Search Results (2,740)

Triple-negative breast cancer (TNBC), characterized by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, is a highly aggressive molecular subtype with high recurrence and metastasis rates. Due to the absence of reliable molecular targets, surgery combined with chemotherapy remains the mainstay of clinical treatment. In recent years, immunotherapy has provided new strategies for TNBC management. Immune checkpoints are key regulatory molecules that maintain immune homeostasis, and blocking these checkpoints can restore T cell activity and enhance tumor cell killing. Immune checkpoint inhibitors (ICIs) have demonstrated clinical benefit, particularly in combination with chemotherapy for patients with locally advanced or metastatic TNBC. This review focuses on immune checkpoint–based immunotherapy in TNBC, providing an overview from mechanistic insights to clinical applications and emerging therapeutic strategies. In addition to ICIs, we discuss alternative approaches, such as bispecific antibodies, antibody–drug conjugates (ADCs), chimeric antigen receptor T cell (CAR-T) therapy, tumor vaccines, and oncolytic viruses (OVs), highlighting their current research progress and clinical applications in TNBC treatment. Full article

This study aimed to identify environmental and hormonal determinants of steroid receptor expression in the bone tissue of men with osteoarthritis. Twenty-six men undergoing total hip arthroplasty were included. Serum hormones, bone turnover markers, and elemental concentrations were assessed, and bone samples were analyzed using immunohistochemistry and multivariate regression models. Results: Estrogen receptor alpha (ERα) expression was a significant positive predictor of the bone formation marker procollagen type I N-terminal propeptide (PINP) (p = 0.0386), indicating its key role in anabolic processes. Androgen receptor (AR) expression showed a positive trend with the resorption marker CTX-I (p = 0.0956). A strong negative association was observed between Body Mass Index (BMI) and ERα expression (β = −0.50; p = 0.0018), suggesting reduced estrogen sensitivity in individuals with higher adiposity. Local accumulation of metals significantly influenced receptor expression. Lead in bone was strongly associated with increased AR expression (β = +1.457; p = 0.0009), whereas manganese was positively associated with ERα expression (β = +2.112; p = 0.0409). These findings indicate that local bone tissue analysis provides more accurate insight into hormonal regulation than serum measurements and highlight the role of environmental factors in modulating bone metabolism in men. Full article

Endocrine therapy is an effective and common treatment strategy for estrogen receptor (ER)-positive breast cancers. However, the development of endocrine resistance, through genetic mutations and epigenetic alterations, in about 40% of treated patients remains a significant therapeutic challenge. Liver X receptors (LXRs) are nuclear receptors that regulate lipid metabolism and cholesterol homeostasis and have been implicated in metabolic reprogramming in breast cancers and other malignancies. We previously identified a novel LXR ligand GAC0001E5 (1E5), with potent antiproliferative activity across breast cancer subtypes. Here, we investigate its mechanisms of action in responsive (MCF-7) and endocrine-resistant (MCF-7-TamR) ER-positive breast cancer cells. Treatment with 1E5 resulted in the downregulation of LXR and its target genes, and significantly reduced ERα expression and the expression of ER-responsive genes. Aberrant expression of androgen receptor (AR) and human epidermal growth factor receptor 2 (HER2), both implicated in endocrine resistance, were downregulated following 1E5 treatment. siRNA-mediated knockdown of LXR expression only partially recapitulated the actions of 1E5, suggesting the involvement of LXR-dependent and independent mechanisms. Collectively, these findings reveal potential crosstalk between LXR and the genetic and epigenetic regulation of pathways involved in endocrine response and alternative signaling mechanisms, highlighting potential targets in endocrine-resistant breast cancer. Full article

Background/Objectives: Obesity and menopause are major determinants of skeletal deterioration; however, their combined effects on bone remodeling and associated cellular bioenergetics remain incompletely understood. This study aimed to determine whether obesity induces osteoporotic alterations under both estrogen-replete and estrogen-deficient conditions and to evaluate the therapeutic potential of dental tissue-derived mesenchymal stem cells (D-MSCs). Methods: Female mice were subjected to ovariectomy (OVX) and/or high-fat diet (HFD) feeding for 16 weeks to establish obesity-associated osteoporosis models. D-MSCs were administered intraperitoneally at defined intervals. Body weight and serum leptin levels were measured to assess metabolic status. Femoral tissues were analyzed by quantitative real-time PCR for estrogen receptors (ERα, ERβ), inflammatory markers (Il-1β, Tnf-α), mitochondrial regulators (Pgc1α, Pgc1β), and the OPG/RANKL ratio. Histological analysis was performed to evaluate bone marrow adiposity. Results: HFD significantly increased body weight and serum leptin levels in both intact and OVX mice. Obesity was associated with reduced expression of ERα and ERβ, decreased Pgc1α levels, and a lower OPG/RANKL ratio, accompanied by increased Il-1β, Tnf-α, and Pgc1β expression. D-MSC administration attenuated body weight gain and reduced leptin levels, particularly in OVX mice. In femoral tissue, D-MSC treatment restored estrogen receptor expression, increased Pgc1α, decreased Pgc1β, and normalized the OPG/RANKL ratio. In addition, inflammatory marker expression and bone marrow adiposity were reduced following MSC administration. Conclusions: Obesity induces bone remodeling dysregulation under both intact and estrogen-deficient conditions, characterized by altered estrogen signaling, inflammatory activation, and mitochondrial imbalance. D-MSC administration was associated with partial restoration of these alterations, suggesting a potential role in modulating metabolic and skeletal homeostasis in obesity-associated bone loss. Full article

Background: Therapeutic resistance following cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) represents a key unmet need in hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer (mBC). Treatment paradigms have advanced from non-targeted options, such as fulvestrant monotherapy or everolimus-based combinations, to precision medicine strategies, including inhibitors of the PI3K/AKT pathway, oral selective estrogen receptor degraders (SERDs), and novel ER-modulating agents, often guided by biomarkers and molecular surveillance. Methods: This narrative review synthesizes evidence from randomized clinical trials, real-world studies, and biomarker-driven analyses published from 2010 to 2026, with emphasis on next-generation sequencing (NGS)-guided genomic profiling, targeted pathway therapies, and circulating tumor DNA (ctDNA)-based proactive interventions in the post-CDK4/6i setting. This review was conducted and reported in accordance with the SANRA recommendations for narrative reviews. Results: Early second-line standards, including fulvestrant and alpelisib for PIK3CA-mutated tumors, established the basis for biomarker-guided treatment in hormone receptor–positive, HER2-negative metastatic breast cancer. With the widespread use of CDK4/6 inhibitors in the first-line setting, the optimal post-progression strategy has shifted toward molecularly selected combination approaches rather than single-agent endocrine therapy, as endocrine monotherapy has shown limited efficacy in acquired resistance. Multiple randomized studies have demonstrated that adding targeted agents to endocrine therapy improves progression-free survival compared with hormonal therapy alone, supporting combination regimens as the preferred strategy after CDK4/6 inhibitor progression, except in carefully selected patients with low disease burden, indolent biology, or frailty where tolerability is a major concern. Precision-based trials have further refined this approach. Elacestrant improved progression-free survival in ESR1-mutated disease in the EMERALD trial, capivasertib plus fulvestrant demonstrated significant benefit in tumors harboring AKT/PIK3CA/PTEN pathway alterations in CAPItello-291, and inavolisib plus palbociclib and fulvestrant achieved both progression-free and overall survival improvement in PIK3CA-mutated patients with early relapse in INAVO120. Real-world analyses further support the effectiveness of these biomarker-directed strategies across diverse clinical subgroups. Comprehensive genomic profiling has identified multiple resistance mechanisms, including ESR1 mutations, PI3K/AKT/mTOR pathway activation, RB1 loss, and FGFR alterations, which may co-occur and reduce sensitivity to endocrine monotherapy. While ESR1 and PI3K pathway alterations now guide approved therapies, FGFR alterations remain investigational targets, with ongoing trials evaluating selective FGFR inhibitors. Proactive switching approaches evaluated in SERENA-6 and PADA-1 demonstrate that serial circulating tumor DNA (ctDNA) monitoring can detect emergent ESR1 mutations before radiographic progression, providing a clinically actionable lead time for early therapeutic modification and extending endocrine-based disease control by approximately 5 to 7 months. Conclusions: Post-CDK4/6i management increasingly relies on NGS-guided precision approaches, integrating pathway-specific therapies and ctDNA surveillance to tailor sequencing based on resistance profiles, prior ET response, and tumor heterogeneity. Future investigations into novel ER degraders and multi-targeted combinations hold potential to further optimize algorithms, extend non-chemotherapy options, and enhance survival in HR+/HER2− mBC. Full article

Ovarian granulosa cells (GCs) ensure proper follicular development and oocyte maturation through gap-junction-mediated intercellular communication. Zearalenone (ZEA), a mycotoxin with estrogen-like activity, specifically targets and impairs ovarian function. Most existing studies have focused on ZEA-induced apoptosis in GCs, but whether ZEA disrupts gap junctions in ovarian GCs remains unclear. Therefore, the aim of this study was to investigate whether and how ZEA induces gap junction injury in ovine ovarian GCs, with a particular focus on the roles of G protein-coupled receptor 30 (GPR30), oxidative stress, and the NLRP3 inflammasome. In the present study, primary ovine ovarian GCs were isolated, cultured, and treated with different concentrations of ZEA to establish a gap junction injury model, and specific inhibitors/antagonists were used to investigate the underlying mechanisms. The results showed that ZEA decreased granulosa cell viability and significantly inhibited the expression of the gap junction proteins Connexin 43 (Cx43) and Connexin 37 (Cx37) in a concentration-dependent manner. ZEA treatment also significantly upregulated the expression of the NOD-like receptor familypyrindomain containing 3 (NLRP3) inflammasome-related proteins (NLRP3, ASC, Cleaved Caspase-1, and the downstream pro-inflammatory cytokine IL-1β) in a concentration-dependent manner. Pretreatment with the NLRP3-specific inhibitor MCC950 significantly reversed ZEA-induced downregulation of Cx43 and Cx37 and effectively blocked NLRP3 inflammasome activation, indicating that NLRP3 is a key target in ZEA-induced gap junction injury. Further experiments confirmed that ZEA treatment significantly increased oxidative stress levels in granulosa cells; pretreatment with the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) restored the ZEA-induced downregulation of Cx43 and Cx37 and suppressed NLRP3 inflammasome activation, suggesting that ROS acts as an upstream regulator of NLRP3 inflammasome activation. Moreover, ZEA treatment altered GPR30 expression levels, and pretreatment with the GPR30 antagonist G15 effectively inhibited ZEA-induced ROS production, NLRP3 inflammasome activation, and downregulation of Cx43/Cx37, indicating that ZEA exerts its effects through functional activation of GPR30. Collectively, ZEA activates the GPR30 receptor, induces ROS accumulation in granulosa cells, and subsequently triggers NLRP3 inflammasome activation, ultimately leading to downregulation of Cx43 and Cx37 and gap junction dysfunction. This study reveals a previously unrecognized molecular mechanism by which ZEA induces gap junction injury in ovarian GCs, providing potential therapeutic targets and a theoretical basis for preventing ZEA-induced ovarian dysfunction and improving animal reproductive health. Full article

Allergic rhinitis (AR) is one of the most prevalent allergic disorders worldwide. Current pharmacological treatments are often limited by suboptimal efficacy and notable adverse effects. Herbal medicines, with their multi-component and multi-target therapeutic characteristics, have attracted increasing attention. Artemisia ordosica Krasch. (AOK), a traditional Chinese/Mongolian medicine has demonstrated immunomodulatory, antioxidant, and anti-inflammatory activities. The anti-AR potential of AOK extract fractions was evaluated using in vitro mast cell degranulation inhibition assays, network pharmacology analysis, molecular docking, and molecular dynamics simulations to elucidate underlying pharmacological mechanisms. The P815 mast cell model induced by compound 48/80 was employed to assess the inhibitory activity and cytotoxicity of different extract fractions. Among the tested fractions, the ethyl acetate fraction exhibited the most potent inhibitory effect on mast cell degranulation without significant cytotoxicity. Network pharmacology analysis identified 254 potential AR-related targets of AOK, with Signal Transducer and Activator of Transcription 3(STAT3), Src protein(SRC), Tumor protein 53(TP53), AKT Serine/Threonine Kinase 1(AKT1), Heat Shock Protein 90 Alpha Family Class A Member 1(HSP90AA1), Estrogen Receptor 1(ESR1), and Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha(PIK3CA) identified as key hub proteins. Gene Ontology and KEGG pathway enrichment analyses indicated that AOK primarily modulated inflammatory and oxidative stress-related processes through the lipid and atherosclerosis, hypoxia-inducible factor-1, and AGE-RAGE signaling pathways. Molecular docking and dynamics simulations demonstrated strong binding affinities and stable interactions between major active constituents, particularly hydroxygenkwanin, and key targets such as SRC. The ethyl acetate fraction of AOK extract exhibited significant mast cell degranulation inhibitory activity, likely mediated via a synergistic multi-component, multi-target mechanism involving regulation of inflammatory and immune-related signaling pathways. These findings provide a pharmacological basis for the potential application of AOK in AR treatment. Full article

Colorectal cancer (CRC) is the third most diagnosed malignancy and the second leading cause of cancer-related mortality worldwide. A consistent and epidemiologically well-documented feature of CRC is its sexual dimorphism: age-standardized incidence rates are 33–45% higher in men than in women, and mortality rates differ by 43–50%. Beyond epidemiology, biological sex influences tumor location, molecular subtype, and clinical outcome. Women more frequently develop right-sided, microsatellite-unstable tumors driven by the CpG island methylator phenotype pathway, whereas men predominantly present with left-sided, chromosomally unstable tumors harboring APC, KRAS, and TP53 mutations. Sex steroid hormones play a central modulatory role: estrogens, primarily via estrogen receptor β (ERβ), exert tumor-suppressive effects on colonic epithelium, whereas androgens promote pro-inflammatory and pro-tumorigenic signaling through androgen receptor (AR)-dependent pathways. The gut microbiome displays sex-specific compositional profiles (‘microgenderome’) and contributes to sex-specific CRC susceptibility through bidirectional interactions with sex hormones, shaping distinct immunological and metabolic microenvironments. Finally, sex influences the pharmacokinetics of fluoropyrimidines, the toxicity of targeted agents, and the response to immune checkpoint inhibitors. This review summarizes current evidence on sex-related differences in CRC epidemiology, molecular pathology, hormonal regulation, gut microbiota composition, and treatment outcomes, highlighting the need to systematically incorporate sex as a biological variable in CRC research and clinical practice. Full article

Breast cancer is one of the leading causes of cancer incidence and mortality in many countries worldwide although there is considerable geographic variation. Diet is thought to impact risk of developing breast cancer but identifying specific dietary factors involved in the etiology of this disease has proven difficult. The two primary factors that initially led to an interest in soy are the historically low breast cancer incidence and mortality rates in Japan and the uniquely high concentration of isoflavones in soybeans and foods derived from this legume. Isoflavones bind to both estrogen receptors although preferentially to estrogen receptor-β. Prospective cohort studies indicate that isoflavone intake is associated with a reduced risk of developing breast cancer, but randomized controlled trials in which the impact of soy and isoflavones on markers of breast cancer risk has been evaluated are not supportive of this protective association. It may be that for isoflavones to reduce risk, intake needs to occur during childhood and/or adolescence. The notion that consuming soy early in life reduces risk of adult breast cancer, herein referred to as the “early soy intake hypothesis” (ESIH), was proposed >30 years ago. The results of rodent studies and retrospective observational studies that examined incidence and/or markers of breast cancer risk support the ESIH. However, a lack of randomized controlled trials precludes a clear recommendation for soy consumption during childhood and/or adolescence specifically for breast cancer prevention. Although soy foods provide high-quality protein and a variety of nutrients and can be part of a healthy diet for young and adolescent girls, more research is needed to advance the ESIH. Full article

Background/Objectives. Breast cancer is the most frequently diagnosed cancer worldwide, with approximately 15% classified as Triple-Negative Breast Cancer (TNBC). TNBC is characterized by the absence of estrogen receptor (ER) and progesterone receptor (PR), and the lack of HER2 overexpression, limiting use of targeted therapies. Current TNBC treatment relies heavily on chemotherapy, most commonly taxanes including paclitaxel that stabilize microtubules, disrupt chromosome separation and induce apoptosis. TNBCs frequently develop chemoresistance after multiple treatment cycles, highlighting a critical unmet need for novel therapeutic strategies. This study addresses this challenge by targeting salt-inducible kinase 2 (SIK2), which is overexpressed in 85% of TNBCs compared to normal breast tissue. Methodes. In collaboration with Arrien Pharmaceuticals and Greenfire Biologics, we developed ARN-3261/GRN-300, a novel orally bioavailable SIK2 inhibitor and evaluated its ability to sensitize TNBC cells to paclitaxel in vitro and in vivo. Results. GRN-300 demonstrated strong synergy with paclitaxel in all eight TNBC cell lines tested, as indicated by favorable combination indices. In xenograft models, the combination therapy significantly enhanced tumor growth inhibition and prolonged survival compared to either agent alone. Mechanistic studies showed that GRN-300 disrupts the anaphase-promoting complex/cyclosome (APC/C) pathway by downregulating key mitotic regulators, including CDC27, CDK1, and PLK1, thereby potentiating G2/M cell cycle arrest and apoptosis. Conclusions. Together, these findings establish GRN-300 as a promising therapeutic agent that enhances paclitaxel efficacy through complementary disruption of mitotic regulatory pathways, providing strong preclinical rationale for clinical development in TNBC. Full article

Endometriosis (EMs) is an estrogen-dependent inflammatory disease characterized by the presence of endometrial-like tissue outside the uterine cavity, yet its precise pathogenesis remains incompletely elucidated. TICAM1, a key adaptor protein in the Toll-like receptor (TLR) signaling pathway, is known to be involved in inflammatory responses; however, its specific role in EMs has not been defined. This study integrated evidence from clinical tissue samples of patients with ovarian endometriomas, in vitro studies, and in vivo models to explore the role of TICAM1 in EMs. TICAM1 expression was significantly upregulated in both eutopic and ectopic endometrium, with the highest levels observed in ectopic lesions, where it was primarily localized to stromal and glandular epithelial cells. Functional experiments showed that TICAM1 overexpression promoted the proliferation, migration, and invasion of human endometrial stromal cells (hESCs), while TICAM1 knockdown suppressed these activities. Concurrently, TLR3 and TLR4 were also upregulated in EMs tissues, and their activation increased TICAM1 expression. Knockdown of TICAM1 attenuated the enhanced cellular activities induced by TLR3/TLR4 activation. Mechanistically, IRF3 and IFN-β levels were elevated in both EMs tissues and TICAM1-overexpressing hESCs, while TICAM1 knockdown inhibited TLR3/TLR4-induced IRF3 phosphorylation and subsequent IFN-β production. These findings were further corroborated in a mouse model of EMs. Together, our findings suggest that TICAM1 may enhance the proliferation, migration, and invasion of hESCs by mediating TLR3/TLR4 signaling and promoting IRF3 phosphorylation and subsequent IFN-β production, thereby potentially contributing to EMs progression. Therefore, targeting TICAM1 may represent a potential therapeutic direction for ovarian endometrioma-associated EMs, while its relevance to superficial peritoneal and deep infiltrating EMs requires further investigation. Full article

Arctigenin (Arc), a novel anti-inflammatory lignan derived primarily from Arctium lappa, has demonstrated promising anticancer activity in multiple cancer types. This study was designed to evaluate the anticancer efficacy of Arc across distinct molecular subtypes of breast cancer in vitro and in vivo and to gain mechanistic insights into its mode of action. In vitro evaluation was conducted in estrogen-receptor-positive MCF-7, human epidermal growth factor receptor 2 (HER2)-positive SKBR3, and triple-negative MDA-MB-231 breast cancer cell lines. In vivo efficacy and safety were evaluated using female severe combined immunodeficient (SCID) mice (5–7 weeks old) bearing MCF-7 or MDA-MB-231 xenografts. Mice received daily oral gavage of Arc at 50 mg/kg body weight for 8 weeks. In vitro, Arc inhibited cell proliferation across all three breast cancer subtypes in a dose-dependent manner. PCR-array analysis of gene expression revealed that Arc targets multiple signaling molecules involved in cell proliferation, cell cycle regulation, apoptosis, migration/invasion, and drug transport, demonstrating a subtype-specific target profile. Arc induced cell-cycle arrest at the G2/M phase in MCF-7 cells and at G0/G1 in MDA-MB-231 cells, accompanied by significant induction of apoptosis in both cell lines. Migration assays further demonstrated marked inhibition of wound closure in Arc-treated cells. In vivo, Arc treatment significantly inhibited tumor growth in both xenograft models, decreased Ki67 expression, and produced no overt toxicity. In summary, Arc exhibits potent anticancer activity against distinct breast cancer subtypes through multi-targeting mechanisms. Given the heterogeneity of breast cancer, Arc appears to be a promising candidate for further preclinical investigation. Full article

Metastatic triple-negative breast cancer (mTNBC) remains one of the most challenging therapeutic settings in oncology. Although it has traditionally been defined by the absence of hormone receptor expression—estrogen receptor (ER) and progesterone receptor (PR)—and HER2 amplification or overexpression, this simplified definition fails to capture the biological complexity that drives its marked clinical heterogeneity, therapeutic resistance, and prognostic variability. Over the past decade, multiple studies have challenged the notion of TNBC as a single disease entity, identifying distinct molecular subtypes, including Basal-like 1 (BL1), Basal-like 2 (BL2), Mesenchymal (M), Mesenchymal Stem-like (MSL), Immunomodulatory (IM), and Luminal Androgen Receptor (LAR), each characterized by specific biological programs and therapeutic vulnerabilities. In parallel, clinically oriented systems such as the Fudan classification have enabled the prospective evaluation of subtype-guided therapeutic strategies in metastatic disease, as illustrated by the FUTURE and FUTURE-SUPER trials. In this review, we examine the molecular classification and clinical behavior of mTNBC subtypes, integrating genomic, transcriptomic, epigenetic, immunologic, stromal, and biomechanical dimensions of tumor heterogeneity. We also discuss emerging tools, including single-cell RNA sequencing, spatial transcriptomics, circulating tumor DNA analysis, long non-coding RNA profiling, and surrogate immunohistochemistry-based classifiers, as well as their potential role in refining patient stratification. From a therapeutic perspective, we review subtype-guided strategies involving chemotherapy, platinum agents, PARP inhibitors, immunotherapy, antiandrogen therapy, PI3K/AKT/mTOR pathway inhibition, antiangiogenic approaches, and antibody–drug conjugates. Redefining mTNBC through biologically driven stratification represents a rational strategy to optimize treatment selection, support clinical trial design, and accelerate the development of precision oncology approaches. However, clinical implementation requires greater methodological standardization, validated predictive biomarkers, accessible diagnostic platforms, and dynamic monitoring strategies capable of capturing subtype evolution under therapeutic pressure. TNBC should therefore not be regarded as a single disease, but as a spectrum of biologically distinct and clinically evolving entities whose integrated characterization may be essential to improving outcomes in this historically poor-prognosis population. Full article

Background/Objectives: The optimal surgical margin width after breast-conserving surgery (BCS) for pure ductal carcinoma in situ (DCIS) remains controversial; although current guidelines consider a surgical margin of ≥2 mm sufficient, the clinical safety of narrower margins is unclear. This study aimed to evaluate the association between surgical margin width and ipsilateral breast tumor recurrence (IBTR), with a focus on the 1 mm threshold. Materials and Methods: In this retrospective single-center cohort study, 107 patients with pure DCIS treated with BCS followed by adjuvant radiotherapy (RT) between 1 January 2009 and 1 January 2025 were analyzed. Final surgical margins were categorized as <1 mm, 1–2 mm, and ≥2 mm. The primary endpoint was IBTR. Kaplan–Meier analysis was performed. Results: The median age of the study population was 52 years (IQR: 46–61). High-grade DCIS was present in 48 patients (44.9%), comedo necrosis in 68 (63.6%), and estrogen receptor positivity in 87 (81.3%). Overall, 10 patients (9.3%) underwent re-excision for margin widening. Final surgical margin widths were <1 mm in 36 patients (34%), 1–2 mm in 18 (17%), and ≥2 mm in 53 (49%). IBTR occurred in seven patients (6.5%) during a median follow-up of 48 months (range, 12–217 months), with a median time to recurrence of 33 months. Kaplan–Meier analysis showed no significant difference in recurrence-free survival according to a 2 mm margin threshold, whereas margins < 1 mm were associated with significantly worse outcomes (p = 0.002). Conclusions: Margins < 1 mm were associated with increased IBTR risk, whereas margins < 2 mm did not appear to confer uniform risk. These findings suggest that margin widths between 1 and 2 mm may represent a heterogeneous group, and clinical decision-making in this range should be individualized. However, further studies are needed to validate these outcomes. Full article

Background: Temporomandibular disorders (TMDs) exhibit a marked female predominance, suggesting a potential role for estrogen in their pathophysiology. However, evidence linking estrogen status to TMD remains inconsistent. Objective: To systematically review the association between estrogen-related factors and TMD prevalence and clinical presentation in women. Methods: PubMed, Embase, Scopus, Web of Science, and Google Scholar were searched through September 2025. Observational studies evaluating hormonal contraceptive use, menopausal status, menstrual cycle variation, pregnancy, or estrogen receptor polymorphisms in women with TMD were included. Two reviewers independently performed study selection, data extraction, and risk-of-bias assessment using the Newcastle-Ottawa Scale. Due to substantial heterogeneity, a narrative synthesis was conducted. Results: Seven studies met the inclusion criteria, including six clinical studies involving 2735 participants and one mechanistic supportive study. Moderate-certainty evidence suggested associations between hormonal contraceptive use, menopausal/climacteric status, and increased TMD risk or symptom severity. Additional low-certainty evidence supported associations involving menstrual cycle variation, pregnancy, and estrogen receptor polymorphisms. Conclusions: Current evidence suggests that hormonal factors may influence TMD risk and symptom presentation in women. However, heterogeneity in definitions of hormonal exposure and diagnostic criteria limits definitive conclusions. Further prospective studies using standardized diagnostic protocols and real-time biochemically validated hormonal assessments correlated with clinical symptoms are needed. Full article