Mild Toxicity Research Articles

Ultrahypofractionated Adjuvant Breast Radiotherapy (+/- Boost) and Virtual Consultations: Patient Perspectives at One Year

Purpose/Objectives: In March 2020, a 1 week ultrahypofractionated adjuvant breast radiotherapy schedule, 26 Gy in 5 fractions and telehealth were adopted to reduce the risk of COVID-19 for staff and patients. This study describes real world 1 year late toxicity for ultrahypofractionation (including a sequential boost) and patient perspectives on this new schedule and telehealth workflows. Materials and Methods: Consecutive patients were enrolled Mar-Aug 2020. Patient reported outcome measures including the presence of breast pain, swelling, firmness, and others were recorded using the EORTC QLQ BR45 at baseline, 3 months, 6 months and 1 year. Virtual teleconferencing without video was utilised. Patients were invited to use video at 1 year for a physician based assessment including breast inspection. Patient reported experience measures were also collected at 1 year to capture how a shortened schedule and telehealth influenced patient experience. ResultsIn total, 121/135 patients completed at least two assessments of which 33 (25%) received a sequential boost. The majority of patients reported no toxicity or a mild toxicity at all three time points, 76% at 3 months, 76% at 6 months, and 82% at 1 year. When comparing 26Gy in 5 fractions alone versus 26 Gy in 5 fractions followed by a sequential boost, there was no difference in toxicity reported at one year.94% felt supported by the medical team throughout their treatment course using telehealth only consultations. Only 27% actually agreed to video consultation for the purpose of breast inspection when offered. ConclusionsUltrahypofractionated breast radiotherapy leads to acceptable late toxicity at 1 year even when followed by a hypofractionated tumour bed boost. Patient satisfaction with ultrahypofractionated treatment and virtual consultations without video was high. Further investigation concerning the patient acceptance of video consultations for a physician-based assessment including breast inspection is warranted.

Biotoxicity Evaluation of Biodegradable Polymeric Particles: Exploring the Possible Adverse Impacts on Biological Systems

ABSTRACTThis study aimed to investigate the impact of plastic particles on cell viability and tissue toxicity. The cells were subjected to incubation with plastic particles immobilized in agar gels, resulting in minimal cell death and cytotoxicity. Furthermore, direct exposure of various cell types to suspended plastic particles showed negligible effects on cell viability, with no observed lysis or growth inhibition. Staining techniques revealed minimal plastic particle‐induced cell death, with the majority of cells remaining viable. However, histological evaluations of mouse tissues demonstrated that the nondegradable low‐density poly(ethylene) (LDPE) groups exhibited severe irritation, characterized by an excessive presence of macrophages, neutrophils, fibrosis, fat infiltration, and increased blood vessel formation in subcutaneous tissue. In contrast, biodegradable neat poly(butylene succinate) (KRICT‐PBS) and cellulose nanocrystals/PBS nanocomposite (CNC‐PBS) groups induced minimal toxicity. Interestingly, the intravenous injection of KRICT‐PBS and CNC‐PBS degradate solutions in mice exhibited mild toxicity, suggesting no significant damage to normal kidney and liver function.

Clinical outcomes of conversion surgery after induction immunochemotherapy for borderline resectable T4 esophageal squamous cell carcinoma

BackgroundThe current treatment strategies for borderline resectable esophageal squamous cell carcinoma remain controversial. This study aimed to evaluate the efficacy and safety of programmed cell death 1 inhibitors combined with chemotherapy, followed by conversion surgery, for borderline resectable esophageal squamous cell carcinoma.MethodsPatients with borderline resectable esophageal squamous cell carcinoma treated with induction immunochemotherapy from January 1, 2020 to July 1, 2023 at our hospital were retrospectively analyzed. The primary study outcome was the R0 resection rate. Secondary study outcomes included progression-free survival (PFS), overall survival (OS), pathological complete remission (pCR) rate, and safety.ResultsForty patients with borderline resectable esophageal squamous cell carcinoma were included in the analysis. The R0 resection rate was 23/40 (57.5%); the conversion success rate was 27/40 (67.5%), and the pCR rate was 11/40 (27.5%). The median follow-up was 23.6 months (95% CI, 19.1–28.2). One-year OS and PFS rates were 77.7% and 71.8%, respectively. The incidence rate of Grade 3–4 adverse events was 10%. There was a significant difference in PFS between patients who underwent surgery and those who did not (P = 0.008, HR: 0.144 95%CI: 0.034–0.606). However, the difference in OS was not significant (P = 0.128, HR: 0.299 95%CI: 0.063–1.416). Patients who achieved clinical downstaging after induction therapy had significantly better OS (P = 0.004 h: 0.110 95%CI: 0.025–0.495) and PFS (P = 0.0016, HR: 0.106 95%CI: 0.026–0.426) compared to those who did not.ConclusionsConversion surgery after induction immunochemotherapy is a promising new strategy with a high conversion rate, inspiring R0 resection rate, significant pathological remission rate, and mild toxicity for borderline resectable esophageal squamous cell carcinoma.

Bioactivity of biogenic silver/silver chloride nanoparticles from Maranta arundinacea rhizome extract: Antibacterial and antioxidant properties with anticancer potential against Ehrlich ascites carcinoma and human breast cancer cell lines

IntroductionThis study explores the synthesis and characterization of silver/silver chloride nanoparticles (Ag/AgCl-NPs) using Maranta arundinacea rhizome extract and evaluates their bioactivities, including antibacterial, antioxidant, and anticancer potentials. MethodsThe synthesis of Ag/AgCl-NPs was initially confirmed by a color change and a sharp peak at 463 nm in UV–visible spectroscopy. Further characterization was conducted using scanning electron microscopy (SEM), X-ray powder diffraction (XRD), and fourier transform infrared spectroscopy (FTIR). Antibacterial properties were checked against four pathogenic bacteria (Shigella boydii, Escherichia coli, Shigella dysenteriae, and Staphylococcus aureus), and antioxidant activities were assessed using DPPH (2,2-diphenyl-1-picrylhydrazyl) and ABTS (2,2-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid) assay. In addition, the anticancer potential was evaluated in vitro using MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) colorimetric assay and in vivo using the mouse models. Finally, toxicity was determined by employing the brine shrimp nauplii lethality assay. ResultsAg/AgCl-NPs most effectively inhibited the growth of Staphylococcus aureus, showing maximum zone of inhibition and 7 μg/mL of minimum inhibitory concentration (MIC), and prevented the biofilm formation by Escherichia coli at 40 μg/mL. They displayed antioxidant activities against DPPH and ABTS with IC50 values of 90.65 and 24.34 μg/mL, respectively. In vitro, they inhibited 61.96 % EAC and 49.63 % MCF-7 cells growth at 32 and 128 μg/mL, respectively. Subsequently, inhibition rates of EAC cells growth in mice were measured as 38.30 %, 57.38 %, and 31.81 % after employing 2.5, 5, and 10 mg/kg/day of Ag/AgCl-NPs, respectively. Moreover, Ag/AgCl-NPs treated mice were found to carry more apoptotic EAC cells with distorted morphology. Treated mice showed decreased tumor weight, increased mean survival time, and a lifespan increase of up to 30 %, with improved hematological parameters. Later, Ag/AgCl-NPs exhibited moderate toxicity with an LC50 value of 208.41 μg/mL in brine shrimp nauplii lethality assay. ConclusionThe promising antibacterial, antioxidant, and anticancer activities along with mild toxicity suggest the potential biomedical uses of Maranta arundinacea rhizome extract-mediated Ag/AgCl-NPs.

Copper excess in psychiatric disorders: a focus on mood spectrum disorders and sex

BackgroundMeta-analyses show increased copper (Cu) levels in major depression disorder. However, the association of Cu biomarkers with clinical classification in other mental health disorders has not been fully explored. MethodsTo this aim, we compared an extensive panel of Cu biomarkers, composed of Cu, ceruloplasmin (Cp) Cp activity, Cp specific activity, Cu not bound to ceruloplasmin (non-Cp Cu, also known as ‘free’ copper) in 171 consecutive patients affected by psychiatric disorders and in 61 healthy controls (HC) using MANOVA adjusting for the effect of sex and age, and studied their association with the clinical scale outcomes at psychiatric examination, namely Global Assessment of Functioning, Clinical Global Impression, and Brief Psychiatric Rating Scale. Resultsindividuals with psychiatric disorders were classified as 109 patients affected by mood spectrum disorders (MSD), 20 patients with schizophrenia spectrum disorders (SSD), and 42 with personality disorders (PD). Cu and non-Cp Cu were increased in psychiatric individuals than in HC, which also differed among the patients stratified per the clinical classification, being higher in the MSD individuals. The analysis stratified for sex revealed that women from the patient group, and specifically from the MSD group, had increased levels of Cu and non-Cp Cu than healthy women, while no difference was revealed in men. A logistic regression model considering the effect of sex and age revealed that non-Cp Cu could explain 26 % increased odds of having MSD per µmol/L unit increase (OR = 1.26; p = 0.0008; 95 % CI 1.099–1.436), that reached 40 % when considering only women. This result was driven by non-Cp Cu that correctly classified 64.1 % MSD (70 % in women) individuals vs. HC in a decision tree model, with values higher than 2.1 µmol/L which could distinguish the majority of MSD patients (86.3 % MSD vs. 13.7 % HC in women). None of the biological variables under study correlated with outcomes of the clinical scales, substances, or alcohol abuse. ConclusionCurrent results suggest mild Cu toxicity in women with MSD, as revealed by a value of non-Cp Cu higher than 2.1 µmol/L, which can be further investigated to assess its potential diagnostic accuracy in bigger and longitudinal cohorts.

Immune-related adverse events in a nationwide cohort of real-world melanoma patients treated with adjuvant anti-PD1 – Seasonal variation and association with outcome

IntroductionImmune checkpoint inhibitors (ICIs) carry the risk of immune-related adverse events (irAEs), a significant concern as therapy has transitioned to the adjuvant setting. Balancing therapeutic benefits against potential risks is crucial, necessitating real-world data from an unselected patient population in addition to clinical trial data to ensure optimal clinical decision-making. MethodsThis nationwide real-world study assessed irAEs in patients receiving adjuvant anti-PD1 therapy, primarily nivolumab, for resected stage III-IV melanoma between 2018-2022. Data were retrieved from two national databases: the IMMUNOTOX database and the Danish Metastatic Melanoma Database (DAMMED). IrAEs were sub-grouped according to organ systems graded using CTCAE ver. 5.0 ranging from mild toxicities (grade 1-2) to severe (grade 3-4) and fatal (grade 5). ResultsAmong 792 included patients, (55% male, median age 62 years (range 16-88)), 697 patients (88%) experienced an irAE. Severe irAEs occurred in 116 patients (15%) and five (0.6%) died due to toxicity. A landmark analysis showed that patients who experienced at least one irAE before the 1st evaluation at 90 days had an increased progression free survival (PFS) (p=0.032) and overall survival (OS) (p=0.0071). Additionally, a seasonal pattern was noted with higher incidence of irAEs during summer. ConclusionThe prevalence of irAEs in real-world patients is comparable to the observed risk in clinical trials. Patients experiencing irAEs demonstrate a lower risk of melanoma relapse. Further, gender, age and seasonal variation may impact the incidence of irAEs.

Stereotactic Ablative Radiation Therapy for Oligometastatic Ovarian Cancer Lymph Node Disease: The MITO-RT3/RAD Phase II Trial

PurposeMITO-RT3/RAD (NCT04593381) is a prospective multicenter Phase II trial designed to assess the effectiveness and safety of stereotactic body radiotherapy (SBRT) in patients diagnosed with oligometastatic ovarian cancer (oligo-MPR-OC). In this report, we provide the results of the trial in the setting of lymph node disease. MethodsThe primary endpoint was the complete response (CR) rate, secondary endpoints included local control (LC), progression-free survival (PFS), overall survival (OS), treatment-free interval (TFI), and toxicity rates. Sample size was based on a previous study reporting an average 70.0% CR with SBRT. The study was powered to detect an improvement in the CR rate from 70.0% to 85.0%, with an α error of 0.05 (one-side) and a β error of 0.1. ResultsThe study met its primary endpoint of a statistically significant improvement of CR. 135 patients with 249 lesions were enrolled across fifteen Institutions from May 2019 to November 2023. CR were observed in 194 lesions (77.9%), PR in 40 (16.1%), SD in 14 (5.6%), and Progressive Disease (PD) in one lesion (0.4%). The ORR was 94%, with an overall clinical benefit rate of 99.6%. CR lesions exhibited a significantly higher LC rate than partial or not responding lesions (12-month LC: 92.7% vs. 63.1%, p<0.001). The 12-months actuarial rates for PFS and for OS were 36.6% (CR 38.3% vs not-CR 18.8%; p: 0.022) and 97.2% (CR 97.8% vs not-CR 93.8%; p: 0.067), respectively. The 12-months actuarial rate for Treatment Free Interval was 52.7% (CR 58.4% vs not-CR 24.4%; p: 0.004). CR was substantially associated with higher PFS (p: 0.036) and TFI (p: 0.006) rates at the univariate analysis. Twenty-three patients (17.0%) experienced mild acute toxicity. Late toxicity was reported in 9 patients (6.7%), mostly Grade 1. ConclusionsThis trial confirms the efficacy of ablative SBRT, with minimal toxicity observed. SBRT offered a high CR rate, promising long-term outcomes and systemic-therapy-free survival rate for complete responders.

Exploring Radiotherapy as a Promising Alternative for Managing Advanced Upper Tract Urothelial Carcinoma: Rescuing Chemotherapy-Intolerant Patients

PurposeTo investigate the safety and effectiveness of radiotherapy for advanced upper tract urothelial carcinoma (UTUC) patients intolerant to chemotherapy. MethodsData for 21 patients with advanced UTUC intolerant to chemotherapy were retrospectively collected. All patients were treated with conventionally fractionated radiotherapy (50-70 Gy/20-33 f) or partial-SABR boost to the lesions (50-60 Gy/20-25 f with tumor center boosted with 6-8 Gy/f, 3-5 f) for bulky tumors. ResultsThe median age was 75 years (range, 58-87 years). Primary tumor resection was performed for all patients and none underwent metastatic resection. Seventeen (81%) patients had oligometastasis (1-5 metastases) at diagnosis. Eighteen (85.7%) received irradiation to all tumor lesions. Lymph node metastasis was predominant in the whole group (17/21). Other lesions were distributed as local recurrence (7/21), bone metastases (2/21) and abdominal wall/muscle (2/21). The median follow-up time was 38.5 months (interquartile range, 15.2-48.7 months). Rate of local control (LC), progression-free survival (PFS) and overall survival (OS) of the whole group at 1 year were 90%, 46.6%, and 80.4%, respectively. At 3 years, LC, PFS and OS were 65.6%, 26.6%, and 40.9%, respectively. Fourteen patients developed acute mild gastrointestinal toxicity, generally of grade 1-2; 8 patients developed acute grade 1-2 hematological toxicity, consisting mainly of anemia and leukopenia. No grade 3 or higher acute or late toxicities were observed. ConclusionFor patients with advanced UTUC who are not able to tolerate chemotherapy, radiotherapy is a safe treatment and can achieve good local tumor control.

PD-1 blockade with camrelizumab after chemoradiotherapy in nasopharyngeal carcinoma.

129 Background: Approximately 30% of locoregionally advanced nasopharyngeal carcinoma (NPC) experience disease relapse despite definitive chemoradiotherapy. The programmed death-1 (PD-1) blockade camrelizumab has demonstrated considerable value in recurrent/metastatic NPC, while its role in locoregionally advanced NPC is worth exploring. Methods: We conducted a randomized, open-label, phase 3 trial to evaluate adjuvant camrelizumab in locoregionally advanced NPC after definitive chemoradiotherapy. Patients with T4N1M0 or T1-4N2-3M0 NPC who have undergone induction chemotherapy and concurrent chemoradiotherapy were randomized in a 1:1 ratio to receive adjuvant camrelizumab (200mg intravenously once every 3 weeks for up to 12 cycles; Camrelizumab group) or observation ( Standard-therapy group). The primary endpoint was event-free survival (freedom from randomization to locoregional recurrence, distant metastasis, or death from any cause). The secondary endpoint included locoregional recurrence-free survival, distant metastasis-free survival, overall survival, safety, and quality of life. Results: A total of 226 patients were randomized to the Camrelizumab group and 224 to Standard-therapy group. At a median follow-up of 37 months, the 3-year event-free survival was 86.9% in the Camrelizumab group and 77.4% in the Standard-therapy groups (stratified hazard ratio, 0.61; 95% confidence interval [CI], 0.38 to 0.96; P = 0.03). Grade 3 or 4 adverse events were reported in 11.2% patients in the Camrelizumab group and 3.2% of those in the Standard-therapy group. The most common adverse event of grade 3 or 4 was leukopenia (4.9% and 1.4%, respectively). There was no meaningful deterioration in quality of life associated with the use of adjuvant camrelizumab. Conclusions: Adjuvant PD-1 blockade with camrelizumab significantly improved event-free survival, with mild toxicity, highlighting its compelling role in the management of locoregionally advanced NPC. (DIPPER,ClinicalTrials.gov numberNCT03427827). Clinical trial information: NCT03427827 . [Table: see text]

Financial toxicity in patients with cancer: a cross-sectional study at an oncology hospital in central Vietnam.

Cancer imposes a substantial financial burden on patients because of the high out-of-pocket expenses and the significant hardships. Financial toxicity describes the impact of cancer care costs at the patient level. Although the financial impact of cancer has been recognized, understanding the extent and determinants of financial toxicity in specific contexts is crucial. This study investigated the level of financial toxicity and its associated factors among patients with cancer at an oncology hospital in central Vietnam. This cross-sectional study included 334 patients with cancer. Direct interviews and medical record reviews were used for data collection. Financial toxicity was assessed using the 11-item Comprehensive Score for financial Toxicity (COST). A logistic regression model was used to determine factors associated with financial toxicity. A notable 87.7% of patients experienced financial toxicity due to cancer cost, with 37.7% experiencing mild financial toxicity and 49.7% suffering from moderate financial toxicity, 0.3% reporting severe financial toxicity. Individuals with low household income exhibited a higher proportion of financial toxicity compared to that of those with higher income (odds ratio (OR) = 5.78, 95% confidence interval (CI): 1.29-25.68). Compared with that of participants in the early stages, a higher burden was found in patients with advanced-stage cancer (OR = 3.88, 95% CI: 1.36-11.11). Our study indicates that patients with cancer in Vietnam facefinancial toxicity. It is thus necessary for interventions to mitigate the financial burden on patients with cancer, focusing on vulnerable individuals and patients in the advanced stages.

Preoperative Magnetic Resonance Guided Single-Dose Partial Breast Irradiation: 5-Year Results of the Prospective Single-Arm ABLATIVE Trial

Preoperative partial breast irradiation (PBI) can increase accuracy of target volume definition and decrease irradiated volumes compared with postoperative PBI. In the ABLATIVE trial (NCT02316561), 15/36 patients achieved pathologic complete response (pCR) 6-8 months after preoperative PBI and breast conserving surgery (BCS). We now present the 5-year results. The ABLATIVE trial is a Dutch prospective cohort study in four hospitals. Women aged ≥ 50 years with unifocal, non-lobular breast cancer, ER-positive, HER2-negative, and a tumor negative sentinel node were treated between 2015-2018 with preoperative single-dose PBI followed by BCS after six or eight months. The primary endpoint was pCR. Secondary endpoints were yearly evaluated oncological outcomes, toxicity, cosmetic outcome (assessed by patients and physicians) and quality of life. Thirty-six patients were treated with BCS six (n=15) and eight (n=21) months following PBI. Median tumor size was 13 mm (IQR 9-16). After a median follow-up of 5.5 years (IQR 5.1-6.0 years), two (6%) patients had ipsilateral breast events and two (6%) distant metastases. The 5-years overall survival was 94% [95% CI 87-100%]. The 5-year cumulative incidence of clinician-reported grade 1/2 breast fibrosis and breast discomfort/pain were 94%/6% and 75%/6%, respectively. The proportion of patients (very) satisfied with the cosmetic results was 89% at baseline and 78% at 5 years. Cosmetic results evaluated using the BCCT.core software were excellent or good in all patients. The 4-year median global quality of life score was 83 (IQR 67-92), similar to baseline (83 (IQR 75-83), p=0.42). Preoperative single-dose PBI and BCS may be an oncologically safe treatment with mild late toxicity, and no decline in cosmetic results and quality of life during 5 years of follow-up. This means that preoperative instead of standard postoperative irradiation has the potential to challenge the current clinical practice.

Evaluation of the chemical constituents and toxicological potentials of &lt;i&gt;Asystasia vogeliana benth&lt;/i&gt;. leaf extract

Majority of the tradomedicinal uses of Asystasia vogeliana lack scientific backing. Therefore, this study sought to investigate the phytochemical constituents and the toxicological potentials of methanolic leaf extract of Asystasia vogeliana in Swiss albino mice. Air-dried pulverized leaves (1248 g) of Asystasia vogeliana were extracted with methanol for 48 h. The extract was concentrated using rotary evaporator to obtain crude methanol extract (99.8 g). The extract was screened for phytochemicalconstituents and partitioned with n-exane and dichloromethane (DCM). The two fractions were subjected to GC-MS analysis. Acute toxicity study was conducted in Swiss albino mice based on standard procedures. Biochemical parameters were determined in the liver, kidney and blood of the animals. Flavonoids, steroids, saponins and triterpenes were detected in the extract. GC-MS analysis of the n-hexane fraction showed presence of n-hexadecanioc acid (24.01%) and 6-octadecenioc acid (36.68%) as major constituents while oxypurinol (15.68%), and 2,2- dimethylcyclohexan-1,3- dione dioxime (11.21%) were the main constituents in dichloromethane fraction. No mortality was recorded in the acute toxicity study. Liver and blood serum aspartate transaminase (AST) and alanine transaminase (ALT) activities increased across the group. The creatinine and urea content in the kidney and blood serum increased. The insignificant increase in creatinine and urea levels in the kidney and blood showed mild toxicity. Also, increase in AST and ALT level was noticed in the blood which showed liver injury. Therefore, the study concluded that the extract at the tested concentration is mildly nephrotoxic and hepatotoxic.

Antifungal and antibiofilm activities of flavonoids against Candida albicans: Focus on 3,2′-dihydroxyflavone as a potential therapeutic agent

Effective management of microbial biofilms holds significance within food and medical environments. Candida albicans, an opportunistic fungus, forms mucosal biofilms closely linked to candidiasis and drug-resistant infections due to their drug tolerance. Morphologic change from yeast to filamentous cells is a key virulence factor and a prerequisite for biofilm development. This study investigated the anti-fungal and antibiofilm activities of 20 flavonoids against C. albicans. With their known antioxidant capabilities, flavonoids hold promise in combating infections associated with biofilms. Among them, flavone and its derivatives exhibited moderate antifungal activity, 3,2′-dihydroxyflavone (3,2′-DHF) at 1 μg/mL exhibited strong antibiofilm activity (MIC 50 μg/mL). In addition, 3,2′-DHF dramatically inhibited cell aggregation and germ tube/hyphae formation. Transcriptomic analyses revealed that flavone and 3,2′-DHF behaved differently, as 3,2′-DHF downregulated the expressions of germ tube/hyphae-forming and biofilm-related genes (ECE1, HWP1, TEC1, and UME6) but upregulated the biofilm/hyphal regulators (CHK1, IFD6, UCF1, and YWP1). Tests evaluating toxicity with plant and nematode models revealed that flavone and 3,2′-DHF exhibited mild toxicity. Current results indicate that hydroxylated flavone derivatives can enhance anti-fungal and antibiofilm activities and provide a source of potential anti-fungal agents against drug-resistant C. albicans.

Genotoxicity, acute and sub-acute toxicity profiles of methanolic Cordyceps militaris (L.) Fr. extract in Swiss Albino Mice

Ethnopharmacological relevanceCordyceps militaris, a traditional medicinal fungus, parasitizes the intestines of lepidopteron pupae or larvae, predominantly during the winter, and undergoes fruiting in the summer or autumn. Compounds extracted from C. militaris have demonstrated a broad spectrum of pharmacological effects, including antioxidant, anti-tumor, anti-metastatic, anti-inflammatory, antiviral, anti-diabetic, and various others. Aim of the studyHerein, our study aimed at elucidating the acute, sub-acute toxicity, and genotoxicity profiles of C. militaris methanolic extract following oral administration in Swiss albino mice, representing the inaugural comprehensive exploration of the toxicological and safety profiles of C. militaris. Materials and methodsPrior studies have predominantly focused on its biological activities rather than its toxicity. Acute oral toxicity study was conducted at 500, 1000, and 2000 mg/Kg B.W. doses of C. militaris over a 14-day period. For sub-acute toxicity study, three groups of mice were administered 100, 300, and 600 mg/Kg B.W. of C. militaris extract for 28 consecutive days; one group served as a control. Mice were monitored for their body weight and behavioural changes once daily. Hematological, serum biochemical, histopathological, histomorphometric, seminal parameters, and mutagenic investigations were performed post-treatment period. ResultsAcute oral toxicity study at 2000 mg/Kg revealed no signs of toxicity, with an LD50 value surpassing 2000 mg/Kg. No occurrences of mortality observed, and no significant changes were noted in body weight, organ weight, or behaviour. Hematological analysis illustrated a marked upsurge in RBC, Hb, HCT, PLT, MPV, and PCT, alongside minor variations in differential leucocyte count post 28-day treatment. Liver enzyme tests indicated slight elevation in ALP, while renal enzyme tests showed alterations in CRE and BUN levels. Genotoxicity profile and histopathological assessments of the liver, spleen, testis, and ovary manifested no remarkable irregularities, except for mild renal toxicity. Seminal parameters including sperm concentration, motility and testosterone levels demonstrated a noteworthy increase. ConclusionsThe study sheds light on the potential risks and safety considerations associated with C. militaris-based medicinal products. These findings establish a foundation for further investigations and the refinement of dosage optimization in the application of C. militaris, with the aim of mitigating any potential adverse effects.

Oculometric biomarkers of visuomotor deficits in clinically asymptomatic patients with systemic lupus erythematosus undergoing long-term hydroxychloroquine treatment.

This study examines a set of oculomotor measurements, or "oculometric" biomarkers, as potential early indicators of visual and visuomotor deficits due to retinal toxicity in asymptomatic Systemic Lupus Erythematosus (SLE) patients on long-term hydroxychloroquine (HCQ) treatment. The aim is to identify subclinical functional impairments that are otherwise undetectable by standard clinical tests and to link them to structural retinal changes. We measured oculomotor responses in a cohort of SLE patients on chronic HCQ therapy using a previously established behavioral task and analysis technique. We also examined the relationship between oculometrics, OCT measures of retinal thickness, and standard clinical perimetry measures of visual function in our patient group using Bivariate Pearson Correlation and a Linear Mixed-Effects Model (LMM). Significant visual and visuomotor deficits were found in 12 asymptomatic SLE patients on long-term HCQ therapy compared to a cohort of 17 age-matched healthy controls. Notably, six oculometrics were significantly different. The median initial pursuit acceleration was 22%, steady-state pursuit gain 16%, proportion smooth 7%, and target speed responsiveness 31% lower, while catch-up saccade amplitude was 46% and fixation error 46% larger. Excluding the two patients with diagnosed mild toxicity, four oculometrics, all but fixation error and proportion smooth, remained significantly impaired compared to controls. Across our population of 12 patients (24 retinae), we found that pursuit latency, initial acceleration, steady-state gain, and fixation error were linearly related to retinal thickness even when age was accounted for, while standard measures of clinical function (Mean Deviation and Pattern Standard Deviation) were not. Our data show that specific oculometrics are sensitive early biomarkers of functional deficits in SLE patients on HCQ that could be harnessed to assist in the early detection of HCQ-induced retinal toxicity and other visual pathologies, potentially providing early diagnostic value beyond standard visual field and OCT evaluations.

Management of serotonin syndrome (toxicity)

Serotonin syndrome (toxicity), resulting from an excessive accumulation of serotonin in the central nervous system, it can occur due to various factors such as the initiation of medication, overdose or drug interactions. Diagnosing serotonin toxicity presents challenges as there are no definitive criteria. This review delves into the pathophysiology, incidence, clinical assessment and management of serotonin toxicity, stressing the significance of promptly recognizing and managing severe cases. Diagnosis relies primarily relies on clinical assessment due to the absence of specific laboratory tests. The Hunter Serotonin Toxicity criteria are commonly utilized but have only been validated in the overdose setting. Assessing the severity of toxicity is crucial for guiding management decisions. Supportive care, discontinuation of causative agents and symptomatic treatment are prioritized in management. Mild toxicity often requires withdrawal or reduction of the serotonergic agent, while more severe toxicity requires more aggressive resuscitative and supportive care. Severe serotonin toxicity characterized by hyperthermia and rigidity requires aggressive supportive measures, including benzodiazepines, intubation, paralysis and active cooling. Animal studies suggest potential benefits of 5-HT2A receptor antagonists in preventing hyperthermia and fatalities, but only at high doses. Their clinical effectiveness remains uncertain, and evidence is predominately from case series and case reports. Although commonly used, serotonin antagonists like cyproheptadine lack conclusive evidence of efficacy. Other serotonin antagonists such as chlorpromazine and olanzapine have been explored but evidence is limited to case reports. Hence, the cornerstone of treating severe cases does not lie in 'antidote' administration or even diagnosis but in effective early resuscitative and supportive care.

Adjuvant PD-1 blockade with camrelizumab in high-risk locoregionally advanced nasopharyngeal carcinoma (DIPPER): A multicenter, open-label, phase 3, randomized controlled trial.

LBA6000 Background: Patients with high-risk locoregionally advanced nasopharyngeal carcinoma (NPC) often experience disease relapse even after receiving standard-of-care treatment, e.g. induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT). The benefit of PD-1 inhibitor as adjuvant treatment following IC+CCRT in locoregionally advanced NPC remains unclear. Methods: Patients with high-risk locoregionally advanced NPC (T4N1M0 or T1-4N2-3M0) who have received gemcitabine and cisplatin (GP) IC and CCRT were recruited at 11 centers in China. They were randomly assigned (1:1) within 2 weeks after the last radiation dose to receive intravenous camrelizumab (200 mg once every 3 weeks for 12 cycles; Camrelizumab Arm) or observation (Standard-therapy Arm). The primary endpoint was event-free survival (EFS). It is estimated that approximately 442 patients would provide 80% power to detect a hazard ratio (HR) of 0.52 with a log-rank test at a two-sided α level of 0.05. Quality of life (QoL) was assessed by EORTC-C30. Results: A total of 450 patients were randomly assigned to the Camrelizumab Arm (n=226) and the Standard-therapy Arm (n=224). After a median follow-up of 37 months (corresponding to 41 months when calculated from the start of standard therapy), the estimated 3-year EFS was 86.9% in the Camrelizumab Arm and 77.4% in the Standard-therapy Arm (intention-to-treat population; HR 0.61, 95% CI 0.38–0.96; P = 0.03). The incidence of grade 3-4 adverse events (AEs) was 11.2% in the Camrelizumab Arm and 3.2% in the Standard-therapy Arm, including grade 3-4 immune-related AEs in 8 (3.9%) patients in the Camrelizumab Arm. Reactive capillary endothelial proliferation was the most common adverse event related to camrelizumab (RECP, 87.8%, 4 (1.8%) patients had grade 3 RECP). Treatment-related deaths occurred in 1 (&lt;1%) patients in the Camrelizumab group (subarachnoid hemorrhage) and 1 (&lt;1%) patients in the Standard-therapy group (nasopharyngeal necrosis). During treatment, there was no clinically meaningful deterioration of health-related quality of life associated with the use of adjuvant camrelizumab. Conclusions: Adjuvant PD-1 blockade with camrelizumab significantly improved EFS in high-risk locoregionally advanced NPC, with mild toxicity and comparable quality of life. Clinical trial information: NCT03427827 . [Table: see text]

Antifungal, anti-biofilm, and anti-hyphal properties of N-substituted phthalimide derivatives against Candida species.

Candida species comprise a ubiquitous pathogenic fungal genus responsible for causing candidiasis. They are one of the primary causatives of several mucosal and systemic infections in humans and can survive in various environments. In this study, we investigated the antifungal, anti-biofilm, and anti-hyphal effects of six N-substituted phthalimides against three Candida species. Of the derivatives, N-butylphthalimide (NBP) was the most potent, with a minimum inhibitory concentration (MIC) of 100 µg/ml and which dose-dependently inhibited biofilm at sub-inhibitory concentrations (10-50 µg/ml) in both the fluconazole-resistant and fluconazole-sensitive Candida albicans and Candida parapsilosis. NBP also effectively inhibited biofilm formation in other pathogens including uropathogenic Escherichia coli, Staphylococcus epidermidis, Staphylococcus aureus, and Vibrio parahaemolyticus, along with the polymicrobial biofilms of S. epidermidis and C. albicans. NBP markedly inhibited the hyphal formation and cell aggregation of C. albicans and altered its colony morphology in a dose-dependent manner. Gene expression analysis showed that NBP significantly downregulated the expression of important hyphal- and biofilm-associated genes, i.e., ECE1, HWP1, and UME6, upon treatment. NBP also exhibited mild toxicity at concentrations ranging from 2 to 20 µg/ml in a nematode model. Therefore, this study suggests that NBP has anti-biofilm and antifungal potential against various Candida strains.

Financial toxicity in the background of free health care: A cross-sectional survey in a tertiary care hospital in India.

e13685 Background: The financial toxicity of cancer treatment is a known fact in low to middle-income countries due to poverty, lack of health insurance and illiteracy. We tried to estimate the financial strain and its contributing factors in an Indian population with access to free cancer treatment. Methods: All government employees and their dependents are eligible to receive free treatment including inpatient management, investigations and medicines at our institute. All cancer patients ≥18 years were invited to participate in a survey. The survey included their demographic, cancer and therapy details, the COST-FACIT questionnaire, and information about increase in expenses since cancer diagnosis and source of additional finances. Results: 300 cancer patients completed the survey. 61.3% of the respondents were females and the mean patient age was 43.14 years. Breast cancer was the most common malignancy and stage IV was the most common stage. 44% were residents of a rural area. The average duration of treatment was 8.03 months. Prior to cancer diagnosis, 37.2% of the patients had average monthly expenses between INR 10-25,000 (USD 120 to 300). The approximate increase in monthly expenditures after cancer diagnosis was between INR 5-10,000 (USD 60 to 120) for 33.4% and between INR 10-25,000 (USD 120 to 300) for 31.4% of the population. The primary income source for 65.7% respondents was the salary of the government employee while 48% had two or more earning members in the family. Cancer treatment negatively affected the earning capacity of the patient alone in 40% of the population, while in 28% it affected the earning capacity of the patient and caregiver. 51% had to utilise their savings, 39% sold fixed assets, and 31% borrowed or took a loan to cope with the additional financial strain. Commonest expenses were travel, accommodation, and food (75.7%). 34.5% spent money on other therapy-related costs (second opinion or alternative therapy). The mean COST-FACIT score was 21.38,(20-24) demonstrating mild financial toxicity. Predictors of high financial toxicity were a single-earning member, familial discord and long duration of treatment (&gt; 6 months). Conclusions: Though all participants had access to free cancer treatment, all experienced mild financial toxicity due to non-therapeutic expenses. Despite desperate financial measures to complete treatment, most participants did not express severe financial toxicity. This may be attributed to the stigma of expected high expenditure associated with cancer treatment in India. COST-FACIT scoring may not have suitably assessed the financial strain experienced by patients with free healthcare. Additional financial information collected by the survey, (monthly expenses, earning members, source of additional funds), helped us to better understand financial impact of cancer treatment and identify gaps in our healthcare.

Quantification of treatment-related time toxicity in patients with advanced stage cancer.

12137 Background: Treatment-related Time Toxicity (TrTT) in cancer patients is a recently proposed metric to describe the burden of time spent in pursuing medical care, including office/hospital visits, side effect management, lab tests, imaging scans, and travel time. Time toxicity is a valuable concept in patient-centered shared-decision making, especially in the palliative management of end-stage cancer patients with limited life expectancy. Despite tremendous progress in cancer treatment, most of the guideline-recommended treatment options convey short survival benefits of around 3-6 months when compared to supportive care. While medication toxicities are meticulously reviewed with patients, the cumulative burden and impact of time are rarely included in the discussion, partly due to the lack of standardized measurement of TrTT, and the absence of data from clinical trials. Thus, there is a compelling need for the quantification of time toxicity to guide clinical practice and patient preference. Methods: This was an observational analysis of the time toxicity from palliative treatment for patients with incurable solid tumors at a regional safety-net oncology office that focuses on underserved communities. Time toxicity is calculated as the number of days a patient spent with any healthcare-related encounters during a 3-month period from our medical record system. Results: The median age of the total 94 included patients was 57. 54% of the population were Hispanic. The ratios for mild, moderate, and severe time toxicity were 38%, 44%, and 18%, respectively. Immunotherapy was associated with significantly less time toxicity (TrTT = 8.5 days, 95% CI = 6.3-9.7) compared to chemotherapy (26.3 days, 95% CI = 18.3-34.4, P &lt; 0.001), while targeted therapy (13.4, 95% CI = 7.0-19.8, P = 0.01) and hormone therapy (11.9, 95% CI = 4.1-19.7, P &lt; 0.01) also has lower TrTT than chemotherapy. Patients with a worse performance status (ECOG PS 3-4, 30.1 days, 95% CI = 18.3-41.9) experienced higher time toxicity than fitter patients (PS 0-2, 16.7 days, 95% CI = 13.2-20.2, P &lt; 0.05). Among different cancer types, gastrointestinal malignancies were associated with the highest time toxicity with average TrTT of 30.2 days/3 months (95% CI =22.5-37.2). Conclusions: This is the first comprehensive study to quantify real-world Treatment-Related Time Toxicity across multiple cancer and therapy types in an underserved population. We found 18% of patients with incurable solid malignancies experienced severe time toxicity (&gt; 1 in 3 days). Higher TrTT was associated with cytotoxic chemotherapies, GI malignancies, and poor performance status. Time toxicity should be taken into account with other quality-of-life outcomes in treatment pathways and patient-centered oncology care.