To describe the properties of a newly approved oral glucagon-like peptide-1 receptor agonist for the treatment of obesity.

A literature search of MEDLINE and SCOPUS was performed without date range exclusions using the search terms orforglipron and obesity. Additional articles were identified from review of clinical trial bibliographies and product monograph.

Two phase 1 studies in healthy individuals and in patients with type 2 diabetes mellitus and 4 phase 2/3 clinical trials specifically evaluating orforglipron use for obesity were identified for analysis, using no date exclusion criteria.

Orforglipron was evaluated in 4 phase 2/3 trials regarding its efficacy for weight loss. These trials showed a mean 7.1% to 10.6% placebo-adjusted weight reduction with orforglipron. Adverse events seen with its use were primarily gastrointestinal.Relevance to Patient Care and Clinical Practice in Comparison With Existing Drugs:Orforglipron provides an oral weight management option that is potentially more effective than liraglutide, similarly effective compared with semaglutide, and less effective than tirzepatide. As a non-injectable option that does not require strict oral administration parameters, orforglipron has advantages in certain patient populations.

Orforglipron is a potentially useful addition for the treatment of obesity, but it still requires additional data on efficacy in treatment of obesity-related comorbidities for full comparison.

Diabetic ulcers (DUs) are severe and prevalent complications of type 2 diabetes, characterized by impaired macrophage efferocytosis and sustained chronic inflammation within the wound microenvironment. Pachymic acid (PA) is a natural triterpenoid with potent anti-inflammatory and immunomodulatory properties. This research is aimed at exploring whether PA facilitates healing of DUs by activating the MEK/ERK/TGFβ1 signaling axis to restore macrophage efferocytosis.

In vitro, cell viability was evaluated using CCK-8 assay. An inflammatory macrophage model was established via LPS/IFN-γ induction to assess the impact of PA on reactive oxygen species (ROS) and proinflammatory mediator levels. Macrophages were cocultured with apoptotic cells to evaluate efferocytosis. Transcriptome sequencing, bioinformatics analyses, and RT-qPCR validation were conducted on PA-treated macrophages to explore the core regulatory networks, whereas western blot was utilized to verify the underlying proefferocytotic mechanisms. In vivo, a diabetic wound (DW) mouse model was established and treated with PA. Western blot, immunofluorescence, and histological staining were performed to evaluate macrophage polarization, the activation of the MEK/ERK/TGFβ1 pathway, angiogenesis, and the expression levels of efferocytosis-related proteins.

In vitro experiments demonstrated that PA exhibited minimal cytotoxicity, significantly reduced ROS levels, and suppressed the secretion of proinflammatory mediators in macrophages while enhancing their ability to engulf apoptotic cells. Transcriptomic profiling, RT-qPCR validation, and protein-protein interaction network analyses revealed that PA's regulatory targets were enriched in efferocytosis and the MEK/ERK pathway. In the DW mouse model, PA treatment alleviated inflammatory cell infiltration, promoted collagen deposition and angiogenesis, improved the SPOT skin wound score, and accelerated wound closure. Both in vitro and in vivo analyses confirmed that PA upregulated the expression of P-MEK1/2, P-ERK1/2, and TGFβ1, and key efferocytosis receptors, which drove the phenotypic transition of wound macrophages from a proinflammatory state to an anti-inflammatory and restorative state.

PA upregulated the expression of vital efferocytosis receptors by activating the MEK/ERK/TGFβ1 signaling axis, enhancing macrophage efferocytosis, and alleviating local oxidative stress. This study elucidated the mechanism of PA in treating DUs, providing a theoretical foundation for its clinical translation as a novel drug to promote DW healing.

Asthma exacerbations (AE) impose a significant burden on children and the healthcare systems, highlighting the need for objective biomarkers and functional assessment tools.

This study aimed to evaluate serum endocan levels and respiratory function parameters during AE and the post-recovery (PR) period, and to compare the results with healthy controls.

In this prospective longitudinal observational study, children aged 6-18 years were evaluated during AE (n = 66), 1 month after recovery (PR group, n = 54), and as age- and gender-matched healthy controls (HC, n = 50). All participants underwent spirometry, impulse oscillometry (IOS), and serum endocan measurement.

Serum endocan levels were significantly higher in the AE group than in the PR and HC groups [267.33 (186.68-370.20) vs. 133.07 (38.26-226.78) and 118.11 (42.93-180.20) pg/mL, respectively; P < 0.001]. Spirometric indices, including zFEV1, zFVC, zFEV1/FVC, and zFEF25-75, were significantly lower in the AE group than in both comparison groups (all P < 0.05). Compared to healthy controls, children in the AE group exhibited higher R5-20, Fres, and AX values and lower zX20 values (all P ≤ 0.002). R5-20 remained significantly higher during AE than in the PR period (P = 0.038), while spirometric indices showed significant improvement after recovery (all P < 0.05). Notably, despite normalization of spirometric parameters and serum endocan levels, the PR group continued to exhibit higher R5-20 and AX values and lower zX20 values than healthy controls (all P < 0.05), suggesting persistent small-airway dysfunctioning. Serum endocan levels showed weak-to-moderate negative correlations with zFEF25-75, zFEV1, and zFEV1/FVC (Spearman's rho = -0.306, -0.291, and -0.223, respectively; all P ≤ 0.013).

These findings suggest that serum endocan is associated with airway dysfunctioning and may reflect disease activity during pediatric AE, while IOS may provide additional information regarding persistent small-airway involvement after recovery.

Although immunotherapy combined with platinum-based chemotherapy is now the standard first-line treatment for extensive-stage small cell lung cancer (ES-SCLC), the benefit of continuing immune checkpoint inhibitors (ICIs) after disease progression (PD) remains uncertain. This real-world study assessed the efficacy and safety of second-line immunotherapy in ES-SCLC patients using propensity score matching (PSM).

ES-SCLC patients who received second-line treatments following first-line chemoimmunotherapy at Zhejiang Cancer Hospital from January 2019 to December 2023 were included. Clinical baseline characteristics were collected and balanced. The efficacy and safety of patients who continued to receive second-line immunotherapy were compared with those who did not.

A total of 187 patients were analyzed. The median overall survival (OS) and progression-free survival (PFS) for the entire cohort were 8.5 months (95% CI: 7.1-9.9) and 3.3 months (95% CI: 2.5-4.1), respectively. After PSM, each group included 76 patients. No significant differences in OS (median OS: 8.3 vs. 7.8 months; HR, 0.97; 95% CI: 0.68-1.39; p = 0.87) or PFS (median PFS: 3.45 vs. 3.1 months; HR, 1.07; 95% CI: 0.77-1.49; p = 0.69) were observed between the rechallenge and non-rechallenge groups. Subgroup analysis suggested in an exploratory manner that immunotherapy rechallenge was associated with poorer outcomes in non-smokers (mOS: 8 vs. 16.6 months; HR, 2.9; 95% CI: 1.1-7.9; p = 0.004). The rate of all-grade immune-related adverse events (irAEs) was higher in the rechallenge group (36.8% vs. 17.1%).

Rechallenge with immunotherapy after first-line chemoimmunotherapy may not demonstrate a significant survival benefit in ES-SCLC patients, particularly among never smokers, and may lead to more frequent irAEs.

For locally advanced oesophageal carcinoma, multimodal therapy is the standard of care, but prognosis remains poor. Obesity has risen markedly in the last decades. The impact of obesity on response to neoadjuvant treatment remains unclear. This study evaluates the association between body mass index (BMI) and histopathological tumour regression following neoadjuvant therapy in oesophageal cancer.

We performed an analysis using the prospective database from the DGAV|registry oesophageal surgery provided by the German Society for General and Visceral Surgery (Deutsche Gesellschaft für Allgemein- und Viszeralchirurgie, DGAV). The primary outcome was histopathological tumour regression grade by the Becker classification. The primary explanatory variable was BMI. Descriptive statistics were followed by uni- and multivariate regression analyses adjusted for tumour histology, neoadjuvant regimen, age, sex, ECOG status, comorbidities, dysphagia and weight loss. Associations were evaluated using a multivariate regression (partial proportional odds) model.

Six hundred and forty-seven patients were included, comprising 432 adenocarcinomas (including AEG I/II) and 215 squamous cell carcinomas (SCC). After adjustment for clinical and tumour-related covariates, higher BMI was independently associated with a favourable histopathological response: No association was observed for the transition to Becker grade ≥ 1b; however, higher BMI was associated with reduced odds of Becker grade ≥ 2 (OR 0.97, 95% CI 0.94-1.00, p = 0.04) and Becker grade ≥ 3 (OR 0.93, 95% CI 0.90-0.96, p < 0.001). In addition, SCC, absence of dysphagia, radiochemotherapy and low ECOG score were independently associated with favourable regression, whereas no independent associations were observed for age, sex, diabetes status, comorbidities or pretherapeutic weight loss.

Analysis of the German DGAV|registry revealed that higher BMI was significantly associated with improved histopathological tumour regression following multimodal therapy for oesophageal cancer. These findings suggest potential differences in tumour biology among patients with elevated BMI, underscoring the need for further mechanistic investigation.

Cancer stem cells (CSCs) are increasingly recognized as metabolically plastic subpopulations within malignant tissues that drive tumor initiation, metastatic dissemination, and relapse after therapy. Although traditional models of cancer metabolism have emphasized aerobic glycolysis, CSCs rarely exhibit a single, clearly defined bioenergetic phenotype. Rather, they dynamically remodel glucose utilization, oxidative phosphorylation, redox regulation, de novo fatty acid synthesis, lipid uptake, lipid sequestration, and fatty acid oxidation in response to hypoxic conditions, nutrient restriction, stromal interactions, and therapeutic perturbations. This review focuses on two interconnected aspects of metabolic flexibility: lipid flux and mitochondrial plasticity. We examine how de novo lipogenesis, CD36-mediated fatty acid uptake, fatty acid-binding protein trafficking, cholesterol biosynthesis, and lipid-droplet turnover contribute to stemness, membrane remodeling, metastatic potential, and resistance to cytotoxic agents. We also examine how mitochondrial dynamics, including fusion, fission, mitophagy, and biogenesis, together with reactive oxygen species buffering and shifts in oxidative phosphorylation, facilitate CSC survival during chemotherapy, radiotherapy, targeted therapy, and immune-mediated cytotoxicity. Particular emphasis is placed on the integration of fatty acid oxidation to respiratory metabolism, on the epigenetic consequences associated with the acetyl-CoA availability, and the metabolic crosstalk linking CSCs to adipocytes, fibroblasts, mesenchymal cells, and immune cell populations in the tumor microenvironment. Finally, we evaluate therapeutic strategies involving inhibitors of fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), stearoyl-CoA desaturase-1 (SCD1), carnitine palmitoyltransferase-1 (CPT1), and OXPHOS. We also discuss combination therapies, nanotechnology-based drug delivery, and emerging artificial intelligence (AI)-guided approaches. Taken together, current evidence identifies the lipid-mitochondrial axis as a critical systems-level driver of therapeutic resistance and a promising target for improving long-term cancer control.

This study aimed to evaluate whether a standardized oral care protocol is associated with reduced oral mucositis (OM) severity among leukemia patients receiving induction chemotherapy. Baseline characteristics were comparable between groups. Severe OM occurred in 17/90 (18.9%) in the protocol group versus 30/90 (33.3%) with usual care (odds ratio 0.46; P = .027); the association remained significant after adjustment (adjusted odds ratio 0.50; P = .044). OM duration was shorter with the protocol (median 6 vs 8 days; P = .003), with faster time to resolution (14 vs 16 days; P = .04). The protocol group reported lower maximum pain (median 3 vs 5; P < .001), less opioid use (44.4% vs 60.0%; P = .036), lower morphine milligram equivalents (60 vs 120 mg; P = .006), and reduced parenteral nutrition use (13.3% vs 24.4%; P = .049). Febrile neutropenia, blood culture positivity, intensive care unit transfer, and length of stay did not differ significantly. A standardized oral care protocol was associated with reduced severe OM and meaningful improvements in OM duration and symptom burden during leukemia induction chemotherapy. Prospective studies are warranted to confirm effectiveness and implementation fidelity. We conducted a single-center retrospective cohort study including adult leukemia inpatients receiving induction chemotherapy. Patients were grouped by exposure to a standardized oral care protocol with per-shift documentation versus usual care (90 vs 90). OM was graded each shift using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0 from induction day 1 to hospital discharge. The primary outcome was peak OM severity; severe OM was defined as CTCAE grade ≥ 3. Secondary outcomes included OM incidence (CTCAE ≥ 1), time to onset, duration, time to resolution, maximum oral pain score (0-10 Numeric Rating Scale), opioid use and cumulative morphine milligram equivalents, parenteral nutrition use, febrile neutropenia (temperature > 38.3°C with neutropenia), blood culture positivity, intensive care unit transfer, and length of stay. Group comparisons used Pearson χ2/Fisher exact tests and appropriate parametric/nonparametric tests. Multivariable logistic regression assessed the association between protocol exposure and severe OM.

This retrospective comparative study evaluated the effect of tranexamic acid (TXA) on perioperative transfusion requirements and clinically documented thromboembolic events in patients undergoing proximal femoral tumor resection and megaprosthetic reconstruction for metastatic bone disease. A total of 32 patients who underwent proximal femoral tumor resection and megaprosthetic reconstruction between 2019 and 2026 were included. The patients were divided according to perioperative TXA administration (TXA group, n = 15; control group, n = 17). TXA was administered intravenously at 10 to 15 mg/kg prior to skin incision. Primary outcomes included transfusion requirements and the number of transfused erythrocyte units. The secondary outcomes included perioperative hemoglobin change, length of hospital stay, postoperative complications, and mortality. Perioperative blood transfusion was required in 60.0% and 82.4% of the patients in the TXA and control groups, respectively (P = .243). The transfusion requirement was numerically lower in the TXA group, corresponding to an absolute difference of 22.4 percentage points (relative risk, 0.73). The mean number of transfused units was similar between groups (1.27 ± 1.22 vs 1.35 ± 0.99, P = .829). Hospital stay was numerically shorter in the TXA group (9.53 ± 4.73 vs 13.94 ± 10.52 days, P = .202). No clinically documented symptomatic thromboembolic events were observed in either group of patients. In this small retrospective cohort, TXA use was associated with a numerically lower perioperative transfusion requirement, although the difference was not statistically significant. These findings should be considered exploratory and hypothesis-generating and require confirmation in larger, adequately powered prospective studies.

The aim of this study was to assess the prognostic value of tumor mutational burden (TMB) as a biomarker for metastatic colorectal cancer (mCRC) in patients receiving immunotherapy-containing regimens. This retrospective cohort study analyzed 221 patients with mCRC. From January 1, 2020 to December 31, 2021, patients diagnosed with unresectable mCRC at the time of initial diagnosis were screened and stratified into 2 groups according to baseline TMB status: a TMB-H group (high tumor mutational burden, n = 113) and a TMB-L group (low tumor mutational burden, n = 108). All patients received anti-PD-1/PD-L1 immunotherapy combined with standard chemotherapy. Data on patient characteristics, tumor molecular features, survival outcomes, adverse events, and posttreatment quality of life were collected and compared between groups. Patients in the TMB-H group demonstrated significantly improved progression-free survival (PFS) and overall survival (OS) compared to the TMB-L group (P < .001). The TMB-H group also demonstrated higher scores across all functional domains of the EORTC QLQ-C30 questionnaire. TMB-H status was positively associated with progression-free survival, overall survival, and quality of life, while adverse event rates were comparable between groups (P = .989). High TMB status is associated with improved survival outcomes and better quality of life in mCRC patients receiving immunotherapy, without an increase in adverse events. These findings support the prognostic value of TMB in this population and warrant prospective validation.

While some retrospective studies have reported that certain dietary habits may affect rectal cancer, the types of dietary habits involved are limited. We employed a classical 2-sample Mendelian randomization approach to investigate the causal relationship between dietary habits and rectal cancer. Rigorous instrumental variable selection included P-value filtering, linkage disequilibrium assessment, and sensitivity analyses utilizing methods like Steiger filtering and Mendelian Randomization Pleiotropy RESidual Sum and Outlier to ensure robust inference. Utilizing Mendelian randomization, we assessed the influence of dietary habits on rectal cancer using data from 706 single nucleotide polymorphisms derived from the UK Biobank. Our analysis, incorporating rigorous instrumental variable (IV) selection and sensitivity checks, revealed significant associations for 5 dietary habits with rectal cancer. Notably, herbal tea intake (raw P = .007; odds ratio = 0.998; 95% confidence interval (CI) 0.997-0.999), average weekly beer plus cider intake (raw P = .038; OR = 0.867; 95% CI: 0.757-0.992), pancake intake (raw P = .040; OR = 0.753; 95% CI: 0.574-0.987), and salad/raw vegetable intake (raw P = .049; OR = 0.809; 95% CI: 0.6554-0.9995) were found to have a protective effect against rectal cancer. Conversely, we found the average weekly spirits intake (raw P = .041; OR = 1.261; 95% CI: 1.010-1.575) to be a potential risk factor for rectal cancer. Our findings suggest that several genetically proxied dietary traits may be associated with rectal cancer risk. These findings should be interpreted cautiously and require validation in independent and ethnically diverse populations before informing dietary recommendations.