Peptide hormones play a central role in maintaining metabolic homeostasis by integrating complex signaling pathways to coordinate interorgan crosstalk. Aberrant production and/or dysfunction of peptide hormones are important contributors to the pathophysiology of a cluster of interrelated chronic metabolic diseases (CMDs), including obesity, type 2 diabetes mellitus, dyslipidemia, metabolic dysfunction-associated steatotic liver disease, and cardiovascular diseases. These CMDs often co-occur, ranking among the top causes of death and disability in the rapidly aging population. Peptide hormone-based pharmacotherapies are the mainstay of treatment for these CMDs. Analogs and agonists of peptide hormones produced by classical endocrine cells, especially insulin and glucagon-like peptide-1, are cornerstones in managing diabetes and obesity. Furthermore, peptide hormones released from nonclassical endocrine organs, such as liver-secreted fibroblast growth factors 21 and growth differentiation factor 15, have emerged as highly promising therapeutic candidates for obesity-related metabolic comorbidities. These peptide hormones act synergistically and/or complementarily to exert pleiotropic metabolic benefits through their distinct receptors in different target organs/tissues. Combination pharmacotherapies with these peptide hormones are much more effective than monotherapy and hold promise to address the multimorbidity issue in patients with CMDs. This review summarizes recent advances in the pharmacoengineering and pharmacology of these peptide hormone-based long-acting analogs and coagonists and discusses their synergistic and antagonistic interactions in the treatment of CMDs. Furthermore, we highlight major challenges and future perspectives in the clinical development of multiple peptide hormone-based coagonists as safe and effective pharmacotherapy for the management of metabolic comorbidities. SIGNIFICANCE STATEMENT: This review highlights recent clinical advances in combination peptide hormone therapies for chronic metabolic diseases, emphasizing their superior efficacy over monotherapies in addressing metabolic multimorbidity. Summarizing the latest developments in long-acting analogs and coagonists of peptide hormones provides critical insights into their synergistic mechanisms, clinical potential, and future challenges, offering a comprehensive perspective for improving the management of complex metabolic disorders.

While invagination pancreaticojejunostomy may reduce the risk of postoperative pancreatic fistula after pancreatoduodenectomy, its long-term impact on anastomotic patency and remnant pancreatic function remains unclear.

To compare long-term anastomotic patency and remnant pancreatic function between duct-to-mucosa pancreaticojejunostomy and invagination pancreaticojejunostomy after pancreatoduodenectomy.

In this retrospective study, we reviewed data from 120 patients from a previous randomized trial comparing the incidence of pancreatic fistula between duct-to-mucosa pancreaticojejunostomy and invagination pancreaticojejunostomy (UMIN000005890; 2011-2015). Remnant pancreatic duct dilatation and anastomotic stricture were evaluated as surrogate markers for late-term anastomotic patency. Benign anastomotic stricture was defined as an endoscopically confirmed narrowing of the anastomosis. Remnant pancreatic volume, fatty liver disease, and new-onset or worsening type 2 diabetes mellitus were evaluated as markers of exocrine and endocrine function.

The frequency of benign remnant pancreatic duct dilatation was 18.6% in patients who underwent invagination pancreaticojejunostomy and 9.8% in those who underwent duct-to-mucosa pancreaticojejunostomy (P = .262). The 3- and 5-year cumulative incidences were 9.3% and 19.9%, respectively, for invagination pancreaticojejunostomy versus 9.5% and 13.4%, respectively, for duct-to-mucosa pancreaticojejunostomy (P = .356). Benign anastomotic stricture occurred in 9 patients (invagination pancreaticojejunostomy: n = 5; duct-to-mucosa pancreaticojejunostomy: n = 4), with no significant difference between groups. Among those with remnant pancreatic duct dilatation, some developed pancreatic pain or pancreatolithiasis, whereas no such symptoms were seen in patients without remnant pancreatic duct dilatation. Remnant pancreatic volume, fatty liver disease, and the incidence of type 2 diabetes mellitus were similar between groups.

Radiologic suspicion of impaired patency and pancreatic functions was comparable between invagination pancreaticojejunostomy and duct-to-mucosa pancreaticojejunostomy. Although remnant pancreatic duct dilatation occurred occasionally, its clinical impact is likely to be relatively minimal.

Early identification of diabetic retinopathy (DR), which is a primary cause of vision impairment globally, is a crucial phasis for effective intervention and treatment. Traditional screening workflows rely on manual diagnosis by ophthalmologists, which remains the gold standard but can be time-consuming and subject to variability due to human factors. To support and enhance the screening process, artificial intelligence (AI)-based tools have shown promise in automating DR detection, particularly with recent advances in deep learning. However, medical images with long-range dependencies and spatial linkages can be challenging for CNN-based algorithms to handle.

This paper proposes a Vision Transformer (ViT)-based model, specifically using a Compact Convolutional Transformer (CCT), for early automated detection of DR. The model uses self-attention techniques to improve feature extraction and classification performance; combining three main stages: the CCT tokenizer, transformer encoder, and sequence pooling. The proposed approach was trained on public datasets (EyePACS and APTOS 2019) and evaluated against state-of-the-art deep learning architectures.

Our experimental findings demonstrate that ViT performs among the best in the current state of the art with an overall accuracy of 97% and F1-scores above 0.95 across all DR severity levels. Our system is primarily designed for the pre-screening stage of diabetic retinopathy workflows, enabling rapid and reliable identification of potential DR cases for further clinical evaluation.

These results highlight the potential of transformer-based designs in medical picture analysis, as well as the implications for telemedicine and e-health solutions in real-time, especially in cases of low-resource settings.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia and represents a growing global health burden. One of its major complications is diabetic kidney disease (DKD), a progressive condition characterized by declining kidney function accompanied by structural alterations in tissue. Among the multiple pathways involved in DKD progression, inflammation has emerged as a key contributor. In parallel, increasing evidence suggests that biological sex influences disease progression; however, whether and how sex modulates inflammatory mechanisms driving DKD progression remains incompletely understood. In this study, we investigated the interplay between inflammation and biological sex in DKD using the BTBR ob/ob model, which closely recapitulates the human disease. Obese diabetic mice exhibited significant albuminuria regardless of sex; however, podocyte-associated proteins displayed sex-dependent molecular regulation. At the inflammatory level, no changes were detected in whole-kidney analyses based on the selected markers, but a compartment-specific response was observed, characterized by increased macrophage infiltration and upregulation of Ccl2 (MCP-1) gene expression in the glomerular compartment, especially in males. Additionally, the tubular compartment exhibited distinct sex- and metabolism-dependent inflammatory gene expression patterns. Together, these findings indicate that inflammation in this model is spatially compartmentalized and also differentially regulated according to sex. This integrated perspective may contribute to a better understanding of DKD progression and support the development of more precise and targeted therapeutic strategies.

Type 2 diabetes mellitus (T2DM) poses a significant global public health challenge with continuously rising incidence rates. Developing safe and effective hypoglycemic agents derived from natural products has become a current research focus. Walnut shells, as a vast agricultural and forestry waste material, hold substantial economic and environmental significance for high-value utilization. In this study, a polysaccharide (WSP-III) was isolated from walnut shells. This polysaccharide has an average molecular weight of 67.576 kDa and exhibits good thermal stability at 200 °C. Analysis of its monosaccharide composition, methylation profile, and nuclear magnetic resonance (NMR) spectroscopy revealed that its backbone of walnut shell polysaccharides consists of →1, 4-β-d-glucose and →1, 4-β-D-mannose, and →1, 4-β-D-galacturonic acid, with →1,4,6-β-D-galactose serving as the branching point, to which 1-α-L-arabinose and 1-α-D-xylose side chains are attached at the C-6 position. WSP-III significantly alleviates hyperglycemia in diabetic mice, regulates dyslipidemia, protects liver and kidney function, increases short-chain fatty acid content, and improves gut microbiota. This study provides preliminary insights into the structural characteristics and hypoglycemic activity of WSP-III, laying a theoretical foundation for further development of functional polysaccharides.

There are few bladder-sparing treatment options for high-risk, BCG-unresponsive, non-muscle-invasive bladder cancer that are effective and have a manageable adverse event profile. Cretostimogene grenadenorepvec (hereafter, cretostimogene) is an oncolytic immunotherapy with dual mechanisms of action-it replicates in and lyses cancer cells with retinoblastoma-E2F pathway alterations and amplifies the immune response. We evaluated the response and safety/tolerability of cretostimogene in patients with high-risk, BCG-unresponsive, non-muscle-invasive bladder cancer.

BOND-003 Cohort C is a single-arm, international, phase 3 study done in 41 centres (community practices and academic centres) located in North America, Asia, and Australia. Sites were selected through a study team-led qualification process that evaluated feasibility, protocol alignment, operational capabilities, and regulatory readiness, as applicable. We enrolled patients aged at least 18 years with Eastern Cooperative Oncology Group performance status of 0-2 and pathologically confirmed, high-risk, BCG-unresponsive, non-muscle-invasive bladder cancer with carcinoma in situ, with or without resected high-grade Ta or T1 disease. Patients received intravesical cretostimogene (1 × 10¹² viral particles per 0·8 mL per week) as 6-week induction followed by maintenance; re-induction was permitted for persistent disease at 3 months. The primary endpoint was centrally confirmed complete response at any time in patients who received at least one dose of cretostimogene and completed the 3-month assessment; safety was assessed in those who received at least one dose of cretostimogene. This trial is registered with ClinicalTrials.gov (NCT04452591) and is ongoing.

Between Oct 9, 2020, and Aug 3, 2023, 165 patients were assessed for eligibility; 115 patients were enrolled in the study and 112 received cretostimogene. 83 (74%) were male and 29 (26%) were female; median age was 74·0 years (IQR 68·5-79·5). As of June 23, 2025, after a median follow-up of 25·8 months (IQR 22·1-33·1), complete response at any time was observed in 83 (75% [95% CI 66·3-83·2]) of 110 patients. 71 (63%) of 112 patients had at least one treatment-related adverse event, the most common being bladder spasm in 28 (25%) patients, pollakiuria in 25 (22%) patients, and micturition urgency in 23 (21%) patients; there were no grade 3 or 4 treatment-related adverse events and no treatment-related discontinuations or deaths. Two (2%) patients had serious treatment-related adverse events (one non-infective cystitis and one urinary bladder haemorrhage, both grade 2).

Cretostimogene showed clinically meaningful anti-tumour response, with an adverse event profile characterised predominantly by low-grade, transient events. Cretostimogene shows promise as an innovative bladder-sparing treatment for high-risk, BCG-unresponsive, non-muscle-invasive bladder cancer with carcinoma in situ.

CG Oncology.

IntroductionRecurrence-related risk factors and the clinical value of adjuvant radiotherapy for stage IIA (pT3N0M0) rectal cancer (RC) remain controversial. This study aimed to explore prognostic factors for disease recurrence in patients with pT3N0M0 RC and screen for subgroups most likely to benefit from postoperative radiotherapy-based regimens.Materials and MethodsWe retrospectively enrolled patients with stage IIA rectal cancer who received radical resection between 2017 and 2023. All participants were divided into three groups according to postoperative treatment: surgery alone (S), surgery plus chemotherapy (S+CT), and surgery plus radiotherapy-based therapy (S+RT based). We collected clinicopathological characteristics, details of postoperative adjuvant therapy, and follow-up data on tumor recurrence. Disease-free survival (DFS) was calculated accordingly. Univariate and multivariate analyses were used to screen independent prognostic factors for recurrence. Subgroup and interaction analyses were further performed to determine factors associated with favorable responses to radiotherapy.ResultsA total of 114 patients with pT3N0M0 RC were included. 37 patients had disease progression during follow-up. Local recurrence rates differed significantly across the three groups (P < 0.001). Compared with surgery alone, both adjuvant chemotherapy and radiotherapy substantially reduced local recurrence (both P < 0.001). The radiotherapy group showed a trend toward lower local recurrence than the chemotherapy group (5.5% vs 10.0%), without reaching statistical significance. Multivariate regression analysis identified S+RT-based therapy and tumor distance from the anal verge (TDA) as independent prognostic factors for DFS (P < 0.001; TDA= 5-10 cm: P = 0.01; TDA ≥ 10 cm: P = 0.028). Subgroup analysis with interaction testing demonstrated that the efficacy of S+RT-based therapy varied significantly according to age, percent circumferential involvement (PCI), and CD34 expression. S+RT-based therapy was associated with significantly improved DFS in patients with PCI of 1/2 to 1, age ≥ 60 years, and CD34-positive tumors (P < 0.001; P = 0.015; P = 0.03, respectively). Radiotherapy also conferred superior DFS in the overall cohort of patients with stage IIA rectal cancer (P = 0.024).ConclusionAdditional radiotherapy after radical resection improves DFS, particularly in those with PCI of 1/2 to 1, age ≥ 60 years, and positive CD34 expression. However, these findings require validation in prospective randomized controlled trials.

The purpose of this study was to determine whether patient's age and their primary tumor type act as independent predictors of their survival after a diagnosis of choroidal metastasis.

This retrospective single-center study (August 2013 - August 2025) included 70 patients with choroidal metastases. Clinical data and multimodal imaging were extracted from medical records. Tumor volume was calculated from ultrasound measurements. Patients were grouped according to primary tumor origin (lung, breast, or other primaries). Survival was compared between these three primary tumor groups and according to age. Group differences in continuous variables were assessed using ANOVA/Kruskal-Wallis testing, and survival distributions were analyzed with Kaplan-Meier curves. Patients were categorized into younger (<59.6 years) and older (≥59.6 years) groups for Kaplan-Meier survival analysis. Univariate and multivariate Cox regression models were performed to identify independent predictors of overall survival.

Median overall survival was 71.6 weeks. Statistically significantly longer survival was found in patients <59.6 years (median 88.3 weeks; estimated 3-year survival 33.2%) compared with those ≥59.6 years (median 41.9 weeks; 3-year survival 16.8%; p = 0.037. Primary tumor group analysis showed a median survival of 94.4 weeks for breast cancer (estimated 3-year survival 38.3%), 52.7 weeks for lung cancer (9,5%), and 40.6 weeks for other primaries (19.7%). However, this difference was not statistically significant (p = 0.269). In multivariate Cox regression analysis, age ≥ 59.6 years (HR 2.10; p = 0.016) and >1 extraocular metastases elsewhere in the body (HR 2.53; p = 0.029) were independent predictors of mortality.

Survival in choroidal metastases is strongly driven by age and the number of extraocular metastatic sites at presentation. Our findings suggest that younger age and a lower metastatic burden are most reliable indicators for a more favorable prognosis.

IntroductionPostoperative recurrence remains a major clinical challenge in invasive breast cancer (IBC), and conventional clinicopathologic factors and routine imaging assessment may not fully capture intratumoral spatial heterogeneity or nonlinear recurrence patterns. This study aimed to evaluate the prognostic value of a magnetic resonance imaging (MRI)-derived intratumoral heterogeneity (ITH) score incorporated into time-to-event machine learning models for predicting postoperative recurrence in patients with IBC.MethodsThis retrospective dual-center prognostic prediction-model study included 428 consecutive patients with IBC from two centers. Patients were randomly assigned to a training cohort (n = 256), validation cohort (n = 86), and independent testing cohort (n = 86). ITH scores were calculated from texture features and pixel intensity distributions on contrast-enhanced T1-weighted MRI using k-means-based intratumoral subregion quantification. Multiple time-to-event machine learning (ML) models were developed to predict recurrence-free survival (RFS), and model performance was assessed using Harrell's concordance index (C-index), time-dependent receiver operating characteristic curves, calibration curves, and SHapley Additive exPlanations (SHAP).ResultsAmong the evaluated models, the random survival forest (RSF) achieved the best predictive performance, yielding a C-index of 0.826 (95% confidence interval [CI], 0.735-0.894) in the validation cohort and 0.814 (95% CI, 0.722-0.905) in the testing cohort. SHAP identified the ITH score as the most critical predictor. Higher ITH scores were significantly associated with shorter RFS and upregulation of tumor proliferation-related pathways.ConclusionsIntegrating an MRI-derived ITH score with an RSF model provides a noninvasive and interpretable framework for recurrence prediction in IBC. This approach may support individualized risk stratification, postoperative surveillance planning, and tailored adjuvant management while requiring further prospective validation before routine clinical implementation.