Toxicity Profile Research Articles

Five-year outcomes with gefitinib induction and chemoradiotherapy in EGFR-mutant stage III non-small-cell lung cancer: LOGIK0902/OLCSG0905 phase II study

Abstract Background We previously showed the 2-year OS rate, the primary endpoint, of 90% in a phase II trial of gefitinib induction followed by chemoradiotherapy (CRT) in unresectable, stage III, EGFR-mutant, non-small-cell lung cancer (NSCLC). However, neither long-term survival data nor late-phase adverse event profiles have been presented. Patients and methods Patients with unresectable, EGFR-mutant, stage III NSCLC were administered gefitinib monotherapy for 8 weeks. After confirming no disease progression during induction therapy, cisplatin and docetaxel on days 1, 8, 29, and 36 with concurrent radiotherapy at a total dose of 60 Gy were subsequently administered. Results In the enrolled twenty patients, the 5-year OS rate and median survival time were 70.0% [95% confidence interval: 45.1–85.3] and 5.5 years [4.91-NE], respectively, whereas 5-year PFS rate and median PFS time were 15.0% (3.7–33.5) and 1.4 years [0.69–2.29], respectively. Efficacy did not seem influenced even if radiation field was re-planed in response to the effect of gefitinib induction. As for late adverse events, pulmonary fibrosis occurred in 7 patients (35%). The median time from completion of CRT to the occurrence of the event was 245 days. All were grade 1, and there was no evidence of cavitation of the lesions or chronic infections such as Aspergillus infection during the course of the disease. One case of small cell lung cancer occurred during the period. Conclusions With longer follow-up time, we demonstrated favorable efficacy with tolerable toxicity profiles in the EGFR-TKI induction followed by standard CRT in EGFR-mutant, stage III, NSCLC. Trial registration numbers UMIN00005086. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&recptno=R000006047&type=summary&language=EjRCTs071180036. https://jrct.niph.go.jp/latest-detail/jRCTs071180036

Cabozantinib in the Treatment of Neuroendocrine Neoplasms: Insights Across Different Tumor Origins.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors arising from neuroendocrine cells, exhibiting a wide range of behaviours from indolent to highly aggressive forms. Treatment options remain limited, particularly for progressive cases. Cabozantinib, a multitarget tyrosine kinase inhibitor, has demonstrated potential in targeting key pathways related to tumor growth, angiogenesis, and metastasis. This review provides a comprehensive analysis of cabozantinib's therapeutic role across various NEN subtypes, including gastroenteropancreatic NENs, lung NENs, pheochromocytomas/paragangliomas, Merkel cell carcinoma, presacral NENs, pituitary neuroendocrine tumors, and neuroendocrine prostate cancer. The paper discusses several preclinical and clinical studies that demonstrate the efficacy of cabozantinib in slowing tumor progression and improving progression-free survival, particularly in patients with progressive, well-differentiated NENs. However, cabozantinib's complex toxicity profile limits its broad application, necessitating further research to optimize dosing, particularly in syndromic NENs. Ongoing trials are investigating cabozantinib in combination with somatostatin analogues, peptide receptor radionuclide therapy, temozolomide and immunotherapies in order to overcome treatment resistance and expanding therapeutic strategies for advanced NENs.

Low-Dose Versus High-Dose Lenvatinib in Radioiodine Refractory Differentiated Thyroid Cancer-A Real-World Safety and Efficacy Analysis.

Lenvatinib, a tyrosine kinase inhibitor, is approved for the treatment of radioiodine refractory differentiated thyroid cancer (RR-DTC) at a dose of 24 mg/day. Given its significant toxicity profile, the present study aimed to compare the safety and efficacy of initial low-dose lenvatinib to that of higher starting doses in patients with RR-DTC. This retrospective study included patients with RR-DTC who were classified as: Group-A: patients receiving 10mg/day, and Group-B: patients receiving ≥ 14mg/day of lenvatinib as starting dose. Safety, radiological response (as per RECIST 1.1) and progression-free survival (PFS) outcomes were analysed and compared. A total of 105 patients with RR-DTC were included in this study (Group-A: 60, Group-B: 45). The study found that Group-B experienced significantly higher rates of drug interruptions (68.9% vs 48.3%, p = 0.035) and dose reductions (60% vs 11.7%; p < 0.001) compared to Group-A. Adverse events such as hand-foot skin reaction (77.8% vs 58.3%), diarrhea (28.9% vs 11.7%), hepatotoxicity (33.3-40% vs 11.7-18.3%), and electrolyte imbalance (15.6% vs 3.3%) were also more frequent in Group-B (p-values < 0.05). However, both groups showed similar objective response rates (47.1% vs 46.3%; p = 0.936) and comparable PFS outcomes (restricted mean survival time at 24 months: 22.8 vs 21.4 months, p = 0.128). The study suggests that starting with lower doses of lenvatinib, followed by dose escalation if tolerated, may offer a safer approach with significantly lower rates of drug interruptions and dose reductions, with comparable efficacy in RR-DTC patients. Further validation by larger prospective trials is warranted.

Toxicity Assessment of River Sediments Impacted by Open-Pit Coal Mining in Colombia Using Caenorhabditis elegans

Coal mining is a critical economic for Colombia. However, mineral extraction is usually carried out near rivers that provide ecosystem services to riverside populations. Cesar River receives discharges from several open-pit coal mines, as well as from other anthropogenic sources. The aim of this work was to assess the chemical and the toxicity profile of the sediments from this river. Bottom sediment samples were collected from 12 points along the river, including tributaries and a Ramsar site, the Zapatosa Marsh. Trace elements were quantified employing ICP-MS, and mercury (Hg) was measured using a direct Hg analyzer. Aqueous extracts (K-medium) were obtained from dried sediments (1:3 ratio) and tested using Caenorhabditis elegans, assessing mortality, locomotion and growth as end points. Transcriptional effects associated with various toxicity mechanisms were evaluated using GFP-related transgenic strains (mtl-2, sod-4 and gst-1). Some trace metals enriched along the course of the river, especially Hg and V. Sediment extract-induced lethality was low (1.5–6.4%); however, nematode growth and locomotion decreased downstream the river, showing inhibition rates up to 23.3 and 35.4%, respectively. Extracts from downstream points increased the mRNA expression of tested genes compared to that elicited by the most upstream site, with greater values on stations receiving domestic sewage and mining outputs. Cobalt and lead were positively associated with metallothioneins and gst-1 expression. In short, coal mining areas should be closely monitored for trace-element release and their impact on biota. The Colombian government should implement laws and programs to protect key ecosystems from mining activities, as a commitment to sustainable development goals.

Perioperative chemotherapy with either S-1 or 5-fluorouracil plus oxaliplatin and docetaxel for locally advanced gastric or gastroesophageal junction adenocarcinoma: A prospective trial and matched comparison.

396 Background: Perioperative triplet chemotherapy improves the survival and surgical outcome of patients with locally advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma in addition to curative surgery. 5-fluorouracil (5-FU), docetaxel, oxaliplatin and leukovorin (FLOT) has been suggested as the treatment of choice. S-1, an oral fluoropyrimidine chemotherapeutic, also shows compelling efficacy as one of the triplet backbone and is exempt from a prolonged infusion time. However, a comparison over efficacy and tolerability between S-1 or 5-FU-containing triplet has not been investigated. Methods: The study contains two parts. The first part was a prospective single-arm multi-centered phase II trial with eight cycles of perioperative leucovorin, oxaliplatin, docetaxel and S-1 (LOTS) in patients with ≥T3 any N or ≥T2N(+) non-metastatic gastric/GEJ adenocarcinoma. The primary endpoint was the treatment response assessed by pathological tumor regression (TRG). After confirming the result passing the statistical threshold, we compared them with an identical and independent patient population who received perioperative FLOT under a prospective observation. A propensity score matching (PPSM) was used to balance the heterogeneity between the two groups. The efficacy, survival and tolerability were compared in a post-hoc manner. Results: From Feb 2017 to Jan 2024 with a comparable median follow-up time (LOTS, 18.7 ms; FLOT, 18.9 ms), a total of 45 and 154 patients were enrolled and received either LOTS or FLOT treatment. After a one-to-two PPSM procedure, the baseline characteristics of patients were comparable (LOTS, n=45; FLOT, n=90). Patients had similar curative resection rates (LOTS, 91%; FLOT, 86%; p=.359) and above nearly complete pathological regression rates (TRG 0-1: LOTS, 23%; FLOT, 27%; p=.669). The 24-ms recurrence-free (RFS) and overall survival (OS) rates were also comparable (LOTS vs. FLOT: 66 vs. 59% in RFS, p=.463; 73 vs. 68% in OS, p=.491). The toxicities were tolerable, except that more diarrhea and nausea events were reported in the LOTS group, whereas neutropenia, thrombocytopenia and mucositis were significantly prominent in the FLOT group. Conclusions: Perioperative LOTS shows reasonable therapeutic efficacy and survival as compared with FLOT in patients with locally advanced gastric/GEJ cancer. While the toxicity profile is distinctive from FLOT, it could be a potential alternative regimen with the convenience to save the prolonged infusion time. Clinical trial information: NCT04999332 . Pathological outcome. Prior to LOTS treatment (n=45) After LOTS treatment (n=43) Prior to FLOT treatment (n=90) After FLOT treatment (n=86) p in LOTS vs. FLOT CAP TRG, n (%) 0.669 0 - - 1 (2.3) - - 3 (3.5) 1 - - 9 (20.9) - - 20 (23.3) 2 - - 14 (32.6) - - 23 (26.7) 3 - - 19 (44.2) - - 40 (46.5)

Comprehensive evaluation of the toxicological effects of commonly encountered synthetic cathinones using in silico methods.

Synthetic cathinones (SCs), a group of new psychoactive substances (NPS), are designer molecules with hallucinogenic and psychostimulatory effects. Although the structural similarities of SCs to amphetamines suggest that they may have similar toxicity profiles to those of amphetamine congeners, little is known about SCs from a toxicological point of view. In the present study, the toxicity profiles of commonly encountered SCs (n = 65), listed in the 2020 Report of the United Nations Office on Drugs and Crime (UNODC), were evaluated using in silico methods. We aimed to gain a deeper understanding of key toxicological endpoints: acute oral toxicity (LD50), mutagenicity, genotoxicity, and carcinogenicity prediction using EPA TEST (v.5.1.2 and 4.2.1), VEGA (v.1.2.3), and ProTox (v.3.0). Physicochemical and pharmacokinetic (ADME) properties were estimated using SwissADME and pkCSM. 2,3-MDMC (41) was predicted to be the most lethal SC by the VEGA KNN and the EPA TEST v.5.1.2 with an oral rat LD50 value of 105.17 and 117.77mg/kg, respectively. 4-BEC (2) was the only molecule with a consensus score of positive prediction greater than 0.90 in both TEST mutagenicity models. 2,3-MDMC (41) and methylone (52) were predicted as carcinogenic by VEGA carcinogenicity CAESAR, ISS, IRFMN-ISSCAN-CGX, oral classification, and ProTox models. These two SCs were predicted to be active by VEGA chromosomal aberration (CORAL) and in vitro micronuclei-inducing activity (IRFMN-VERMEER) models. Our results concluded that given the prolonged exposure duration and age range, the genotoxic and carcinogenic potential of SCs should be considered, among other known toxic effects.

Adjuvant Proton Beam Radiation Therapy for Sinonasal Mucosal Melanoma.

Head and neck mucosal melanoma (HNMM) is rare and carries a poor prognosis with high rates of disease progression. There is little data regarding the use of adjuvant proton radiation therapy in the management of sinonasal HNMM. We performed a retrospective review of patients with nonmetastatic sinonasal HNMM treated with adjuvant proton radiation from 2012 to 2022 at a single academic institution. Kaplan-Meier estimates were used for survival analyses. Eight patients with sinonasal HNMM were treated with surgery and adjuvant proton radiation, and six received systemic therapy. Median follow-up was 15 months (range: 3-68 months). Only one local failure was observed, and two patients developed distant metastases. Kaplan-Meier 1-year results were as follows: local control 88%, distant metastasis-free survival 75%, and overall survival 88%. No Grade 3 or higher late toxicities were observed. Surgical resection and adjuvant proton radiation provided early favorable local control and toxicity profiles in our cohort of patients with sinonasal HNMM. Further multi-institutional work is needed to study this rare malignancy.

Microplastics aggravate the adverse effects of methylmercury than inorganic mercury on zebrafish (Danio rerio).

The potential health risks of microplastics (MPs) and their combined exposure with heavy metals such as mercury (Hg) in aquatic environment are increasingly concerned recently. In this work, zebrafish embryos were exposed to different levels of polystyrene microplastics (PS-MPs, ∼0.1μm) coupled with Hg(II) or/and MeHg at 20μg/L, to investigate the tissue biodistribution and accumulation of PS-MPs and Hg species, and their interaction, as well as embryo toxicity, oxidative stress and metabolic profiles. With zebrafish embryo development, PS-MPs were ingested and then primarily translocated to yolk sac, liver, and intestinal tissues, further acted as a significant vector for improving the bioaccumulation of MeHg vs. Hg(II). Whatever single or combined exposure of PS-MPs and Hg species, embryo disorders, such as delayed hatching, developmental abnormalities, and motor behavioral, and increased oxidative stress indications were obviously found. Herein, PS-MPs+MeHg aggravated oxidative stress compared with MeHg alone, which might been relevant to the high accumulation of Hg level in zebrafish larvae induced by PS-MPs. Non-targeted metabolomics results proved PS-MPs involvement disturbed lipid metabolism, amino acid metabolism, and energy metabolism compared with alone Hg(II) or MeHg exposure, of which excessive energy metabolism by activating the glycolysis process was found in PS-MPs+MeHg treatment. This work reveals the enhancement efficacy of PS-MPs on MeHg induced toxicity and adverse stress, further proving the differentiated effect of elemental chemical forms with microplastics. In the future, elemental species must be considered for the combined toxicity evaluation and ecological risk assessments of microplastics and heavy metals.

Updated results from the phase Ib/II study of fruquintinib combined with SOX and toripalimab in patients with advanced metastatic gastric/gastroesophageal junction adenocarcinoma (GC/GEJC).

423 Background: The efficacy of first-line treatment in advanced GC/GEJC patients (pts) with negative or low PD-L1 expression still needs to be improved. This phase Ib/II, open-label study (NCT05024812) evaluating fruquintinib (a highly selective VEGFR-1, -2, -3 inhibitor) plus toripalimab (anti-PD-1), and SOX has shown preliminary antitumor activity as first-line therapy in GC/GEJC. Here we update the results with longer follow-up duration and a specific focus on PD-L1 CPS features. Methods: The study of phase Ib employed a 3+3 dose escalation design, pts were treated with fruquintinib 3mg/d (dose level; DL1), 4mg/d (DL2), or 5mg/d (DL3) po, d1-14, in combination with fixed dose of toripalimab (240mg, iv, d1), oxaliplatin (130 mg/m 2 , iv, d1) and S-1 (40-60mg based on BSA, po, d1-14) every 3 weeks. It had been reported in phase Ib that fruquintinib 5mg/d was defined as the RP2D. In phase II, a further 64 pts would be treated with the same regimen. Primary endpoint of phase II was PFS per RECIST 1.1. Secondary endpoints included ORR, DCR, OS, DOR and safety. Results: As of August 15, 2024, 32 pts (9 in phase Ib; 23 in phase II) had been enrolled. Pts characteristics included: median age 62 (range 38–73); 66% male; 88% with ECOG PS 1, and 31% with liver metastasis. 31 pts had PD-L1 CPS available. 40.6% were CPS &lt; 1 and 68.8% were CPS &lt; 5. Of the 30 pts evaluable for tumor response, the ORR was 63.5% (95% CI 43.9–80.1) with 4 pts achieving complete responses and DCR was 96.7% (95% CI 82.8–99.9). After a median follow-up of 10.94 months, the median PFS was 9.33 (95% CI: 5.68–NA) months and OS result was not reached. Pts with CPS &lt; 5 were more likely to achieve higher response rate (65.0 vs 55.6%) and longer PFS than CPS ≥5 (12.68 vs 8.11 months). Similar trends were observed in pts with CPS &lt; 1 and CPS ≥1 (ORR: 75.0 vs 52.9%; PFS: 12.68 vs 8.11 months). Treatment-related adverse events (TRAEs) were mainly grade 1-2 and the most common ones were hypoalbuminemia (50%), neutrophil count decreased (34%), anemia (41%), platelet count decreased (34%) and white blood cell decreased (34%). Grade 4 TRAEs occurred in 2 pts (impaired liver function, hypertriglyceridemia). There were no treatment related deaths in the trial. Conclusions: Fruquintinib combined with SOX and toripalimab provided favorable efficacy and manageable toxicity profile as first-line therapy for pts with advanced metastatic GC/GEJC, especially in pts with negative or low PD-L1 expression. More data including the potential predictive response biomarkers would be further analyzed and reported. Clinical trial information: NCT05024812 .

Single-task regression naturally adapts to multi-species (eco)toxicological modelling: a case study on animals.

In silico (eco)toxicological modelling has gained increasing popularity with chemical environmentalists in accelerating toxicity assessment of hazardous chemicals on environments, animal well-being and human health. Existing local and multi-task models commonly exhibit restricted extensibility in multi-species modelling scenarios. In this work, we propose a strategy of single-task regression to naturally adapt modelling to (eco)toxicological measurements on multiple species without requiring a certain number of common pesticides among tested species as multi-task regression does. This strategy treats all species equally in an integral model to facilitate data augmentation and inter-species transfer of common patterns of fragmental toxicities. We aggregate 37,305 measurements of 29,140 pesticides on 10 tested groups of animals to train four machine learning models including extreme gradient boosting (XGBoost), deep neural networks (DNN), random forest (RF) and support vector regression (SVR). Five-fold stratified cross-validation shows that the XGBoost outperforms the other three models with overall 0.67 R2, 0.44 RMSE and 0.29 MAE. As compared to local models focusing on one animal group, the proposed single-task regression model achieves a 0.08 ~ 0.49 R2 increase. XGBoost feature importance shows that Morgan bit 389 (five-atom fraction of the aromatic ring) exhibits top importance to single-task regression and single-animal regression. Lastly, taking the pesticide parathion and dimethoate as control baselines, we demonstrate the credibility of several case studies from the viewpoints of toxicity profile similarities and pesticide structural similarities.

Treatment failure patterns in early versus late introduction of CAR T-cell therapy in large B-cell lymphoma.

CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy has recently been approved as second-line treatment for relapsed/refractory large B-cell lymphoma (LBCL). This study compares patterns of disease relapse and progression across patients receiving CAR-T as second-line (early administration) versus third or subsequent lines (late administration). We analyzed 354 patients treated with Axicabtagene ciloleucel (71%) and Lisocabtagene maraleucel (29%); 80 (23%) received early administration, and 274 (77%) late administration. One-year overall survival was higher in the early group (82% [95% CI 72-93] vs. 71% [95% CI 66-77], p = 0.048). However, the survival benefit was not sustained in multivariable Cox regression modeling and propensity score matching. One-year cumulative incidences of relapse were similar (37% [95% CI 24-50] vs. 43% [95% CI 37-49], p = 0.2), as were 1-year progression-free survival probabilities (62% [95% CI 50-76] vs. 50% [95% CI 44-57], p = 0.14). The early group exhibited a favorable toxicity profile, with lower rate of grade ≥2 cytokine release syndrome (26% vs. 39%, p = 0.031) and reduced cumulative incidence of severe neutropenia (41% [95% CI 30-52] vs. 55% [95% CI 49-60], p = 0.027). Our results indicate favorable outcomes with CAR-T irrespective of treatment line. The equivalence in disease control suggests that CAR-T resistance mechanisms persist in LBCL failing first-line therapy.

Chemotherapy selection for advanced or metastatic pancreatic cancer using machine learning models trained with multi-center datasets.

738 Background: Several factors must be considered when selecting the chemotherapeutic regimen for advanced or metastatic pancreatic cancer. The decision between FOLFIRINOX and Gemcitabine/Nab-paclitaxel (GnP) as the first-line therapy is challenging, as survival is influenced by the efficacy and toxicity profiles of these treatments, along with individual patient characteristics and therapeutic vulnerabilities. This study aims to facilitate the selection of an appropriate first-line regimen for advanced or metastatic pancreatic cancer by employing machine learning (ML) methods trained on multi-center datasets. Methods: Our study is based on a cohort of 191 patients who underwent systemic chemotherapy for advanced or metastatic pancreatic cancer at the Gangneung Asan Hospital and Asan Medical Center in South Korea between 2014 and 2023. The dataset consisted of 17 types of demographic and clinical characteristics, as well as time-course of response and survival outcomes. We divided the cohort into training and test groups (4:1) in a stratified manner. ML models predicting overall survival (OS) were trained on the former group using the CatBoost method. The models utilizing a minimal subset of variables were selected with respect to ROC-AUC during 5-fold cross validation. A patient was classified as having high risk to a therapy when the predicted probability of death following treatment initiation was above the threshold value as determined during training of the respective model. Results: The median age of the entire cohort was 62 years, with 64% being male. The ML models achieved ROC-AUCs of 0.81 and 0.82 when predicting early death within 12 months following the initial administration of FOLFIRINOX or GnP, respectively. The predictive accuracies of the models were 0.77 and 0.80 for the unseen datasets from the two treatment groups, respectively. The median OS of the high- versus low-risk groups of FOLFIRINOX predicted by the ML models were significantly different (9 vs 15 months, P &lt;0.0001), with a hazard ratio (HR) of 2.8. Similarly, the median OS of the high- and low-risk groups of GnP were significantly different (9 vs 18 months, P &lt;0.01, HR of 2.5). We observed that 27% of the patients predicted as high risk to FOLFIRINOX therapy were predicted as low risk to GnP and vice versa for 32% of the patients predicted as high risk to GnP therapy. Conclusions: We developed ML models to compute the probability of early death following FOLFIRINOX or GnP therapy from routinely collected data of the patients with advanced or metastatic pancreatic cancer. After confirming robust predictive performance with multi-center datasets, we believe that these models may assist clinicians in selecting a first-line regimens, potentially enhancing personalized treatment strategies for this challenging disease.

Real-world evidence of nanoliposomal irinotecan and fluorouracil with folinic acid in patients with unresectable or recurrent pancreatic cancer: Final results of a multicenter observational study.

721 Background: Nanoliposomal irinotecan (NAL-IRI) and fluorouracil with folinic acid (NFF) is the standard regimen after gemcitabine-based therapy for unresectable or recurrent pancreatic cancer (urPC). However, we have almost no prospective data on its efficacy and safety in the real-world, so we conducted this study to investigate them both retrospectively and prospectively (NAPOLEON-2 study). We previously reported the retrospective data in ASCO-GI 2023, and here we report the final results of the prospective part. Methods: We prospectively collected data of urPC patients treated with NFF who had received at least one previous chemotherapy line in 17 hospitals in Japan from June 2021 to October 2023. The primary endpoint was overall survival (OS). Secondary endpoints were overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), dose intensity (DI) and adverse events (AEs). In addition, OS and PFS among the therapeutic lines of NFF were also analyzed. Results: A total of 150 urPC patients were prospectively enrolled. The median follow-up period was 7.2 months (95% confidence interval [CI], 6.3–8.8); median age, 72 years (range, 45–85), with 81 female patients (54%). The Eastern Cooperative Oncology Group performance status was 0/1/2/3 in 46/93/10/1 patients, respectively. Sixteen patients (11%) had locally advanced disease; 134 (89%) had metastatic disease; 77 (51%) had liver metastasis; and 47 (31%) had peritoneal metastasis. All patients previously received gemcitabine-based therapy. NFF was administered as 2nd/3rd/4th-or-later-line therapy to 87/53/10 patients, respectively. The median OS was 7.8 months (95% CI, 6.6–9.2); median PFS, 3.7 months (95% CI, 2.8–4.9); overall response rate, 11%; and disease control rate, 56%. The relative dose intensity was 72.7% with NAL-IRI and 79.4% with fluorouracil. The initial dose of NAL-IRI was reduced in 84 patients (56%), mainly owing to decreased organ function (17%), followed by age (12%), worsened performance status (10%), or UGT1A1 examination status (5%). Dosage reduction of NAL-IRI during treatment (independent of the initial dose reduction) was performed in 74 patients (49%), mainly owing to neutropenia (22%) and anorexia (11%). Frequent Grade 3/4 adverse events were neutropenia (27%), anorexia (19%), and leukopenia (16%). Grade 5 peritoneal infection was observed in only one patient. The median OS and PFS for NFF in the 2nd-line group, compared with the 3rd-or-later-line group, were 7.4 vs 7.8 months (hazard ratio [HR], 0.97; 95% CI, 0.68–1.39; p=0.88) and 3.3 vs 4.2 months (HR, 1.04; 95% CI, 0.74–1.45; p=0.84), respectively. Conclusions: NFF had appropriate efficacy and manageable toxicity profiles, consistent with our previous report. NFF can be a candidate for 2nd-or-later-line regimens in the real-world. Clinical trial information: UMIN000043939 .

Efficacy of pembrolizumab in advanced esophageal carcinoma: A systematic review and meta-analysis.

438 Background: Pembrolizumab, a monoclonal immunoglobulin G4 antibody is a programmed cell death protein 1 inhibitor, approved for treatment of advanced (metastatic or recurrent) esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). We performed a pooled analysis to assess the efficacy of pembrolizumab in esophageal carcinoma (EC) and to compare it with chemotherapy alone. Methods: We conducted a systemic literature search, using PubMed, EMBASE, and ClinicalTrials.gov, till July 30, 2024. Initial search yielded 412 articles. We excluded duplicates and irrelevant studies and included 4 clinical trials (CT) that reported pembrolizumab’s efficacy in EC. We estimated pooled objective response rate (ORR), partial response (PR), and hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS), along with 95% confidence interval (CI) and p-value in RevMan v.5.4. Subgroup analysis, based on combined positive score (CPS) for programmed cell death ligand-1 (PDL-1) expression and tumor histology type was also performed. Results: We included four CTs in our study; their characteristics are shown in the table. The estimated pooled ORR and PR of pembrolizumab in all patients was 21% (CI: 0.10-0.41) (p &lt; 0.001) and 19% (CI: 0.08-0.37) (p &lt; 0.001), respectively. Pooled median PFS was 3.05 mo (CI: 0.92-5.17) (p = 0.004), and pooled median OS was 8.05 mo (CI: 5.21-10.88) (p &lt; 0.001). Pembrolizumab use in EC showed a reduced risk of disease progression vs chemotherapy alone [HR: 0.85 (CI: 0.75-0.96) (p &lt; 0.05)] and a 21% reduction in mortality [HR: 0.79 (CI: 0.71-0.88) (p &lt; 0.001)]. Safety analysis revealed less grade ≥3 adverse events [OR: 0.56 (CI: 0.35-0.90), p &lt; 0.05)] with pembrolizumab compared with chemotherapy alone. On subgroup analysis between ESSC and EAC, pembrolizumab exhibited statistically nonsignificant responses with ORR (OR: 1.29, CI: 0.89-1.88, p = 0.18), OS (pooled HR: 0.94, CI: 0.76-1.15, p = 0.53). Pembrolizumab in patients with CPS ≥10 vs CPS &lt;10 also showed statistically non-significant responses with ORR [OR: 1.70, CI: 0.99-2.91, p = 0.06), OS (pooled HR: 0.63 vs 1.00) (p = 0.05) and PFS (pooled HR: 0.62 vs 0.83, p = 0.08). Conclusions: Pembrolizumab alone or combined with chemotherapy compared with chemotherapy alone exhibited favorable responses in terms of ORR, OS and PFS with a manageable toxicity profile, setting a benchmark for future studies. Characteristics of included studies. Trial ID, phase Histology Line Number of patients Regimen Median follow-up (mo) ORR (%) Median PFS (mo) Median OS (mo) KEYNOTE-590, III ESCC, EAC 1 st 749 Pembro + chemo vs chemo 58.8 45 vs 29.3 6.3 vs 5.8 12.3 vs 9.8 KEYNOTE-181, III ESCC, EAC 2 nd 628 Pembro vs chemo 7.1 13.1 vs 6.7 2.1 vs 3.4 9.3 vs 6.9 KEYNOTE-180, II ESCC, EAC 3 rd or later 121 Pembro 5.8 9.9 2.0 5.8 KEYNOTE-028, 1b ESCC, EAC 3 rd or later 21 Pembro 7 30 1.8 7 Pembro: pembrolizumab, mo: month.

Disparities in clinical trial enrollment among LGBTQ+ individuals and its impact on cancer treatment and management: A systematic review.

805 Background: There is a significant gap in oncologic research, which arises from the exclusion of LGBTQ+ individuals from cancer clinical trials, compromising the development of personalized cancer therapies and limiting the generalizability of findings. Despite known health disparities in this population, including higher cancer risk factors and unique psychosocial stressors, data on clinical trial participation remains sparse. This study aims to elucidate the extent of underrepresentation of LGBTQ+ individuals in cancer clinical trials and examine its impact on treatment efficacy, safety, and overall management. Methods: We conducted a systematic review of literature and clinical trial databases, including PubMed, ClinicalTrials.gov, and other registries, focusing on cancer trials from 2010 to 2024. We extracted data on LGBTQ+ enrollment, analyzed demographic inclusivity criteria, and identified barriers to participation. Subgroup analyses evaluated the correlation between LGBTQ+ representation and treatment outcomes, considering variables such as trial design, recruitment strategies, and data collection on sexual orientation and gender identity. The review also examined policy changes and inclusivity initiatives aimed at improving trial access for this community. Results: The review identified a significant underrepresentation of LGBTQ+ individuals in cancer trials, with sexual orientation and gender identity data reported in only 6.2% of trials. Structural and sociocultural barriers, including heteronormative trial designs, lack of inclusive recruitment strategies, and pervasive discrimination, were frequently cited as impediments. Trials that included LGBTQ+ participants rarely conducted stratified analyses to assess differential treatment responses, leading to a paucity of data on drug safety, efficacy, and toxicity profiles specific to this population. The absence of these data may contribute to suboptimal therapeutic decision-making and potential adverse outcomes in clinical practice. Conclusions: The substantial underrepresentation of LGBTQ+ individuals in cancer clinical trials impairs the ability to develop inclusive, evidence-based oncology care. Addressing this gap requires systematic changes, including the integration of sexual and gender minority data collection, implementation of LGBTQ+-specific recruitment frameworks, and stratified analyses of treatment outcomes. Enhancing trial inclusivity will not only improve the external validity of oncologic research but also support the development of tailored therapeutic approaches that address the unique needs of LGBTQ+ cancer patients, ultimately advancing health equity in cancer care.

Microplastic-enhanced chromium toxicity in Scenedesmus obliquus: Synergistic effects on algal growth and biochemical responses.

This study explores the combined toxicity of microplastics (MPs) and chromium (Cr6 +) on the freshwater green algae Scenedesmus obliquus. As emerging contaminants in aquatic ecosystems, MPs have been shown to intensify the toxicity of Cr6+, leading to a more significant impact on algal growth and biochemical responses than either stressor alone. A 30-day experimental simulation revealed that co-exposure to Cr6+ and 5 µm diameter polystyrene MPs resulted in significantly enhanced toxicity compared to individual exposures, characterized by a notable decrease in algal growth, diminished photosynthetic pigments, and protein content, alongside oxidative system damage. 100 nm MPs exhibited a distinct toxicity profile, with more pronounced effects when not combined with Cr6+, suggesting size-dependent interactions with algal cells. Transcriptomic analysis illuminated the complex regulatory mechanisms, indicating that toxicity primarily modulates metabolic pathways essential for photosynthesis, oxidative phosphorylation, the TCA cycle, and ribosome function in Scenedesmus obliquus. This study not only delineates the distinct toxicity effects of single and combined exposure systems but also emphasizes the need for a deeper understanding of the role of MPs in environmental pollution and their potential to modulate the toxicity of heavy metals in aquatic ecosystems.

Efficacy of PD-1 inhibitor plus chemotherapy versus chemotherapy in advanced esophageal carcinoma: A meta-analysis of phase III clinical trials.

397 Background: Programmed death cell death protein-1 (PD-1) inhibitors combined with chemotherapy have demonstrated survival benefits in patients with advanced esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC). Our pooled analysis aims to analyze the efficacy of PD-1 inhibitor plus chemotherapy in advanced esophageal carcinoma (EC) in phase III randomized clinical trials (RCTs). Methods: We collected data from eligible phase III RCTs searched through PubMed, EMBASE, ClinicalTrials.gov, and meeting abstracts till July 5, 2024. Initial screening revealed 792 articles. We excluded duplicates, review articles and irrelevant studies, and we included eight RCTs that reported objective response rate (ORR), treatment-related adverse events (TRAEs), overall survival (OS) and progression-free survival (PFS). Odds ratio (OR) for ORR and TRAEs, and hazard ratio (HR) for OS and PFS were computed along with a 95% confidence interval (CI) and p-value for pooled analysis, using a random effect model in RevMan v.5.4. We performed a subgroup analysis based on a combined positive score (CPS) for programmed cell death ligand-1 (PDL-1) expression and tumor histology. Results: We included eight phase III RCTs (Jupiter-06, Checkmate 648, Keynote 590, ESCORT-1st, Orient-15, Checkmate 649, ESCORT-NEO, and ASTRUM-007), including 4131 patients with 2137 in group A (PD-1 inhibitor + chemotherapy) and 1994 in group B (placebo + chemotherapy, or chemotherapy). PD-1 inhibitors against EC included nivolumab, pembrolizumab, camrelizumab, sintilimab, toripalimab, and serplulimab. A total of 9.9% of patients were diagnosed with EAC, and 90.1% were ESCC. A pooled analysis showed significant achievement in ORR in group A compared to group B with an OR of 2.19 (CI: 1.77-2.69, p &lt; 0.05, I² = 60%). In terms of OS benefit, group A led to a 29% reduction in death risk compared to group B (HR: 0.71, CI: 0.66-0.76, p &lt; 0.05, I² = 0). Group A also showed a significantly reduced risk of disease progression compared to group B (HR: 0.62, CI: 0.54-0.70, p &lt; 0.05, I² = 60%). Safety analysis revealed more TRAEs (OR: 1.93, CI: 1.43-2.60, p &lt; 0.01, I² = 11%) and grade ≥3 AEs (OR: 1.34, CI: 1.08-1.67, p &lt; 0.05, I² = 54%) in group A compared with group B. Sub-group analysis based on CPS revealed that patients with CPS ≥10 showed more OS (pooled HR: 0.59 vs 0.75) (p = 0.04) and PFS (pooled HR: (0.59 vs 0.64) (p = 0.18) benefits as compared to patients with CPS &lt;10. Survival analysis between ESCC and EAC also exhibited statistically non-significant OS benefits (p = 0.28). Conclusions: PD-1 inhibitor plus chemotherapy as a first-line therapy in advanced EC, mainly in patients with CPS ≥10, showed improved antitumor efficacy in terms of superior ORR, OS, and PFS, with a manageable toxicity profile providing a benchmark for future studies.

Fruquintinib plus camrelizumab combined with paclitaxel liposome and nedaplatin as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, phase II clinical trial.

445 Background: Camrelizumab in combination with chemotherapy has become a standard of care for the first-line treatment of advanced ESCC. Previous studies have indicated synergistic effect of fruquintinib in combination with chemotherapy or immunotherapy. Hence, we conducted a phase II trial to evaluate the efficacy and safety of fruquintinib plus camrelizumab, paclitaxel liposome, and nedaplatin as a first-line therapy for advanced ESCC. Methods: This is a single-arm, phase II study consisting of a dose-finding and a dose-expansion phase. A total of 33~36 patients aged 18~80 years with previously untreated advanced ESCC and an ECOG PS of 0-2 were planned to be enrolled. The dose-finding phase followed a 3+3 approach in order to determine the recommended phase II dose (RP2D) of fruquintinib for dose expansion. Patients received fruquintinib (3 mg, 4 mg, and 5 mg once daily on days 1-14, starting at 4 mg) orally, plus intravenous camrelizumab 200 mg d1, paclitaxel liposome 135 mg/m 2 d1, and nedaplatin 70 mg/m 2 d1, 21 days as one cycle. A maximum of 6 cycles was conducted, followed by maintenance therapy with fruquintinib in combination with camrelizumab. The primary endpoint was objective response rate (ORR, RECIST 1.1). Secondary endpoints included RP2D, disease control rate (DCR), progression-free survival (PFS), and adverse events (AEs). Results: As of August 24, 2024, 11 patients (9 males) were enrolled with a median age of 66 years (range 50-76). All patients had distant metastases, and the median number of sites of metastasis was 2 (range 1-5). In the dose-finding phase, 3 patients were treated with 4 mg of fruquintinib, and 6 patients were treated with 5 mg of fruquintinib. No dose-limiting toxicities (DLTs) were observed. Thus, the RP2D of fruquintinib was established as 5 mg once daily on days 1-14, 21 days as one cycle. Of the 7 evaluable patients, 6 achieved partial response, and 1 had stable disease. The ORR was 85.7% (95% CI 42.1%-99.6%), and the DCR was 100.0% (95% CI: 59.0%-100.0%). The median PFS was not reached. The most common treatment-related adverse events (TRAEs) were anemia (7/11), hypercholesterolemia (6/11), hypoalbuminemia (5/11), oral mucositis (5/11), hematuria (4/11), hypertension (4/11), fatigue (4/11), constipation (3/11), and neutropenia (3/11). Grade 3 TRAEs were identified in 2 patients, including oral mucositis (2/11), and anemia (1/11). No treatment-related serious adverse events (SAEs) or deaths occurred. Conclusions: The combination of fruquintinib, camrelizumab, paclitaxel liposome, and nedaplatin demonstrated significant efficacy and manageable toxicity profiles as a first-line treatment for advanced ESCC, suggesting a potential new treatment strategy. Clinical trial information: NCT06010212 .

Preclinical toxicity evaluation of the novel anti-hypertensive compound KSD179019.

The Secretin receptor (SCTR) presents a promising path for hypertension management, with KSD179019 as identified as a Positive Allosteric Modulator (PAM) of SCTR, demonstrating anti-hypertensive effects in animal models. Our objective was to comprehensively evaluate the potential toxicity of KSD179019 through in vitro and in vivo investigations. Initial in vitro studies showed minimal toxicity in liver and kidney cells and non-mutagenicity in bacterial assays. A 14-day acute toxicity test indicated an LD50 over 5000mg/kg body weight, suggesting a safe profile, yet necessitating further in vivo analysis before progressing to human trials. Following OECD protocols, we conducted sub-chronic (90 days) and chronic (180 days) toxicity studies in male and female C57 mice at various dosages. These included comprehensive hematological, biochemical, macroscopic, urinalysis, and histopathological examinations. The sub-chronic study reported minimal toxicity except at the highest doses (700 and 1000mg/kg), while the chronic study suggested a no-observed-adverse-effect-level (NOAEL) at 250mg/kg with limitations. QSAR analysis supported the non-mutagenic nature of KSD179019. KSD179019 demonstrated a favorable general toxicity profile at a dose of 250mg/kg in a 180-day chronic testing study. However, further preclinical investigations, including assessments of in vivo mutagenicity, reproductive and developmental toxicity, and carcinogenicity, are required to comprehensively establish its safety profile.

Clinical outcomes of hypofractionated radiotherapy (5x5 Gy) with a simultaneous integrated boost (5x6 Gy) in locally advanced rectal cancer.

60 Background: Hypofractionated RT (5x5 Gy) with or without subsequent chemotherapy is a standard of care used at the National Institute of Oncology, Warsaw, Poland, as a preoperative treatment for locally advanced rectal cancer. To maximize the chance of achieving a complete response (CR), when surgery is not planned or when there are clinically involved lymph nodes located outside the standard TME field, RT can be augmented with a simultaneous integrated boost (SIB) delivering 5x6 Gy. This report aims to evaluate the clinical outcomes of hypofractionated RT with a SIB in rectal cancer. Methods: From Dec 2018 to Sep 2022, 78 consecutive pts with a median age of 67 years (range 36–89 years), received hypofractionated RT utilizing the SIB-VMAT technique. The radiation dose fractionation was 5x5 Gy to the rectum, mesorectum and elective lymph nodes and a SIB to the GTV for a total dose of 30 Gy. Results: 30 pts (38.5%) received a SIB for the rectal tumor, of which 15 pts (19.2%) were deemed unfit for surgery, 10 pts (12.8%) refused surgical treatment, 3 pts (3.8%) had an oligometastatic disease, and 2 pts (2.6%) had an advanced primary tumor. 48 pts (61.5%) received a SIB to the clinically involved lymph nodes located outside the standard TME field. All 78 pts completed RT as planned without interruptions or dose modifications and with an acceptable toxicity profile. There was a 26.9% (n = 21) incidence of G2 toxicities (diarrhea, proctitis, skin toxicity, cystitis or lumbosacral plexus neuropathy) and a 3.8% (n = 3) incidence of G3 toxicities (diarrhea or proctitis). After a median follow-up of 917 days (range 33–1927 days), an assessment of response was conducted in 68 cases. In 94.1% (n = 64) there was no progression at the site irradiated to a dose of 30 Gy. After completion of RT, mr-TRG was evaluated in 28 pts. In 46.4% (n = 13) mr-TRG 1-2 (cCR) was achieved. Of the 24 pts qualified for the watch and wait strategy, 17 had follow-up. Of this group, 64.7% (n = 11) remained progression-free, and 11 pts had an adequate evaluation for cCR (imaging and endoscopy), resulting in a 63.6% (n = 7) rate of cCR. 43 pts underwent surgery, of which 97.7% (n = 42) had R0 resection. In 41 cases pathological TRG was assessed according to AJCC or Ryan, of which 41.4% (n = 17) achieved TRG 0-1 (pCR). In 40 cases the operated pts had no initial metastatic spread, among them 67.5% (n = 27) remain disease-free. 67 pts reported disease-related symptoms before RT. After treatment, 89.6% (n = 60) of those pts achieved symptomatic improvement in either rectal bleeding, bowel frequency, or pain control. Conclusions: Hypofractionated RT with SIB-VMAT delivering a dose of 30 Gy/25 Gy/5 fractions provides good local control and is a safe and viable option for both young and elderly patients who will not undergo surgery and for patients with involved lymph nodes located outside the standard TME field to maximize the chance of achieving CR.