by MWC as having financial toxicity, Social Workers identified available resources to assist with patients’ out-of-pocket costs. Methods: In July 2022, the CCC launched a patient financial assistance program which included screening of all patients receiving systemic therapy administered at infusion centers. A third-party partner was contracted to provide patient advocates and technology augmenting the EHR. Patient Advocates identified eligible patients and enrolled them into financial assistance programs. Results: A retrospective analysis was performed for the period of May 2022 - December 2023, comparing patients receiving philanthropic medical financial assistance consisting of copay assistance and grants sponsored by drug manufacturers and diagnosis based non-profit foundations with infusion center patient population demographic data. The cohort participating in patient assistance programs included a higher percentage of female, Hispanic, age 27-64, commercially insured, and patients that reside in high and medium-high Social Vulnerability Index (SVI) counties. Conclusions: A proactive patient financial assistance program can help reduce financial distress for patients with cancer, especially those residing in high and medium high SVI counties. Leveraging the expertise of a third party helps mitigate financial toxicity in the short term and can help drive more equitable cancer outcomes.

2874: Interstitial brachytherapy in carcinoma cervix: long term results, toxicity and patterns of failure

2874: Interstitial brachytherapy in carcinoma cervix: long term results, toxicity and patterns of failure

1221: Using routinely collected data for long term toxicity assessment; a case-study from the CHHiP trial

1221: Using routinely collected data for long term toxicity assessment; a case-study from the CHHiP trial

Genome editing approaches for universal chimeric antigen receptor T cells

Autologous chimeric antigen receptor (CAR) T cell therapy has revolutionised the management of certain B-cell malignancies. However, as bespoke therapies, challenges include complex manufacturing logistics and risks ranging from suboptimal harvests to inadvertent transduction and masking of blast populations. Premanufactured, ready -to -use allogeneic CAR T cells could mitigate some of these hurdles if barriers created by HLA (Human leukocyte antigen) mismatching can be addressed. Genome editing to disrupt TCRαβ (T-cell receptor αβ) expression has been shown to be effective in addressing alloreactivity and avoiding graft versus host disease (GVHD). Platforms including transcription activator-like effector nucleases (TALENs), homing endonucleases and clustered regularly interspersed short palindromic repeats (CRISPR) / Cas9 have allowed multiplex editing of TCR genes in combination with CD52, the target antigen of alemtuzumab, as a strategy to evade lymphodepletion used to prevent host v graft rejection effects. Alternative approaches have targeted pathways to prevent HLA expression on donor T cells, and have also allowed targeted insertion of CAR genes, including placing transgene expression under the control of endogenous transcriptional machinery. These tools have rapidly progressed to clinical trials, and applications have extended beyond B-cell malignancies, showing promising early results in other settings, including relapsed/refractory(r/r) T-cell leukaemia. Short term immunological effects and toxicities have been generally manageable, and long-term monitoring is ongoing to help build confidence in safety over time.

Radiation therapy dose escalation achieves high rates of local control with tolerable toxicity profile in pediatric and young adult patients with Ewing sarcoma.

Local control for patients with Ewing sarcoma (EWS) who present with large tumors are suboptimal when treated with standard radiation therapy (RT) doses of 54-55.8Gy. The purpose of this study is to determine local control and toxicity of dose-escalated RT for tumors ≥8cm (greatest diameter at diagnosis) in pediatric and young adult patients with EWS. Eligible patients ≤30years old with newly diagnosed EWS ≥8cm treated with definitive conformal or intensity modulated photon, or proton radiation therapy techniques were included. All patients in the study received dose-escalated RT doses. Outcomes included overall survival (OS), event-free survival (EFS), local failure rates, and toxicity. Thirty-two patients were included, 20 patients presented with metastatic disease and 12 patients with localized disease. The median RT dose was 64.8Gy (range, 59.4-69.4Gy) with variability of doses to protect normal surrounding tissues. All patients received systemic chemotherapy. The 5-year OS and EFS for the cohort was 64.2% and 42%, respectively. The 5-year cumulative incidence of local failure was 6.6%. There were two combined local and distant failures with no isolated local failures. Twenty-nine patients experienced short term toxicity, 90% of those being radiation dermatitis. Twenty-seven patients experienced long-term toxicity, with only one experiencing grade 4 toxicity, a secondary malignancy after therapy. This study demonstrates that definitive RT for pediatric and young adult patients with EWS ≥8cm provides high rates of local control, while maintaining a tolerable toxicity profile.

Emergence of multidrug resistant, ctx negative seventh pandemic Vibrio cholerae O1 El Tor sequence type (ST) 69 in coastal water of Kerala, India

Seventh pandemic Vibrio choleare O1 El Tor strain is responsible for the on-going pandemic outbreak of cholera globally. This strain evolved from non-pathogenic V. cholerae by acquiring seventh pandemic gene (VC 2346), pandemic Islands (VSP1 and VSP2), pathogenicity islands (VP1 and VP2) and CTX prophage region. The cholera toxin production is mainly attributed to the presence of ctx gene in these strains. However, several variants of this strain emerged as hybrid strains or atypical strains. The present study aimed to assess the aquatic environment of Cochin, India, over a period of 5 years for the emergence of multidrug resistant V. cholerae and its similarity with seventh pandemic strain. The continuous surveillance and monitoring resulted in the isolation of ctx negative, O1 positive V. cholerae isolate (VC6) from coastal water, Cochin, Kerala. The isolate possessed the biotype specific O1 El Tor tcpA gene and lacked other biotype specific ctx, zot, ace and rst genes. Whole genome analysis revealed the isolate belongs to pandemic sequence type (ST) 69 with the possession of pandemic VC2346 gene, pathogenic island VPI1, VPI2, and pandemic island VSP1 and VSP2. The isolate possessed several insertion sequences and the SXT/R391 family related Integrative Conjugative Elements (ICEs). In addition to this, the isolate genome carried virulence genes such as VgrG, mshA, ompT, toxR, ompU, rtxA, als, VasX, makA, and hlyA and antimicrobial resistance genes such as gyrA, dfrA1, strB, parE, sul2, parC, strA, VC1786ICE9-floR, and catB9. Moreover, the phylogenetic analysis suggests that the isolate genome is more closely related to seventh pandemic V.cholerae O1 N16961 strain. This study reports the first incidence of environmental ctx negative seventh pandemic V. choleare O1 El Tor isolate, globally and its presence in the aquatic system likely to induce toxicity in terms of public health point of view. The presence of this isolate in the aquatic environment warns the strict implementation of the epidemiological surveillance on the occurrence of emerging strains and the execution of flagship program for the judicious use of antibiotics in the aquatic ecosystem.

Intestinal toxicity alleviation and efficacy potentiation through therapeutic administration of Lactobacillus paracasei GY-1 in the treatment of gout flares with colchicine.

Gout flares have emerged as a significant public health concern. Colchicine (COL) is a first-line and standard drug for treating gout flares. However, its clinical use is limited due to various adverse effects. Besides, COL fails to adequately meet the needs of patients, particularly young patients. In this study, we investigate the therapeutic administration of Lactobacillus paracasei GY-1 (GY-1) to overcome the limitations of COL. Our results demonstrate that GY-1 attenuates COL toxicity in terms of body weight loss, decreased feed intake, mortality, reduced locomotor activity, colon shortening, increased oxidative stress, histological damage, and impaired gut permeability. Meanwhile, we demonstrate that GY-1 enhances the therapeutic effect for gout flares when combined with COL, as evidenced by the reduction in paw swelling, decreased levels of proinflammatory cytokines including IL-1β and TNF-α, and an increase in the anti-inflammatory cytokine IL-10. Additionally, the absolute quantification of the gut microbiota shows that GY-1 restores the gut microbiota imbalance caused by COL. Furthermore, GY-1 reduces the abundance of 4 Alistipes species and 6 Porphyromonadaceae species, which may be responsible for toxicity alleviation. At the same time, GY-1 increases the abundance of Bacteroides sartorii and Enterococcus sp., which may contribute to its therapeutic efficacy. This study demonstrates the feasibility of developing probiotic-based adjuvant therapy or bacteriotherapy for treating gout flares. To our knowledge, GY-1 is the first probiotic that could be used as an alternative synergetic agent with COL for the therapeutic treatment of gout flares.

Перспективные подходы неинвазивной диагностики субклинической кардиоваскулярной токсичности химиотерапии

Objective: to present data on available modern methods of diagnosis of subclinical cardiovascular toxicity of chemotherapy. Modern strategies of treatment of cancer allow to stable remission and increase life expectancy of patients, the success of which is balanced by increased mortality of cancer patients due to the development of side effects of chemotherapy, the most prognostically significant of which are cardiovascular complications. Early diagnosis of cardiovascular toxicity in cancer patients is a “new” priority for collaboration of oncologists and cardiologists, as the development or progression of an already existing heart disease has a significant impact on the duration and quality of life of cancer patients. This review, at the current level of development of medical science, presents methods of diagnosis and monitoring of subclinical cardiovascular toxicity against the background of chemotherapy. Use for the diagnosis of subclinical cardiotoxicity such modern methods of visualization as two- and three-dimensional echocardiography, echocardiography with the definition of global longitudinal deformation of the myocardium - spectrum-tracking echocardiography, myocardial work, magnetic resonance tomography, definition of diastolic dysfunction allows to identify manifestations of cardiovascular toxicity in earlier terms, thereby affecting the prognosis and quality of life in cancer patients receiving chemotherapy treatment.

Long Term Toxicity of Aspartame on Ovaries and Blood Components of Adult Female Albino Rats

Long Term Toxicity of Aspartame on Ovaries and Blood Components of Adult Female Albino Rats

Evolution of therapy for locally advanced rectal cancer

AbstractRectal cancer is a prevalent disease worldwide. The standard treatment of locally advanced rectal cancer (LARC) is preoperative chemoradiotherapy followed by surgery and adjuvant systemic chemotherapy. Studies have been done to determine the best sequence of treatments to improve survival, cure rate and long term toxicity profile. In this paper, we will review the literature regarding the evolution of LARC treatment.

Venetoclax in Combination with Pediatric-Inspired Chemotherapy in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia: Results of a Phase I Trial

Introduction: Young adults with acute lymphoblastic leukemia (ALL) have favorable outcomes compared with historical standards when treated with an asparaginase-containing pediatric regimen (Stock et al., Blood 2019). We have demonstrated the safety and efficacy of pediatric inspired chemotherapy (PIC) for adults up to age 60 (MSK protocol 12-266, Geyer et al., Haematologica 2021). However, cure rates for adults with ALL remain below 60%, prompting the need for novel agents. Venetoclax (ven) is a BCL2 inhibitor being tested in several clinical trials for ALL. Here, we present the first report of ven used in combination with a multiagent, asparaginase-containing chemotherapy regimen for the upfront treatment of ALL. Methods: We conducted a Phase I, single-center, single-arm clinical trial (NCT05386576) to evaluate the safety and efficacy of ven in combination with PIC in adults with newly diagnosed ALL. Adults aged ≤60 years diagnosed with Philadelphia chromosome negative ALL were eligible for the study. The primary objective was to evaluate the safety of ven in combination with asparaginase-based PIC and identify the maximum tolerated dose and recommended phase II dose. The secondary objectives were to assess the rate of complete remission (CR) and measurable residual disease (MRD) negative CR at day 15 and 28 of Induction I, and end of Induction II. The regimen consisted of 6 treatment phases as previously published (12-266). Ven was administered at a final dose of 400mg (with a rapid dose escalation from 100mg over 3 days) during Induction I (days 5-7 dose escalation, days 7-28 full dose), Induction II (days 1-14 and 29-42), Intensification I & II (days 1-22), and Re-Induction I & II (days 1-14 and 29-42). Measurable residual disease (MRD) was assessed by multiparameter flow cytometry with 10 -4 sensitivity. We used historical data from 22 patients (pts) treated on our previous study, who received the same chemotherapy backbone without ven, as a comparator. Median follow up was calculated using the reverse Kaplan Meier indicator. Duration of treatment was compared using the Wilcoxon rank-sum test. Proportions of pts who achieved MRD-CR were compared with the chi squared test. Results: At the time of analysis, 8 pts had enrolled in the study; all 8 pts completed induction I and 6 (75%) pts had completed induction II (Table 1). Median follow up was 171 days. The median age was 38.5 years (min 25, max 60). 50% of pts had B-cell ALL, and 50% T-cell (including 1 patient with early T-cell progenitor). One patient (12.5%) had CNS disease (CNS 3) at diagnosis. Four (50%) pts had intermediate risk cytogenetics by CALGB 19802 classification (Stock et al., Cancer 2013), 2 (25%) had unfavorable, and 1 (12.5%) favorable. Two (40% of B-ALL) had a Philadelphia-like phenotype. During Induction I & II, 4 (50%) pts experienced febrile neutropenia, 6 (75%) grade 4 thrombocytopenia, and all 8 (100%) grade 4 neutropenia. No dose limiting toxicities, as defined per protocol, were observed. The average duration of Induction I on study was 46.6 days compared to 43.6 on 12-266 (p = 0.11). The average duration of Induction II on study for pts who had completed it at the time of analysis was 102 days compared to 74 days on 12-266 (p = 0.02), primarily due to cytopenias. Three (37.5%) of pts achieved an MRD negative CR by the end of Induction I. Of the 6 pts who had completed Induction II by time of analysis, 5 (83%) had achieved an MRD- CR, compared to 81% on 12-266 (p = 0.90) and 1 patient had refractory extramedullary disease. We assessed kinetics and depth of response by plotting the average blast percentage in the bone marrow by flow cytometry across three different timepoints. Pts on the study had numerically lower blast percentages at day 15, end of Induction I and end of Induction II compared to 12-266 (Figure 1). At the time of this analysis, no patient who entered CR had experienced disease relapse. Conclusions: Ven addition to a PIC backbone was overall safe with high MRD negative remission rates in this preliminary report. Compared to historical controls, pts treated with ven had a longer duration of Induction II primarily due to cytopenias, and we are amending the study to shorten ven duration during induction II. Pts treated with ven had a numerically faster reduction in bone marrow blasts compared to historical controls. Longer follow up in a larger patient population in this ongoing study will be required to assess long term toxicity and efficacy of this regimen.

A Review on Long Term Chronic Toxicity Study

Toxicity study of a new drug compound is an essential step in the process of new drug development. Long term toxicity testing is done on various biological systems. Dose specific toxic effect on vital organs of an investigational products is essential. After the acute toxicity testing, sub chronic toxicity can be proceeded by studying the assessment of an investigational product on morphological, behavioral, biochemical, haematological and histopathological parameters on experimental animals.

First report on chemometric modeling of tilapia fish aquatic toxicity to organic chemicals: Toxicity data gap filling

The Toxic Substances Control Act (TSCA) mandates the Environmental Protection Agency (EPA) to document chemicals entering the US. Due to the vast range of toxicity endpoints, experimental toxicological study for all chemicals is impossible to conduct. To address this, in silico methods like QSAR and read-across are strategically used to prioritize testing for chemicals lacking ecotoxicity data. Aquatic toxicity is one of the most critical endpoints directly related to aquatic species, mainly fish, followed by direct to indirect effects on humans through drinking water and fish as food, respectively. Therefore, we have employed the ToxValDB database to curate acute LC50 toxicity data for three Tilapia species covering two different genera, an ideal species for aquatic toxicity testing. Employing the curated dataset, we have developed multiple robust and predictive QSAR and quantitative read-across structure-activity relationship (q-RASAR) models for Tilapia zillii, Oreochromis niloticus, and Oreochromis mossambicus which helped to understand the toxicological mode of action (MoA) of the modeled chemicals and predict the aquatic toxicity of new untested chemicals followed by toxicity data gap filling. The best three QSAR models showed encouraging statistical quality in terms of determination coefficient R2 (0.94, 0.74, and 0.77), cross-validated leave-one-out Q2 (0.90, 0.67 and 0.70), and predictive capability in terms of R2pred (0.95, 0.77, and 0.74) for T. zillii, O. niloticus, and O. mossambicus datasets, respectively. The developed best mathematical models were used for the prediction of aquatic toxicity in terms of pLC50 for 297 untested organic chemicals across three major Tilapia species ranging from 1.841 to 8.561 M in terms of environmental risk assessment.

Heavy Metals Can Affect Plant Morphology and Limit Plant Growth and Photosynthesis Processes

Soil heavy metal pollution caused by human activities has become one of the most critical environmental issues with a global concern. Phytoremediation is widely used due to its low cost and environmental friendliness. However, the impact of heavy metals on plant growth remains unclear. This study investigated the effects on the growth and photosynthetic activity of Picris divaricata Vant. under different cadmium concentrations using a hydroponics cultivation system. The results showed that the growth and photosynthetic processes of P. divaricata exhibited a phenomenon of promotion in low Cd concentrations and inhibition in high Cd concentrations. Under a low to medium Cd concentration (≤25 μM), there was no Cd toxicity in terms of plant growth, but high concentrations of Cd inhibited plant growth. The Fe content of leaves gradually increased as the Cd concentration increased; it reached 201.8 mg kg−1 in 75 μM Cd. However, there was no significant difference in Mn between the 75 μM Cd treatment and the control (p > 0.05). The contents of carotenoid ranged between 3.06 and 3.26 mg/g across the different Cd treatments, showing no significant differences. The treatment with 5–75 μM Cd did not directly affect the photosynthesis of P. divaricata. Higher Cd concentrations reduced the stomatal density on the of P. divaricata leaves, resulting in stomatal and mesophyll conductance limitations, indirectly affecting P. divaricata photosynthesis. These research results provide a reference for evaluating and selecting heavy metal tolerant plants and provide environmentally friendly approaches to remediate heavy metal pollution.

Durée optimale de l’immunothérapie dans les CBNPC de stades avancés: Optimal duration of immunotherapy in advanced NSCLC

Immunotherapy has demonstrated efficacy in Non-Small Cell Lung Cancer (NSCLC) in the first-line setting, alone when tumor PDL-1 is high, or in combination with chemotherapy, as well as in further lines. Duration of immunotherapy is still on debate, taking into account constraints related to long term efficacy, toxicity and cost. This review develops these issues according to the last available data from literature.1877-1203/© 2023 SPLF. Published by Elsevier Masson SAS. All rights reserved.

One Year Follow-up and Toxicity Review in a Series of 6 Patients Receiving Stereotactic Arrhythmia Radioablation for Ventricular Tachycardia

Stereotactic body radiation therapy (SBRT) to arrhythmogenic scar regions defined by noninvasive cardiac mapping has recently been described for patients with treatment refractory ventricular tachycardia (VT). Long-term outcomes and both intra- and extra-cardiac toxicities are not well described in this patient population. We report the outcomes following at least 1-year post-treatment along with toxicity for 6 patients treated with this technique in our institution. A total of 6 patients treated between 2019 and 2022 with refractory VT with previously failed ablations and at least one anti-arrhythmic drug was treated at our institution. All were treated with 25 Gy in a single fraction to the suspected arrhythmogenic scar. Cardiac microstructure contouring was done following the atlas by Duane et al. 2017. Implantable cardioverter defibrillator (ICD) interrogation was performed regularly by the treating cardiologist to assess the number of VT and ICD events, and, patients were seen immediately following SBRT, and at 3, 6, and 12 months respectively. Computed tomography of the chest was done at 3 months to assess for radiation induced pneumonitis and transthoracic echocardiograms were done as per the cardiologist's discretion. Radiation toxicity was evaluated using CTCAE v5.0. The median follow-up time for the 6 evaluated patients is 24 months. Three patients (50%) remained VT free during the one-year period post SBRT. Two of these patients remain VT free and are either on reduced or discontinued anti-arrhythmic drugs, while another failed at 24 months in an area of the arrhythmogenic substrate that was intentionally not irradiated due to organ at risk safety concerns. Among those that failed, the median time to failure was 4 months (range 3-5 months). All 6 patients tolerated treatment with no immediate acute side effects. Three (50%) of patients had no acute clinical or radiographic side effects. Grade 1 esophagitis, grade 1 fatigue, and grade 1 cough was reported in 1 (17%) patient each (all different patients), and 1 patient required hospitalization 4 months after SBRT for a heart failure exacerbation (potentially SBRT related). One patient (17%) died within 3 months following treatment but their death was not attributed to radiation treatment. No cardiac microstructure toxicity has been reported to date. Despite increasing reports in the literature, there are no established criteria to predict success for SBRT in the context of treatment-refractory VT, or the optimal treatment dose for success, making it difficult to identify optimal patients. Current limited evidence suggests that this technique may be a relatively safe approach to provide an acute reduction in VT burden for those refractory to standard of care and has an acceptable acute toxicity profile however longer term follow-up is required. Long term toxicity, specifically to cardiac microstructures, and dose optimization is currently are the focus of ongoing study.