Search Results (46)

Colorectal cancer (CRC) remains the third most common malignancy worldwide and a leading cause of cancer mortality, largely driven by metastatic dissemination. Among metastatic routes, lymphatic spread is crucial to determine the prognosis and establish an adequate therapeutic strategy. Lymph node metastasis (LNM) defines stage III disease in the TNM classification, guiding adjuvant chemotherapy and surgical planning. However, nodal staging based on lymphadenectomy and histopathology is invasive, time-consuming, and may lead to overtreatment. Conventional imaging modalities, including computed tomography, magnetic resonance imaging, and endorectal ultrasound, show limited sensitivity and specificity for small or micro-metastatic nodes. Despite multimodal progress, no non-invasive technique reliably identifies malignant nodes in real time. PET–MRI, contrast-enhanced ultrasound, photoacoustic and fluorescence approaches, ICG mapping, and sentinel node biopsy improve detection but remain limited by specificity, cost, or availability. Extranodal extension (ENE) and tumor deposits (TDs) carry major prognostic value, reflecting aggressive biology and association with distant spread. Meanwhile, phylogenetic studies challenge linear dissemination models, indicating that some metastases arise directly from the primary tumor or TDs rather than LNMs. These data support refinement of staging and surgical strategies according to tumor biology rather than purely anatomical criteria. High-frequency quantitative ultrasound (HF-QUS) enables real-time, operator-independent, three-dimensional nodal assessment with reported sensitivity and specificity exceeding 85%. Combined with artificial intelligence and molecular profiling, it may support biologically informed staging, reduce unnecessary surgery, and foster precision oncology. Lymphatic dissemination in CRC offers a platform to merge tumor biology with technological innovation, where advanced imaging, molecular insight, and artificial intelligence may redefine nodal staging toward precision, non-invasive care. Full article

Lymph node involvement in prostate cancer has major prognostic and therapeutic implications, yet conventional imaging based on size and morphology remains limited in detecting small-volume metastatic disease. Although extended pelvic lymph node dissection is considered the reference standard for nodal staging, it is invasive, associated with morbidity, and primarily diagnostic in intent. Prostate-specific membrane antigen positron emission tomography (PSMA PET) has reshaped staging by enabling molecular detection of nodal metastases, consistently demonstrating superior accuracy compared with conventional imaging. This narrative review critically evaluates the role of PSMA PET in lymph node staging, with a primary focus on primary diagnosis and selected considerations on biochemical recurrence, focusing not only on diagnostic accuracy but on clinical utility and decision-making. PSMA PET shows high specificity but moderate sensitivity for pelvic nodal metastases, with reduced performance for micrometastatic disease; therefore, a negative scan cannot reliably exclude nodal involvement in high-risk patients. Evidence indicates frequent stage migration and management changes, including refinement of surgical planning, radiotherapy target delineation, and treatment intensification strategies. However, most pivotal therapeutic trials were based on conventional imaging, and long-term outcome data validating PSMA PET-guided treatment adaptations remain limited. We discuss biological rationale, radiotracer characteristics, interpretation frameworks, guideline perspectives, real-world variability in adoption, and current limitations, including false-positive findings, PSMA heterogeneity, and lack of universal standardization. Rather than replacing established staging paradigms, PSMA PET should be integrated within a comprehensive, risk-adapted framework. Ongoing prospective trials will clarify whether molecularly defined nodal staging translates into improved oncologic outcomes and will determine its definitive role in contemporary prostate cancer management. Full article

Ewing sarcoma (ES) is a bone malignancy primarily, well known by its t(11;22)(q24;q12) chromosomal translocation. Despite high initial treatment success, ES frequently recurs, likely due to micrometastatic disease present at diagnosis but undetected during primary treatment. This study aims to characterize transcriptomic differences between primary and metastatic ES to identify genes and pathways associated with the metastatic phenotype. Using the Search Tag Analyze Resource for National Center for Biotechnology Information’s Gene Expression Omnibus, seven independent gene expression series were identified, yielding 37 metastatic and 82 primary ES tumor samples. Differentially expressed genes were defined using a significance threshold of p < 0.05 and absolute experimental log ratio > 0.1 and were analyzed using Ingenuity Pathway Analysis. This integrative transcriptomic analysis identified 753 significant molecules. Metastatic ES was characterized by upregulation of lung-associated surfactant proteins and secretoglobin family members, along with downregulation of genes involved in extracellular matrix organization. Additional genes of interest included SLC6A14, CXCL14, and TBX3, which have been implicated in tumor progression in other malignancies. These findings provide a computationally derived molecular profile associated with metastatic ES and highlight candidate genes and pathways that warrant further validation. This integrative approach offers a framework for future studies focused on understanding metastatic biology in rare pediatric cancers. Full article

Background/Objectives: Penile squamous cell carcinoma (SCC) is a rare but aggressive malignancy in which survival declines sharply once regional lymph nodes are involved. Neoadjuvant therapy is recommended for clinically node-positive disease to improve resectability and address micro-metastatic spread; however, the supporting evidence remains limited. We systematically reviewed contemporary data on neoadjuvant strategies for penile SCC, including cytotoxic chemotherapy, radiotherapy, immunotherapy, and molecularly targeted agents. Methods: A systematic search of MEDLINE, EMBASE, ClinicalTrials.gov, and CENTRAL was conducted from inception to January 2026 in accordance with MECIR guidance. Eligible studies included patients with histologically confirmed penile cancer treated with neoadjuvant intent prior to curative surgery. Primary outcomes were objective response rate (ORR), pathological complete response (pCR), progression-free survival (PFS), and overall survival (OS). Data were synthesised narratively by treatment modality. Results: Forty-two studies met the inclusion criteria (32 chemotherapy, five radiotherapy, five immunotherapy, three targeted therapy). The evidence base was dominated by retrospective cohorts with limited prospective phase II data and no completed randomised trials. Across chemotherapy studies, the median reported ORR was 50% (range 29–90%), with pCR/ypN0 rates ranging 10–25%. Median reported PFS and OS were approximately 11 and 18 months, respectively, with durable survival concentrated among responders undergoing complete surgical consolidation. Radiotherapy data were sparse and heterogeneous. Early-phase immunotherapy combinations reported higher short-term response and pCR signals than historical chemotherapy, though the results were based on small single-arm cohorts. Molecularly targeted systemic monotherapy demonstrated modest activity. Conclusions: Neoadjuvant taxane–platinum-based chemotherapy remains the guideline-supported standard for cN2-3 penile SCC, supported by phase II and retrospective data but limited by methodological heterogeneity and absence of randomised evidence. Emerging combination immunotherapy strategies show promising efficacy signals and warrant prospective validation within biomarker-informed trial frameworks. Full article

Background and Objectives: Pulmonary neuroendocrine carcinomas (NECs) are characterized by aggressive clinical behavior and heterogeneous postoperative outcomes. Early recurrence, often reflecting occult micrometastatic disease, remains a key determinant of prognosis and is insufficiently captured by conventional staging systems. We hypothesized that the lactate dehydrogenase-to-albumin ratio (LAR), as an integrative tumor–host biomarker, may provide biologically informed risk stratification in this setting. Materials and Methods: We conducted a multicenter retrospective cohort study including 88 patients with resected small cell lung cancer (SCLC) or large cell neuroendocrine carcinoma (LCNEC). Preoperative LAR and comparator inflammatory indices were evaluated. The primary endpoints were disease-free survival (DFS) and overall survival (OS), with early recurrence (≤12 months) as a prespecified secondary endpoint. Time-dependent receiver operating characteristic analyses, Cox proportional hazards models, and logistic regression analyses were applied within a predefined analytical framework. Results: Using a cut-off derived from 12-month DFS (LAR = 45.58), elevated LAR was associated with significantly shorter DFS (median 12.3 vs. 26.1 months; p = 0.018) and OS (median 20.7 vs. 52.8 months; p = 0.010). In multivariable analyses, LAR remained independently associated with both DFS (HR 1.012, 95% CI 1.001–1.023; p = 0.037) and OS (HR 1.016, 95% CI 1.005–1.027; p = 0.003). Elevated LAR was also associated with an increased risk of early recurrence (adjusted OR 4.656, 95% CI 1.520–14.262; p = 0.007). In time-dependent receiver operating characteristic (ROC) analyses, LAR demonstrated the highest overall discriminatory performance across evaluated biomarkers and showed a statistically significant advantage over neutrophil-to-lymphocyte ratio (NLR) for 24-month OS. Conclusions: Preoperative LAR captures a clinically relevant tumor–host phenotype associated with early disease progression and adverse survival outcomes in resected pulmonary NECs. As a biologically integrative and readily accessible biomarker, LAR may complement existing risk stratification strategies in this heterogeneous disease context. Prospective validation and integration into multimodal risk models are warranted. Full article

Background: When tumors are surgically removed, an immediate rise in circulating tumor cells is often observed, accompanied by several postoperative changes that can enable these cells to evade immune detection and metastasize. The perioperative period following tumor resection can often promote the formation of new distant micrometastatic foci triggered by upregulation of distinct molecules. Our lab previously reported an increase in distinct inflammatory cytokine molecules following surgical resection in prostate, breast, and colorectal cancer patients, and the secretion of these signals begins as early as 2–24 h after surgery. Here, we investigated whether these distinct cytokines could orchestrate the formation of tunneling nanotube (TNT) conduits to enhance cancer cell migration. Methods and Results: Here, we provide supporting evidence that specific pro-inflammatory cytokines upregulated following cancer surgery may be potential triggers of disease recurrence and migration through TNT formation. In the tumor microenvironment, TNTs act as conduits between cancer and normal cells, facilitating the transfer of organelles that contribute to cancer cell survival and metastasis. Here, The effects of TGF-β1, IL-6, and HGF cytokines on the development of TNT conduits between adjacent cancer cells, as well as the effects of oseltamivir phosphate (OP) treatment, were measured using fluorescent microscopy and image analysis software. In PANC-1 pancreatic cancer cells, the addition of these cytokines significantly increased (p < 0.009) the quantity and extent of TNTs compared with untreated control cells. MCF-7 breast cancer cells yielded comparable results, with a significant increase in TNT observed in cells treated with TGFβ-1, IL-6, and HGF. In contrast, SW620 colorectal cancer cells did not express TNTs in response to any of the three cytokines tested. OP treatment with cytokines significantly reduced TNT formation in pancreatic and breast cancer cells, with no effect on the colorectal SW620 cancer cell line. Cell migration in response to cytokines was assessed using the scratch wound assay. Out of the three cell lines analyzed, the PANC-1 cells fully closed after 12 h of the wound gap. In contrast, the SW620 and MCF-7 cells had no significant change in wound closure rate following cytokine treatment. The SW620 cells exhibited a slight but insignificant increase in the wound closure rate with TGFβ-1 and HGF treatment, while IL-6 in the SW620 cells and all three cytokines in the MCF-7 cells were comparable to the control. OP significantly reduced the scratch wound closure rate on PANC-1, SW620, and MCF-7 cells treated with these cytokines. Conclusions: These findings further support the link between perioperative cytokine activity and increased metastatic potential by promoting the formation of intercellular tunneling nanotube conduits. OP, a specific inhibitor of the mammalian neuraminidase-1 (NEU-1) enzyme, disrupts this process. Full article

Background/Objectives: Cribriform architecture is an adverse histopathologic feature in prostate cancer and has been associated with poor oncologic outcomes. Emerging evidence suggests that cribriform-positive tumors may behave as a biologically non-localized disease, raising the possibility of early occult dissemination. Lymphovascular invasion (LVI) is a key pathological marker of metastatic potential, but its relationship with cribriform architecture has not been evaluated. We examined the association between cribriform morphology and LVI to provide biological context for the aggressive clinical course of cribriform-positive prostate cancer. Methods: We performed a retrospective analysis of patients with prostate adenocarcinoma who underwent radical prostatectomy and had available clinicopathologic data. Cribriform architecture was determined by a centralized pathology review, and LVI status was obtained from original pathology reports. Unadjusted associations were evaluated using contingency tables. Multivariable logistic regression was used to assess whether cribriform architecture was independently associated with LVI after adjustments for Gleason score, tumor stage, and nodal status. Results: Among 338 patients, 28 (8.3%) had LVI and 123 (36.4%) had cribriform architecture. LVI was more common in cribriform-positive than cribriform-negative tumors (17.9% vs. 2.8%; p < 0.001), corresponding to a crude odds ratio (OR) of 7.6 (95% CI, 3.0–19.3). Cribriform architecture remained independently associated with LVI after adjustment (adjusted OR, 5.20; 95% CI, 2.12–1.40; p < 0.001). Conclusions: Cribriform architecture is strongly and independently associated with LVI, supporting a biological link between cribriform morphology and early metastatic dissemination. These findings support the design of prospective, biomarker-driven studies to evaluate treatment intensification strategies in this high-risk subgroup. Full article

Background/Objective: Early detection of metastatic progression remains a major challenge in precision oncology. Conventional radiological imaging cannot reliably identify micrometastatic disease. Although circulating tumor DNA is promising for minimal residual disease detection, organ-derived response biomarkers reflecting tissue adaptation to secreted factors remain unexplored. We hypothesized that integrating such biomarkers with global laboratory parameters would generate a synthetic variable with improved discrimination for de novo metastasis and mortality. Methods: This prospective observational pilot study enrolled 30 patients (median age 64.4 years; 56.7% female) with heterogeneous solid malignancies. Peripheral blood biomarkers responsive to tumor-secreted soluble factors (n = 11) were quantified using a multiplexed beads Luminex immunoassay. Global analytical parameters (n = 20) were derived from routine laboratory assessments. Hierarchical agglomerative clustering analysis generated two synthetic variables: Stigma (Ϛ) and Qoppa (Ϙ). Receiver operating characteristic curve analysis, Kaplan–Meier survival analysis, and Cox regression were used to evaluate the performance. Results: Qoppa demonstrated acceptable discriminatory performance for de novo metastasis (AUC = 0.78). For mortality prediction, performance varied by disease status (overall AUC = 0.78): superior in non-metastatic patients (AUC = 0.98) but negligible in those with baseline metastases. Kaplan–Meier analysis confirmed significant survival differences (p = 0.042 overall survival; p = 0.024 for metastasis-free survival in the non-metastatic subgroup). Differences in biomarker expression and clinical variables (stage, tumor burden, and metastatic burden) were observed between the high and low Qoppa strata. Conclusions: In this small heterogeneous pilot cohort, Qoppa provides a proof of concept that integrating organ-derived response biomarkers with routine laboratory parameters may capture clinically relevant signals for metastatic risk stratification in oncology patients. This composite parameter supports the generation of hypotheses for future biomarker-driven research and clinical test development. External validation in larger multicenter cohorts is required before clinical implementation. Full article

Background: Oligometastatic bladder cancer (OMBC) is increasingly recognised as an intermediate state between localised and widespread metastatic disease, although its definition and optimal management remain uncertain. Patients with OMBC have a generally more favourable prognosis compared to patients with metastatic disease. However, its definition, diagnostic criteria, and optimal management remain poorly standardised. Methods: This narrative review summarises current evidence on the definitions, diagnostic approaches, and treatment strategies for OMBC, with an emphasis on emerging biological and molecular insights that may refine disease classification and guide therapy. Results: Existing definitions of OMBC rely on lesion count and anatomical distribution, overlooking molecular and clinicopathological heterogeneity that influences prognosis and treatment response. Advances in Positron Emission Tomography (PET)/Computed Tomography (CT) and magnetic resonance imaging (MRI) have improved detection of small-volume disease, while liquid biopsy and circulating tumour DNA show promise for assessing micrometastatic burden. Therapeutic approaches, including metastasis-directed and consolidative therapies, are under investigation. Nonetheless, most data are derived from small, retrospective series, and evidence from prospective studies remains limited. Conclusions: Prospective, biomarker-integrated, and randomised trials are essential to refine definitions, optimise patient selection for therapy, and define the role of precision-based multimodal therapy in OMBC management. Full article

High-risk and locally advanced prostate cancer represents 20–25% of new diagnoses of prostate cancer and is associated with high rates of recurrence, morbidity, and mortality. The neoadjuvant window provides a unique opportunity for systemic control prior to definitive therapy with radical prostatectomy or radiotherapy (RT). Early trials with first-generation androgen deprivation therapy (ADT) achieved pathological downstaging but no survival benefit. In the 2000s, the advent of chemohormonal regimes using docetaxel provided excitement but mixed results tempered expectations and is now not recommended prior to surgery. Second-generation androgen receptor pathway inhibitors (ARPIs) combined with ADT have demonstrated significant survival benefit in metastatic prostate cancer and are currently being evaluated in large phase III trials in the neoadjuvant setting. RT remains an alternative curative modality, and recent data highlights similar issues to surgery in eradicating micrometastatic disease despite excellent local control. This has driven parallel efforts to evaluate intensified systemic therapy in the pre-RT/neoadjuvant settings. In addition to the excitement surrounding ARPIs, radioligand therapy, such as [¹⁷⁷Lu]Lu-PSMA-617 has shown promise in the neoadjuvant setting and continues to be investigated. Future research aims to incorporate genomic and molecular factors to enable personalised neoadjuvant therapies by identifying damage immunologically responsive subtypes that may derive greater benefit from immune-directed therapies in the peri-operative setting. This narrative review synthesises current evidence for neoadjuvant therapies in high-risk prostate cancer and future directions. Full article

Cholangiocarcinoma (CC) is a rare and aggressive malignancy that arises from the epithelial cells (cholangiocytes) of the biliary tree. Biliary tract cancers (BTC) include both CC and gall bladder cancer. Surgical resection is considered the only curative treatment. Recently, however, a fundamental shift in the understanding of the molecular profiles of these tumors has led to a molecular-targeted approach with improved survival rates in some patients with these tumors. In patients with local or limited regional disease, neoadjuvant therapies offer a way to downstage tumors, assess tumor biology, potentially achieve R0 resection, and potentially prevent both locoregional and distant recurrence by treating occult micrometastatic disease. Because BTC are rare and surgery is the standard of care for patients with non-metastatic disease, there is very little data evaluating neoadjuvant strategies in resectable disease. Immunotherapies and molecularly targeted agents originally developed for advanced disease in the adjuvant or palliative settings are now being considered for neoadjuvant use. This review aims to summarize the data and provide a rationale for the role of neoadjuvant treatment in patients with resectable BTC. While there is no high-level evidence, studies show that neoadjuvant therapy that incorporates targeted treatments and immunotherapies under multidisciplinary oversight benefits select patients and is a valuable tool in the treatment of BTC. We favor molecular testing to guide neoadjuvant therapy for patients with BTC, when feasible, to prevent unnecessary operations and minimize the risk of recurrence or metastasis. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a 5-year overall survival below 12% and high recurrence rates even after R0 resection. Traditionally managed with a “surgery-first” approach, two consistent observations—the near-universal presence of micrometastatic disease at diagnosis and the frequent inability to complete adjuvant therapy—have driven the integration of neoadjuvant therapy (NAT) into clinical practice. NAT offers several theoretical and practical advantages: early systemic control of occult disease, improved delivery and completion of multimodal treatment, biological selection of surgical candidates, and increased R0 resection rates. While in borderline resectable PDAC, randomized trials have consistently demonstrated improved margin-negative resection rates and early survival benefits compared with upfront surgery, in resectable PDAC, evidence is more heterogeneous. Real-world studies corroborate trial findings, reporting higher R0 rates and reduced lymph node positivity without increased perioperative risk, but also highlight substantial heterogeneity in regimens, duration, and radiotherapy use. Limitations to universal NAT adoption include reliance on anatomy-based resectability criteria, absence of validated predictive biomarkers, challenges in response assessment, and concerns over disease progression during preoperative treatment. Future developments will focus on integrating molecular profiling, circulating tumor DNA dynamics, and advanced imaging into patient selection and treatment adaptation, supported by biomarker-enriched and adaptive trial designs. NAT is thus evolving from a selective strategy for borderline disease to an innovative framework to optimize multimodal treatment delivery and refine patient selection in PDAC, with the potential to improve surgical outcomes and inform systemic therapy decisions in both resectable and borderline resectable settings Full article

Penile cancer is a rare malignancy, with approximately 2100 cases diagnosed annually in the United States. The 5-year overall survival rate varies significantly depending on the node involvement status, at 79% in node-negative disease versus 51% for patients with inguinal metastasis. Inguinal lymph nodes are involved in micrometastatic disease in up to one out of four patients. Early inguinal lymph node dissection (ILND) has been shown to provide a survival advantage, which is why many patients undergo inguinal lymph node dissection for diagnostic and therapeutic purposes. Unfortunately, ILND is associated with high morbidity rates, which have led to potential overtreatment and decreased quality of life in the penile cancer population. Several advancements have been made to mitigate these challenges, such as dynamic sentinel node dissection, modifications to the technique or surgical templates, the introduction of minimally invasive procedures, and changes to the postoperative pathway. This manuscript examines the evolution in managing the inguinal lymph nodes in penile cancer, its associated complications, and effective strategies for their prevention and management. Full article

Background/Objectives: The current staging of non-small cell lung cancer (NSCLC) relies on conventional imaging, which lacks the sensitivity to detect micrometastatic disease. The functional assessment of NSCLC progression may provide independent information to enhance the prediction of metastatic risk. The objective of this study was to determine if we could identify a metabolomic signature predictive of metastasis in patients with NSCLC treated with definitive radiation. Methods: Plasma samples were collected prospectively from patients enrolled in a clinical trial with non-metastatic NSCLC treated with definitive radiation. Metabolites were extracted, and mass spectrometry-based analysis was performed using a flow injection electrospray (FIE)–Fourier transform ion cyclotron resonance (FTICR) mass spectrometry (MS) method. Early metastasis was defined as metastasis within 1 year of radiation treatment. Results: The study cohort included 28 patients. FIE-FITCR produced highly reproducible profiles in technical replicates. A total of 51 metabolic features were identified to be different in patients with early metastasis compared to patients without early metastasis (all adjusted p-values < 0.05, Welch’s t-test), including glycerophospholipids, sphingolipids, and fatty acyls. In the follow-up samples collected after the initiation of chemotherapy and radiation treatment, a total of 174 metabolic features were significantly altered in patients who developed early metastasis compared to those who did not. Conclusions: We identified several distinct changes in the metabolic profiles of patients with NSCLC who developed metastatic disease within 1 year of definitive radiation. These findings highlight the potential of metabolomic profiling as a predictive tool for assessing metastatic risk in NSCLC. Full article

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality in the United States, with poor overall survival across all stages. Less than 20% of patients are eligible for curative surgical resection at diagnosis, and despite adjuvant chemotherapy, most will experience disease recurrence within two years. The incorporation of immune-based strategies in the adjuvant setting remains an area of intense investigation with unrealized promise. It offers the potential of providing durable disease control for micro-metastatic disease following curative intent surgery and enabling personalized treatments based on mutational neoantigen profiles derived from resected specimens. However, most of these attempts have failed to demonstrate significant clinical success, likely due to the immunosuppressive tumor microenvironment (TME) and individual genetic heterogeneity. Despite these challenges, immune-based strategies, such as therapeutic vaccines targeted towards neoantigens, have demonstrated promise via immune activation and induction of T-cell tumor infiltration. In this review, we will highlight the foundational lessons learned from previous clinical trials of adjuvant immunotherapy, discussing the knowledge gained from analyses of trials with disappointing results. In addition, we will discuss how these data have been incorporated to design new agents and study concepts that are proving to be exciting in more recent trials, such as shared antigen vaccines and combination therapy with immune-checkpoint inhibitors and chemotherapy. This review will evaluate novel approaches in ongoing and future clinical studies and provide insight into how these immune-based strategies might evolve to address the unique challenges for treatment of PDAC in the adjuvant setting. Full article