Major Toxicity Research Articles

An Overview of the Phytochemical and Therapeutic Potential of Wrightia Tinctoria

Introduction: Several natural phytomedicines derived from Chinese herbs demonstrate a wide range of pharmacological effects. Wrightia tinctoria (WT) is a small deciduous tree known as sweet indrajao. It belongs to the Apocynaceae family. Many diseases have been treated with this plant's phytoconstituents, such as skin disorders, dysenteric, diarrhea, and hair treatments. In addition, the therapeutic elements of WT demonstrate significant anti-inflammatory and anti-dandruff properties. However, there is a difference between this plant's preclinical and clinical significance. The purpose of this study is to collect and evaluate the various chemical, medicinal, and pharmacological characteristics of WT in relation to multiple disorders using preclinical evidence. This will serve as a valuable foundation for researchers to explore its effectiveness in clinical trials further. Materials and Methods: A comprehensive search was conducted across several databases, including PubMed, Web of Science, Scopus, Academic Journals Embase, Google Scholar, and Science Direct. The search utilized specific keywords such as "Wrightia tinctoria" as well as terms like "Traditional Chinese Medicine," "Pharmacological activities," "Anti-cancer," "Anti-viral," "Anti-microbial," "Anti-psoriatic," "Anti-Inflammatory," "Quercetin" and their combinations mainly from 1993 to 2024. Results: The pharmacological and therapeutic potential of WT is gathered and summarized based on existing research reports. WT substances consist of various phytoconstituents, including flavonoids, steroids, alkaloids, volatile oils, esters, and others. These components are primarily responsible for the various pharmacological effects of WT, such as anti-oxidant, anti-bacterial, antifungal, anti-diabetic, anti-cancer, anti-microbial, anti-inflammatory, and anti-ulcer effects. Conclusion: This review focuses on current research findings regarding WT's therapeutic potential and pharmacological activities. Additionally, it addresses the major safety and toxicity issues related to WT.

Effect of acute kidney injury and overall survival in patients with postoperative head and neck cancer who received chemoradiotherapy with cisplatin: A supplementary analysis of the phase II/III trial of JCOG1008.

In a randomized phase II/III trial (JCOG1008), weekly cisplatin (40 mg/m2) was non-inferior to 3-weekly cisplatin (100 mg/m2) for postoperative high-risk head and neck cancer. We investigated how acute kidney injury (AKI), a major dose-limiting toxicity effect of cisplatin, affects overall survival (OS). We analyzed 251 patients from JCOG1008 receiving chemoradiotherapy. AKI was defined based on AKI Network criteria (serum creatinine increase of ≥0.3 mg/dL or ≥1.5-fold [≥ stage I]) within 30 days after completing chemoradiotherapy. OS in the two arms was compared according to AKI development using the log-rank test. The total incidence of AKI was lower in the weekly arm than in the 3-weekly arm (38/122 [31.1%] vs. 56/129 [43.4%]). Additionally, stage II/III AKI occurred less frequently in the weekly arm than in the 3-weekly arm (8/122 [6.6%] vs. 19/129 [14.7%]). Cisplatin doses were similar in the weekly arm for patients with and without AKI (median, 238.6 mg/m2 vs. 239.2 mg/m2; p = 0.94), but lower in the 3-weekly arm for those who developed AKI (median, 276.3 mg/m2 vs. 297.4 mg/m2; p = 0.007). In the weekly arm, there was no difference in OS between patients with and without AKI (hazard ratio [HR], 1.06; 95% confidence interval [CI], 0.53 to 2.10). However, in the 3-weekly arm, patients with AKI had poorer OS than those without AKI (HR, 1.83; 95% CI, 1.04 to 3.21). In this supplementary analysis of JCOG1008 data, AKI impacted the OS of patients with head and neck cancer undergoing postoperative chemoradiotherapy in the 3-weekly arm but not in the weekly arm. Our results further endorse the utilization of weekly cisplatin at 40 mg/m2 in this setting.

Study of the toxicity of the essential oil of Brocchia cinerea

Brocchia cinerea is a North African plant belonging to the Asteraceae family, widely utilized in Algerian folk medicine to treat a variety of illnesses. These therapeutic virtues are mainly due to the plant essential oil. The chemical components of this oil were identified using GC-MS, and the variability in these components' levels was examined in nine samples that were taken at different times from two locations in Algeria's northern Sahara. The contents of the essential oil were found to consist of eight components, varying in concentrations: beta-thujone (46.80%), 1-Methyl-2-(1' methylethenyl) -3'- ethenylcyclopropylmethanol (14.59%), 1,8-Cineole (12.63%), limonen-10-ol (9.47%), 1(7),3,8 o Menthatriene (3.45%), and (-)-Camphor (2.11%). Toxicity studies were conducted in order to assess the safety of the essential oil, namely: LD50 estimation and biochemical blood parameters evaluation. The results showed an LD 50 of 507.5mg/kg close to the LD50 of Beta-thujone (442mg/kg): the main component of the essential oil, making it accountable for the major toxicity. The apparition of seizures as toxic manifestations for higher concentrations confirmed that. The essential oil of Brocchia was noted to be classified as slightly, weakly toxic, and the Beta-thujone contents showed to be within the regulatory accepted values, which makes the use of Brocchia safe within the indicated standards.

E-Cyanoacrylamides and 5-Imino Pyrrolones against Trypanosoma cruzi: Activity and Induced Mechanisms of Cell Death.

Chagas disease is caused by a protozoan parasite called Trypanosoma cruzi. The infection produces a first clinical phase, commonly asymptomatic or showing non-specific symptoms, and a second chronic phase characterized by cardiac and digestive dysfunctions in some individuals with the disease. This disease affects 7 million people and has been categorized by the World Health Organisation as a neglected tropical disease. In addition, the drugs used to combat it were developed in the 1970s and present major toxicity problems and limited efficacy in the chronicity of the disease. This has led to research into new active compounds that are effective against the disease, with studies on cyanoderivatives showing promising activity. In this work, eight active E-cyanoacrylamides/5-imino pyrrolones were studied. Compounds B and F showed excellent activity, while compounds C and G stood out for their lower cytotoxicity. After correlating the activity and cytotoxicity of the compounds, it was observed that compounds B, C, and G obtained the most favourable results. Various cell death studies were carried out with these compounds, and it was determined that all of them produced programmed cell death, with compound B standing out as being at a late stage in the process.

NIR-II Responsive Fe-Doped Carbon Nanoparticles for Photothermal-Enhanced Chemodynamic Synergistic Oncotherapy.

Phototherapy has demonstrated substantial development because in the second near-infrared (NIR-II) window it has a larger tissue penetration and fewer adverse consequences. In this work, a particular kind of NIR-II responsive Fe-doped carbon nanoparticles (FDCNs) is synthesized using a one-pot hydrothermal method for combined photothermal and chemodynamic therapy. The mesoporous nanostructure of FDCN, which has a size distribution that exceeds 225 nm, allows for effective acidification. The iron ions released from these nanoparticles can catalyze the decomposition of hydrogen peroxide (H2O2) into hydroxyl radical (•OH) for chemodynamic therapy (CDT). In addition to their CDT utility, FDCN can effectively adsorb and transform 1064 nm light into local heat, achieving a photothermal conversion efficacy (PCE) of 36.3%. This dual functionality not only allows for the direct eradication of cancer cells through photothermal therapy (PTT) but also enhances the chemodynamic reaction, creating a synergistic effect that amplifies the therapeutic outcome. The FDCN has demonstrated remarkable anticancer activity in both cellular and animal tests without incurring major systemic toxicity. This suggests that the compound has great promise for use in clinical cancer therapy.

Factors affecting peripheral neuropathy induced by nanoparticle albumin-bound paclitaxel in patients with pancreatic cancer.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major toxicity limiting the use of nab-paclitaxel (Nab-P) in treating patients with pancreatic cancer. The aim of this study was to identify the factors affecting CIPN using patient-reported outcome measures and the minimally invasive volumetric absorptive microsampling (VAMS) technique. The maximum concentrations of paclitaxel (Cmax) were measured from 81 VAMS samples collected from 44 participants with pancreatic cancer. The association between CIPN development and demographic, clinical and pharmacokinetic factors was determined using univariable and multivariable logistic regression. The association between CIPN severity and the factors was evaluated using Spearman's rank correlation. The impact of Cmax and the number of treatment cycles on the severity was assessed using multivariable linear regression. The development of CIPN was significantly associated with cumulative dose (odds ratio 1.005, 95% confidence interval [CI] 1.003-1.007), treatment cycles (3.47, 2.25-5.85), alkaline phosphate (0.992, 0.985-0.998) and age (1.092, 1.020-1.179), with an area under the receiver operating characteristic curve of 0.89 (95% CI 0.83-0.95). The severity of CIPN significantly worsened with increasing cumulative dose (coefficient 0.58, 95% CI 0.44-0.69), treatment cycles (0.57, 0.44-0.68) and age (0.18, 0.00-0.35). The severity of CIPN was predictable from treatment cycles (P = .0002) and Cmax (P = .01). The higher the cumulative dose of Nab-P, treatment cycles and age, the more frequently and severely do the patients experience CIPN. In predicting the severity of CIPN using Cmax, minimally invasive VAMS is a feasible alternative to venous blood sampling.

Formation Mechanism and Source Apportionment of Hydrochemical Components in Groundwater in the Yinchuan Plain

Groundwater is one of the major water sources for production, living, and agricultural irrigation in the Yinchuan Plain. Owing to the influence of the regional environmental background and long-term effects of human activities, groundwater quality is generally inferior. To deeply analyze the formation mechanism and source of hydrochemical components in groundwater in the Yinchuan Plain, the traditional hydrochemical graphic method and mathematical statistics and principal component analysis-multivariate linear statistical model were used. Based on inorganic component contents of 100 phreatic water samples and 46 confined groundwater samples, the hydrochemical characteristics and quality status, spatial distribution of over-limit toxicological components, and contribution rate of hydrochemical components were analyzed. The results showed that the chemical components of groundwater were controlled by rock weathering and evaporation concentration. Dissolution-enrichment （F1）, original geological environment （F2）, and human activities（F3） were the principal factors that influenced groundwater hydrochemistry with the contribution rates of 73.67%, 14.45%, and 11.88%, respectively. The major over-limit toxicity indices in groundwater were NO3--N and F-. High NO3--N phreatic water was mainly influenced by agriculture activities, followed by the discharge of domestic sewage. Enrichment of groundwater F- was mainly caused by leaching of F-bearing minerals and cation exchange adsorption.

Comparison of EPIC Versus HIPEC in the Treatment of Colorectal Peritoneal Metastases and Appendix Tumors Using Inverse Probability of Treatment Weighting.

The selection of hyperthermic intraperitoneal chemotherapy (HIPEC) or early postoperative intraperitoneal chemotherapy (EPIC) for peritoneal metastases from colorectal cancer or appendiceal neoplasms following cytoreductive surgery (CRS) depends on the surgeon's discretion. This study was designed to compare postoperative and oncologic outcomes of HIPEC and EPIC using inverse probability of treatment weighting (IPTW). This study included 175 patients who received HIPEC or EPIC following CRS at a single tertiary university hospital between December 1999 and December 2020. Inverse probability of treatment weighting analysis was performed to control for pretreatment characteristics between the two groups. Multivariate analysis was performed to determine factors associated with postoperative and survival outcomes. After IPTW, no significant differences in baseline demographics and tumor characteristics were observed between the two groups. The HIPEC group had a significantly longer operation time than the EPIC group. The EPIC group showed a significantly higher postoperative mortality rate than the HIPEC group. Operation time (odds ratio [OR] 1.01; 95% confidence interval [CI] 1.01-1.02; p < 0.001), bowel anastomosis (OR 7.25; 95% CI 1.16-45.2; p = 0.034), neoadjuvant chemotherapy (OR 7.62; 95% CI 1.85-31.4; p = 0.005), and EPIC (OR 8.76; 95% CI 2.16-35.5; p = 0.002) were independent risk factors for major surgical complications. No association was observed between intraperitoneal chemotherapy type and major hematologic toxicity, overall survival, progression-free survival, or peritoneal progression-free survival. EPIC was a risk factor for major surgical complications. Survival outcomes were similar between the two types of intraperitoneal chemotherapy.

Feasibility, tolerability, and first experience of intracystic treatment with peginterferon alfa-2a in patients with cystic craniopharyngioma.

Children with craniopharyngiomas (CPs) typically suffer from a life-long chronic disease. The younger the child, the more vulnerable the maturing brain is to invasive therapies such as surgery or radiotherapy. Therefore, treatment modalities facilitating avoidance or delay of invasive therapies are beneficial for these patients. In the last decade, intracystic injection of interferon alfa-2a or alfa-2b evolved as a treatment of choice based on efficacy and minor toxicity. However, the drug is no longer available internationally. After an extensive pharmacological review, peginterferon alfa-2a was identified as the agent with closest similarity. A retrospective case series is described, including five patients treated with intracystic peginterferon alfa-2a for cystic CP according to an innovative care protocol. After initial CP cyst aspiration, peginterferon alfa-2a was injected once per week via an Ommaya reservoir for 6 weeks followed by response assessment with MRI. Patients' age ranged from 4 to 54 years (four patients <12 years, one adult patient). Intracystic therapy with peginterferon alfa-2a was tolerated well by all five individuals without any major toxicities and resulted in cyst shrinkage in all of the five patients. The importance of a permeability study prior to commencing intracystic therapy became apparent in one patient who suffered from cyst leakage. Intracystic treatment with peginterferon alfa-2a was found to be a tolerable and efficacious treatment modality in patients with cystic CP. This experience warrants further research with a larger number of patients with measurement of long-term efficacy and safety outcomes.

Evaluation of the Protective Effect of Cystone against Cisplatin Induced Nephrotoxicity in Cancer Patients

Abstract Purpose Cisplatin is a cost effective widely used antineoplastic drug to treat a number of solid tumors. The major dose-limiting toxicity is nephrotoxicity. Cystone is one of drugs that have been tested to reduce the incidence of cisplatin-induced acute kidney injury (CIAKI). This study aimed to investigate the protective effect of Cystone against CIAKI in larger number of patients relative to previously conducted pilot studies . Methods A prospective phase II, open-label randomized controlled study was conducted in patients receiving cisplatin-based chemotherapy in Ain Shams University Hospitals, using cystone tablet (manufactured by the Himalayan Pharmaceutical Company, India) administered as two pills every 8 hours continuously through course of chemotherapy starting from the day before receiving chemotherapy. A total of 99 patients were randomized between the control and cystone arms. The primary endpoint was the incidence of AKI according to Common Terminology Criteria Adverse Events (CTCAE) in each treatment arm. Secondary endpoints include need to dose modification between both arms. Results There was clinical difference in the incidence of CIAKI any grade between the two arms (12% in cystone arm vs 34 % in control arm P = 0.4. Need to dose modification is 10.4% vs 12 % (P = 0.8). There was a statistically significant difference between the two arms as regards the difference between values (mean) of serum creatinine and creatinine clearance values initially and at the end of treatment favoring drop of renal functions in control group (P = 0.000 and 0.003) respectively. Conclusion Our study did not demonstrate clearly a protective role of cystone in decreasing the incidence of CIAKI in patients receiving cisplatin based chemotherapy. However, drop of renal function in control arm with comparison to study arm may give an indication to further study cystone in different doses to assess its protective role against CIAKI.

A multicenter, phase 1, Adult Brain Tumor Consortium trial of oral terameprocol for patients with recurrent high-grade glioma (GATOR)

Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5days/month), a transcriptional inhibitor of specificity protein 1 (Sp1)-regulated proteins, is 1,700mg/day with median area under the plasma concentration-time curve (AUC) of 31.3μg∗h/mL. Given potentially increased efficacy with sustained systemic exposure and challenging logistics of daily IV therapy, here we investigate oral terameprocol for rHGGs in a multicenter, phase 1 trial (GATOR). Using a 3+ 3 dose-escalation design, we enroll 20 patients, with median age 60 years (range 31-80), 70% male, and median one relapse (range 1-3). Fasting patients tolerate 1,200mg/day (n= 3), 2,400mg/day (n= 6), 3,600mg/day (n= 3), and 6,000mg/day (n= 2) oral doses without major toxicities. However, increased dosage does not lead to increased systemic exposure, including in fed state (6,000mg/day, n= 4), with maximal AUC <5μg∗h/mL. These findings warrant trials investigating approaches that provide sustained systemic levels of transcription inhibitors to exploit their therapeutic potential. This study was registered at ClinicalTrials.gov (NCT02575794).

EUS-guided hydrogel injection to separate pancreatic head carcinoma from duodenum for enhanced radiotherapy: Multi-site feasibility study.

Background and study aims The proximity of a pancreas head tumor to the duodenum often limits delivery of an ablative dose of radiation therapy. This study evaluated the feasibility and safety of using an injectable polyethylene glycol (PEG) hydrogel between the head of the pancreas and duodenum. Patients and methods In a multi-site feasibility cohort study of patients with localized pancreatic cancer, PEG hydrogel was injected under endoscopic ultrasound guidance to temporarily position the duodenum away from the pancreas. Procedure characteristics were recorded, including hydrogel volume and space created. Patients were monitored for adverse events (AEs) and radiotherapy toxicity. Results In all six intent-to-treat patients (four with borderline resectable, two with locally advanced disease), the ability to place and visualize PEG hydrogel and create space between the duodenum and the head of the pancreas was successful. There were no procedure-related AEs resulting in radiotherapy delay. There were no device-related AEs and no reports of pancreatitis. Conclusions PEG hydrogel was successfully placed, created space between the duodenum and the head of the pancreas, and was not associated with major toxicity. Enhancing radiotherapy for pancreatic cancer by using PEG hydrogel to create peri-duodenal space could have beneficial implications for treatment and warrants more exploration.

Hematological toxicity of disinfection by-product iodoacetic acid

To clarify the effect of iodoacetic acid(IAA) on the blood system and electrolyte balance, hence further study the intrinsic relation of blood routine parameters and electrolyte levels, major hematological toxicity effects and their pattern after IAA treatment. Forty-eight 21-day-old male SPF grade Sprague-Dawley(SD) rats were gavaged with 0, 6.25, 12.5 and 25 mg/kg IAA for 31 days. After detections of blood routine and plasma inorganic ion levels, Spearman correlation coefficients were performed to evaluate their relationship. Changes in ferritin, transferrin, hepcidin, C-reactive protein and glyceraldehyde-3-phosphate dehydrogenase(GAPDH) were assessed by enzyme-linked immunosorbent assays. The EDock bioinformatics tool was applied to docking model of IAA and GAPDH. Compared to the control, high-dose IAA exposure had obvious inhibition effect on rat leukocytes with the total number declined by 51.12%, and neutrophils were particularly sensitive to IAA with the number reduced by 73.66%(P&lt;0.01), and rat erythrocytes exhibited a small cell low pigment effect with hemoglobin and hematocrit decreased by 8.60% and 8.70%, respectively(P&lt;0.05). But IAA had little effects on the platelet. Plasma iron, phosphorus, zinc and potassium levels were repressed significantly, while chlorine, sodium and magnesium levels were elevated obviously through IAA exposure. However, plasma calcium levels were hardly affected by IAA. In comparison with the control, iron levels declined by 67.09%, whereas magnesium levels increased by 131.82% in the high-dose group(P&lt;0.01). Overall, correlation analyses uncovered that plasma iron metabolism was most strongly and positively correlated with levels of leukocyte, erythrocyte and platelet system parameters after IAA exposure, and the correlation coefficients of leukocyte number, mean hemoglobin content and mean erythrocyte volume were 0.637, 0.410 and 0.365, respectively(P&lt;0.05). Compared to the control, in the high-dose IAA group, the plasma content of C-reactive protein was significantly upregulated by 13.30%(P&lt;0.05), and plasma levels of transferrin and ferromodulin were also respectively elevated by 12.73% and 11.02%(P&lt;0.05). But plasma levels of ferritin and GAPDH did not differ between groups. The docking model exhibited that IAA could bind to the 150 Cys active site of rat GAPDH did. IAA not only had toxic effects on rat leukocytes and the plasma electrolyte balance, but also generated inflammation and iron deficiency, leading to smaller erythrocytes and lower pigment.

Biomimetic cytotoxicity control of select nitrogenous disinfection byproducts in water

Nitrogenous disinfection byproducts (N-DBPs) in water are carcinogenic, teratogenic, and mutagenic. In this work, we developed a biomimetic reduction approach based on the cysteine thiol that destructed the highly toxic, select nitrogenous haloacetamides (HAMs) and haloacetonitriles (HANs) while effectively controlling the cytotoxicity of the degradation products to serve as a basis for further technological applications (e.g. immobilized contact bed for terminal users). Mechanisms on toxicity control were elucidated. Results showed the degradation and cytotoxicity control of HAMs as more efficient than that of the HANs. The cytotoxicity of the chlorinated, brominated, and iodinated HAMs and HANs was reduced to 25 %− 0.25 % of the original after biomimetic reduction using a reasonable concentration ratio. Through a combination of thiol-specific reactivity, dehalogenation, and quantitative structure-activity relationship analyses, the major toxicity control mechanisms were found to be the reductive dehalogenation of the N-DBPs. The halogenated functional groups on the N-DBPs had a more pronounced effect than the amide and nitrile groups on the cytotoxicity and detoxification effect. Patterns of toxicity interaction variations with DBPs concentrations were identified to detect possible synergistic cytotoxicity interactions under various combinations of HAMs and HANs in the presence of the cysteine thiol. Results could benefit future N-DBPs control efforts.

Sorafenib maintenance in FLT3-ITD mutated AML after allogeneic HCT: a real-world, single-center experience.

Despite allogeneic hematopoietic stem cell transplant (allo-HCT) and the development of novel FLT3 inhibitors in both induction (midostaurin) and in the relapsed/refractory setting (gilteritinib), FLT3-ITD mutated leukemia (FLT3-ITD+ AML) still represents a challenge for modern hematology. Sorafenib is, to this date, the only inhibitor that demonstrated efficacy in improving both progression-free and overall survival as post-HCT maintenance therapy, even if its use in this setting has not been approved so far by regulatory agencies. The aim of our study was to evaluate the feasibility, safety, and efficacy of sorafenib maintenance in preventing early relapse in FLT3-ITD+ AML after HCT in a single-center experience. We analyzed 26 consecutive patients who received post-HCT 2-year maintenance with sorafenib at our center between 2017 and 2023. The median time from HCT to sorafenib start was 130 days, and the median dosage was 200 mg per day. Two (8%) and three (12%) patients discontinued maintenance due to toxicity and disease relapse, respectively. Eight (31%) patients terminated the 2-year maintenance and stopped sorafenib, while 13 patients are still under treatment. Overall, 21/26 patients (81%) are alive and in stable complete remission as outlined by a 2-year disease-free survival of 83.61%. No major long-term toxicity was reported at the last follow-up. Our real-world experience supports the use of sorafenib as a feasible and effective therapeutic option in post-HCT maintenance for FLT3-ITD+ AML.

Reducing baseline toxicity in fishery product-related sediments from land to sea: Region-specific solutions are required

Eastern China is a major producer of fishery products (including inland aquaculture, coastal mariculture, and coastal fishing products). The quality of the products is affected by hydrophobic organic contaminants (HOCs) in the sediments. Based on in-vitro luminescent bacterial assay, the baseline toxicity (BEQBio) of 56 common HOCs were assessed in the present study. Specifically, the BEQBio of sediments declined from land (31–400 mg/kg) to sea (9.1–270 mg/kg). However, the toxicity contribution explained by the HOCs increased gradually from land (0.70 %) to sea (10 %) using Iceberg Modeling. In the inland pond, current use HOCs (pyrethroid pesticide (PEs), organic tin (OTCs), and antibiotic) exhibited considerable concentrations, although their toxicity contribution was very small (0.076 %), thus more regulations on the use of HOCs should be proposed and further screening is needed to confirm the major toxicants. In coastal mariculture area, the toxicity contribution of current use HOCs further declined (0.010 %), whereas environmental background HOCs, such as polycyclic aromatic hydrocarbons (PAHs), became increasingly significant, with the contribution ratio increasing from 0.37 % to 2.4 %. To minimize the negative impacts of PAHs, optimization of energy structure in transportation and coastal industry is required. In the coastal fishing area, the phased-out persistent organic pollutants (POPs) remained a major concern, in terms of both concentration and toxicity contribution. The phased-out POPs explained 7.0 % of the toxic effects of the sediments from the coastal fishing area, due to historical residue, industrial emissions, and their high toxicities. For this reason, it is critical to improve the relevant emission regulations and standards, so as to eventually reduce the unintentional discharges of POPs.

Triple Blockade of Oncogenic RAS Signaling Using KRAS and MEK Inhibitors in Combination with Irradiation in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of human malignancies and carries an exceptionally poor prognosis. It is mostly driven by multiple oncogenic alterations, with the highest mutation frequency being observed in the KRAS gene, which is a key oncogenic driver of tumorogenesis and malignant progression in PDAC. However, KRAS remained undruggable for decades until the emergence of G12C mutation specific KRAS inhibitors. Despite this development, this therapeutic approach to target KRAS directly is not routinely used for PDAC patients, with the reasons being the rare presence of G12C mutation in PDAC with only 1-2% of occurring cases, modest therapeutic efficacy, activation of compensatory pathways leading to cell resistance, and absence of effective KRASG12D or pan-KRAS inhibitors. Additionally, indirect approaches to targeting KRAS through upstream and downstream regulators or effectors were also found to be either ineffective or known to cause major toxicities. For this reason, new and more effective treatment strategies that combine different therapeutic modalities aiming at achieving synergism and minimizing intrinsic or adaptive resistance mechanisms are required. In the current work presented here, pancreatic cancer cell lines with oncogenic KRAS G12C, G12D, or wild-type KRAS were treated with specific KRAS or SOS1/2 inhibitors, and therapeutic synergisms with concomitant MEK inhibition and irradiation were systematically evaluated by means of cell viability, 2D-clonogenic, 3D-anchorage independent soft agar, and bioluminescent ATP assays. Underlying pathophysiological mechanisms were examined by using Western blot analyses, apoptosis assay, and RAS activation assay.

Dendritic cells loaded with allogeneic tumour cell lysate plus best supportive care versus best supportive care alone in patients with pleural mesothelioma as maintenance therapy after chemotherapy (DENIM): a multicentre, open-label, randomised, phase 2/3 study

Dendritic cell immunotherapy has proven to be safe and induces an immune response in humans. We aimed to establish the efficacy of dendritic cells loaded with allogeneic tumour cell lysate (MesoPher, Amphera BV, 's-Hertogenbosch, Netherlands) as maintenance therapy in patients with pleural mesothelioma. In this open-label, randomised, phase 2/3 study, patients with histologically confirmed unresectable pleural mesothelioma, aged 18 years or older, with an Eastern Cooperative Oncology Group performance status score of 0-1, and non-progressing disease after four to six cycles of standard chemotherapy (with pemetrexed 500 mg/m2 plus platinum [cisplatin 75 mg/m2 or carboplatin area under the curve of 5]) were recruited from four centres in Belgium, France, and The Netherlands. Participants were randomly assigned (1:1), using block randomisation (block size of 4), stratified by centre and histology (epithelioid vs other), to MesoPher treatment plus best supportive care or best supportive care alone. Patients received up to a maximum of five MesoPher infusions, with treatment administered on days 1, 15, and 29, and weeks 18 and 30. At each timepoint, participants received an injection of 25 × 106 dendritic cells (two-thirds of the dendritic cells were administered intravenously and a third were injected intradermally). Best supportive care was per local institutional standards. The primary endpoint was overall survival, assessed in all participants randomly assigned to treatment (full analysis set) and safety assessed in all randomly assigned participants, and who underwent leukapheresis if they were in the MesoPher group. This study is registered with ClinicalTrials.gov, NCT03610360, and is closed for accrual. Between June 21, 2018, and June 10, 2021, 176 patients were screened and randomly assigned to the MesoPher group (n=88) or best supportive care alone group (n=88). One participant in the MesoPher group did not undergo leukapheresis. Mean age was 68 years (SD 8), 149 (85%) of 176 were male, 27 (15%) were female, 173 (98%) were White, two were Asian (1%), and one (1%) was other race. As of data cutoff (June 24, 2023), after a median follow up of 15·1 months (IQR 9·5-22·4), median overall survival was 16·8 months (95% CI 12·4-20·3; 61 [69%] of 88 died) in the MesoPher group and 18·3 months (14·3-21·9; 59 [67%] of 88 died) in the best supportive care group (hazard ratio 1·10 [95% CI 0·77-1·57]; log-rank p=0·62). The most common grade 3-4 treatment-emergent adverse events were chest pain (three [3%] of 87 in the MesoPher group vs two [2%] of 88 in the best supportive care group), dyspnoea (none vs two [2%]), anaemia (two [2%] vs none), nausea (none vs two [2%]), and pneumonia (none vs two [2%]). No deaths due to treatment-emergent adverse events were recorded. Treatment-related adverse events consisted of infusion-related reactions (fever, chills, and fatigue), which occurred in 64 (74%) of 87 patients in the MesoPher group, and injection-site reactions (itch, erythema, and induration), which occurred in 73 (84%) patients, and all were grade 1-2 in severity. No deaths were determined to be treatment related. MesoPher did not show improvement in overall survival in patients with pleural mesothelioma. Immune checkpoint therapy is now standard of care in pleural mesothelioma. Further randomised studies are needed of combinations of MesoPher and immune checkpoint therapy, which might increase efficacy without adding major toxicities. Amphera BV and EU HORIZON.

Efficacy of nimotuzumab added to concurrent chemoradiotherapy after induction chemotherapy for patients with locally advanced nasopharyngeal carcinoma.

6024 Background: To investigate the efficacy and toxicities associated with adding nimotuzumab to concurrent chemoradiotherapy (CCRT) in locally advanced nasopharyngeal carcinoma (LANPC) patients who received induction chemotherapy (IC). Methods: Patients with stage III-IVA nasopharyngeal carcinoma who received IC (TPF/TP/GP) and platinum-based CCRT between January 2017 and October 2021 were retrospectively included. We performed propensity score matching (PSM) to balance and control confounding factors, and the matching variables included gender, age, T stage, N stage, and Epstein-Barr virus (EBV) status. Patients were divided into two treatment groups: CCRT+nimotuzumab (200mg iv, weekly for 7 courses) and CCRT alone. Primary endpoints were overall survival (OS) and disease-free survival (DFS), the secondary endpoints were locoregional recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS). Results: We screened 242 patients in the analysis. After PSM, 121 (50.0%) and 121 (50.0%) had CCRT+nimotuzumab and CCRT alone, respectively. The 3-year OS was 95.4% and 88.0% in those with and without nimotuzumab treatment (P=0.041), and the 3-year DFS of the CCRT+nimotuzumab group was significantly better than that in the CCRT alone group (90.3% vs. 77.5%, P=0.003). Similar LRFS was found between those with and without nimotuzumab treatment (96.5% vs. 93.7%, P=0.297). The 3-year DMFS for CCRT+nimotuzumab versus CCRT alone was 92.9% versus 82.5% (P=0.008). No significant differences in major toxicities were found between the two treatment arms including hematologic toxicities, hepatoxicity, nephrotoxicity, gastrointestinal reactions, and mucositis (P&gt;0.05). Conclusions: The addition of nimotuzumab to CCRT after IC in LANPC has shown promising results in treatment outcomes and acceptable toxicities.

AcEXPA1, an α-expansin gene, participates in the aluminum tolerance of carpetgrass (Axonopus compressus) through root growth regulation.

AcEXPA1, an aluminum (Al)-inducible expansin gene, is demonstrated to be involved in carpetgrass (Axonopus compressus) root elongation under Al toxicity through analyzing composite carpetgrass plants overexpressing AcEXPA1. Aluminum (Al) toxicity is a major mineral toxicity that limits plant productivity in acidic soils by inhibiting root growth. Carpetgrass (Axonopus compressus), a dominant warm-season turfgrass widely grown in acidic tropical soils, exhibits superior adaptability to Al toxicity. However, the mechanisms underlying its Al tolerance are largely unclear, and knowledge of the functional genes involved in Al detoxification in this turfgrass is limited. In this study, phenotypic variation in Al tolerance, as indicated by relative root elongation, was observed among seventeen carpetgrass genotypes. Al-responsive genes related to cell wall modification were identified in the roots of the Al-tolerant genotype 'A58' via transcriptome analysis. Among them, a gene encoding α-expansin was cloned and designated AcEXPA1 for functional characterization. Observed Al dose effects and temporal responses revealed that Al induced AcEXPA1 expression in carpetgrass roots. Subsequently, an efficient and convenient Agrobacterium rhizogenes-mediated transformation method was established to generate composite carpetgrass plants with transgenic hairy roots for investigating AcEXPA1 involvement in carpetgrass root growth under Al toxicity. AcEXPA1 was successfully overexpressed in the transgenic hairy roots, and AcEXPA1 overexpression enhanced Al tolerance in composite carpetgrass plants through a decrease in Al-induced root growth inhibition. Taken together, these findings suggest that AcEXPA1 contributes to Al tolerance in carpetgrass via root growth regulation.