Search Results (4,565)

Background: Biliary drainage is a key component of palliative management in patients with malignant biliary obstruction. In cases where endoscopic approaches are unsuccessful or cannot be performed, percutaneous transhepatic biliary drainage (PTBD) represents an established alternative for achieving biliary decompression. The C-reactive protein–albumin–lymphocyte (CALLY) index combines inflammatory, nutritional, and immune-related parameters into a single marker, while the modified Glasgow Prognostic Score (mGPS), based on C-reactive protein and albumin concentrations, reflects the systemic inflammatory status of the patient. This study aimed to evaluate the prognostic value of the preprocedural CALLY index and mGPS in predicting 30-day mortality among patients with advanced malignant biliary obstruction undergoing palliative PTBD. Methods: This single-center retrospective study was conducted in a total of 179 patients who underwent palliative PTBD for malignant biliary obstruction at Ankara Etlik City Hospital between December 2022 and June 2025. Results: The 30-day mortality rate was 25.1%. The cut-off value for CALLY was determined as 67 based on receiver operating characteristic (ROC) curve analysis, and mGPS was categorized as 0–1 versus 2. In univariable Cox regression analyses, pancreaticobiliary tumor type, mGPS = 2, and CALLY < 67 were associated with early mortality. In multivariable Cox analysis, CALLY ≥ 67 was independently associated with a reduced risk of 30-day mortality, whereas pancreaticobiliary tumor type was independently associated with an increased risk. In the CALLY–mGPS risk stratification, 30-day mortality rates were 8.0%, 13.5%, and 44.1% in the low-, intermediate-, and high-risk groups, respectively. Conclusions: In this retrospective cohort, preprocedural inflammation- and nutrition-based markers were found to be associated with early mortality in patients with malignant biliary obstruction undergoing PTBD. Accordingly, risk stratification using readily available parameters such as CALLY and mGPS appears feasible in the preprocedural setting. The CALLY–mGPS-based approach may provide a practical framework for clinical risk assessment; however, prospective multicenter validation, including tumor-specific subgroup analyses, is warranted. Full article

Breast cancer remains one of the most frequently diagnosed malignancies and a leading cause of cancer-related mortality among women worldwide. The growing interest in natural bioactive compounds has highlighted plant-derived phytochemicals as promising agents for cancer prevention and adjunctive therapy due to their pleiotropic biological activities and relatively low toxicity. In parallel, increasing attention has been directed toward agro-industrial by-products generated during food processing, which represent abundant and sustainable sources of valuable phytochemicals. This review provides a comprehensive overview of recent advances in the identification, extraction, and biological evaluation of phytochemicals derived from plants and agro-industrial residues, using pomegranate (Punica granatum) peels, onion (Allium cepa) skins, and citrus by-products as representative examples of phytochemical-rich agro-industrial residues. These by-products are rich in polyphenols, flavonoids, and other secondary metabolites—including punicalagins, ellagic acid, quercetin, hesperidin, and naringin—that have demonstrated significant antioxidant, anti-inflammatory, and anticancer properties. Recent in vitro and in vivo studies indicate that these compounds can modulate key molecular pathways involved in breast cancer initiation and progression, such as oxidative stress regulation, apoptosis induction, inhibition of cell proliferation, and suppression of signaling cascades including PI3K/Akt, NF-κB, and MAPK pathways. Furthermore, the valorization of agro-industrial waste offers a sustainable strategy to recover high-value bioactive compounds while reducing environmental impact. Overall, phytochemicals obtained from plant materials and food processing by-products represent promising functional agents for breast cancer prevention and therapy, although further studies are required to improve bioavailability, elucidate mechanisms of action, and validate their clinical potential. Full article

Background/Objectives: Despite advances in the TNM staging system, prognostic heterogeneity persists in early-stage non-small cell lung cancer (NSCLC). Lymphatic invasion (LI) is a known marker of aggression, but its independent significance in the critical, low-risk Stage I, N0 subgroup—typically ineligible for adjuvant therapy—remains poorly defined. We hypothesized that LI acts as a powerful, yet hidden, risk factor in this highly favourable cohort. Methods: This retrospective cohort study included 988 consecutive patients who underwent curative anatomical resection for NSCLC. All patients underwent complete resection with pathologically confirmed negative surgical margins (R0 resection). Cases were staged according to the 9th Edition of the TNM Classification of Malignant Tumours (TNM-9) and grouped as LI-positive or LI-negative. A critical subgroup analysis focused on 347 truly low-risk patients (TNM Stage I, N0, no vascular or pleural invasion). Overall survival (OS) was evaluated using the Kaplan–Meier method and multivariable Cox proportional hazards models. Results: In the entire cohort (n = 988), LI was present in 40.9% of cases. LI positivity was an independent predictor of worse OS in multivariable analysis (HR: 1.520, 95% CI: 1.004–2.301, p = 0.048). In the low-risk subgroup (n = 347), the presence of LI resulted in a drastic survival divergence, with 5-year OS declining from 96.1% (LI-negative) to 83.8% (LI-positive). Multivariable analysis confirmed LI as an independent adverse prognostic factor in this subgroup (HR: 4.002, 95% CI: 1.567–10.221, p = 0.004). Conclusions: Lymphatic invasion is a robust, independent adverse prognostic factor in resected NSCLC. LI may identify a subset of early-stage N0 NSCLC patients who warrant closer postoperative surveillance and prospective evaluation for adjuvant treatment strategies. Validation in prospective cohorts is required before LI can be formally integrated into staging algorithms or treatment guidelines. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) have changed the treatment landscape for several advanced malignancies, but their use is accompanied by immune-related adverse events, including liver injury. Some cases resemble autoimmune hepatitis (AIH), although many are more accurately described as AIH-like immune-mediated hepatitis rather than classical AIH. This distinction matters, as diagnosis is often based on exclusion and management must balance hepatic recovery against interruption of potentially life-prolonging cancer therapy. This systematic review summarised the clinical phenotype, diagnostic assessment, treatment strategies, treatment response, ICI discontinuation, and rechallenge outcomes in patients with ICI-associated AIH-like liver injury. Methods: A systematic PubMed search was performed for English-language human studies reporting autoimmune hepatitis, AIH-like liver injury, or immune-mediated hepatitis following exposure to ICIs. Eligible studies included case reports, case series, retrospective cohorts, prospective cohorts, and pharmacovigilance-type studies with extractable clinical, treatment, or outcome data. Reviews, guidelines, non-original articles, animal studies, non-English publications, and reports without usable liver injury data were excluded. The review followed PRISMA principles. Risk of bias was assessed using Joanna Briggs Institute tools and summarised with ROBVIS. Given the heterogeneity of study design, diagnostic criteria, treatment definitions, and outcome reporting, formal meta-analysis was not appropriate; results were therefore synthesised descriptively. Results: Twenty-two studies were included, comprising 195 patients with ICI-associated AIH-like or immune-mediated hepatitis. Of these, 140 patients received active treatment, and 133/140 achieved clinical or biochemical recovery with varying therapies. Corticosteroids were the most frequently used first-line therapy, with recovery reported in 102/105 patients treated with corticosteroids alone. Mycophenolate mofetil was the main second-line agent for steroid-refractory disease, with response reported in 9/10 treated patients. Other therapies, including tacrolimus, azathioprine, ursodeoxycholic acid, bezafibrate, tocilizumab, basiliximab, infliximab, budesonide, and double plasma molecular adsorption system with or without plasma exchange, were described only in small numbers or isolated cases. Spontaneous recovery without pharmacological treatment was reported in 19 patients. ICI interruption or discontinuation occurred in 141 patients, and rechallenge was reported in 55 patients after recovery, with no recurrent hepatic toxicity documented in the extracted dataset. Conclusions: ICI-associated AIH-like liver injury is an important immune-related toxicity, but the available literature remains fragmented and methodologically heterogeneous. Most reported patients recovered, particularly with corticosteroids, and MMF appears to be the most consistently used escalation therapy in steroid-refractory cases. However, the strength of evidence is limited by uncontrolled designs, variable terminology, inconsistent diagnostic work-up, and non-standardised outcome definitions. Future studies should separate classical AIH from AIH-like immune-mediated hepatitis, use uniform criteria for severity and response, and report treatment denominators clearly, especially for rechallenge and steroid-refractory disease. Full article

Background/Objectives: There is limited data on treatment outcomes under immune checkpoint inhibitor (ICI) administration in solid organ transplant recipients (sOTRs). This study aims to evaluate cancer outcome and allograft rejection risk in sOTRs receiving ICI. Methods: This is a retrospective multicenter study. The data had been collected within the Swiss Transplant Cohort Study (STCS) database. We searched for matching individuals from May 2008 up to the end of 2024. The primary outcomes were treatment response and survival; the secondary outcome was allograft rejection. Additional analyses included associated factors such as tumor, transplant, and treatment characteristics. Results: We identified ten patients, six of whom received a kidney allograft, while the remaining four received a liver, lung, pancreas, or combined kidney–pancreas transplant. Treatment response was achieved in half of the sOTRs, with a complete response (CR) in three and prolonged stable disease (SD) in two patients. CR was achieved in all three patients after only a few infusions. At the time of data analysis, four out of ten patients were still alive. Graft rejection occurred in six out of ten cases, five of which occurred after the first cycle of ICI administration. Conclusions: Data is limited and definitive conclusions from this study cannot be drawn given the limited sample size. However, ICI displays promising effects on cancer outcomes in sOTRs with advanced malignancies. The study’s findings demonstrate an overall response in half of sOTRs, but with graft rejection occurring in a similar number of patients. We propose initiating immunotherapy as early as possible, given the promising results, particularly in patients with kidney transplants. We further suggest that in sOTRs, a few ICI infusions could potentially be a cautious option, pending further evidence. Full article

Autophagy is an essential mechanism through which cells break down and reuse intracellular proteins and organelles to preserve cellular homeostasis. Under physiological conditions, autophagy primarily exerts a cytoprotective effect; however, aberrant activation or deficiency of autophagy pathways can disturb cellular balance and even trigger apoptosis, thereby contributing to the occurrence and progression of multiple diseases. Flavonoids are natural bioactive components widely distributed in plants, characterized by distinct benefits of synergistic regulation via multiple targets and pathways. This review summarizes the primary mechanisms of flavonoids, focusing on their potential underlying mechanisms against various diseases—including atherosclerosis, cardiovascular diseases, liver diseases, lung diseases, Parkinson’s disease, leukemia, and malignant tumors—via regulating autophagy (including selective autophagy), and sorts out the latest advances in related experimental research over the past five years. In conclusion, flavonoids can effectively ameliorate the pathological processes of multiple diseases by modulating autophagy pathways with favorable biosafety. Nevertheless, low bioavailability remains the core bottleneck restricting their clinical translation. Further optimization of pharmaceutical formulations is warranted to enhance their uptake efficacy in vivo, and rigorous clinical trials are needed to assess their prolonged effectiveness and potential drug interactions, so as to offer new feasible approaches and research directions for the prophylaxis and therapy of various diseases. Full article

Background: Accurate prognostication in terminal cancer patients receiving best supportive care (BSC) is essential for guiding end-of-life decision-making and avoiding non-beneficial interventions. Several prognostic models have been developed for advanced cancer, including the Palliative Prognostic Index (PPI) and the Objective Prognostic Score (OPS). However, prospective data evaluating their performance specifically in patients managed with BSC are limited. This study evaluated the prognostic performance of PPI and OPS in terminal cancer patients receiving BSC. It also examined whether their combined use provides additional value for short-term mortality risk stratification. Methods: This prospective observational cohort study included hospitalized adult patients with terminal-stage cancer and a documented BSC decision. Terminal-stage cancer was operationally defined as stage IV malignancy with poor performance status and no remaining feasible disease-directed oncological treatment option due to severe clinical deterioration and/or major organ dysfunction. Patients were prospectively enrolled from 12 April 2024 to 13 December 2024 and followed until death. Eligible patients had poor Eastern Cooperative Oncology Group performance status (ECOG 3–4) and had not received oncologic treatment within the preceding month. PPI and OPS were calculated at baseline using predefined criteria. Survival time was defined as the interval between baseline assessment and death. The prognostic performance of the scores for 3-, 4-, and 6-week mortality was evaluated, and survival outcomes were analyzed using standard survival analysis methods. Results: A total of 112 patients were included in the final analysis. The mean age was 62.3 ± 12.3 years; 66 patients (58.9%) were male and 46 (41.1%) were female. The most common primary tumor sites were colon cancer (20.5%), non-small cell lung cancer (17.0%), and gastric cancer (15.2%). Both PPI > 6 and OPS ≥ 3 were associated with higher short-term mortality, although their individual discriminatory performance was modest. The combined OPS–PPI approach showed statistically significant but still modest discrimination at all time points. Although this difference was limited, the combined approach supported the stratification of a clinically relevant subgroup at particularly high risk of imminent death. Patients with both OPS ≥ 3 and PPI > 6 had the poorest survival, with a median overall survival (OS) of 11 days. In multivariable Cox regression analysis, the combined high-risk group remained independently associated with poorer OS (HR 1.53, 95% CI 1.01–2.31; p = 0.046). Conclusions: Although the individual discriminatory performance of PPI and OPS was modest, their combined use may provide additional risk stratification value and may help identify patients at particularly high risk of short-term mortality among terminal cancer patients receiving BSC. These findings should be interpreted as supporting bedside risk stratification rather than indicating a definitive individual-level prediction model. Full article

Introduction: Breast cancer is the most common malignancy in women of reproductive age, and treatment advances have heightened the importance of fertility preservation (FP) for young patients. Despite heterogeneity across subtypes—hormone receptor-positive (HR+), HER2-positive, triple-negative (TNBC), and BRCA1/2-associated—existing guidelines lack subtype-specific FP guidance. Methods: This systematic review compared FP strategies across subtypes, identified subtype-specific challenges, and proposed pathways toward precision oncofertility care. PubMed, Scopus, and Web of Science were searched following PRISMA guidelines for English-language studies from 2004 to 2024. Results: After screening 1837 records, 19 studies met eligibility criteria (2 RCTs, 17 cohort studies); 11 of 17 non-randomized studies were at low overall risk of bias, and 6 at moderate risk due to confounding. Discussion: COS using letrozole- or tamoxifen-modified protocols was feasible, yielding 8–14 mature oocytes per cycle with reduced estradiol exposure suitable for HR+ disease. Evidence was strongest for HR+ patients; TNBC and HER2+ data were more limited, with some studies noting reduced ovarian reserve. GnRH agonists during chemotherapy reduced ovarian failure rates and improved post-treatment recovery, most consistently in hormone receptor-negative disease. BRCA1/2 carriers showed broadly comparable FP outcomes to non-carriers, though BRCA1-positive patients had modestly reduced oocyte yields in some studies with inconsistent results. Conclusions: Among studies with medium-term follow-up (3–5.5 years), no significant increase in recurrence or mortality attributable to FP was identified; long-term data beyond 5 years remain sparse. Substantial heterogeneity precluded meta-analysis; all synthesis is narrative. Standardized outco reporting and larger prospective subtype-stratified studies are required to establish precision oncofertility recommendations. Full article

Sinonasal malignancies are rare, accounting for fewer than 3% of head and neck cancers, but their early presentation often overlaps with benign rhinosinusitis. Unilateral nasal obstruction, rhinorrhoea, facial pressure, and intermittent epistaxis may initially appear inflammatory, which contributes to diagnostic delay and late-stage presentation. Recent clinical guidance emphasizes that persistent unilateral symptoms, especially when accompanied by bleeding, focal endoscopic abnormalities, or orbital, dental, or neurologic features, should prompt specialist assessment rather than repeated empiric treatment. This commentary argues that the central clinical problem is not failure to recognize advanced disease, but failure to reconsider a benign working diagnosis when “sinusitis” stops behaving like sinusitis. This commentary proposes a pragmatic triage framework for unilateral or refractory sinonasal disease that prioritizes pattern recognition, focused nasal endoscopy, appropriate imaging, and timely biopsy where indicated. Its contribution is to connect three clinically relevant observations: sinonasal malignancy is rare and therefore easily deprioritized; unilateral, progressive, refractory, bleeding, orbital, dental, or neurologic features should prompt earlier cancer exclusion; and emerging AI-assisted endoscopy should currently be viewed only as a triage adjunct, not a substitute for imaging, histopathology, or multidisciplinary assessment. Full article

Tumors of the lacrimal drainage system are rare and include benign and malignant variants. Their presentation frequently mimics inflammatory or obstructive lacrimal disease, which often results in delayed diagnosis and diagnostic uncertainty. A high index of suspicion, appropriate imaging, and timely biopsy are required to verify the histology and guide management. Surgical excision remains the cornerstone of treatment for most lesions, with the aim of achieving histologically clear margins. Advances in endoscopic and combined surgical approaches have enabled radical tumor resection whilst reducing morbidity and improving globe preservation. Adjuvant radiotherapy is commonly employed in malignant disease, while systemic chemotherapy, immunotherapy, and targeted therapies may be considered in selected advanced or recurrent cases. Emerging molecular insights and evolving surgical techniques may further refine future treatment strategies. This review summarizes current evidence and clinical principles to provide a practical framework for the diagnosis and management of lacrimal drainage system tumors. Full article

5-Aminolevulinic acid (5-ALA) has emerged as an important theranostic agent in oncology due to its selective intracellular conversion to protoporphyrin IX (PpIX), enabling both photodynamic diagnosis (PDD) and photodynamic therapy (PDT). This narrative review summarizes current knowledge regarding the biological mechanisms underlying 5-ALA metabolism, selective tumor accumulation, and the clinical applications of 5-ALA-based approaches across multiple oncological indications. Particular emphasis is placed on glioblastoma, head and neck lesions, dermatological malignancies, urological cancers, gynecological lesions, and emerging translational applications. The review also discusses key biological and technical limitations, including tumor hypoxia, restricted light penetration, heterogeneous PpIX accumulation, resistance mechanisms, and tumor-specific variability. Recent advances in drug delivery systems, nanotechnology, sonodynamic therapy, radiodynamic strategies, and combination immunotherapeutic approaches are also highlighted. Collectively, current evidence indicates that while 5-ALA has established clinical utility in selected indications, many applications remain preclinical or early translational, underscoring the need for further well-designed clinical studies. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy. The identification and management of precursor lesions, particularly the increasingly common intraductal papillary mucinous neoplasms (IPMNs), pose a significant challenge, creating a profound clinical dilemma between intercepting pancreatic ductal adenocarcinoma and avoiding surgical overtreatment. This literature review aims to synthesize the latest evidence to facilitate a transition from purely morphology-based surveillance toward a biologically informed risk stratification paradigm. This approach could provide a personalized risk-stratification algorithm that optimizes therapeutic management and enables timely intervention for pancreatic cancer. By using PubMed, Embase, Scopus, and Web of Science, we analyzed and summarized key findings from recent literature (2020–2025), including cohort studies, mechanistic analyses, evidence-based guidelines, and systematic reviews on cyst fluid biomarkers (CEA panels, DNA/RNA sequencing), and emerging AI applications. Prospective and multicenter studies consistently report that NOD is independently associated with high-risk stigmata, cyst progression, and malignant transformation. Mechanistic research suggests a bidirectional interplay between the evolving neoplasia and pancreatic endocrine dysfunction. Updated guidelines underscore the need for more precise diagnostic algorithms. Recent work demonstrates that advanced cyst fluid markers—CEA panels, DNA/RNA sequencing, and multi-omic signatures—significantly improve diagnostic accuracy. Furthermore, explainable AI models show encouraging performance in predicting malignancy and assisting patient triage. Risk stratification in PCLs is shifting from morphology-based assessment toward integrated, multimodal approaches combining clinical, endocrine, imaging, molecular, and computational data. Recent evidence positions new-onset diabetes as a clinically accessible and biologically plausible marker of high-risk IPMNs. Similarly, molecular assays and AI-enhanced analytics provide an additional layer of diagnostic precision. The development of personalized risk prediction algorithms could improve early detection of malignancy while reducing unnecessary surgical resections. Full article

Background/Objectives: Malignant transformation of soft tissue lesions is uncommon but represents a significant diagnostic challenge with substantial clinical consequences. This spectrum encompasses four interrelated processes but biologically distinct processes: (1) true malignant transformation of benign lesions; (2) dedifferentiation of low-grade or intermediate malignancies; (3) secondary malignancy arising in chronic inflammatory or non-neoplastic conditions; and (4) apparent progression related to tumor heterogeneity and sampling error. Although these four entities involve biologically distinct mechanisms, they are grouped under “malignant progression” for conceptual clarity. While this umbrella approach has limitations due to biological heterogeneity, this unified radiologic framework aims to supplement, rather than oversimplify, their distinct biological behaviors. Representative examples include neurofibroma and epidermal inclusion cyst among benign lesions; atypical lipomatous tumor/well-differentiated liposarcoma, dermatofibrosarcoma protuberans, and solitary fibrous tumor among lesions showing dedifferentiation or malignant progression; and chronic inflammatory or scar-related conditions and previously irradiated tissue associated with secondary malignancy. Some lesions that appear to progress during follow-up may represent initial underdiagnosis rather than true biologic progression. Methods: This narrative review summarizes current imaging features, underlying pathologic mechanisms, and clinical risk factors associated with these processes in soft tissue lesions. Particular emphasis is placed on radiologic–pathologic correlation and conditions prone to histopathologic misinterpretation. Results: Imaging red flags—including interval or rapid growth, deep fascial invasion, heterogeneous enhancement, perilesional edema, and necrosis—should raise concern for malignant progression across these categories. However, overlapping imaging features and sampling errors may result in pathologic misdiagnosis and delayed treatment. Particularly, atypical lipomatous tumors are frequently misdiagnosed as simple lipomas, while fibrosarcomas may be erroneously interpreted as aggressive fibromatosis. Advanced imaging and multidisciplinary review may help reduce diagnostic errors. Patients with predisposing factors such as genetic syndromes, chronic inflammation, prior burns, or previous radiation exposure warrant close surveillance. Conclusions: Accurate diagnosis of soft tissue lesions with true malignant transformation, dedifferentiation, or secondary malignancy—as well as recognition of diagnostic pitfalls—is essential for appropriate management. Integrated radiologic–pathologic assessment may help improve diagnostic accuracy and clinical decision-making in soft tissue oncology. Full article

Background: Cutaneous melanoma (CM) is a highly immunogenic malignant neoplasm. It features high mutational burden and intense lymphocytic infiltration, supporting the use of immunotherapies, especially inhibitors of the programmed cell death protein 1 (PD-1) checkpoint. Despite advances with anti-PD-1 therapies, such as nivolumab and pembrolizumab, many patients still experience resistance. This result highlights additional immunosuppressive mechanisms within the tumor microenvironment (TME) that limit T-lymphocyte-mediated responses. Objectives: The aim was to discuss the immunologic and metabolic bases of PD-1- and CD73-mediated pathways and evidence that CD73 inhibition can boost PD-1 inhibitor efficacy by acting on convergent immunosuppressive pathways. Methods: We conducted a narrative literature review focusing on tumor immunosuppression, purinergic signaling and checkpoint inhibitor-based immunotherapy. Results: The purinergic pathway, mediated by the ectonucleotidase CD73, is a critical regulator of tumor immunosuppression. CD73 converts extracellular adenosine monophosphate (AMP) into adenosine. This adenosine accumulates in the hypoxic and inflamed TME, exerting immunosuppressive effects. Adenosine acts as a “metabolic brake,” inhibiting proliferation, cytokine production, and cytotoxic activity of CD8⁺ T lymphocytes and natural killer (NK) cells. It also promotes the expansion of regulatory T cells (Tregs) and tumor progression. This axis may limit responses to PD-1 blockade, suggesting that complementary pathways are active. Conclusions: Integration of PD-1 and CD73 pathways suggests that CD73 inhibition may enhance PD-1 blockade by targeting convergent immunosuppressive mechanisms. This supports the exploration of combination strategies to broaden the benefits of immunotherapy in CM. Full article

Introduction: Lung cancer, the leading cause of cancer-related mortality worldwide, is a heterogeneous malignancy comprising distinct histological and molecular subtypes, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases and adenocarcinoma (ADC) representing the most prevalent histotype. An emerging pathological feature of NSCLC, spread through air spaces (STAS)—defined as the extension of tumor cells into the lung parenchyma beyond the main tumor margin—has been associated with worse disease-free and overall survival and has been proposed as a possible predictor of recurrence to guide surgical extent. Concurrently, recent comprehensive genomic profiling of early-stage NSCLC has highlighted the need to interpret multi-omics data and their relationship with pathological variables, including IASLC histological subtypes, to better personalize treatment strategies. In this context, we investigated the overall distribution of STAS and its association with tumor mutational profiles and IASLC histological subtypes in a large real-world cohort of lung adenocarcinoma patients from the LANTERN project. Materials and Methods: In a prospective, multicenter observational study (March 2023–December 2024), 271 NSCLC patients were enrolled, and clinicopathological, immunohistochemical, and genomic data were collected; comprehensive genomic profiling was performed using the TruSight Oncology 500 assay to analyze 523 cancer-related genes, tumor mutational burden (TMB), and microsatellite instability; and STAS was assessed according to IASLC criteria. Adenocarcinoma accounted for roughly 90% of the cases, with a median age of 69 years and a predominance of stage IV disease (49.5%). STAS was evaluable in 162 cases and was detected in 17.9% of tumors. Results: STAS-positive tumors showed a higher trend towards locally advanced and advanced disease; no differences were observed in sex, age, smoking status, tumor mutational burden, or PD-L1 expression. Additionally, STAS-positive tumors showed a higher association with micropapillary, mucinous, and papillary patterns, whereas the acinar pattern was more frequent in STAS-negative tumors. The most frequently mutated genes were TP53, KRAS, EGFR, and STK11, with no significant differences between groups; ROS1 alterations were absent in STAS-negative tumors but detected more frequently in STAS-positive cases. Conclusions: Overall, these findings indicate that STAS positivity is associated with high-risk histological subtypes and advanced disease, suggesting its importance as a marker of tumor aggressiveness and emphasizing the need for its systematic evaluation in lung adenocarcinoma to better guide surgical planning and patient risk assessment. Full article