Search Results (443)

Background: The approach to adenocarcinoma in situ (AIS) is challenged by diagnostic complexity, limited high-quality evidence, and heterogeneous guidance. Methods: We conducted a narrative comparative review of global guidelines/recommendations (2012–2025; search updated 1 October 2025), extracting data across 38 topics related to AIS management and classifying indications into five categories of coverage/consensus. Results: Twenty documents from national or supranational bodies were included. A cross-guideline consensus emerged on eight core items (colposcopy for any glandular cytologic abnormality; role of HPV test; mandatory histologic confirmation; excisional treatment for histologic AIS; re-excision when margins are involved; criteria and type of hysterectomy; and expert/centralized management). Operational variability emerged in the excisional technique, pathways for discordant results, management during pregnancy, and follow-up protocols. Divergent guidance was most evident for indications to endocervical sampling, criteria for conservative management, and the need for hysterectomy after completed childbearing. Limited-coverage consensus involved the technique of initial histologic sampling, endometrial assessment, and pathways for cytology subtypes. Several areas remained unaddressed. Conclusions: While the essential management of AIS is well defined, uncertainty increases when treatment must be personalized. A core outcome set and rigorous multicenter studies are needed to reduce heterogeneity and enable truly evidence-based personalization. Full article

Objectives: This study aimed to characterize the expression patterns and interrelationship of key fibrosis-related markers—TGF-β1, SMAD2, SMAD3, and fibronectin—in human endometrial tissue, and to explore their potential diagnostic relevance in differentiating intrauterine adhesions (IUAs) from cesarean scar defects (isthmocele), with a particular focus on underlying fibrotic remodeling processes. Methods: Endometrial samples were obtained from women diagnosed with IUAs, isthmocele, or without uterine pathology. Total RNA was extracted from all specimens, and gene expression levels were quantified using real-time quantitative polymerase chain reaction (PCR). Statistical analyses included intergroup comparisons, parametric and non-parametric correlation analysis, multivariable linear and logistic regression models, and receiver operating characteristic (ROC) curve analysis to explore the discriminatory potential of the evaluated markers. Results: Significant positive correlations were observed across the study population between SMAD2 and SMAD3 (r = 0.892; p = 0.001), SMAD2 and TGF-β1 (r = 0.697; p = 0.001), and SMAD3 and TGF-β1 (r = 0.910; p = 0.001), indicating coordinated activation of profibrotic signaling pathways. ROC curve analysis showed high discriminatory performance for isthmocele across all evaluated markers, with area under the curve (AUC) values of 0.976 for SMAD3, 0.961 for TGF-β1, 0.913 for fibronectin, and 0.928 for SMAD2 (all p = 0.001). In contrast, although elevated expression levels of fibrotic markers were observed across different American Fertility Society (AFS) stages in IUAs, these differences did not reach statistical significance. Conclusions: This study provides molecular evidence distinguishing isthmocele from IUAs with respect to fibrosis-related signaling in human endometrial tissue. The markedly elevated and coordinated expression of TGF-β1, SMAD2, SMAD3, and fibronectin in isthmocele reflects activation of post-cesarean fibrotic remodeling pathways. However, given the limited sample size and the exploratory nature of the analyses, larger cohorts and future studies are required to validate these findings and to allow extrapolation of the results to the general population. At this stage, these biomarkers should therefore be regarded as indicators of underlying pathophysiological processes. Full article

The peri-implantation window is a tightly regulated temporal phase during which the human endometrium undergoes coordinated molecular remodeling to establish receptivity. MicroRNAs (miRNAs) contribute to implantation-related processes; however, whether dynamic endometrial regulatory signals are functionally reflected in circulation within a defined temporal framework remains unclear. We hypothesized that although individual miRNA identities differ between endometrial tissue and plasma, temporally regulated miRNAs in both compartments may exhibit overlap at the level of enriched biological pathways during the peri-implantation window. To test this hypothesis, we performed time-resolved small RNA sequencing on paired endometrial and plasma samples collected from 62 participants across progesterone exposure days P+3 to P+7 in hormonally controlled cycles. Temporal modeling identified 27 dynamic miRNAs in endometrial tissue and 17 in plasma (FDR < 0.05). Despite limited overlap at the individual miRNA level, functional enrichment analysis revealed recurrent overlap in apoptosis-, cell cycle-, aging-, inflammatory-, and metabolic-related pathways across compartments. Four miRNAs exhibited concordant directional temporal trends between tissue and plasma with moderate correlation coefficients. These findings suggest that dynamic miRNA-associated enrichment patterns during the peri-implantation window may exhibit pathway-level overlap despite divergence in specific molecular identities. This temporally aligned integrative framework provides a pathway-centric perspective for interpreting cross-compartment miRNA-associated temporal patterns and supports a hypothesis-generating systems-level view of human implantation biology. Full article

Infertility affects a substantial proportion of women of reproductive age and is frequently associated with impaired endometrial receptivity. Successful implantation depends on tightly regulated hormonal, immune, apoptotic, and stress-response pathways within the endometrium. This pilot study aimed to evaluate the expression and distribution of granulocyte colony-stimulating factor (G-CSF), bone morphogenetic proteins 2/4 (BMP-2/4), heat shock protein 70 (HSP-70), apoptosis, progesterone, estrogen, and pentraxin-3 (PTX-3) in the endometrium of infertile women across different menstrual cycle days. A descriptive cross-sectional analysis was performed on endometrial tissue samples obtained from six infertile women aged 21–49 years at various menstrual cycle days. Routine histology, immunohistochemistry, TUNEL assay, and chromogenic in situ hybridization were used to assess tissue morphology, protein expression, apoptotic activity, and PTX-3 gene expression. Quantitative evaluation was applied to immunohistochemical markers and apoptosis, while PTX-3 expression was assessed semi-quantitatively. G-CSF expression showed low-to-moderate levels with a relative mid-cycle increase. BMP-2/4 demonstrated the highest overall positivity across most cycle days, with marked inter-sample variability. HSP-70 exhibited pronounced cycle-dependent variability. Apoptotic activity increased toward mid-to-late cycle days. Progesterone and estrogen positivity was heterogeneous and limited to selected cycle days. PTX-3 gene expression was highest during mid-cycle days and decreased toward later phases. No clear association with patient age was observed. Conclusions: The findings indicate distinct and cycle-dependent patterns of immune, morphogenetic, apoptotic, hormonal, and inflammatory markers in the endometrium of infertile women. These results highlight the dynamic nature of endometrial regulation and suggest that altered temporal coordination of these pathways may contribute to impaired endometrial receptivity. Full article

Background: CDKN2A (p16^INK4a^) is integral to the regulation of the RB–E2F cell-cycle checkpoint and is widely acknowledged as a surrogate marker for high-risk human papillomavirus (HPV)-related cervical neoplasia. Nevertheless, its diagnostic and prognostic significance in uterine corpus endometrial carcinoma (UCEC), a predominantly HPV-independent malignancy, remains inadequately characterized. This study utilized an integrated multi-omics approach to examine CDKN2A dysregulation in cervical squamous cell carcinoma (CESC) and UCEC. Methods: Pan-cancer and tumor–normal differential expression analyses were performed using TIMER2.0 and GEPIA2 (TCGA/GTEx). Clinicopathological correlations were assessed with UALCAN. Protein expression patterns were analyzed using immunohistochemistry data from the Human Protein Atlas (HPA). Prognostic significance and immune-infiltration associations were evaluated using TCGA survival data and TIMER modules. Independent transcriptomic validation and diagnostic classification performance were assessed using GEO datasets GSE9750 (CESC) and GSE63678 (UCEC), including ROC-AUC analysis with cross-validation. Results: Integrated analyses revealed elevated CDKN2A expression in both CESC and UCEC across multiple transcriptomic cohorts, with pronounced tumor-specific protein expression on immunohistochemistry. TCGA-only tumor–normal RNA comparisons were non-significant, likely due to limited normal sample representation. In independent GEO cohorts, CDKN2A exhibited excellent tumor–normal discrimination in CESC (AUC = 0.982) and moderate discrimination in UCEC (AUC = 0.761). Survival analysis indicated tumor-specific patterns, with limited prognostic stratification in CESC and context-dependent associations in UCEC. Immune-infiltration analysis suggested tumor-type-specific interactions between CDKN2A expression and immune cell subsets. Conclusions: CDKN2A exhibits strong diagnostic performance in HPV-associated cervical cancer and moderate, cohort-dependent discriminatory ability in endometrial carcinoma. These findings reinforce its established diagnostic role in CESC and propose adjunctive utility in UCEC, underscoring the importance of tumor-contextual interpretation of CDKN2A expression in gynecologic malignancies. Full article

This study developed and validated a Self-competitive Fishing (SCF) primer qPCR system as a rapid, cost-effective alternative to next-generation sequencing (NGS) for detecting POLE exonuclease domain mutations (EDMs) in endometrial cancer. The system detects 11 pathogenic POLE EDMs using SuperSelective primers combined with wild-type-blocking oligonucleotides that prevent amplification of wild-type DNA, thereby enhancing mutant DNA detection. The validation process involved comparing specificity using genomic DNA from tumors with known POLE mutations identified by NGS. Sensitivity testing used POLE-mutated DNA diluted in wild-type DNA, while precision was confirmed by analyzing 86 endometrial cancer samples against NGS results. The SCF qPCR system demonstrated superior specificity compared to the original SuperSelective primer-based qPCR, achieving 1% mutation-detection sensitivity across various mutation points. Importantly, results from all endometrial cancer cases showed complete concordance with NGS analysis for the 11 pathogenic POLE-EDM points tested. This cost-effective and efficient SCF primer qPCR system provides an accessible method for routine molecular classification of endometrial cancer in clinical settings, offering a practical alternative to NGS for detecting pathogenic POLE mutations and supporting clinical decision-making. Full article

The human microbiota is increasingly recognized as a key component of women’s reproductive health. This narrative review examines the vaginal, endometrial, and gut microbiota and their roles in the pathogenesis of gynecologic and obstetric disorders, aiming to integrate current evidence into a clinically relevant framework. We review intrinsic (genetic, hormonal, and immunological) and extrinsic (environmental, lifestyle, and pharmacological) factors shaping microbial composition, with particular focus on dysbiosis and the role of the gut estrobolome within the microbiome in estrogen metabolism. The review synthesizes data on microbiota alterations associated with endometriosis, adenomyosis, uterine fibroids, endometrial polyps and hyperplasia, gynecologic malignancies, pelvic inflammatory disease, bacterial vaginosis, infertility, and adverse obstetric outcomes, including preterm birth and fetal growth restriction. Methodological approaches used to characterize the reproductive tract microbiota, such as vaginal swabs, endometrial sampling, and fecal analysis, are critically discussed, together with limitations related to low-biomass environments and contamination risk. Evidence regarding therapeutic modulation of the microbiota, including antibiotics, probiotics, hormonal therapies, and emerging microbiota-based interventions, is summarized, alongside the impact of gynecologic surgery on microbial translocation and long-term microbial balance. Overall, the available literature supports an association between microbiota alterations and multiple reproductive conditions, although causality remains incompletely established. Further standardized and longitudinal studies are needed to clarify mechanisms and guide microbiota-informed diagnostic and therapeutic strategies. Full article

Background/Objectives: Endometriosis is a prevalent gynecological illness associated with chronic pain, inflammation, and infertility, as ectopic endometrial lesions are formed. No fully effective treatment is available, and the pathogenesis of this disease is unclear. The survival of ectopic endometrial cells is facilitated by their low susceptibility to apoptosis, an immunosuppressive environment, and local angiogenesis. Chromogranin A (CgA), a glycoprotein prohormone, modulates various processes including angiogenesis and innate immunity, and its higher levels are detected in neuroendocrine tumors and inflammatory disorders. Since endometriosis may be considered an autoinflammatory disorder, this study aimed to evaluate serum and peritoneal fluid concentrations of CgA and its derivatives, catestatin and pancreastatin, and to correlate these levels with disease severity. Methods: The study was conducted on samples of serum and peritoneal fluid (PF) obtained from 65 women diagnosed with endometriosis and from 60 control individuals who underwent surgery for other reasons. The concentrations of CgA, catestatin, and pancreastatin were assessed in the collected samples by specific enzyme-linked immunosorbent assays. Results: CgA, catestatin, and pancreastatin concentrations were significantly higher in the sera and PF of endometriosis patients compared to controls. There was a correlation between their serum and PF levels, and all tested factors were correlated with each other in both serum and PF. Serum concentrations of CgA, catestatin, and pancreastatin were also associated with disease progression. Receiver operating characteristic (ROC) analysis further confirmed that endometriosis is associated with increased circulating CgA, catestatin, and pancreastatin levels, suggesting that they may be considered markers of endometriosis. Conclusions: The upregulation of CgA and its derivatives in endometriosis may indicate their role in the disease pathogenesis and implicate them as potential diagnostic markers and/or therapeutic targets. Full article

In the past, bacteria detected in the mare’s uterus were generally interpreted as a sign of endometritis, since the uterus was considered a sterile environment. This assumption has been challenged by the introduction of culture-independent molecular techniques, particularly 16S rRNA amplicon sequencing, which have demonstrated that healthy mares harbor an endometrial microbiota. The aim of this study was to characterize the endometrial microbiota of healthy mares and to determine whether microbial composition differs between estrus and diestrus. Endometrial samples were collected from eleven healthy Standardbred mares during estrus and diestrus and analyzed by sequencing the V1–V2 region of the bacterial 16S rRNA gene. A total of 24 bacterial phyla and 599 genera were identified. At the phylum level, Firmicutes, Proteobacteria, Bacteroidota, and Actinobacteriota accounted for most of the relative abundance, while the most abundant genera were Staphylococcus, Acinetobacter, Sphingomonas, Corynebacterium, Streptococcus, Clostridium, and Pseudomonas. Alpha diversity was significantly higher during estrus, likely due to hormonally mediated changes in cervical opening and local immunity. Beta diversity analyses showed substantial overlap between estrus and diestrus samples. The phase of the cycle had a weak effect on microbiota structure, while inter-individual differences between mares explained a larger proportion of the observed variation. These findings suggest that the uterine microbiota of healthy mares is largely stable across the estrous cycle, with phase-dependent and mare-specific fluctuations in microbial composition. Full article

The coatomer complex has been implicated in cancer progression; however, a comprehensive pan-cancer analysis is lacking. Therefore, it is essential to identify the critical roles and essentiality of coatomer genes across pan-cancer. We systematically profiled the genetic alterations, expression patterns, prognostic relevance, and functional dependencies of all coatomer subunits across multiple cancers using more than 10,000 tumor samples from The Cancer Genome Atlas, complemented by functional perturbation data from CRISPR (n = 1178) and RNAi (n = 707) screens in DepMap. Functional validation was also performed to identify the essentiality of selectively essential coatomer genes in hepatocellular carcinoma (HCC). Gene amplification, most notably of COPB2, was the most frequent alteration and was associated with poor survival in bladder and esophageal cancers. Mutations in COPA and SEC31A also demonstrated prognostic significance in endometrial carcinoma. Expression analyses revealed broad upregulation of coatomer genes across cancer types, with COPG1 and COPB1 emerging as strong risk-associated genes (HR > 2). Integrative functional dependency analyses identified COPG1 as selectively essential in multiple cancers, and its loss was associated with increased drug sensitivity. Functional validation in hepatocellular carcinoma revealed that COPG1 knockdown impaired malignant phenotypes and reduced tumorigenicity in vivo. Mechanistically, COPG1 depletion induced Golgi disruption and ER stress, increased ROS production, and suppressed PI3K–AKT signaling, thereby sensitizing cells to sorafenib and doxorubicin. Collectively, this pan-cancer analysis reveals the context-dependent roles of coatomer subunits and identifies COPG1 as a novel oncogenic driver and potential therapeutic target in HCC, mediating chemoresistance through redox modulation and PI3K–AKT pathway inhibition. Full article

Background and Objectives: Endometriosis is a chronic, estrogen-dependent inflammatory disease with multifactorial pathogenesis. Increasing evidence suggests that alterations in the gut and reproductive tract microbiota may contribute to disease development, progression, and associated symptoms through immune, hormonal, and metabolic mechanisms. This systematic review aimed to synthesize current human evidence on microbiota composition and function in women with endometriosis. Materials and Methods: A systematic literature search was conducted according to PRISMA 2020 guidelines across PubMed, Embase, Web of Science, Scopus, and the Cochrane Library. Observational human studies published in English between January 2015 and September 2025 evaluating gut, vaginal, cervical, endometrial, or peritoneal microbiota in women with endometriosis were included. Two reviewers independently screened studies, extracted data, and performed a qualitative synthesis due to methodological heterogeneity. Results: Nineteen studies were included, encompassing gut and reproductive tract samples analyzed primarily by 16S rRNA sequencing. Across cohorts, endometriosis was consistently associated with microbial dysbiosis characterized by enrichment of Proteobacteria and Firmicutes and depletion of Bacteroidetes, Lactobacillus, and Bifidobacterium. Increased abundance of opportunistic taxa, particularly Escherichia coli, Streptococcus, and Klebsiella, was frequently reported. Functionally, dysbiosis was linked to increased β glucuronidase activity, enhanced estrogen enterohepatic recirculation, reduced short-chain fatty acid production, and activation of pro-inflammatory immune pathways. Several studies reported correlations between microbial profiles, disease stage, pelvic pain, and infertility. Conclusions: Current evidence supports a reproducible association between gut microbiota dysbiosis and endometriosis. Altered microbial composition and function may contribute to chronic inflammation, hormonal imbalance, and disease persistence. Longitudinal and multi-omic studies are needed to clarify causality and to evaluate microbiota-based diagnostic and therapeutic strategies. Full article

Background and Objectives: Uterine FIGO grade 3 endometrioid carcinoma (EC) is an uncommon but aggressive subtype of endometrial cancer with limited biomarker data to guide prognosis and management. This study aimed to evaluate the prognostic significance of programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) expression in tumor tissue (TT) and tumor microenvironment (TME). Materials and Methods: We retrospectively analyzed tumor samples from 53 patients with FIGO grade 3 EC. Immunohistochemistry was performed to assess PD-1 and PD-L1 expression in TT and TME. Clinicopathological data including age, stage, lymph node invasion (LNI), lymphovascular space invasion (LVSI), depth of myometrial invasion (MI), adjuvant therapy, and survival outcomes were collected. Survival analyses were conducted using Kaplan–Meier and Cox proportional hazards models. Results: PD-1 expression was identified in 34% of TT and 41.5% of TME, while PD-L1 was expressed in 22.6% of TT and 34% of TME. Except for PD-1 in TME, positive expression of these immune checkpoint molecules correlated with significantly shorter survival (log-rank p < 0.05) outcomes. In univariate analysis, PD-1 and PD-L1 expression in TT, deep MI, LNI and LVSI were associated with adverse outcomes. Multivariate analysis confirmed PD-1 and PD-L1 positivity in TT as independent prognostic factors (PD-1: HR 3.2, 95% CI 1.4–7.0; PD-L1: HR 3.3, 95% CI 1.4–7.8). Patients with concurrent PD-1 and PD-L1 expression in TT showed the poorest overall survival, suggesting a cumulative negative effect. Conclusions: PD-1 and PD-L1 expression in tumor tissue are independent predictors of poor prognosis in FIGO grade 3 EC. These findings support their role as clinically relevant biomarkers and potential therapeutic targets. Incorporating checkpoint evaluation into routine pathological assessment could improve prognostic accuracy and guide treatment strategies, particularly in high-risk patients who might benefit from immunotherapy approaches. Full article

Endometriosis is a chronic, estrogen-dependent inflammatory condition affecting approximately 10% of women of reproductive age worldwide. It is characterized by the presence of endometrial-like tissue outside the uterine cavity, which frequently results in dysmenorrhea, chronic pelvic pain, dyspareunia, and infertility. While hormonal medications and surgical procedures are common treatments, they are often constrained by adverse effects and high recurrence rates. The aim was to systematically identify, critically appraise, and synthesize randomized controlled trials evaluating vitamin D, C, and E supplementation in women with endometriosis, focusing on their effects on pelvic pain, dysmenorrhea, dyspareunia, quality of life, oxidative and inflammatory biomarkers, and fertility-related outcomes, and to highlight methodological gaps that can inform future research and integrated therapeutic strategies. Following PRISMA guidelines, seven eligible RCTs were identified from databases including PubMed, Scopus, and ScienceDirect. The quality of these studies was assessed using the Jadad Scoring System and Cochrane RoB 2 tool. High-dose supplementation of vitamin D (50,000 IU) was found to significantly reduce pelvic pain and improve biochemical markers such as hs-CRP and total antioxidant capacity (TAC). Vitamin D appears to modulate endometrial pathways by reducing active β-catenin protein activity, which may disrupt signaling associated with lesion invasion and survival. Additionally, combined Vitamin C and E therapy (typically 1000 mg/day of Vitamin C and 800 IU/day of Vitamin E) acts synergistically to scavenge free radicals. This intervention significantly decreased oxidative stress markers, including malondialdehyde (MDA) and reactive oxygen species (ROS). Patients reported significant improvements in symptoms, including a 43% reduction in daily pelvic pain and a 37% reduction in dysmenorrhea. Despite physiological improvements, there was no statistically significant increase in pregnancy rates observed across the trials. Vitamin supplementation with D, C, and E represents a safe, low-cost adjunct therapy that can effectively mitigate endometriosis-related oxidative stress and pelvic pain. While these vitamins show promise for symptom relief, further research with larger sample sizes is required to determine their long-term impact on fertility outcomes and lesion regression. Full article

Aim: Finding innovative paraclinical parameters is necessary for advancing clinical research, in obstetrics and gynecology for subjective symptoms such as pain, especially in patients with a weakened immune system, following, for example, different obstetrical and gynecological surgeries. The purpose of this study was to analyze if genetic markers can correlate with the postoperative outcome and surgical results in obstetrics and gynecology. We wanted to analyze whether patients carrying the G gene responsible for the A11G polymorphism of the OPRM1 receptor really have a higher need for analgesic doses for postoperative pain control, depending on the histopathological results, benign or malignant tumors, dimensions of tumors, type of incision performed, and hospitalization period. Materials and Methods: We analyzed 111 patients, including both obstetrical and gynecological cases. Blood samples (2 mL) for DNA analysis were obtained before surgery in a tube containing EDTA as an anticoagulant and immediately stored at −20 °C until required for further use. The blood samples, which were collected at the time of intravenous cannulation before surgery, were analyzed for the presence of SNP 118AG. Results: We examined the mutation of the opioid receptor called OPRM1 for the polymorphism noted with AG with a plus sign (+) (present) in 24.3% of the patients, with a minus sign (−) (AA) (absent) in 66.7% of the patients, and with a result with both genes modified (GG) in 9%. We correlated the data obtained in histopathology and clinical anamnesis with these results. The OPRM1(+) morphine receptor mutation was more frequently encountered in patients with biopsy uterine curettage (60%) with benign results in anatomopathology, uterine myomectomy of at least 5 cm fibromas with benign results in anatomopathology (50%), Madden mastectomy (50%), interventional hysteroscopy (33.3%) with extraction of benign tumors such as polyps or endometrial hyperplasia, caesarean section-associated surgeries (20.7%), and ovarian cystectomy (20%) (p = 0.048) that had a final benign anatomopathology result. Conclusions: Pain management in the postoperative phase is difficult for clinicians because of the response of patients to opioid therapy. Some of this variability in pain response may result from single nucleotide polymorphisms (SNPs) in the human opioid receptor mu-1 (OPRM1) that alter receptor binding or signal transduction. Part of the difficulty in identifying genes and variants that affect postsurgical pain is the inconsistent findings and poor replicability of results. Full article

Despite the introduction of novel therapeutic options, the prognosis of advanced endometrial cancer remains poor. In recent years, increasing attention has been directed toward the molecular characterization of endometrial cancer. However, data specifically focusing on advanced-stage disease are still limited. In our single-center, retrospective, exploratory study with a limited sample size, we analyzed 32 patients with advanced or recurrent endometrial cancer treated at the Modena Cancer Center. Comprehensive molecular profiling was performed to assess DNA mutations, copy number variations, and RNA expression. We characterized the molecular landscape of this cohort, evaluated selected genomic alterations across predefined clinical subgroups, and explored their association with overall survival. Consistent with previous reports, a high prevalence of PTEN and PIK3CA mutations were observed. Patients experiencing relapse more than six months after diagnosis were more likely to harbor CTNNB1 mutations. KRAS mutations were more frequently detected in younger patients and in those with endometrioid histology, whereas PPP2R1A and TP53 mutations were enriched in tumors with non-endometrioid histology. Notably, CTNNB1 mutations were associated with a favorable prognostic impact, while KRAS mutations correlated with poorer overall survival. Our findings underscore the need for further investigation into the molecular landscape of advanced endometrial cancer, particularly in the context of therapeutic implications. Combinatorial treatment strategies targeting specific molecular alterations, such as KRAS, in combination with other targeted agents or therapeutic approaches, warrant further exploration. Full article