Adjuvant CDK4/6 inhibitors in breast cancer: Interpreting trial design, evidence, and uncertainty.
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Dronedarone, a multichannel antiarrhythmic drug, was developed as a safer alternative to amiodarone for atrial fibrillation. Although initially considered to have a lower proarrhythmic risk, post-marketing data and clinical experience suggest otherwise. We describe the case of a 44-year-old male with paroxysmal atrial fibrillation and no structural heart disease who developed marked QTc prolongation while receiving dronedarone, despite being asymptomatic. This case highlights the potential for clinically silent but significant QTc prolongation during dronedarone therapy, underscoring the importance of careful ECG monitoring, even in low-risk patients. Mylabris, a traditional Chinese medicine (TCM), is derived from the dried forms of Mylabris phalerata Pallas or Mylabris cichorii Linnaeus. It was recorded in Shennong Bencaojing in Han Dynasty and used for the treatment of psoriasis, facial paralysis, amenorrhea, and carbuncle. As a key component in antitumor formulations, Mylabris contains numerous bioactive compounds, including organic acids, terpenoids, amino acids and their conjugates, metal complexes, cantharimide dimers and peptides and proteins. Traditionally, Mylabris has been employed in the treatment of malaria, suppurative infectious diseases, and lymph node tuberculosis. Pharmacological studies have demonstrated its antitumor, anti-inflammatory, leukocytosis-inducing, and immune function-enhancing activities, as well as its pest resistance and skin blistering effects. Clinical prescriptions containing Mylabris have been used in the treatment of cancer and skin diseases. However, strong penetration and rapid absorption in all tissues contribute to multi-organ toxicity on the liver, kidney, heart, nerves and reproduction and gastrointestinal systems. Therefore, traditional processing methods and targeted drug delivery systems have been designed for increasing efficacy and decreasing toxicity. Here, we provide a comprehensive overview of Mylabris in terms of entomology, active ingredients, traditional use, pharmacology, clinical application, pharmacokinetics, toxicity, and detoxification strategies to provide a rational application in the future. Mylabris ("''), derived from the dried bodies of the Chinese blister beetles Mylabris phalerata Pallas and Mylabris cichorii Linnaeus, which has the effect of breaking blood and chasing blood stasis (""), dispersing knots and eliminating symptoms (""), and attacking poison and eroding sores (""). This review provides the firstly comprehensive summary of mylabris, covering its biological characteristics, chemical composition, pharmacological, toxicology, pharmacokinetics, and clinical use. A systematic literature search was conducted in databases ("Web of Science", "PubMed", "Google Scholar", "CNKI", and "WanFang") using the following query ("Mylabris phalerata Pallas" OR "Mylabris cichorii Linnaeus" OR "Mylabris" OR "Banmao" OR "Cantharidin") AND ("Pharmacology" OR "Toxicity" OR "Pharmacokinetics" OR "Marketed drugs"), to identify literature published between 2000 and 2025, focus on referring to 2015-2025. Articles with methodological defects (e.g., sample size less than 5 per group, no standardized purity detection method used), incomplete data (e.g., no access to the original literature, lack of key data values), and ethical problems (no declaration of ethical approval) were excluded. Online websites were also used, including https://ydz.chp.org.cn/#/main (Chinese Pharmacopoeia), https://www.nmpa.gov.cn/datasearch/home-index.html#category=yp (National Medical Products Administration), to obtain information on mylabris- or cantharidin-marketed drugs. Chemical structures in SMILES format were retrieved from the PubChem, and two-dimensional chemical structures were generated using ChemDraw 22.0.0. The major components of mylabris include terpenoids, metallic elements, fatty acids, and peptides. Pharmacological research have demonstrated its anticancer, antithrombotic, and antiviral effects in preclinical study, as well as insecticidal and antifungal in agriculture. Cantharidin is considered to be the main active and toxic component, which can cause gastrointestinal, cardiovascular and respiratory toxicity if used improperly. Pharmacokinetic studies reveal that orally cantharidin predominantly accumulates in the liver and kidneys, exhibiting strong irritancy and low bioavailability. Given its therapeutic efficacy, researchers have also developed various mylabris and cantharidin-based drugs in clinical setting. Mylabris has been used in traditional Chinese medicine for millennia. Now, it treats various diseases and shows development potential. Future studies should focus on four key aspects: comprehensive characterization of active components, elucidation of pharmacological mechanisms, supplementation of pharmacokinetic data, and clarification of toxicological mechanisms. This paper reviews the research progress of mylabris, bridging traditional applications and modern investigations to advance contemporary research and evaluate its therapeutic potential for human diseases. This meta-analysis aimed to evaluate the efficacy of combining CDK4/6i with ET, compared with ET alone, in improving invasive disease-free survival (iDFS), distant recurrence-free survival (DRFS), and overall survival (OS) in early-stage hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2-) breast cancer. Given the inconclusive findings of previous meta-analyses, an updated synthesis of the latest phase III trial data was performed. A systematic review and meta-analysis were conducted following PRISMA guidelines. Randomized Controlled Trials (RCTs) comparing CDK4/6i plus ET versus ET alone were identified through PubMed, Scopus, and ClinicalTrials.gov. Hazard ratios and adverse events were analyzed using appropriate statistical models. Four RCTs (monarchE, NATALEE, PENELOPE-B, PALLAS) including 17,749 patients were analyzed. CDK4/6 inhibitors improved iDFS (HR 0.80; 95% CI: 0.67-0.96; p = 0.01), while a strong trend toward improved DRFS was observed (HR 0.79; 95% CI: 0.61-1.02; p = 0.07), suggesting a potential clinically relevant benefit that requires longer follow-up to confirm. The effect on OS (HR 0.95; 95% CI: 0.79-1.16; p = 0.63) remains inconclusive. Adverse events, including neutropenia and diarrhea, were more frequent with CDK4/6i. The addition of CDK4/6i to ET improves iDFS and shows a favorable trend in DRFS in early-stage HR+/HER2- breast cancer, highlighting the need for longer follow-up to clarify their long-term benefit. In a preliminary survey study, the authors measured intraocular pressure in the right and left eye of 63 (32 females and 31 bucks) 3-8 month old, clinically healthy European brown hares (Lepus europaeus, Pallas, 1778). The mean intraocular pressure was 25.35 millimeters of mercury (mmHg) (n = 63), 25.4 mmHg for bucks and 25.3 mmHg for females. The average standard deviation was 4.86. The difference in intraocular pressure (IOP) between rabbits aged 3-5 months and 6-8 months was not significant, nor was the difference between females and bucks. In the phase III PALLAS trial, the addition of 2 years of palbociclib to adjuvant endocrine therapy (ET) did not improve short-term invasive disease-free survival (iDFS) compared with ET alone in high-risk early-stage hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. In this article, we report 5-year efficacy outcomes, including updated iDFS and overall survival (OS). PALLAS is an international, open-label, randomized phase III trial evaluating the addition of 2 years of palbociclib to adjuvant ET in patients with stage II-III HR-positive/HER2-negative breast cancer. The primary endpoint was iDFS. The trial enrolled 5753 patients, with 2883 randomized to receive palbociclib plus ET and 2870 to receive ET alone. With a median follow-up of 59.8 months, the 5-year iDFS was 84.2% [