This study assessed the preclinical and clinical pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of ribupatide (HRS9531), a novel dual agonist of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors.

Preclinical assessments of ribupatide included in vitro functional receptor potency assays, PK evaluations in Sprague-Dawley (SD) rats and cynomolgus monkeys and PD assessments in diet-induced obese (DIO) mice. The Phase 1 study comprised single-ascending dose (SAD; 0.1, 0.3, 0.9, 2.7, 5.4 and 8.1 mg) and multiple-ascending dose (MAD; 0.9, 2.7 and 5.4 mg [2.7/2.7/4.0/5.4 mg]) parts. In the MAD part, ribupatide or placebo was administered subcutaneously once weekly for 4 weeks. The primary endpoints were safety and tolerability.

Ribupatide is a chemically synthesised polypeptide that activates both GLP-1 and GIP receptor signalling pathways in vitro. In SD rats and cynomolgus monkeys, ribupatide demonstrated good subcutaneous bioavailability. In DIO mice, it significantly reduced body weight and cumulative food intake over 28 days compared with vehicle-treated controls. These preclinical PK/PD findings provided a rationale for clinical studies. A total of 90 healthy Chinese participants were randomised and received study treatment, of whom 87 (96.7%) completed the study. Ribupatide was well tolerated across all dose levels, with all treatment-emergent adverse events (TEAEs) being mild-to-moderate in severity and no serious TEAEs or deaths reported. In the MAD, the mean half-life was 7-8 days across the dose range. Fasting plasma glucose decreased dose-dependently after single and multiple dosing. After four weekly doses, mean weight change in ribupatide groups ranged from -4.3 kg (-6.7%) to -7.7 kg (-9.6%), compared with -1.2 kg (-1.4%) in the placebo group.

Ribupatide exhibited a favourable safety and tolerability profile, along with PK properties consistent with once-weekly administration. Its glucose-lowering and weight-loss effects support further clinical development for the treatment of type 2 diabetes mellitus and obesity.

ClinicalTrials.gov identifier: NCT05152277.

Heart failure with preserved ejection fraction (HFpEF) is a systemic disease in which metabolic comorbidities obesity, type 2 diabetes (T2D), and chronic kidney disease (CKD) converge to drive systemic inflammation, endothelial dysfunction, and myocardial fibrosis. Microvascular dysfunction represents an important link between these comorbidities and abnormalities within and beyond the heart, although its causal contribution to HFpEF remains incompletely established. In addition to promoting myocardial stiffness and diastolic dysfunction, impaired microvascular function across the pulmonary and peripheral circulations may contribute to reduced tissue perfusion, exercise intolerance, and dyspnoea. CKD may further aggravate this process through volume and neurohormonal pathways as well as circulating uraemic and inflammatory factors that impair endothelial function, through a kidney-microvascular axis. Despite its high prevalence and poor prognosis, therapeutic options for HFpEF have historically been limited. Recent advances, including sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 (GLP-1) receptor agonists and dual incretin therapies (GLP-1/GIP RAs), and (non-steroidal) mineralocorticoid receptor antagonists, have reshaped the therapeutic landscape by improving cardiovascular and renal outcomes in patients with HFpEF. These agents exert complementary effects on hemodynamic stress, metabolic dysregulation, inflammation, and fibrosis, and may also improve microvascular function across multiple vascular beds. In this narrative review, we provide an organ-by-organ synthesis of the pathophysiological interactions among the heart, kidney, systemic microvasculature, pulmonary circulation, and skeletal muscle in CKMS-related HFpEF. We further map the clinical and mechanistic effects of aforementioned therapies across these interconnected organ systems and highlight areas in which mechanistic and clinical evidence gaps remain.

Tarlatamab, a delta-like ligand 3-targeted bispecific T-cell engager, has shown activity in previously treated small cell lung cancer (SCLC); however, real-world data on cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) remain limited. We evaluated the efficacy and safety of tarlatamab and laboratory findings associated with CRS in patients previously treated for extensive-stage SCLC.

We retrospectively analyzed 11 patients who received tarlatamab through an expanded access program between October 2024 and May 2026. Repeated laboratory measurements were analyzed using generalized estimating equations and mixed-effects models.

The objective response and disease control rates were 54.5% and 72.7%, respectively. The mean and median tumor size changes from baseline were -9.1% and -25.0%, respectively. The median progression-free survival and overall survival were 3.8 months (95% confidence interval [CI]: 1.9-not reached) and 10.1 months (95% CI: 4.5-not reached), respectively. CRS occurred in seven patients (63.6%), with 10 events, all occurring during the first cycle and limited to Grade 1 or 2. No CRS event required tocilizumab treatment, intensive care unit admission, dose reduction, or treatment discontinuation. One patient developed Grade 3 ICANS and recovered fully. CRS events were associated with higher neutrophil percentages, lower lymphocyte percentages, and higher neutrophil-to-lymphocyte ratios than no-CRS events.

Tarlatamab shows encouraging antitumor activity and manageable toxicity in heavily pretreated Korean patients with SCLC. The neutrophil-to-lymphocyte ratio may represent an exploratory, concurrent hematologic correlate of CRS.

Central neurocytoma is a rare intraventricular tumor with favorable prognosis following gross total resection (GTR). However, the role of Ki67-MIB1 values in the postoperative decision making-process of treatment, as well as the indication for adjuvant radiotherapy, remain debated. Medical record data of patients with confirmed diagnosis of central neurocytoma who underwent surgical resection at Department of Neurosurgery of "Ospedale del Mare" in Naples - Italy, between January and December 2022, were retrospectively reviewed. Inclusion criteria were adult patients (> 18 years old), minimum follow up 42 months, complete demographic, clinical, neuroradiological and histopathological data, type of management, complications and outcome, time to recurrence, follow-up duration. Five adult patients were enrolled according to the inclusion criteria. Most patients were women (80%), with mean age 24 years old. Main presenting symptoms were headache and visual deficit. Lesions always involved lateral ventricles, with extension to the third ventricle in all but one cases. Transcortical approach to the ipsilateral lateral ventricle with extension to the third ventricle was the main adopted surgical route. GTR was achieved in all cases without postoperative complications nor postoperative new onset neurological deficits. No patients required ventricular shunting procedures for hydrocephalus during the surveillance period. Follow-up ranged from 43 to 54 months. Ki67-MIB1 values ranged from 5% to 10%. No patients underwent adjuvant radiotherapy. Our findings suggest that GTR alone may be sufficient even in patients with moderately elevated Ki-67. A tailored, risk-adapted postoperative strategy is recommended rather than routine adjuvant treatment.

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) induce regressions and extend progression-free survival (PFS) in ovarian cancer, especially in tumors with BRCA1 or BRCA2 mutations that impair homologous recombination repair. While recent studies have clarified the key roles of BRCA1, BRCA2, and PARP1 in replication fork stability, the downstream mechanisms that mediate PARPi-induced cytotoxicity and resistance remain incompletely understood. Here we delineate cell fate outcomes following PARPi treatment in homologous recombination-deficient high-grade serous ovarian cancer and identify actionable pathways to overcome acquired resistance. Our findings reveal that PARPi-induced DNA damage simultaneously triggers apoptosis, which primarily occurs through the BAX/BAK-dependent intrinsic apoptotic pathway, while also driving cellular senescence, as manifested by the expression of senescence-associated β-galactosidase, CDKN1A upregulation and a senescence-associated secretory phenotype. Notably, the PARPi-induced senescent cells persist as resistance develops and exhibit multinucleation, a hallmark of nuclear atypia, both in vitro and in patient-derived xenografts (PDXs). Building on the observation that the anti-apoptotic protein BCLX_L restrains pro-apoptotic BCL2 family members after PARPi treatment, we show that addition of the BCLX_L inhibitor A-1155463 to PARPi therapy diminishes resistance in multiple high-grade serous ovarian cancer cell lines in vitro and significantly enhances PARPi-induced tumor response in a PDX model with acquired PARPi resistance in vivo. Overall, these preclinical findings strongly support the potential of combining BH3 mimetics with PARPis to treat resistant ovarian cancer.

To evaluate and compare the prognostic value of the 8th and 9th editions of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system in patients with non-metastatic nasopharyngeal carcinoma (NPC).

Clinical data from 470 patients with NPC treated between November 2019 and June 2022 were retrospectively analyzed. Patients were restaged according to the 8th and 9th editions of the AJCC/UICC staging system. OS was the primary endpoint; locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and disease-free survival (DFS) were secondary endpoints. Kaplan-Meier curves were compared using global and pairwise log-rank tests. Prognostic discriminative ability was evaluated using the concordance index (C-index) and Akaike information criterion (AIC).

Seventeen patients (3.6%) classified as T3 by TNM-8 were reclassified as T4 by TNM-9. Thirty-one patients (6.6%) were reclassified to N3 because of advanced iENE. TNM-9 improved discrimination for DMFS across N categories (log-rank p < 0.001 vs. p = 0.016 for TNM-8) and for OS (p < 0.001 vs. p = 0.042). T categories discriminated LRFS in both editions (p = 0.012 for each), whereas OS differences were not significant (TNM-8 p = 0.139; TNM-9 p = 0.137). TNM-9 overall stage discriminated OS (p = 0.002), unlike TNM-8 (p = 0.121). Both editions discriminated DFS (both p < 0.001), but TNM-9 provided better pairwise separation between early and advanced overall stages. The 9th edition exhibited enhanced predictive performance compared with the 8th edition, as evidenced by higher C-index values and lower Akaike information criterion (AIC) values for both DFS and OS prediction across overall stages.

The 9th edition of the AJCC/UICC staging system demonstrated superior prognostic discriminative ability compared with the 8th edition, enabling more accurate risk stratification and supporting more informed clinical decision-making for patients with NPC.

While psychological distress is a well-documented concern among cancer patients, the prevalence and severity of depression and anxiety in breast cancer patients in Saudi Arabia remain insufficiently explored. This study aimed to evaluate depression, anxiety, and quality of life (QoL) among patients with breast cancer undergoing adjuvant pharmacotherapy in Saudi Arabia.

A cross-sectional observational study was conducted among patients with breast cancer receiving adjuvant therapy. Data were collected using the Patient Health Questionnaire-9 (PHQ-9) for depression, the Generalized Anxiety Disorder-7 (GAD-7) for anxiety, and the Quality-of-Life Questionnaire-C30 (QLQ-C30) for QoL assessment.

Among 246 patients, the most prevalent cancer subtype was hormone receptor-positive (65.0%), followed by human epidermal growth factor receptor 2 (HER2)-positive (13.4%), triple-negative (11.0%), and HER2/hormone receptor-positive (10.6%). Trastuzumab (20.3%) and pembrolizumab (11.0%) were the most commonly administered biological therapies, while letrozole (45.5%) and tamoxifen (22.8%) were the most used hormonal agents. Notably, 48.4% of patients received chemotherapy. The mean ± standard deviation (SD) of PHQ-9 score was 12.87 ± 7.63, and the mean ± SD of GAD-7 score was 9.55 ± 5.53, with clinical significant depression and anxiety of 54.1% and 49.6%, respectively. The mean ± SD of the QLQ-C30 score was 58.84 ± 24.98. Multivariate analysis revealed that chemotherapy and the number of cycles were significantly associated with higher levels of depression and anxiety. Quality of life was negatively impacted by chemotherapy, endocrine therapy, and the number of treatment cycles.

Depression, anxiety, and reduced QoL are prevalent among breast cancer patients undergoing treatment in Saudi Arabia. Chemotherapy and endocrine therapy contribute significantly to psychological distress, and diminished QoL.

Pulmonary metastasis in high-grade conventional osteosarcoma remains a leading cause of treatment failure and mortality. Traditional monitoring methods are insufficient for early detection. This study aims to develop and validate an interpretable machine learning (ML) model using multi-dimensional data from electronic medical records (EMR) to predict the early risk of pulmonary metastasis in high-grade conventional osteosarcoma patients.

This retrospective study included data from 522 high-grade conventional osteosarcoma patients. After rigorous feature selection, 12 independent predictive factors were identified: prothrombin time (PT), international normalized ratio (INR), fibrinogen, globulin, prognostic nutritional index (PNI), eosinophil percentage, monocyte percentage, neutrophil percentage, monocyte count, maximum tumor diameter, gender, and amputation status. Eleven ML models were constructed and compared, with Shapley Additive Explanations (SHAP) analysis applied to enhance model interpretability and clinical transparency.

The gradient boosting model exhibited superior performance, achieving an area under the curve (AUC) of 0.891 in the training set and 0.742 in the independent test set. SHAP analysis revealed that tumor maximum diameter was the most influential predictor of pulmonary metastasis risk, while inflammation and coagulation-related indicators also demonstrated significant contributions.

The gradient boosting model effectively predicts the early risk of pulmonary metastasis in high-grade conventional osteosarcoma and provides interpretable risk factors. This model shows potential as a clinical decision support tool, facilitating personalized risk management and precision medicine, aiming to improve patient outcomes.

Objectives: To evaluate the safety, short-term efficacy and prognostic characteristics of spatially fractionated radiation therapy (SFRT) in patients with advanced or metastatic solid tumors. Methods: Clinical data of patients with advanced/recurrent metastatic malignant tumors who received SFRT in Shenzhen Hospital of Cancer Hospital, Chinese Academy of Medical Sciences from June 2023 to August 2024 were retrospectively analyzed. Patients were divided according to radiotherapy modality into the lattice radiation therapy (LRT) group (high-dose irradiation delivered in a spherical lattice pattern within the target area) and the stereotactic central ablative radiation therapy (SCART) group (ablative dose irradiation delivered to the tumor core area). All patients underwent at least one imaging follow-up after treatment. Results: A total of 49 patients were enrolled; 12 patients who did not complete imaging follow-up were excluded, and finally 37 patients were included in the analysis. The median age was 58 years (range, 28 to 77 years), male accounted for 67.6% (25/37), and the median Eastern Cooperative Oncology Group (ECOG) performance status score was 1 point (range, 1 to 2). The most common primary tumor type was gastrointestinal tumors (48.6%, 18/37). The median number of prior lines of chemotherapy before radiotherapy was 3 (range, 0 to 11). The median maximum diameter of the target area was 9.3 cm (range, 4.9 to 33.4 cm), and the median volume was 236.6 cc (range, 28.6 to 5 053.0 cc). There were 21 cases (56.8%, 21/37) in the LRT group and 16 cases (43.2%, 16/37) in the SCART group. The median SFRT vertex dose was 12 Gy (range, 6 to18 Gy), and the median number of fraction was 5 (range, 1 to 5). A total of 40.5% (15/37) of patients received conventional fractionated radiotherapy or stereotactic body radiotherapy (SBRT) before or after SFRT. Furthermore, 35.1% (13/37) of patients received sequential immunotherapy, with a median of 3 cycles (range, 2 to 4). As of May 16, 2025, the median follow-up time was 13.2 months (range, 9.4 to 22.7 months); 21 patients were alive, 12 died (11 due to tumor progression, 1 due to immune checkpoint inhibitor-related pneumonia), and 4 were lost to follow-up. Efficacy evaluation showed that the median time for first imaging assessment was 3 months (range, 0.5 to 6 months), the in-field disease control rate was 94.6%, and the 6-month in-field disease control rate was 85.0% (17/20). Among the 21 patients with pre-treatment symptoms, pain relief was achieved in 11 patients (11/15), and the overall symptom control rate was 81.0% (17/21). No grade Ⅲ or higher radiotherapy-related acute/chronic adverse events were observed. Grade Ⅰ-Ⅱ radiation gastroenteritis occurred in 9 patients, and grade Ⅰ elevated transaminase occurred in 3 patients. Conclusions: SFRT can effectively alleviate clinical symptoms and provide favorable local control in patients with advanced/recurrent metastatic large-volume malignant tumors, with manageable safety. Preliminary results suggest that SFRT can serve as a palliative treatment option for this patient population. The synergistic effect and long-term efficacy of sequential drug therapy (including immunotherapy) require validation with larger sample size or prospective studies.

Objective: To analyze the clinicopathological and molecular characteristics of non-small cell lung cancer (NSCLC) with human epidermal growth factor receptor 2 (HER-2) variations (including mutations and amplifications) and their correlation with prognosis.​ Methods: Clinicopathological data of NSCLC patients with HER-2 variations who underwent targeted next-generation sequencing (NGS) at Ningbo Clinical Pathology Diagnostic Center from September 2022 to June 2024 were collected. The clinicopathological and molecular features were retrospectively analyzed, and a literature review was conducted. Results: Among 2 795 NSCLC patients, HER-2 variations were identified in 148 cases (5.3%, 148/2 795). Of these, 128 cases had HER-2 mutations [86.5%, 128/148, including 63 exon 20 (Exon20) mutations], 16 cases had HER-2 amplifications (10.8%, 16/148), and 4 cases had concurrent HER-2 mutation and amplification (2.7%, 4/148). Compared with the HER-2 mutation group, patients with HER-2 amplification were more likely to have larger tumor size, lymph node metastasis, distant metastasis and higher TNM stage (all P＜0.05). Among HER-2 mutations, Exon 20 mutations were more common in females and associated with lower risks of larger tumor size, lymph node metastasis and distant metastasis (all P＜0.05). Cox regression analysis indicated that HER-2 amplification, larger tumor size, lymph node metastasis, distant metastasis and higher TNM stage were associated with poor prognosis (P＜0.05). Molecular analysis revealed that Exon20 mutations rarely co-occurred with other gene variations, whereas non-Exon20 mutations were frequently accompanied by other genetic alternations, most commonly epidermal growth factor receptor (EGFR) mutations (55.4%, 36/65). In addition, 16 cases of HER-2 p.A270S mutation were identified, of which 11 were at advanced TNM stage (68.8%, 11/16), and 5 patient died.​ Conclusions: Different types of HER-2 variations (mutations/amplifications) exhibit distinct clinicopathological and molecular characteristics. Patients with HER-2 amplification have a poor prognosis, and the HER-2 p.A270S mutation may be associated with malignant phenotypes of NSCLC. It is necessary to integrate the characteristics of HER-2 variations to provide references for individualized treatment.​.