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PubMed2026

Genomic Profiling of Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer after Progression on First-line Osimertinib: Phase II ORCHARD Study.

PURPOSE: Osimertinib is the standard of care for first-line treatment for epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC). Understanding the tumor molecular profile of patients following progression on osimertinib could help inform optimal second-line treatment. PATIENTS AND METHODS: ORCHARD (NCT03944772), a phase II biomarker-directed study, enrolled patients with EGFRm NSCLC who progressed on first-line osimertinib to receive treatment based on their tumor molecular profile after progression. The study comprised three groups into which patients were allocated based on the molecular profile of their tumor, determined via next-generation sequencing (NGS) of a tumor biopsy. We report results from a prespecified, exploratory analysis of baseline tumor tissue and plasma samples to evaluate mechanisms of resistance to first-line osimertinib identified by tissue and plasma NGS. Agreement between tissue and plasma NGS data was also assessed. RESULTS: This study provided a comprehensive dataset exploring tissue (n = 400) and plasma (n = 191) genomics, enabling characterization of the histogenomic landscape after first-line osimertinib treatment. TP53 and MDM2/4 alterations were mutually exclusive and occurred in 86% of tumors. When combining tissue and plasma genomics, resistance alterations were detected in 87% of samples, with multiple resistance alterations in 46%. Alterations in the PI3K pathway, SOX2, and MYC were frequently detected in histologically transformed tumors. Additionally, differential patterns of co-occurring EGFR mutations in tumors with L858R versus exon 19 deletion were observed. CONCLUSIONS: This comprehensive analysis highlights potential heterogeneous resistance to first-line osimertinib treatment, providing a rationale for combining treatments with broad activity to improve patient outcomes. See related commentary by Gupta et al., p. 3718.

Humans↗

PubMed2026

Metabolic Dysfunction-Associated Steatotic Liver Disease Is Associated With Adverse Social Factors: An Analysis Using All of Us.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is progressive, with estimated global prevalence exceeding 30%. Social determinants of health (SDOH) may impact MASLD risk and progression. However, this has not been fully characterized. We harnessed the power of the All of Us Research Program (AoU) dataset to conduct a comprehensive analysis examining the association between various SDOH and MASLD. METHODS: We conducted a retrospective cross-sectional analysis of the AoU database. We identified participants with MASLD using ICD-9 and -10 codes and excluded individuals with other chronic liver diseases or self-reported heavy alcohol use. Healthy control participants were devoid of chronic liver diseases, heavy alcohol use, and comorbidities associated with MASLD if obese. We examined SDOH by combining relevant questions from various AoU surveys and conducted univariate and multivariate logistic regression to examine the association between various SDOH and MASLD. RESULTS: After matching cases to controls by age and race/ethnicity, the sample of 57,895 participants had a 1:3 case to control ratio; 16,666 had complete SDOH survey data (MASLD to controls, 1:3.4). Compared to controls, individuals with MASLD were more likely to have less than a high school education (10.7% vs 9.7%; P < .001) and annual income ≤$35,000 (42.4% vs 34.3%; P < .001). Compared to controls, participants with MASLD had significantly higher levels of social isolation, neighborhood disorder, perceived stress, food insecurity, and transportation insecurity (P < .001 for all). CONCLUSION: The study identified significant associations between MASLD and multiple SDOH. Future studies should investigate how SDOH interact to drive MASLD risk and progression.

All of Us↗

PubMed1989

[Investigation on calcifications in the breast].

This article reported the result of analysis of 96 cases with heaps of calcifications in the breast all verified by operation. The calcifications, according to the appearances on X-ray film were classified into 4 patterns: club-shaped, fine sandy, fragmented stonelike and coalescent. A comprehensive analysis was made in regard to spatial distribution and amount of calcification and the presence of a mass. The results indicated that club-shaped calcification is highly suggestive of malignancy regardless of the amount of calcification and the presence or absence of a mass. Simple fine sandy calcification in the absence of a mass can not differentiate benign from malignancy because of wide range of overlapping, whereas simple fragmented stone and coalescent types, according to the authors opinion denote benign.

Adenofibroma↗

PubMed1990

[A clinical evaluation of lymphography in bladder tumor].

A study was conducted in a total of 51 patients with urinary bladder tumor who had received surgical operation associated with removal of regional lymph nodes after lymphography. Abnormal findings were observed in lymphogram of 22 patients. The other 29 patients showed no such abnormality. After the operation pathological metastasis was confirmed in 7 patients. Lymphograms of these patients ith positive lymphatic metastasis revealed filling defects in 85.7% and collaterals in 57.4%. There as correlation between the occurrences of these two findings based on quantification analysis III of multivariate analysis. Lymphography before operation showed 87.5% of sensitivity, 65.1% of specificity and accuracy of 68.6%, not having higher accuracy compared to other studies. These results suggest that lymphography, which may have clinical significance, is not a decisive method in exploration of bladder tumor. Comprehensive analysis of diagnostic imaging should be performed, including CT after lymphography.

Female↗

PubMed2026

Phenotypes of Hereditary Diseases Associated With Rauch-Steindl Syndrome.

PURPOSE: Prenatal phenotypic manifestations of genetic disorders associated with NSD2 variants remain poorly characterized. This study presents our institutional experience with the prenatal diagnosis of NSD2-associated genetic disorders, specifically Rauch-Steindl syndrome (RAUST), aiming to improve understanding of both the molecular and clinical features of RAUST. METHODS: We performed a retrospective analysis of six fetuses and one adult diagnosed with RAUST at our institution and thoroughly reviewed the prenatal ultrasound reports of six fetuses. Prenatal and postnatal phenotypes of RAUST cases were summarized alongside findings from previously published literature. Correlations between NSD2 variant locations, variant types, and phenotypes were analyzed. Additionally, protein modeling was used to visualize structural changes in NSD2 protein before and after C-terminal variants. We integrated single-cell transcriptomic and gene expression data from multiple public databases to investigate spatiotemporal expression patterns of NSD2 during human fetal development. RESULTS: Fetal growth restriction (FGR) was the most prevalent prenatal manifestation in RAUST fetuses, followed by microcephaly. Bilateral renal hypoplasia emerged as a novel prenatal ultrasonographic feature. Postnatally, speech and motor developmental delays were the most commonly reported phenotypes, followed by physical developmental delays and intellectual disability. Genotype-phenotype correlation analysis revealed an association between N-terminal truncating variants in NSD2 and impaired fetal growth parameters. Notably, C-terminal truncating variants-predicted not to directly impact NSD2 functional domains-also exerted disease-causing effects. CONCLUSION: This study provides a comprehensive analysis of prenatal phenotypes in RAUST cases, enriching the prenatal phenotypic spectrum of the disease and facilitating early diagnosis and clinical management of RAUST. Furthermore, our genotype-phenotype correlation findings lay a foundational basis for future research into the complex molecular mechanisms underlying NSD2-associated genetic disorders.

Humans↗

PubMed1990

Radiological assessment of hemifacial microsomia by three-dimensional computed tomography.

Hemifacial microsomia (HFM) is the commonest asymmetrical craniofacial deformity leading to underdevelopment of the craniofacial skeleton and soft tissues on the affected side. Timing of reconstructive surgery is based on a comprehensive analysis and classification of the deformity. Lateral cephalometric radiographs are of limited value because of superimposition of normal and abnormal bony structures. The skeletal and soft-tissue findings of six patients with HFM who underwent three-dimensional (3D) CT are presented. This method allows a comprehensive assessment of the deformity at a low radiation dose, 22% of that of a conventional CT scan, by the use of a low dose technique.

Adolescent↗

PubMed2026

Identifying potential drug targets for physical and cognitive frailty: an integrative analysis of CHARLS cohort, mendelian randomization, and gene colocalization.

With the aging of the population, frailty has become a common syndrome that severely affects the quality of life of older adults. This study aims to analyze the correlation between cognition and frailty, physical activity and frailty, and elucidate the potential pharmacological targets of cognitive frailty and physical frailty.We conducted logistic regression analyses using data from the China Health and Retirement Longitudinal Study (CHARLS) to examine the associations between total cognition and frailty, physical activity and frailty. Furthermore, summary-data-based Mendelian randomization (SMR) and two-sample Mendelian randomization (TSMR) were employed to explore potential pharmacological targets for frailty. Genes associated with physical frailty and cognitive frailty were identified, followed by analysis via colocalization analysis, phenome-wide association studies (PheWAS), and DsigDB drug prediction. Cross-sectional analysis of CHARLs revealed that total cognition(OR 0.93, 95% CI 0.92-0.95) and middle physical activity(OR 0.95, 95% CI 0.92-0.97) were negatively correlated with frailty. SMR identified 41 drug genes associated with frailty, and subsequent TSMR validation and co-localization analysis showed that 11 candidate genes exhibited strong colocalization (PP.H4 > 0.8). GRPEL 1, PABPC 4, and WBP 2NL were ultimately identified as potential drug targets associated with physical frailty, while LANCL1, LRPPRC, FADS1, and WBP2NL were identified as potential drug targets associated with cognitive frailty. Phenome-wide association analysis(PheWAS) did not reveal any significant associations between these genes and other phenotypes at the genome-wide significance threshold. Laudanosine, 25-hydroxycholesterol, and hexadecanal emerged as the top three candidate compounds for therapeutic intervention. We identified potential drug targets for physical frailty and cognitive frailty through comprehensive analysis and elucidated drugs associated with potentially relevant genetic markers, thereby laying the foundation for a deeper understanding of the mechanisms of frailty.

Humans↗

PubMed2026

Coral color morphs exhibit distinct microbial and proteomic profiles linked to stress and immune mechanisms in a changing ocean.

BACKGROUND: Coral phenotypic plasticity facilitates acclimation and adaptation to environmental variability. Coral species often display a variety of color morphs, yet key biological and ecological implications of such phenotypic variation remain underexplored. Here, we present the first proteomic and untargeted lipidomic and metabolomic survey to explore the biological characteristics and potential ecological significance of different color morphs (pink and brown) of healthy Pocillopora verrucosa sampled along a latitudinal gradient. RESULTS: Our multi-omic approach elucidated distinct mechanisms associated with these dominant color morphs. We discovered bacterial indicators specific to each morph: putative pathogens such as Salmonella, Escherichia-Shigella, and carotenoid-producing Gemmatimonas were notably associated with the pink morph, whereas the brown morph was associated with potentially beneficial bacteria, such as Lysobacter, Acinetobacter, and Endozoicomonas. Despite these microbiome differences, the lipidome and metabolome of P. verrucosa were surprisingly homogeneous across colors and locations, suggesting similar metabolic performances during summer conditions. Key polar and apolar lipid classes, such as fatty acids, glycerophosphocholines, and retinoids, were prevalent. Notably, our proteomic analysis revealed morph-specific expressions, with pink morphs exhibiting enhanced levels of GFP-like proteins, Ankyrin, and the enzyme pullulanase, suggesting novel putative protective roles. In contrast, the brown morphs showed a higher abundance of heat shock proteins, indicating putative differential stress response capabilities. CONCLUSION: This comprehensive study provides the first proteomic survey of P. verrucosa and identifies key physiological pathways and trade-offs linked to color morphs, which can further contribute to enhancing our understanding of coral resilience in the face of climate change. SIGNIFICANCE STATEMENT: Understanding the phenotypic plasticity of corals is crucial for uncovering mechanisms of resilience in warming oceans, yet the biological significance of coral color morphs still needs to be explored. Using an innovative multi-omic approach (proteomics, lipidomics, and metabolomics), we provide the first comprehensive analysis of differences between pink and brown morphs of Pocillopora verrucosa. Our data reveal key taxa, potentially pathogenic or beneficial, associated with each morph, and suggest different strategies for each color morph to cope with heat stress, either expressing proteins involved in UV protection and heterotrophic activity or enhanced levels of heat stress resilience and DNA repair. These findings offer insights into the phenotypic plasticity of coral color morphs and their differential responses to climate change. Video Abstract.

Anthozoa↗

PubMed1979

Detection of drugs using XAD-2 resin. I:Choice of resin, chromatographic conditions, and recovery studies.

Amberlite XAD-2, a nonionic polystyrene divinylbenzene resin, was first used for the analysis of drugs in urine and a number of reports have described the development at optimal conditions for extraction, including type of resin columns, pH conditions, and eluting solvents. XAD-4 and XAD-7 resins were compared to the similarly structured XAD-2 resin and no significant advantage over the XAD-2 resin for drug screening was observed. A quantity of 5 to 6 g of resin was found to have sufficient capacity for the extraction of 200 ml of pentobarbital solution (1 mg/100ml). A column flow rate of approximately 15 ml/min (gravitational flow) was sufficient for analysis and slower rates were not more efficient. A mixture of ethyl acetate and 1,2-dichloroethane (3:2) was found to give best overall recovery (66 to 94%) of drugs, the resulting extracts being reasonably free of interfering substances. A pH value of 8.5 is recommended as optimum for comprehensive analysis of acidic and basic drugs. Recovery studies were conducted on spiked samples to determine drug losses occuring during various steps in the XAD-2 extraction procedure for four acidic (amobarbital, secobarbital, pentobarbital, and phenobarbital) and four basic (morphine, codeine, meperidine, and methadone) drugs. A relatively small amount (0 to 5%) of the drugs was not adsorbed by the resin and amounts varying from 6 to 40% failed to be desorbed by the eluting solvent. Additional losses occurred during the removal and analysis of TLC spots. Recovery of drugs from aqueous solutions analyzed with the XAD-2 resin were compared to recoveries reported in the literature with other XAD-2 resin methods for the extraction of drugs from urine. Recovery of phenobarbital, morphine, and codeine improved by 4 to 23% while recoveries of amobarbital, pentobarbital, secobarbital, methadone, and meperidine were 4 to 28% less efficient when compared to literature data.

Barbiturates↗

PubMed2026

narrowPASEF: A Sample-Aware diaPASEF Method Optimization Strategy Improving Differential Proteomics Performance on Low-Abundance Proteins.

Recent instrumental and computational innovations in mass-spectrometry-based proteomics offer new promise in biomarker discovery, thanks to unprecedented proteome coverage and depth. Data-independent acquisition (DIA) methods are very promising in this context as they allow improved proteome coverage, reduced missing value rates, and enhanced quantification precision. However, DIA methods also suffer from their own challenges, such as increased data complexity, cycle times, and background noise. In this work, we propose a sample-aware diaPASEF method optimization strategy for a timsTOF platform. Thorough method optimizations have first been conducted on standard HeLa lysates. Then, a ground-truth calibrated sample series, consisting of a range of UPS amounts spiked into a complex Arabidopsis background, was used to mimic differential analyses under controlled conditions. These benchmark experiments demonstrate clear benefits of using narrowPASEF for differential protein discovery. Finally, our strategy was applied to real use case biological samples to conduct a differential analysis of purified mouse astrocyte cells across two different conditions. narrowPASEF improved the proteome depth by 13%, considering proteins quantified with a coefficient of variation (CV) of <20%, and led to a 68% (435 vs 729) increase in differentially expressed proteins. These results provide an opportunity for a more precise and comprehensive analysis of the biological functions of biomarkers, offering a more profound understanding of the disease mechanisms. The benefits of our sample-aware narrowPASEF strategy demonstrated the most substantial impact on low-abundance proteins. Overall, these results show promise for more valuable and robust biomarker discoveries in the future.

Proteomics↗

PubMed1992

Classification of nonspecific low back pain. II. Clinical diversity of organic forms.

A classification study was conducted in an unselected sample of outpatient subjects with localized nonspecific low back pain. The heterogeneity of a subgroup of patients without a psychiatric disorder according to the DSM-III classification (axis I), and whose low back pain may be labeled as 'purely organic' (see part 1 of the study in the companion paper), led to further evaluation of this group by correspondence and cluster analysis. A seven-cluster population structure emerged from the cluster analysis. Comprehensive description of these clusters suggests at least four well-differentiated clinical entities or 'syndromes.' Although no satisfactory correlation with pre-existing 'pathoanatomic' classification or hypotheses was found, this variable clinical presentation suggests different etiological or physiopathologic patterns for low back pain (and possibly more specific management of this condition). More comprehensive descriptions and evaluations of clinical symptoms and syndromes appear necessary in order to elaborate a clinical classification of LBP.

Acute Disease↗

PubMed2025

Genome-Wide Identification, Phylogenetic Analysis, and Expression Pattern of Polyamine Biosynthesis Gene Family in Pepper.

Polyamines (PAs), including putrescine, spermidine, spermine, and thermospermine, play essential roles in plant growth, development, and responses to stress. However, the structure and function of PA biosynthetic genes in pepper remain poorly characterized. This study aimed to identify PA biosynthesis genes in the pepper genome using bioinformatics approaches and to assess their expression under various stress conditions. A total of 16 PA biosynthesis-related genes were identified, representing members of the arginine decarboxylase (ADC), ornithine decarboxylase (ODC), agmatine iminohydrolase (AIH), N-carbamoylputrescine amidohydrolase (CPA), S-adenosylmethionine decarboxylase (SAMDC), spermidine synthase (SPDS), spermine synthase (SPMS), and ACAULIS5 (ACL5) gene families. These genes encode proteins with an average molecular weight of approximately 40 kDa, primarily localized in the mitochondria and cytoplasm. Promoter analysis revealed multiple cis-acting elements associated with stress and phytohormone responsiveness. Gene expression was induced by various abiotic stresses, including saline-alkaline, drought, heat, cold, and hydrogen peroxide, as well as by phytohormones such as abscisic acid, ethylene, salicylic acid, auxin, and gibberellin. Overall, this study provides a comprehensive analysis of PA biosynthesis genes in pepper and highlights their potential roles in stress adaptation and hormone signalling, offering a foundation for further exploration of PA-mediated stress tolerance mechanisms.

Capsicum↗

PubMed1992

[The management procedure for patients with cholelithiasis and the results of rehabilitative treatment after cholecystectomy based on polyclinic observations].

Based on an analysis of the dynamic ultrasonic, biochemical and hormonal data on 550 patients operated on for cholelithiasis and comparison of preoperative and pathomorphological diagnoses, indications for surgical treatment of cholelithiasis patients in the stage of so-called "lithocarriership" were developed and a group at risk for cancer was identified as well. A comprehensive analysis of the clinical and instrumental data on 185 patients operated on for cholelithiasis, made in the long-term periods (from 1 to 3 years) after cholecystectomy indicates the efficacy of differentiated rehabilitation treatment, including elderly subjects and the necessity of early surgical treatment of cholelithiasis before there may develop irreversible alterations in the choledochus, liver and pancreas and in the gallbladder itself. Comparison of the dynamic ultrasonic data, liver and pancreas functions and factors such as sex, age, obesity and physical exercise makes it possible to predict the course of cholelithiasis to a certain degree of probability at the asymptomatic stage and to specify the policy of managing such patients under ambulatory conditions.

Absenteeism↗

PubMed2026

[Optical genome mapping analysis of a Chinese pedigree with a complex balanced translocation involving four chromosomes].

OBJECTIVE: To explore the genetic characteristics of a complex balanced translocation involving four non-homologous chromosomes in a Chinese pedigree using optical genomic mapping (OGM). METHODS: A woman with primary infertility and her family members who presented at the Prenatal Diagnosis Center of the Sixth Affiliated Hospital of Sun Yat-sen University in October 2021 were selected as study subjects. Comprehensive analysis and verification of chromosomal abnormalities were conducted through conventional G-band karyotyping analysis, single nucleotide polymorphism microarray (SNP array) and OGM. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: E2022210). RESULTS: G-band karyotyping analysis indicated that the proband, her father, and younger brother have all carried a complex translocation involving four chromosomes. SNP array analysis revealed a duplication of approximately 21.63 Mb in the 9p24.1-p21.1 region in the proband's younger brother, while no abnormality was detected in other family members. OGM confirmed that the complex balanced translocation has involved chromosomes 5, 8, 9, and 10. CONCLUSION: The proband has harbored a complex balanced translocation. OGM has demonstrated certain advantages in characterization of complex chromosomal structural abnormalities.

Humans↗

PubMed1992

Molecular genetic analysis of HLA-DR and HLA-DQ genes among anti-U1-70-kd autoantibody positive connective tissue disease patients.

OBJECTIVE: We have recently found that the presence of autoantibodies against the 70-kd polypeptide of U1 RNP (U1-70-kd) is associated with HLA-DR4 and DR2. To further characterize this association, we performed a molecular genetic analysis of HLA-DR and DQ genes among patients with autoantibodies against U1-70-kd. METHODS: The polymerase chain reaction (PCR), sequence-specific oligonucleotide hybridization, and solid-phase direct DNA sequencing of PCR-amplified DNA were utilized to analyze HLA-DRB1, DRB5, DQA1, and DQB1 genes. RESULTS: A comprehensive analysis of HLA-DRB1, DRB5, DQA1, and DQB1 from 27 patients and controls identified shared amino acids FDYFYQA (Phe, Asp, Tyr, Phe, Tyr, Gln, Ala) at positions 26, 28, 30-32, 70, and 73 of HLA-DRB1 on disease-associated haplotypes. CONCLUSION: A common cluster of shared amino acids, or a shared epitope, identified within HLA-DRB1 among anti-U1-70-kd autoantibody positive connective tissue disease patients may be important in regulating an autoimmune response to the U1-70-kd antigen.

Amino Acid Sequence↗

PubMed2025

A comparative genomic analysis of left- and right-sided colon cancer using real-world data from the AACR project GENIE BPC dataset.

Left- and Right-sided colon cancers (LCC and RCC) are increasingly recognized as distinct clinicopathological and molecular subtypes with divergent prognoses and therapeutic responses. Leveraging a large, multi-institutional cohort from the AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC) (n = 750; LCC: 363 vs. RCC: 387), we conducted a comprehensive analysis of mutational profiles, tumor mutation burden (TMB), and survival outcomes. Our findings revealed a markedly higher TMB in RCC compared to LCC (6.65 ± 11.3 vs. 3.17 ± 4.35; adjusted P = 3.12×10-32), suggesting greater genomic instability in RCC. After applying functional annotation filters (PolyPhen > 0.85, SIFT < 0.05), RCC tumors were significantly enriched for mutations in BRAF (23.1% vs. 6.7%), KMT2D (8.6% vs. 3.2%), and SMAD4 (13.1% vs. 7.3%), while TP53 mutations predominated in LCC (40.6% vs. 31.8%). Multivariate Cox regression analysis identified RCC as an independent predictor of poorer overall survival (OS) relative to LCC (HR: 1.30, 95% CI: 1.02-1.66, P = 0.033). Notably, KRAS mutations were associated with significantly worse OS in LCC (HR: 1.68, 95% CI: 1.06-2.70, P = 0.027), while BRAF mutations predicted adverse outcomes in RCC (HR: 1.58, 95% CI: 1.05-2.37, P = 0.028). These results underscore the prognostic value of tumor sidedness and specific genetic alterations in colon adenocarcinoma. Our study highlights the need for sidedness-specific molecular profiling to inform precision oncology strategies in colon cancer management.

BRAF↗

PubMedDate not supplied

[Perinatal mortality in Spain. The need of an epidemiologic approach].

Autonomovi Communities perinatal mortality evolution in Spain from 1975 to 1983 is studied aimed at the assessment of existing inequalities in our country concerning this important public health problem. Although a positive evolution has been reported in all of them, differences in their mortality figures have rosen, showing higher rates those communities ranking lower socioeconomic indicators. Epidemiological analysis is needed so as to planning health activities as well as to study social processes responsible for this problems. Embodiment of social services into existing medical services is proposed, especially in Communities where the "sociodemographic disadvantage" is an essential problem. An optimum action in public health throughout the perinatal period world require a comprehensive analysis of the health situation assessing the problems which produce a greater number of survivors with serious sequalae as a result of a lower mortality.

Humans↗

PubMed2026

Relationship between menopausal hormone therapy and incidence risk of breast cancer: systematic review and meta-analysis.

BACKGROUND: Menopausal hormone therapy (MHT) is widely prescribed for alleviating menopausal symptoms. Prior studies have mainly focused on individual hormone therapy formulations. This meta-analysis comprehensively synthesized evidence across various regimens to systematically evaluate the association between MHT and breast cancer risk. MATERIALS AND METHODS: We systematically searched CNKI, Wanfang, PubMed, and Web of Science from inception through August 2024. Eligible studies examining breast cancer risk following MHT were independently screened and assessed by two reviewers. The review and meta-analysis followed PRISMA guidelines. RESULTS: Thirty-four studies were included. The random-effects model showed a significant but heterogeneous overall association (OR = 1.15, 95% CI: 1.09-1.22; I² = 92.4%). Subgroup analysis identified hormone type, use status, and region as key determinants (P for interaction < 0.001). Stratification by hormone type resolved much of the heterogeneity, revealing risk confined to estrogen-progestin therapy (EPT; OR = 1.44, 95% CI: 1.26-1.64), while estrogen-only therapy (ET) showed no overall association (OR = 1.00, 95% CI: 0.91-1.10). Study type, region, and sample size were significant effect modifiers. For ET, randomized controlled trials demonstrated a protective effect (OR = 0.78, 95% CI: 0.70-0.87), contrasting with neutral findings from observational studies. CONCLUSIONS: MHT is associated with a modest but significant increase in breast cancer risk, primarily driven by EPT. This risk was not observed with ET in observational studies, though trials suggested a protective effect. Crucially, the association shows marked geographical heterogeneity, indicating risk is modified by regimen and regional factors.

Humans↗