Search Results (712)

Difenoconazole is a triazole fungicide used to ensure sustainable agricultural, although it may also affect the aquatic environment. This study assessed the effects of this fungicide by both an experimental and a computational approach. The experimental assessment involved the acute exposure of Lemna minor to different concentrations of difenoconazole and the determination of main endpoints such as number of fronds and colony, as well as secondary endpoints represented by gravimetric, morphometrical and biochemical parameters. The in silico analysis consisted of the testing of difenoconazole and 14 of its transformation residues (TRs), using three computational tools (admetSAR, ADMETlab and T.E.S.T.) to assess either their toxicological endpoints (EC₅₀, IGC₅₀) or their probability of affecting a range of model aquatic organisms. The results highlighted a concentration-dependent effect of difenoconazole on both main and secondary endpoints. The calculated EC₅₀ value was 2.47 mg/L (data validated by EC₅₀ on Lemna gibba from Pesticides Properties DataBase), which categorizes difenoconazole as moderately toxic in the aquatic environment. The in silico assessment showed that two of the TRs showed lower toxicity, with these having only one aromatic ring compared to the others analyzed. Full article

Background/Objectives: Cancer is the second leading cause of death globally, and resistance to immunotherapy requires new strategies. One promising approach is cross-line immunotherapy, defined as retreatment with the same or different immune checkpoint inhibitors after progression on prior immunotherapy. Understanding the efficacy and safety of this innovative treatment modality is critical for advancing cancer care. Methods: In this study, we evaluated outcomes of cross-line immunotherapy in a cohort of 105 patients with various malignant tumors at Beijing Friendship Hospital. The primary endpoints of the study included progression-free survival (PFS2) and overall survival (OS), measured from the initiation of cross-line immunotherapy. All patients received treatment regimens determined by their physicians. The study aimed to evaluate the efficacy of cross-line immunotherapy, with or without other therapies. Results: The study reported a median PFS2 of 6.9 months (95% CI: 4.7–8.1) and a median OS of 12.9 months (95% CI: 11.7–NA). The objective response rate (ORR) was 11%, while the disease control rate (DCR) was 77%. Although 35.2% of patients experienced grade 3 or higher immune-related adverse events, primarily hematological toxicities, no specific immune treatment-related hematological events were noted. Additionally, elevated D-dimer levels and hyponatremia emerged as prognostic factors associated with poorer outcomes, whereas hypertriglyceridemia correlated with enhanced survival. A nomogram developed for predicting PFS2 and OS demonstrated high discriminative capacity. Conclusions: These findings show that cross-line immunotherapy is safe and effective for patients with malignant tumors. It offers a viable option for patients who are progressing after initial treatments, which highlights the need for personalized strategies. Full article

The rapid emergence of New Psychoactive Substances (NPS), particularly pyrrolidinophenone derivatives, poses a significant challenge for public health and forensic toxicology. While their neuropharmacological profiles as dopamine transporter inhibitors are well-documented, their cardiac toxicity remains poorly understood. This study employs a multiparametric New Approach Methodology (NAM) using zebrafish embryos to integrate neurobehavioral and cardiotoxic endpoints for comparative hazard prioritization. We evaluated nine pyrrolidine-containing cathinones, including α-PVP, MDPV, α-PiHP, MDPiHP, α-D2PV, 3-Cl-, 4-Cl-, and 3,4-Cl-α-PVP, and 4-F-3-Me-α-PVP, on locomotor activity and cardiac rhythmicity using high-speed video microscopy and dynamic pixel analysis. Across the series, compounds induced concentration-dependent negative chronotropy and, in most cases, locomotor suppression. Crucially, we identified a functional dissociation between atrial rate control and atrioventricular (AV) conduction. The 3,4-dichloro substitution (3,4-Cl-α-PVP) was the most potent inducer of negative chronotropy (EC₅₀ = 52.6 μM), whereas 4-Cl-α-PVP exhibited a distinct pro-arrhythmic liability, increasing the incidence of 2:1 AV block. Time-course locomotor profiling indicated that α-PVP and chlorinated analogs were among the most potent behavioral modifiers. Using a Functional Safety Index (AV block EC₅₀/locomotor EC₅₀-like), we show that most compounds exhibit wide separations between neurobehavioral inhibition and severe conduction impairment, while specific substitutions, particularly para-chlorination, are associated with comparatively reduced functional separation between these endpoints within the assay. Overall, these data demonstrate that subtle structural changes within the pyrrolidinophenone scaffold can shape distinct arrhythmic phenotypes and functional safety profiles, supporting zebrafish-based integrated screening as a rapid platform for prioritizing emerging synthetic cathinones with comparatively higher cardiac liability within this experimental framework. Full article

Predicting acute toxicity across species is essential for early-stage drug safety evaluation. While recent efforts have primarily focused on improving predictive accuracy, they often fail to address two critical issues: the substantial divergence in toxicity mechanisms among different species, and the inherent noise present in experimental data. To bridge this gap, we introduce a Probabilistic Multitask Active Learning (PMAL) framework for multi-species acute toxicity prediction. Our framework integrates two key modules: a Probabilistic Multitask Learning (PML) component which jointly models the predictive distributions of multiple toxicity endpoints from a probabilistic viewpoint, and an Uncertainty-based Active Learning (UAL) component which strategically selects the most informative compounds for experimental annotation based on predictive uncertainty. Empirical evaluations demonstrate that PMAL surpasses state-of-the-art methods and is capable of providing well-calibrated uncertainty estimates for small molecules across diverse toxicity endpoints. Beyond advancing multi-species toxicity prediction, the core design principles of PMAL offer a generalizable paradigm for learning in noisy multi-task environments. Full article

Alzheimer’s (AD) and Parkinson’s disease (PD) are prominent neurodegenerative disorders characterized by early synaptic loss, which correlates more closely with clinical symptoms than neuronal death. This synaptic impairment is primarily driven by disruptions in synaptic vesicle (SV) trafficking, a critical process for maintaining synaptic integrity through a tightly regulated cycle involving clustering, docking-priming, Ca²⁺-triggered fusion, and endocytosis. In AD, amyloid-β (Aβ) oligomers interfere with SNARE-mediated fusion and endocytosis, while hyperphosphorylated tau obstructs vesicle mobility and docking, resulting in cumulative toxicity that aggravates SV defects. Conversely, in PD, α-synuclein (α-syn) aggregation alters vesicle clustering, membrane fusion, and recycling, and these effects are further influenced by Leucine-rich repeat kinase 2 (LRRK2)-Rab-related trafficking defects and the selective vulnerability of dopaminergic terminals. Different from previous reviews that address synaptic dysfunction in a broader manner, the present review is specifically organized around the SV trafficking cycle and compares both shared presynaptic endpoints and disease-specific upstream mechanisms in AD and PD. In addition, recent mechanism-oriented therapeutic strategies are summarized. This vesicle-cycle-centered perspective may provide a clearer framework for understanding presynaptic pathology and for guiding the development of earlier and more targeted interventions. Full article

Background/Objectives: Accurate target delineation is critical in radiotherapy for head and neck non-melanoma skin cancer (NMSC), where tumor depth and subclinical extension are often underestimated by clinical and dermoscopic assessment alone. While high frequency ultrasound has shown value in surface-based radiotherapy techniques, the role of ultra-high frequency ultrasound (UHFUS) within external beam radiotherapy (EBRT) workflows remains poorly defined. Methods: We conducted a single-institution observational feasibility study including all consecutive patients with head and neck NMSC treated with definitive or adjuvant radiotherapy between July 2022 and July 2023 using a structured multidisciplinary workflow integrating pre-treatment UHFUS. UHFUS was systematically performed prior to CT simulation and incorporated into radiotherapy planning. The primary endpoint was the impact of UHFUS on radiotherapy decision-making, predefined as modification of target delineation, treatment intent, or beam modality selection. Secondary endpoints included feasibility, early local control, and late toxicity (descriptive). Results: Thirty patients were included (median age 85 years; range 66–99). UHFUS influenced at least one decision endpoint in 13 patients (43.3%). In the definitive radiotherapy cohort (n = 18), UHFUS modified gross tumor volume delineation in eight patients (44.4%), with an increase in median GTV from 17.5 cm³ to 24.3 cm³. Among patients initially referred for adjuvant radiotherapy (n = 12), UHFUS identified macroscopic residual disease in two cases, leading to a change in treatment intent from adjuvant to definitive radiotherapy. UHFUS supported beam modality selection in three patients by enabling safe use of electron therapy for superficial lesions. After a median follow-up of 24 months (range 12–24), no local recurrences were observed. Late toxicity was limited to grade 1 cutaneous events. Conclusions: Integration of UHFUS into EBRT planning for head and neck NMSC is feasible and clinically informative. UHFUS acts as a decision-shaping tool, influencing target delineation, treatment intent, and modality selection within a multidisciplinary workflow. These findings support further prospective evaluation of UHFUS-guided radiotherapy planning to standardize decision algorithms and assess long-term clinical impact. Full article

Dopaminergic neurodegeneration is a hallmark of Parkinson’s disease (PD), and environmental contaminants have been implicated in disrupting dopaminergic pathways. However, practical in vivo workflows for rapid, standardized, and accessible assessment of dopaminergic neurotoxicity remain limited. In this study, we built on our laboratory’s established high-throughput framework and implemented a high-content imaging workflow to quantify DA neurodegeneration in Caenorhabditis elegans following exposure to representative per- and polyfluoroalkyl substances (PFAS). We evaluated the neurotoxic effects of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonic acid (PFHxS), perfluorohexanoic acid (PFHxA), and three PFAS mixtures with environmentally relevant component ratios. Functional relevance was assessed using dopamine-dependent behavioral endpoints, including basal slowing response (BSR) and area-restricted search (ARS). PFOS exhibited the greatest potency, followed by PFHxS, PFHxA, and PFOA, based on morphological degeneration and benchmark concentration modeling. Structural neuronal damage was significantly associated with behavioral impairment. Under mixture conditions, neurotoxicity was more strongly associated with PFOS molar fraction than with total PFAS concentration (ΣPFAS), suggesting a composition-dependent toxicity profile. Collectively, these findings establish a scalable in vivo framework for assessing PFAS-induced dopaminergic neurotoxicity and support the potential use of this platform for screening environmental pollutants with dopaminergic neurotoxic potential. Full article

Background: The EXTREME regimen (cetuximab with cisplatin/carboplatin and 5-fluorouracil) has long been a standard first-line treatment for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC), particularly in patients ineligible for immunotherapy. However, real-world evidence remains limited, especially in regions with delayed access to novel therapies. Methods: We conducted a retrospective, multicenter study of 217 patients with R/M HNSCC treated with cetuximab-based chemotherapy at six Croatian oncology centers between 2016 and 2022, prior to reimbursement of pembrolizumab. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), response rates, and safety. Results: The majority (91%) received the EXTREME regimen. Median OS was 14 months (95% CI, 12–17), and median PFS was 6.2 months (95% CI, 6.0–7.2). Objective response rate was 21%, and disease control rate was 63%. Cetuximab-induced rash correlated with longer PFS. Grade ≥ 3 toxicity occurred in 18.9% of patients. No treatment-related deaths were observed. Conclusion: In routine clinical practice, cetuximab combined with platinum-based chemotherapy remains an effective and well-tolerated first-line treatment for R/M HNSCC, particularly in patients who are ineligible for immunotherapy or with PD-L1–negative tumors. These findings support its continued use in appropriately selected patients. Full article

Background: Radiotherapy (RT) combined with androgen deprivation therapy (ADT) is a standard treatment for non-metastatic high-risk (HR) prostate cancer (PC). However, the benefit of elective nodal irradiation (ENI) in clinically node-negative (cN0) patients, although suggested, remains controversial, particularly in the elderly. We report the outcomes of elderly HR PC patients treated with prostate-only RT (PORT) and ADT in a “real-word” setting. Methods: Between 2016 and 2022, 43 consecutive elderly patients (median age 76 years) with HR- or very HR-PC according to NCCN criteria version 1.2026 (cN0, cT3-cT4 and/or ISUP Grade Group 4–5 and/or PSA serum levels at diagnosis ≥ 20 ng/mL) were treated at our institution. All patients were staged with abdominal MRI or CT and bone scan; nineteen patients (44.2%) also underwent 68Ga-PSMA-11 or 18F-fluorocholine PET/CT. All patients received PORT (predominantly moderate hypofractionation, 67.5–70 Gy in 25–28 fractions) and ADT (median duration 24 months). To ensure consistency, all oncological endpoints—Biochemical Failure-Free Survival (BFFS; Phoenix criteria), Disease-Free Survival (DFS), Metastasis-Free Survival (MFS), Prostate Cancer-Specific Survival (PCSS), and Overall Survival (OS)—were calculated from a unified time-zero (initiation of first oncological treatment). DFS was defined as a composite endpoint including biochemical failure, radiological recurrence, or initiation of salvage therapy. Results: at a median follow-up of 60 months, no patient reached the Phoenix threshold, resulting in a 100% 5- and 7-year BFFS. However, 4 patients (9.3%) experienced radiological recurrence detected via PET/CT before reaching the nadir + 2 threshold, yielding an estimated 5-year and 7-year DFS of 94.7% and 71.8%, respectively. The 5- and 7-year MFS was of 97.6% and 88.7%, respectively. Seven deaths occurred, all non-PC related, resulting in a 5-year OS of 86.7% and a Prostate Cancer-Specific Survival of 100%. Gastrointestinal toxicity was notably low (no acute or late G3-G4 events). Conclusions: Our findings suggest that PORT, when combined with long-term ADT and modern staging, provides excellent disease control and a favorable safety profile in elderly HR PC patients. Given the high rate of competing mortality in this population, treatment de-escalation via PORT appears to be a clinically reasonable strategy. These results are hypothesis-generating and warrant validation in prospective randomized trials. Full article

Rare earth elements (REE), such as gadolinium (Gd) and erbium (Er), are increasingly recognised as emerging environmental contaminants due to their widespread use in industrial processes, electronics, and medical imaging applications. Despite their extensive presence in aquatic ecosystems, little is known about their developmental toxicity. In this study, Xenopus laevis embryos were exposed to environmentally relevant concentrations of Gd and Er during critical early developmental stages. The assessed endpoints included survival, malformations, growth (body length), and heart rate. Both Gd and Er caused significant sublethal effects, including increased axial malformations, reduced growth, and altered cardiac activity. To explore potential mechanisms of toxicity, the expression patterns of key developmental genes (fgf8, bmp4, sox9, egr2, rax1, pax6) and pro-inflammatory cytokines (tnfα, il1β, p65) were analysed using Real-Time PCR. The results showed dysregulation of gene expression, indicating disruption to pathways involved in morphogenesis and neurodevelopment. Elevated reactive oxygen species levels suggested that oxidative stress was a contributing factor. Raman spectroscopy confirmed biochemical changes affecting proteins, lipids, and nucleic acids, providing evidence of cellular stress and metabolic imbalance. Overall, our findings demonstrate that even low-level exposure to Gd and Er can impair amphibian embryonic development and disturb molecular homeostasis. These results emphasise the ecological risks of REE pollution and highlight the importance of ongoing environmental monitoring and long-term toxicological research. Full article

The present work set out to examine the antidiabetic capacity of Abelmoschus esculentus (okra) fruit extract through a combined experimental and computational framework. Enzyme inhibition assays were carried out against four metabolic targets, and IC₅₀ values stood at 7.66 ± 0.31 mg/mL for alpha-glucosidase, 5.21 ± 0.18 mg/mL for alpha-amylase, 2.11 ± 0.15 microg/mL for DPP-4, and 9.17 ± 0.54 mg/mL for pancreatic lipase. The extract showed moderate-to-weak activity relative to standard inhibitors acarbose, sitagliptin, and orlistat. Sixteen drug-like phytochemicals obtained from the IMPPAT 2.0 database were docked against the crystal structures of all four tested enzymes (PDB: 8CB1, 5E0F, 2ONC, 1LPB). Alpha-Carotene, Vitamin E, and Spiraeoside emerged as the top-ranked compounds across all targets, with alpha-Carotene recording the strongest binding affinity of −11.1 kcal/mol against pancreatic lipase, which was 4.2 kcal/mol more negative than the positive control orlistat (−6.9 kcal/mol). PLIP-based interaction profiling mapped out hydrogen bonds, hydrophobic contacts, pi-stacking, and salt bridges at the atomic level. Absorption, distribution, metabolism, and excretion (ADME) and toxicity screening of alpha-Carotene returned a favourable pharmacokinetic profile with predicted LD₅₀ of 1510 mg/kg (Class 4) and inactivity across most toxicity endpoints. A 100 ns molecular dynamics simulation of the pancreatic lipase-alpha–Carotene complex, alongside the orlistat control, showed stable root mean square deviation (RMSD) (0.15–0.22 nm), a consistent Rg (~1.97 nm), and sustained hydrogen bonding throughout the trajectory. Free-energy landscape analysis revealed a well-defined single energy basin for alpha-Carotene, suggesting a thermodynamically stable binding conformation. These findings lay the molecular basis for using okra phytochemicals as adjunctive agents in diabetes management, though in vivo validation remains necessary. Full article

Background: Neoadjuvant chemotherapy plus dual HER2 blockade is standard for HER2-positive early breast cancer (EBC), but the impact of hormone receptor (HR) status and PIK3CA mutations with anthracycline-free regimens remains unclear. Methods: We retrospectively analyzed 56 patients with stage II–III HER2-positive EBC treated with neoadjuvant pertuzumab–trastuzumab–taxane (THP) at a single institution. Pathological complete response (pCR, ypT0/is ypN0) was the primary endpoint; secondary endpoints were safety and early disease-free/overall survival (DFS/OS), while associations of HR status and PIK3CA mutations with pCR were explored. Results: The overall pCR rate was 60.7%, in line with major dual-HER2 neoadjuvant trials. HR-negative patients achieved higher pCR rates than HR-positive patients (85.7% vs. 45.7%; p = 0.007; odds ratio 7.125), identifying HR status as the main clinical factor associated with response. Among 36 patients with PIK3CA testing, pCR rates appeared similar in mutated and wild-type tumors (62.5% vs. 60.7%), but the small number of mutated cases precludes firm conclusions. At a median follow-up of 42 months, only five DFS and one OS event had occurred, so survival analyses are exploratory and should be interpreted cautiously. THP demonstrated an excellent safety profile, with minimal grade 3–4 toxicity, and no clinically relevant hematological, cardiac, or pulmonary events. Conclusions: Anthracycline-free THP is a highly active, well-tolerated neoadjuvant option for HER2-positive EBC, with particularly high pCR rates in HR-negative disease. HR status emerged as a key determinant of pCR, whereas the role of PIK3CA mutations remains inconclusive and requires confirmation in larger prospective studies. Full article

Objective: This study aimed to elucidate the association between hematologic toxicity (HT) and pelvic bone marrow (PBM) dosimetric parameters in patients with cervical cancer (CC) undergoing radiotherapy (RT) combined with artificial intelligence (AI)-assisted organ at risk (OAR) delineation (Software Copyright Registration Number 2023SR0150365). Accurate delineation of bone marrow (BM) regions and analysis of radiation doses may provide a theoretical foundation for the application of AI in predicting HT. Methods: This retrospective study included 141 patients with CC who received chemotherapy (sequential or concurrent) and/or pelvic volumetric modulated arc therapy (VMAT) at the Department of Gynecology, Cancer Hospital of the Chinese Academy of Medical Sciences, between March 2019 and December 2019. PBM and its subregions (ilium, lower pelvis, lumbosacral spine, and femoral heads) were delineated using AI-based automatic segmentation of CT images. The volumes receiving 10–40 Gy (V10, V20, V30, V40) were calculated, and baseline clinical characteristics were assessed. HT endpoints included grade ≥ 2 (HT2+) and grade ≥ 3 (HT3+) leukopenia, neutropenia, anemia, or thrombocytopenia. Associations between dosimetric parameters and HT were evaluated using logistic regression models. Results: Of the 141 patients, 107 (75.8%) developed HT2+ and 33 (23.4%) developed HT3+. Univariate analysis showed that chemotherapy and age were correlated with HT2+. Multivariate analysis identified femoral head V30, femoral head V40, and chemotherapy as independent predictors of HT3+. Conclusions: This study highlights the potential of AI-based OAR delineation for assessing PBM dosimetric parameters in patients with CC. Optimizing RT to minimize BM dose and volume may mitigate HT and enhance treatment tolerance. In our cohort, receipt of combined neoadjuvant and concurrent chemotherapy (NACT+CCRT) was a stronger predictor of HT than most BM dosimetric parameters, suggesting that the systemic effect of chemotherapy may dominate the hematologic toxicity profile in this setting. Consequently, patients receiving this combined modality treatment are at particularly high risk for HT and warrant close hematologic monitoring. Full article

Trace metals are persistent stressors in coastal ecosystems, yet most marine algal toxicity assessments still rely on freshwater model species and growth-based endpoints that provide limited mechanistic resolution. Here, we quantified the sensitivity of two ecologically contrasting marine diatoms—the benthic Cylindrotheca closterium and the planktonic Thalassiosira weissflogii—to ten environmentally relevant metals using a dual-endpoint approach that integrates chlorophyll fluorescence (photosystem function) and Nile Red-based lipid-body fluorescence (metabolic reallocation). Fluorescence-based EC₁₀ values revealed distinct species- and metal-specific patterns, with C. closterium consistently responding at lower concentrations and Hg producing the strongest inhibition in both species (EC₁₀ ≈ 0.04–0.06 mg L⁻¹). Lipid-body accumulation detected earlier metabolic disturbance for several metals, particularly Hg, As, Cr(VI), and Cd, and frequently occurred at concentrations where fluorescence remained minimally affected. These sequential thresholds indicate that pigment impairment and metabolic reallocation represent mechanistically distinct stages of the cellular stress response that differ among metals and between diatom guilds. Comparison with published toxicity data shows that the dual-endpoint sensitivities observed here fall within, or slightly above, the upper range of reported microalgal responses, underscoring the pronounced susceptibility of benthic diatoms to redox-active and thiol-reactive metals. The strong agreement between fluorescence-based EC values and traditional growth-derived benchmarks for key metals further supports fluorescence as an operationally efficient endpoint suitable for integration into emerging ISO marine algal bioassays. Overall, this study demonstrates that pairing a rapid functional marker with a mechanistically informative metabolic biomarker enables metal-specific toxicity fingerprinting and provides an ecologically grounded basis for incorporating benthic diatoms into coastal metal risk assessment frameworks. Full article

Background: First-line chemoimmunotherapy (I + C) is the standard of care for advanced non-squamous non-small cell lung cancer (NSCLC) without oncogenic mutation. Bevacizumab has been shown to enhance the efficacy of chemotherapy in non-squamous NSCLC, yet its added value when combined with I + C (I + C + B) remains unclear. To address this gap, we conducted a real-world comparative study and a network meta-analysis to evaluate I + C + B versus I + C in this setting. Methods: This retrospective study included patients with advanced EGFR/ALK-negative non-squamous NSCLC treated with first-line I + C + B or I + C. Propensity score matching (PSM) was employed to balance baseline characteristics between groups. Efficacy endpoints were progression-free survival (PFS) and overall survival (OS). Subgroup analyses examined outcomes by PD-L1 expression, age, metastases, and chemotherapy, among other factors. In parallel, a network meta-analysis of four randomized trials (n = 2026) indirectly compared I + C + B against I + C for PFS, OS, and safety outcomes. Results: A total of 277 patients were included, with 167 (60.3%) receiving I + C + B and 110 (39.7%) receiving I + C. Before PSM, the I + C + B regimen significantly prolonged PFS versus I + C (hazard ratio [HR] = 0.69, 95% CI 0.52–0.92, p = 0.010), with this benefit maintaining post-matching (HR = 0.70, 95% CI 0.49–0.99, p = 0.045). However, OS did not differ significantly between groups in either the pre-PSM (HR = 0.93, 95% CI: 0.67–1.30; p = 0.665) or matched analyses (HR = 0.84, 95% CI: 0.54–1.29; p = 0.421). Subgroup analyses suggested greater PFS benefit from I + C + B among PD-L1-negative, older patients, those with brain metastases or multiple metastatic sites, and in patients receiving specific chemotherapy doublets. The network meta-analysis confirmed a PFS advantage for I + C + B over I + C (HR = 0.84, 95% CI: 0.71–0.98) without an OS benefit (HR = 0.95, 95% CI: 0.79–1.14). Toxicity was higher with I + C + B; rates of grade 3–5 adverse events, serious adverse events, and treatment discontinuation were all significantly increased compared to I + C. Conclusions: In the first-line treatment of advanced EGFR/ALK-negative non-squamous NSCLC, adding bevacizumab to I + C improved PFS but did not translate into an OS gain. Although PFS benefits were observed in certain subgroups, these were accompanied by significantly increased treatment-related toxicities. Our findings suggest that no clear subgroup has been identified where the benefit outweighs the risks, necessitating extreme clinical caution. Full article